RANCH HAND ADVISORY COMMITTEE

	Department of Health and Human Services

	Monday, January 22, 2001

	Meeting

	 Parklawn Conference Center
	Conference Room K
	Parklawn Building
	5600 Fishers Lane
	Rockville, Maryland

	ATTENDANCE
Committee:
Robert W. Harrison, M.D., Univ of Rochester, Chairman
Michael A. Stoto, Ph.D., George Washington University
Michael Gough, M.D., Consultant
Elissa Favata, M.D., Robert Wood Johnson Med School
Paul R. Camacho, Ph.D., Univ of Massachusetts-Boston
Ronald F. Coene, P.E., Consultant [former staff]
Leonard M. Schechtman, NCTR, staff
Barbara Jewell, NCTR, staff
Attendees:
LTC Karen A. Fox, M.D., Brooks Air Force Base 
LTC Bruce Burnham, Chief of Population Research
Dr. Joel Michalek, Principal Investigator
Richard Ogershok, U.S. Air Force
Dr. Judson Miner, Program Management Support
Manuel A. Blanca, Program Management Support
Meghan Yeager, SAIC
William Grubbs, SAIC
Maurice Owens, SAIC
David Banks, SAIC
Bill Chism, EPA
Rick Weidman, VVA
Gary Kayajanian, Ph.D. 
Kim Penland, FDA Week

	C O N T E N T S	

Introductions	4

Review of Minutes from October 19-20 Meeting
	Committee 	7

Review and Discussion of the SOW for the 6th Cycle of the AF Health Study

	Statistical Models	40-55
	Covariates and Interactions	140
	Analytical Planning	140
	Clinical Category Anlyses	177

Open Public Session	104

	P R O C E E D I N G S
	[1:10 p.m.]
		DR. HARRISON:  Good morning.  I'm Bob Harrison, chair of the Advisory Committee meeting.  We'll go around the room and introduce ourselves, I guess starting with the people here at the table and then proceeding to the representatives from the Air Force and the contractor, and then those members of the public who are here.
		I've already said I'm Robert Harrison, I'm Professor of Medicine at the University of Rochester, with no particular expertise that lends itself to this committee.
		MR. COENE:  I'm Ron Coene, and I currently am a contractor to NCTR.  I served as the exec sec to this committee, and former exec sec and a few other things.  But I have retired and I'm here to help out for the next day and a half, two days. 
		MR. SCHECHTMAN:  I'm Leonard Schechtman, I'm the new Associate Deputy Director, NCTR-Washington operations, and I'll be replacing Ron in his position as Exec Sec to this committee.  That's a big pair of shoes to fill, and I've got some real little shoes right now.
		DR. GOUGH:  I'm Michael Gough, this is my second stint on the committee; I was here for five years, from 1990-95, and this is my second meeting, second time.  What else is there to say?
		DR. STOTO:  I'm Mike Stoto from George Washington University, I'm Professor of Epidemiology and Biostatistics.
		DR. HARRISON:  Paul?
		DR. CAMACHO:  I'm Paul Camacho, I'm a sociologist at the William Joiner Center at U-Mass-Boston.
		DR. HARRISON:  Thank you.
		However you all want to do this; let's do the Air Force and then the contractors.
		LTC FOX:  I'm Lieutenant Colonel Karen Fox, one of the physicians at Brooks Air Force Base.
		LTC BURNHAM:  I'm Bruce Burnham, Director of the Air Force Health Study.
		DR. MICHALEK:  Joel Michalek, Principal Investigator of the Air Force Health Study.
		MR. OWENS:  Maurice Owens, I'm with SAIC, supporting contractor.
		DR. GRUBBS:  Bill Grubbs, SAIC. 
		MR. OVERSHOK:  Richard Overshok, program management of the Air Force Health Study, plus other things.
		MS. YEAGER:  Meagan Yeager, SAIC.
		DR. BLANCAS:  Manny Blancas, OP-TIK. I'm a contractor providing program support to the Air Force.
		DR. MINER:  I'm Jay Miner, I'm a contractor with Operational Technologies, also working in support of Mr. Overshok.
		MR. BANKS:  I'm David Banks, I'm a subcontractor with SAIC.
		MS. :  My name is Kim Penlan, I'm with FDA Week. 
		DR. KAYAJANIAN:  And I'm Gary Kayajanian, I'm an independent consult, and I've published in the area of dioxin. 
		DR. HARRISON:  Great.  Welcome.
		I've already mentioned that Dr. Elissa Favata is on her way here, and will hopefully make an appearance fairly soon.  But while we're waiting, why don't we go ahead and begin our review of the minutes from the October 19th and 20th meeting.
		We've received one set of comments on the agenda from Mike Gough.  
		Do you want me to read them, Mike, or do you want to read them?
		DR. GOUGH:  Well, they're rather extensive, but let me introduce them by saying I think these minutes are atrocious.  I mean, I don't know what we expect in the minutes, but this is a project that's probably going to cost a billion dollars before it's all finished, it's going to take 25 years to complete.  
		I can imagine in two or three years a history student or a policy student or a public health student is going to be interested in what this study did and in what the Ranch Hand Advisory Committee did, and if they read this set of minutes, with atrocious ‑‑ I mean atrocious English, I think it's the only paragraph in the history of the world where the first, second and third person are used in the same paragraph, when they all should be third person.  
		Plus factual errors.  And I think, as I understand it, this is a machine transcription and it is put together by people who probably don't have much information or knowledge about the field, and I don't hold anybody responsible, I don't blame anybody; but I would refuse to sign off on these minutes and would dissent from them, and I have a lot of notations about them.
		That's all I have right now. 
		(Laughter) 
		LTC BURNHAM:  Other than that, they're okay.
		DR. GOUGH:  Well, I was glad to hear it wasn't a person who did it; it's a machine.
		DR. HARRISON:  I think that one of the first questions that you ask is really a good one; as someone who is probably not good at process, I thought "Well, my, that's really nice"; and that is, are these minutes supposed to be a record of our deliberations or just what purpose are these minutes supposed to serve?
		Should they be a checklist of things that we've recommended to the Air Force so that we can check back and judge whether the checklist was done or not?  
		DR. STOTO:   I think there's probably a law that describes the purpose of the minutes and what they need to do, and so on.  I'm sure it's covered by the Federal Advisory Committee Act.
		DR. GOUGH:  Let's ask our former executive secretary.
		MR. COENE:  And we have ‑‑ they're supposed to be what they are, is a summary; because we have a verbatim copy of what's taken place at the last meeting.  So this was an attempt to summarize those.  Obviously we've got some work to do on those.
		Both are available to the public, if requested.
		Joel?
		DR. MICHALEK:  I'd just like to say that, at the end of ‑‑ a parallel.  At the end of every congressional hearing we receive a verbatim set of minutes, which are full of errors and double-spaced, and we're asked to proofread, and we do.
		But I have not seen the minutes from the previous meeting.  If you would have sent them to me I would have proofread them for you and sent them on to the Chairman through the secretary.
		DR. GOUGH:  I think that would help a lot.  Somebody, particularly you, Joel, because in the first example I give of accuracy, you're quoted as saying concerns developed after the war.  Well, the concerns developed during the war.  And we'd look just silly as hell if that stayed in here.
		Why couldn't it just be a process record, say that Dr. Michalek reviewed the origins and the progress of the study; make references to the written documents, make references to the URL, and be done with it.  And then have conclusions and recommendations.
		MR. COENE:  And that was the type of minutes we had in the past, was process.  And I guess we got ‑‑ that's just a fact, we did have process minutes.  If you go back and read them, that's ‑‑ you know, we said that certain people discussed certain things, and didn't go into a lot of detail beyond that.
		We got somewhat gun-shy, I guess, and so we decided to go to the verbatim trip and then the summary; and quite frankly, we ran out of resources to do anything more than that ‑‑ and so we probably made an error in doing that.  But that's the fact.
		DR. HARRISON:  It's really interesting at this point in this committee's lifetime, we're still trying to decide how to do things.  But it seems to me that some content is helpful in the minutes because of the sort of erratic way we meet.  Some attempt needs to be made, at least to jog my memory about what we actually said the last time and what the issues were the last time, not just that we met and things were said.
		So I think I would be in favor of something with a little more substance, and I guess that the real question is, having pointed out that the minutes have problems, maybe the real thing to do is not focus so much on the specifics of the problems in this set of minutes, but discuss what kind of process we can have in place to ensure that the next set of minutes, and maybe even this revised set of minutes, is more reflective of what happened, even though it's now several months after the fact.
		DR. STOTO:  I think one thing we have to recognize is it takes a lot of effort to get good minutes, and this goes to the resources issue.  I don't want to demand something of the staff that's impossible for them to do.  
		Maybe we should say how important it is to get good minutes, and that could be communicated in terms of the amount of resources that are available for this kind of effort.
		DR. HARRISON:  Well, I was feeling kind of funny about it myself, because obviously my job is to review the minutes as well and make corrections, and when I look at an extensive set of minutes, it is quite time-consuming and requires quite a bit of an effort; and I've been trying to decide whether I really want to place myself in the position of feeling obligated to do that; but I think I probably should.  Joel can do it because he's good at stuff like that, but it takes me a lot of effort.
		DR. MICHALEK:  Well, you would send those minutes to me; e-mail them to me, and I'll proofread them and send them back.  We'll circulate in our office and send back to you.
		DR. HARRISON:  Paul, do you have any ideas?
		DR. CAMACHO:  Well, I like the idea of the standardization.  Maybe we could flesh some parameters out and then have what we have in front of us now as a kind of an appendix idea, if people wanted to go into it.  So you had a summary of standardized issues; what we voted on, key topic, or however we wanted to arrange this.  And then have this kind of summary of the exact ‑‑ the tape as a kind of an appendix.
		DR. HARRISON:  Maybe we could standardize on the, essentially each minute, each set of minutes would have the equivalent of an executive summary that would serve the purpose that Mike and Ron were talking about, and the different actions that took place.  That would be fairly easy, I think, to accomplish.
		DR. CAMACHO:  Yes.
		DR. GOUGH:  Well, I think it would be a good idea to have a ‑‑ at the end or the beginning, say "the following votes were taken."  And then I think if we did that, whoever wrote it, he could key the minutes to that, because those are clearly the more important things we discuss, and that might help a lot.
		Now I do think that we should pass it by Joel for factual comments; and if you redline it, it's not a problem for anybody to go back and say "Well, that's not what I said."  Even though Joel said it correctly and I said it incorrectly, that's not what I said, which is going to happen.
		MR. COENE:  Application, are you talking about the transcript now or this summary document?
		DR. GOUGH:  No, whatever the summary is.  The transcript ‑‑ everybody's used to reading these transcripts and finding out that ‑‑ at least I've found out I've never spoken a complete sentence in my life. 
		(Laughter) 
		MR. COENE:  There lies ‑‑ summarized.
		DR. HARRISON:  So would this sound like the sense of the group, not just the committee but also of the Air Force participants, that we do have concern about the accuracy and intelligibility of the minutes, that Joel will review the minutes in terms of the accuracy of the Air Force statements.  I think that I should review the minutes, and particularly with respect to the accuracy of the committee's positions, and that there should be a summary of the minutes, to include the actions recommended and votes taken, either at the beginning or at the end of the document, to the extent that FDA resources allow those things to be accomplished, that's what we would like to see done.
		Yes?
		LTC BURNHAM:  We'd really like that list of actions recommended, because in the past we get a lot of different responses and there's a lot of discussion, and we never get any finalization, consensus.
		DR. HARRISON:  Okay.  So the Director really does want that list.
		I think a good point was made, though; and that is that the FDA has allocated a certain level of resources for this, and obviously they have to do what they can within the limits of the resources allocated.
		LTC BURNHAM:  Hasn't that changed, though. recently?  Hasn't HHS ‑‑?
		DR. HARRISON:  Resources are always allocated.  There may be more --
		LTC BURNHAM:  I thought part of the deal is you were going to continue doing it, but they were ‑‑ that didn't happen.
		MR. COENE:  This is it, I'm finished.
		DR. HARRISON:  No, what he's saying is, doesn't the committee have more money now than it used to?
		MR. COENE:  It has resources; it was given resources for last year and this year, yes.  It has some resources.
		DR. HARRISON:  So at least we can do it this year.  Whether we can do it next year is another question.
		MR. COENE:  It's in dollar resources and not in people resources, and the issue becomes one of having somebody that understands and understands what he's reading or she's reading and makes some sense out of it, and therein lies where we're shorthanded; we don't have anybody that ‑‑ you know, I come as close to it, and even then.  See, I would not have picked up that, and we need ‑‑.
		Look at the Air Force ‑‑ I mean, you guys sit over there and I'm going to take you on a little bit, with resources that goes beyond us, and you can recommend a lot of things.  HHS doesn't even come close to having those kind of resources to put to bear on this.
		I'll tell you something, I'll go on the record here a little bit, I'm a little bit concerned, I deal with a new document ‑‑ and I'm going to take off a little bit ‑‑ I get this new document here and it's different than the one I had in September that I had to give to the committee.  So when I put an agenda together, I find new sections that weren't there when ‑‑ what you gave me in September to send out to the committee.
		I mean, come on, guys.
		LTC BURNHAM:  Those aren't different?  I mean --
		MR. COENE:  They're different, yes.
		LTC BURNHAM:  That's the writeup.  I mean, that's the reworked ‑‑ the second one was the reworked --
		MR. COENE:  Yes, I know.  But here I'm asking the committee to respond to a scope of work, and you keep changing ‑‑ it's not a steady target.
		I got two different drafts, and even as late as last night I was going through and I said, Okay, I want to try to organize today to get to your point, Bruce, where it says, you know, 'we reach some conclusions on specific things' ‑‑ I find two new sections in the clinical section that weren't there when I put the agenda together back in December.
		LTC BURNHAM:  Those are different than the rewrite?  What you've --
		MR. COENE:  The January rewrite, the January ‑‑ the September rewrite and the January are different.
		LTC BURNHAM:  The last one that we sent you was intentionally different because you wanted the updated --
		MR. COENE:  The marked up one.
		LTC BURNHAM:  The marked up one, yes.
		MR. COENE:  Right, and I assigned, Bob assigned sections to the committee, and there are two new sections.  
		DR. HARRISON:  And when the marked up one had new sections ‑‑ 
		MR. COENE:  And it's not a big deal, but ‑‑ I just --
		DR. MICHALEK:  I can respond to that; I get your point, and that's just the way the process is at this point.  We're running out of time.  We're trying to give you the latest material, and you're right, the document changed.
		DR. STOTO:  I think the issue is having enough staff resources at the HHS end.
		MR. COENE:  You're not going to get that.  I'm a private citizen.  You're just not going to get all of the resources --
		DR. STOTO:  I'm not saying that you personally should do it.  
		DR. HARRISON:  NO, what he's saying is the office receives a very small budget, there's not a funding line for an editorial assistant, and so what are we going to do about it?  Shall we --
		DR. STOTO:  Is there no possibility of transferring funds from the Air Force to do it?  It certainly would be in their interest to get good records.
		MR. COENE:  They have ‑‑ in their behalf, it's awkward to do this.  And the appropriateness of that is --
		DR. HARRISON:  We talked about this once before. 
		MR. COENE:  ‑‑ and the fox in the chicken coop --
		DR. HARRISON:  Yes.
		LTC BURNHAM:  I don't know if that would go over real good with --
		DR. STOTO:  Well, as a member of this committee, I make an investment in this, we all make an investment in this; we want the investment to pay off.  And that takes a kind of effort that I'm not able to do, myself.
		DR. HARRISON:  I don't believe that it would affect any of us if the Air Force contributed funds to the operation of the committee.  But it would certainly seem like it to somebody who wasn't a participant.  And that was the concern that I felt was most important; that is that if we ever appear to lack a level of independence in terms of at least what we expressed, whether it gets expressed clearly in written form or not, then our usefulness as a committee is gone.  And it's hard to launder the money well enough ‑‑ 
		(Laughter) 
		DR. STOTO:  No, I don't think it should be in any way laundered; I think it should be above board.  I mean, the Air Force is doing the study; it's well-recognized in a lot of other areas of scientific research that to do a good study you need to have external advice, peer review in one form, and that it's part of the cost of doing business.  And we have a committee that is set up and is staffed by an independent agency, so I think there should be no question about whether or not the conclusions that we come to are appropriate or inappropriate or are fairly represented, but I don't think it is inappropriate for the Air Force to pay for it.
		DR. HARRISON:  Well, I respect your opinion.  But in terms of what we're going to try go do, in terms of ‑‑ what we can do as a committee is, it seems to me, is to say what we would like the minutes, how we would like the minutes to be structured.  We can complain if they're not structured that way.
		I don't know that we can ‑‑ if you have something in addition that you think we can do, then --
		DR. STOTO:  Well, I guess if it were up to me, I would say explicitly that it takes resources to do this well, more than apparently exists in HHS, and that we should try to find a way to get money transferred from the Air Force.
		DR. HARRISON:  So the criticism ‑‑ and Mike's certainly got an extensive critique of the minutes here, is that that's a direct consequence of inadequate funding of the FDA staff.
		DR. STOTO:  Inadequate staffing.  I don't know what the budget looks like, but it's certainly inadequate staffing.  
		DR. HARRISON:  Inadequate staffing, and needs to be corrected.
		Are you okay there, Paul?
		Did we lose you, Paul?
		[No response.] 
		DR. HARRISON:  So is anything more to be done with the issue of the minutes right now?
		DR. GOUGH:  Well, I want to ask a couple of specific questions.  Is it okay then if we send, as part of the process ‑‑ I mean, I think it's okay if, as part of the process, we review the minutes, we send them to the Air Force.  I just want to be clear.
		[Reconnecting speakerphone to Dr. Camacho]
		DR. HARRISON:  But my point is, I think that ‑‑ I think we have to recognize though that, at least I think it's fine for Joel to correct what the Air Force says; I don't think it's fine for Joel to correct what I say.
		DR. GOUGH:  No.
		DR. HARRISON:  That was all I was ‑‑ but in terms of ‑‑ so I think that any corrections have to follow two tracks.  There has got to be a committee, the committee has to be involved somewhere in the corrections, and the Air Force has to be involved.
		DR. GOUGH:  I think if we do that ‑‑ how much does it cost to get an editor for getting verbs to agree with nouns and things like that?  That doesn't cost very much, does it?
		MR. SCHECHTMAN:  If I could add something here.
		DR. GOUGH:  Yes.
		MR. SCHECHTMAN:  I think we're not only dealing with that level of modification of the minutes.  We're talking about expertise that's lacking in the individuals and the HHS staff that are capable of recording the factual material in the way that you would like to see it down on the record.
		And that certainly is a reflection of say lack of funding, or the funding requirements that are just not there to support such a staff.  And we wouldn't necessarily need such an individual full time on the NCTR-HHS staff; however, if that expertise is available say through the Air Force, that could work with us in recording the factual material, because we're using the verbatim transcript to do the first cut, do the second cut, wind down to some level of minute-taking that is at least comprehensible by people who don't have the expertise, don't have the background to do this kind of reporting.  But working in conjunction with those folks that do have the expertise, we could probably give you the kind of record that you want.  But that person has to be actively engaged in the note-taking.
		DR. STOTO:  I think that as long as we as a committee review everything, and take responsibility for the final minutes, the final product would be a lot better if it's done that way.
		DR. GOUGH:  Me, too.
		DR. HARRISON:  Why don't we leave it ‑‑ well, first of all, to try to work out the details of this operation as a committee is probably not the most efficient thing.  I think all the committee members have expressed their concern about the minutes; I think here have been several excellent suggestions made about how we can improve the minutes.  Why don't we give our Executive Secretary a chance to demonstrate his expertise ‑‑ 
		MR. SCHECHTMAN:  Or lack thereof.
		DR. HARRISON:  ‑‑ and put together a mechanism for us to do this.  It may mean that we're going to have to work out a way for me to spend a half a day or so on a telephone call, a teleconference or something, going over the minutes with you.  Maybe they should go to Joel first, and then you and I can go over them.  Maybe we can do something like that.
		I'm just saying I think we have reached a level of granularity here that we don't need to go below.
		DR. GOUGH:  I'm satisfied; I just wanted to draw attention to it.
		DR. HARRISON:  Well, I think you did a good job of that.
		Okay.  Mike also had a question about whether Dr. Michalek could discuss --
		DR. CAMACHO:  Hello.
		DR. HARRISON:  We're sorry we dropped you.  
		DR. CAMACHO:  Yes.
		MS. JEWELL:  Paul, let me give you the number you can dial back in, if it happens again.  It's 301 443 9178. 
		DR. CAMACHO:  All right.  
		DR. HARRISON:  Okay; we're back now, we've agreed that the minutes, the process needs more work, and we're going to work on that.
		I was just about to mention ‑‑ a question was raised about whether the Air Force presentation concerning body burdens and diabetes and carotid wall thickness could be done, but Joel has done that he's not prepared to make that presentation at this session, period. 
		So I think that we should go ahead and start on the scope of work review.  No?
		MR. COENE:  Clarification.
		DR. CAMACHO:  Is there a motion on those minutes, or we don't need one?
		DR. HARRISON:  We're deferring approval of the minutes for further editorial correction.
		DR. CAMACHO:  Did people decide whether you're going to have like a summary sheet with the votes and --
		DR. HARRISON:  We're going to try to do that, yes.
		DR. CAMACHO:  And then the appendix is just sort of a summary of what people said?
		DR. HARRISON:  Right.  
		DR. CAMACHO:  All right.
		DR. HARRISON:  And Joel is going to vette this for accuracy to the best of his ability.
		DR. CAMACHO:  Fine.  Well, we can look at it like a committee hearing document, you know?  And everybody gets sent a piece and you look up where you are mentioned, and that's it.  You know, you can sign off on yourself or something.
		DR. HARRISON:  That's a good idea.
		MR. COENE:  Okay, are you clear?  I don't think Joel saw Mike's comments.  So you're talking past each other?
		DR. HARRISON:  Let me read this, then.  Dr. Michalek --
		DR. MICHALEK:  I have not seen the minutes and I have not seen Mike's comments.
		DR. HARRISON:   [reading]  Dr. Michalek's discussions about the relationship between dioxin body burdens and diabetes, and between dioxin and carotid wall thickness, now scheduled for Wednesday a.m., would be better if they came before our review of the scope of work.
		As I understand it, there is essentially no difference in rates of diabetes or carotid wall thickness between Ranch Hands and comparisons.  I asked Mr. Coene to send a letter to Dr. Michalek, asking him to prepare graphs of the relationships between dioxin and diabetes and dioxin and carotid wall thickness in the comparisons.
		I assume that this is what Dr. Michalek is prepared to discuss.  That discussion, which may confirm me in my belief that dioxin is a measure of propensity to disease, and has no causal importance in disease, may influence my discussion of the scope of work.
		DR. MICHALEK:  Should I respond to that?
		DR. HARRISON:  Go.  
	I have the correspondence from Mike Gough requesting the graphs, it's on my desk.  I've begun to work the graphs that you requested. I've begun with staff to update our analysis of the carotid wall thickness and diabetes data.
		We are not ready to present.  Our work in those directions didn't begin until the 3rd of January because of our data release.  
		The picture is complicated by confounding, with body fat, age and family history of diabetes, and by other risk factors associated with heart disease.  The picture will become clear as the appropriate adjustments are made, as you will see, and I propose to present the data in great detail at the next meeting later this year, I hope, if we can have a meeting before the end of calendar year 2001.
		And I think that's important for many reasons, that we have a meeting near the end of the year, because that will be our last chance to meet before the clinical activities begin at the next physical exam, which will begin early 2002.  We will already have, at that time, our contractors on board, won't we, Scripps?
		Scripps Clinic and all of the ‑‑ the National Opinion Research Center, University of Chicago, and all of our contractors will be on contract at that time; and that would be a good time for us to meet and for us to give you an update of these research areas.
		I can tell you that we have updated our diabetes file based on the very latest diagnoses; we have revisited the concept of area under the curve, which is a metric for exposure that accommodates not just dioxin body burden but the amount of time that the burden has been in the body.
		We have revisited our definition of diabetes to require either, as we've been using in the past, doctor's diagnosis or a two hour postprandial greater than 200 milligrams per deciliter.  We find that if we restrict the file to only those individuals who have an unambiguous diagnosis, with no qualifiers, such as borderline, tendency to or probably ‑‑ in other words, a clear diagnosis, we find that the results are sharpened.
		We find that by using the area under the --
		DR. GOUGH:  Sharpened in the sense of comparisons versus Ranch Hands or sharpened --
		DR. MICHALEK:  Sharped in both directions.  That the Ranch Hand is experiencing an elevated risk of diabetes as a group, and that the dose response pattern becomes sharper and clearer and easier to visualize.
		DR. GOUGH:  I want to emphasize this -- this started out as a cohort study.  And it seems to me that one of the fundamental reports has to be what happens to comparisons, what happens to the Ranch Hands.  So if you're telling me now that there's a difference now between Ranch Hands and comparisons, that makes this much more real to me than it has in the past when the comparison and Ranch Hands were very, very, very close.
		DR. MICHALEK:  Yes, sir, but in order to reveal and elicit and describe the difference that you and I are talking about requires a lot of work.  There are a lot of reasons why.
		DR. GOUGH:  Well, fundamentally it requires no work at all; you have the Ranch Hands and comparisons, the diabetes is higher in the Ranch Hands.  Wait a minute, I know there are such things as confounders.  But the first cut is what do the two populations look -- do they look the same or do they look different?  You're telling me they look different now.
		DR. MICHALEK:  Well, unadjusted you're going to find no difference.
		DR. HARRISON:  Let's return to the original problem.  The original problem was that Mike wanted information ‑‑ Mike thought that you were going to make a presentation here, and he simply wanted the presentation to be made before the review of the scope of work rather than afterwards.
		You're not prepared to make the presentation here.  So I think that's ‑‑ any further discussion is all in the sky kind of stuff, because if you were prepared, if you had the data, then you'd be showing it.
		DR. MICHALEK:  That's right, we're not ready yet.  
		DR. HARRISON:  Is that fair enough to ‑‑?
		DR. GOUGH:  Sure.  That's fine.
		DR. HARRISON:  Thanks.
		DR. GOUGH:  That's why you're the chairman.
		DR. MICHALEK:  What we wanted to do was replace those topics with a new topic.  And the new topic was, the disposition of the specimens and the disposition of the study.
		I think we're reaching a critical point here in the timeline, and I think we need to talk about it.  The issues need to be put on the table in front of the committee, and we need to elicit your opinion on these issues.  And that's the material I want to present, in replacement to the diabetes.
		DR. HARRISON:  And that doesn't have to be done before we review --
		DR. GOUGH:  Oh, no, no.
		DR. MICHALEK:  No, it can be done tomorrow or the next day.
		DR. GOUGH:  Well, that anticipates the second item of mine, under A.
		DR. HARRISON:  We have at least one person for the open public discussion.
		DR. GOUGH:  Okay.  But at our last meeting, Bob appointed a subcommittee to deal with archival and retrieval of samples.  And two of us are here and Paul's on the telephone.  And I thought we should schedule a meeting in our open session today, if our open session is not filled up, of that subcommittee ‑‑ but maybe we can wait until the end when you're going to make your presentation, too.
		DR. MICHALEK:  I can make it anytime; we were not on the agenda to speak today, so I didn't even bring the laptop.  
		DR. GOUGH:  Well, then let's wait.  We'll wait.
		DR. MICHALEK:  We can do it tomorrow.
		DR. HARRISON:  It looks to me like we should have enough ‑‑ I mean, if we go ahead with what we're doing here and don't fool around, we're going to have plenty of time to, as a committee, discuss the archival question later.
		Anything else before we start to discuss the --
		DR. MINER:  We had a latecomer.
		DR. HARRISON:  We had all introduced ourselves before, and ‑‑
		MR. CHISOLM:  My name is Bill Chisolm; I'm with the EPA.
		DR. HARRISON:  Okay.  I'm from Yazoo City, Mississippi, so I always want to know where you're from and who's your daddy. 
		(Laughter) 
		Okay, I don't have the assignments, so.
		MR. COENE:  All of you were to read 363, 361, 362 and 363.
		DR. HARRISON:  Okay, all right.
		MR. COENE:  And no one was assigned that. And then 37, and then Health Study Examiner's Handbook. 
		DR. GOUGH:  May I ask, did we start with ‑‑ is this yours?
		DR. HARRISON:  No.
		DR. GOUGH:  Who wrote the one little page that said: Open Issues Not Addressed in this Document?
		I think those are good questions.  I haven't any idea about 2 through 6 because I'm not a statistician, but they seem like really good questions, Joe.
		DR. MICHALEK:  There is another question I forgot to ‑‑ 
		DR. HARRISON:  Oh, no.  Let me --
		MR. COENE:  Maybe we should clarify, what are you ‑‑ 
		DR. GOUGH:  Well, on the back of the cover page, there were open issues, and the first number is, Increase the number of invited Comparisons.
		DR. HARRISON:  Oh, I see.  That's this red ‑‑.
		DR. CAMACHO:  Are we on the draft now?
		DR. HARRISON:  Yes, we're going ‑‑ I'm not sure what we're doing.
		We're supposed to be discussing the statistical models right now, and the questions --
		DR. STOTO:  Those issues are statistically --
		DR. HARRISON:  Yes, the questions that are here are fair enough to be a part of that.
		DR. GOUGH:  I have a question.
		DR. HARRISON:  Go ahead.
		DR. GOUGH:  What has been the policy about replacing comparisons?
		DR. HARRISON:  If you read this document, it basically says all the comparisons that you can find are going to be invited.
		DR. MICHALEK:  That's true.  The overriding rule is, anyone who has ever been invited to the study will be re-invited.
 		Secondly, any comparison who was invited last time and refuses to come this time is to be replaced.  And there are rules for replacement.  There are rules associated with replacement, too, completely elicited; and they are all spelled out in the Statement of Work.
		DR. HARRISON:  But in your Statement of Work, you make the statement that all Ranch Handers and all comparisons in the first six categories are invited.  The seventh category, for the comparisons, are comparisons that you can't find.
		DR. MICHALEK:  What paragraph is that?
		DR. HARRISON:  Page ‑‑ I think it should be page 8.
		I believe it's invitation to the exam.
		DR. STOTO:  3.1.3.4.
		MR. COENE:  3137.
		DR. STOTO:  It starts on page 6; 3131.
		DR. MICHALEK:  All right, would you like a summary?  Would you like to talk or would you like me to talk?
		Now you guys need to correct me if I make a mistake.  Bill Grubbs, there you are.
	Anyone who has ever been invited to the study in past years will be invited again.  The only people we intentionally do not call are individuals who have distinguished themselves as being hostile:  "Do not call me again or I will sue you."  "You call me again, I'm going to go out to Scripps with a rifle."  Those individuals are called hostile.  
		They're about, how many of them?  Maybe a hundred, total.  
		DR. GOUGH:  I hope they're evenly divided between Comparisons and Ranch Handers.
		DR. MICHALEK:  Well, I don't know; we haven't done a careful analysis of that.
		But those are specially listed and are not to ever be called again.  We know who they are and we do not call them.  This rule was specified early on in the study; anyone who was ever invited will be invited again.
		In addition to that there is a very detailed replacement strategy that was spelled out in the protocol, and has been implemented since the beginning.  And that's what all this text is about in these paragraphs.
		The fundamental idea of replacement is that an individual in the comparison group who fails to be compliant; says "I don't want to come, period" is questioned about his health.  "What's your status of health?  Excellent, good, fair or poor?"  And he's asked that during the telephone interview, telephone contact that was there to invite him.
		DR. HARRISON:  Joel, all that I wanted to say was that in the first sentence here, it simply states that all subjects in the three Ranch Hand categories and the first six comparison categories listed above shall be invited to the examination even though this may mean at times that two or more comparisons assigned to a single Ranch Hand are invited.
		DR. MICHALEK:  Exactly right. 
		DR. HARRISON:  That seemed to me that that said that everybody got invited.
		DR. MICHALEK:  Exactly right.  And it has happened; there are more than one comparison matched to a Ranch Hander that has come to the physical.  
		DR. GOUGH:  But there are comparisons that have not been called, aren't there?
		DR. MICHALEK:  There are comparisons that have not been called because we haven't had to call them --
		DR. HARRISON:  That's not what this says.  That's not what that sentence says.
		DR. MINER:  Yes, it does.
		DR. MICHALEK:  Please clarify.
		DR. MINER:  Who were never contacted to be invited.  Perhaps if that were added.
		DR. HARRISON:  Well, perhaps if that were added it might say that.  I'm saying right now ‑‑ right now it just says the first six --
		DR. MINER:  On Category 7.
		DR. HARRISON:  The first six categories, on category 7, is replacement comparisons who were never ‑‑ 
		DR. MICHALEK:  Yes.  Who were never contacted means ‑‑ there are up to 10 comparisons matched to Ranch Hander based on date of birth, military rank and job in Vietnam, and race.  They are matched perfectly almost on those factors.  They are matched to within one year on date of birth, most of them.  They are matched perfectly on all the other factors.
		The individuals in that matched set consist of one Ranch Hander and up to ten controls.  The ten controls are randomized, according to their position in the matched set. At the very beginning of the study, the first person in that randomized comparison array was invited.  He was called a so-called "original comparison."
		Then, as the study proceeds --
		DR. HARRISON:  I understand now, the only difference is never contacted.
		DR. MICHALEK:  Never contacted. Because --
		DR. HARRISON:  That answered my question.   
		DR. MICHALEK:  ‑‑ what can happen is that the first comparison contacted, complies, "Sure, I'll come" and he continues to come, and so we never need to call any of the other comparisons in that matched set, and we never do.  And so the contractor is not to call those individuals because they had never been contacted and didn't have to be contacted.  But anyone who was called would be called again.
		DR. GOUGH:  But didn't you have a system that, if not enough of them are compliant, then you add ‑‑ that's what this question is about; increase the number of invited comparisons?
		DR. MICHALEK:  That was Bruce Burnham's suggestion.  
		Bruce, would you like to amplify that?
		LTC BURNHAM:  Well, it was just the idea of increasing the power of our study, because one of the limitations is the lack of power; and so I thought ‑‑ really, you could add up to five controls per study subject.  Technically, not financially.
		DR. STOTO:  But you wouldn't add much power.
		DR. MICHALEK:  No, a small amount of power.  Very small.
		DR. GOUGH:  Because you can't increase the number of Ranch Handers, right?
		DR. MICHALEK:  Cannot increase the number of Ranch Handers, no.
		At the last physical, we had about 900 Ranch Handers and 1,300 controls came.  
		DR. HARRISON:  So what is matched analysis?
		DR. MICHALEK:  That's another way to analyze data without resorting to multivariate modeling, which is one of the methods we've used, is multivariate logistic regression, for example.  Well, in the area of diabetes, we've been using that model a lot.
		The advantage of the model is that it's well known and its properties are well understood and we've been using the model for years and years, and it's in textbooks and it's a standard technique of analysis.
		However, it's not easy to visualize matching, the logistic model.  Another approach is a 1:1 or 1:many matched analysis where individuals are literally selected and matched on factors relevant to diabetes, such as family history and father, mother, brother or sister.
Body fat in Vietnam, date of birth, and change in body fat from Vietnam to the present.
		Very careful 1:1 matching of individuals based on those criteria can yield a defensible and a very compelling matched analysis of the data; and this approach is advocated in some textbooks; for example Rothman's text on Epidemiology.
		And it can be used as a supplement or as a complement to the standard multivariate analysis that we've seen in multivariate analysis that we've seen in all of our reports.  And we've been doing that recently; we've been doing matched, 1:1, very tight matching to within 1 percent of body fat in Vietnam, matched perfectly on all the risk factors that we know about for diabetes.
		And sometimes when we do that, the results become very clear, and they're very easy to defend and present to an audience, because they don't rely on any multivariate statistical model.  What you end up with at the end is a 1:1 matched dataset where the computations become very trivial.  In the area of a continuous analysis such as insulin, you're simply doing a paired T test, that's all there is to it.
		DR. STOTO:  So that the pairs include one from the Ranch Hand --
		DR. MICHALEK:  We've been doing one to one.
		DR. STOTO:  ‑‑ and one from the control.
		DR. MICHALEK:  Yes, one to one.
		DR. STOTO:  But they always include one from the Ranch Hand and --
		DR. MICHALEK:  Right.
		DR. STOTO:  ‑‑ at least one from the control.
		DR. MICHALEK:  Right.  Always one Ranch Hander and one control, that's true.   And they have computations on relative risk and confidence interval that says, you know, from the Rothman's text and others; and the Mantels papers become very clear and very compelling type of analysis.
		That's why the matched analysis is a favorite in some studies.
		DR. STOTO:  This makes use of the design of the study --
		DR. MICHALEK:  Exactly.
		DR. STOTO:  ‑‑ which Mike should like.
		DR. GOUGH:  Oh, I like matching with comparisons.
		DR. MICHALEK:  And it eliminates the need--
		DR. GOUGH:  I like data, actually.
		DR. MICHALEK:  -- to present and summarize the sometimes very complicated multivariate model, which to a statistician may be clear, but to non-statisticians may not be clear.  So that's why the matched analysis is such a favorite.
		DR. HARRISON:  Are you required to show that if you match comparisons that you would not see a difference?
		DR. MICHALEK:  Matched comparisons 1 to 1?  is that what you're saying?
		DR. HARRISON:  Yes.
		DR. MICHALEK:  You could ask that ‑‑ well, what's the purpose of your question?  To ask whether nonexposure is related to nonexposure?
		See, the purpose of the hypothesis in the matched analysis was exposed versus non-exposed.  Now you're matching unexposed versus unexposed. 
		DR. HARRISON:  Yes.
		DR. MICHALEK:  Mike.
		DR. STOTO:  Are you saying this to see whether or not --
		DR. HARRISON:  I mean, it sounds like a stupid question, but I agree.  But you know, one way ‑‑ if I matched like-to-like and I saw no difference, and I matched unlike-to-unlike and saw a difference then it would seem to me that it would be even more compelling than if I just assumed that like-to-like would not show a difference.
		DR. STOTO:  I think that the logic behind that is that you're saying, just to be sure that we didn't get a fluke by here, let's do a matching where we don't expect to find a result, and make sure we really don't.
		DR. HARRISON:  Yes.
		DR. MICHALEK:  The answer is yes, that could be done.  We could randomize the comparison group into two sub-cohorts and match them 1:1 on the same factors.  And we expect to see nothing.  
		DR. STOTO:  But there are statistical tests that tell you that, answer that question in a more formal way, and that use all the data; and that's presumably what you would do in the matched analysis.
		DR. HARRISON:  What is the question about the matched analysis?
		DR. MICHALEK:  The issue is, is exposure related to diabetes after controlling for the risk factors that we already know about that are related to diabetes?
		DR. HARRISON:  Is the question, should a matched analysis be added?  To the Statement of Work.
		DR. MICHALEK:  There's a question about whether we should add a matched analysis as a component of the Statement of Work.
		DR. GOUGH:  Would you do that; do you do the matched analysis or does SAIC do the matched analysis?
		DR. MINER:  Depends on whether it's in the Statement of Work or not.
		DR. GOUGH:  Oh, I see.  All right.
		DR. MICHALEK:  First of all, I've given you all the shining attributes of the match analysis, so let me tell you all the downside of the matched analysis.
		DR. GOUGH:  Sort of data-intensive?
		DR. MICHALEK:  Yes.  If you were to require the contractor, namely SAIC, to do the matched analysis in several clinical areas, what you would have would be a different sample size, for one thing.  You'd have different cohorts being analyzed in different chapters.
		For example, when you match on body fat, family history of diabetes, age and other factors, you're going to get a different matched cohort than you would if you were matching for factors related to heart disease or cancer.  So you're going to have different matched sets in every chapter, which would maybe confuse people, but you're not talking about the same people when you write the diabetes chapter, as when you're writing the cardio chapter or the cancer chapter.
		[Speakerphone connection interrupted.]
		DR. MICHALEK:  So that's one complication.  Another is that you have to write special software to do the matching.  We have Fortran code that we wrote that does a 'nearest neighbor' match on these factors.  And we've written it over a period of several months and we use it a lot.
		If we required Bill Grubbs and SAIC to do that, they would either have to write their own code, or we'd have to give to them and they would have to test it out.  I'm not sure they have Fortran on their machine.  They'd have to try to translate that into SAS.
		DR. HARRISON:  I'm not sure that anybody has Fortran on their machine.
		DR. GOUGH:  Except for the U.S. Air Force.
		DR. MICHALEK:  Right.  We have got Fortran, we also wrote the program in SAS, too.
		In other words, there's a task there of writing the software to create the matched datasets, and that's not trivial.
		DR. HARRISON:  Okay, hold on here.  Isn't it the committee's ‑‑ the committee's scope of work is to say whether or not this is desirable.  It's up to the Air Force to figure out whether or not they have the money to fit it in.
		DR. STOTO:  Well, I think it's a slightly different issue.  I think first of all we're talking about Section 3.6.1 now, right?  Statistical Models.
		DR. MICHALEK:  Yes, that's a good place to talk about.
		DR. STOTO:  Yes.  And it's been the tradition over the last couple of things that they have these four models that they're running, and that they do separate and sometimes more sophisticated analyses in their own papers that are not in these blue books.
		DR. MICHALEK:  That's right.
		DR. STOTO:  And in fact, you are doing some of this on your own right now.
		DR. MICHALEK:  Right now.
		DR. STOTO:  So I think the question is not whether or not they should do a matched analysis; the question is whether or not the matched analysis should be incorporated as Model No. 5, something like that.
		DR. MICHALEK:  In some clinical areas, maybe not others.
		DR. STOTO:  See, that's one of the drawbacks.  I don't like the fact that they sort of have this canned approach of doing exactly the same analysis for every outcome.  It would be funny to kind of do it in some and not in the others in these blue books.
		So I guess I would be in favor of doing, having these guys ‑‑ having the Air Force continue to do that analysis in their own publications, but not necessarily making it part of the ‑‑.
		DR. CAMACHO:  Where are you now, 3.6.6.1?
		DR. STOTO:  No.
		DR. HARRISON:  What we're talking about --
		DR. STOTO:  No, it's 3.6.1.
		DR. HARRISON:  What we're talking about, though, is whether or not it would be desirable in some cases to do a matched analysis or whether or not it would be desirable to add to the scope of work a matched analysis in some of the categories.
		So you can just kind of pick any section.
		DR. GRUBBS:  To paraphrase a little bit of what Dr. Stoto is saying, there's benefits and deficits to it; of course I think the question is, we go by the Statement of Work as to what should be in our voluminous 1800-page report.  Is that the appropriate place for it, or is it end papers, or supplemental documents?
		DR. MICHALEK:  Personally, I tend to feel that's really not the place for it.  Because we generally are motivated to do a matched analysis based on a referee comment to a submitted article to a journal.  "Okay, you did the logistic regression, that's fine, but please do it this way in addition, and summarize the results in a sentence."  The main body of the article will have the logistic regression modeling results, and a sentence in the text will be the results of a matched analysis.
		To cover all of the concerns people would have about a possible loss of adjustment that may have crept in to the multivariate modeling.
		Another drawback to doing that matched analysis in the big report is that if we do that, we'll have no frame of reference relative to the previous reports, because we've never done that previously in a big fat report.  We've done it in articles, but not in the reports.  So you wouldn't be able to track that backwards to other findings from previous physicals.
		DR. GOUGH:  Why are we talking about this?
		DR. MICHALEK:  Well, because it's an issue.
		DR. HARRISON:  It's a --
		DR. GOUGH:  Well, I brought it up because it's written here, but it seems to me--
		DR. HARRISON:  It's in red because it's a red herring.
		DR. STOTO:  No, I think I was good to have discussed it and decided not to add it.
		DR. GOUGH:  All right, to continue as before.
		DR. HARRISON:  Okay.  
		DR. MICHALEK:  That's exactly right.
		DR. HARRISON:  So the next item then is multivariate analysis.
		What's the question there?
		DR. MICHALEK:  Well, some people, and I am included, have the feeling that we may be missing an effect.  Because the reports that we have been doing are concentrated one clinical area at a time.  And that we know that many of these areas are related, such as general health, cardiovascular and diabetes. 
		Individuals in general health report fair or poor health, and we'll find out through subsequent analyses, "Well, they're really telling us about their diabetes."  And individuals who are having heart attacks are also having diabetes and so that the outcome in our cardiovascular chapter is related to the outcome in our endocrine chapter; and that's related to our outcome in general health.
		We've never made an attempt to put it altogether into a multivariate analysis, and that's ‑‑ actually, we've worked with Michael and Bonnie LaFleur, and we gave Michael a dataset, and Bonnie's going to be looking at it from that point of view.
		So the issue is where we should include that kind of multivariate approach in the next report.
		DR. HARRISON:  And again, that suffers from the same problem as before; it lacks the continuity that the study has now in terms of how it's analyzed this data.
		DR. STOTO:  And it's not the kind of thing that you want to just crank out. 
		DR. MICHALEK:  No.
		DR. STOTO:  You need to think very carefully about how to structure that.
		DR. MICHALEK:  Now you're putting your finger on a kind of quandary we're in, in that we only have a few number of years left; that we who have been looking many years at the data have the feeling we may be missing something; and this is sort of the thinking we've had.
		This kind of modeling is fairly complicated.  It's not a simple presentation of the results even when you're finished.  It's a complicated presentation of results, because you've got inter-correlations between the endpoints, you've got correlations between the endpoints over time, and you've got interrelations between the risk factors and the endpoints.  It's a difficult analysis to summarize; and on top of that, it requires a certain amount of exploration.
		This company will not be in the position of doing data exploration; we can't afford it.  They have a fixed, 13 month time period to write this report, from the middle of September of the year 2003 until 13 months later.  That's the typical period, because we have a time frame for release of the report to the public.  Those are the issues.
		DR. HARRISON:  Joel, I wonder, though, if you haven't already solved the problem to some extent.  A lot of the Ranch Hand data has been published by you and your colleagues; accessibility of the Ranch Hand data is more or less open --
		DR. MICHALEK:  Complete.
		DR. HARRISON:  ‑‑ and if there's anything that academicians love is being able to use somebody else's data to write a paper.
		DR. MICHALEK:  Good point.
		DR. HARRISON:  So I really think the kinds of analytical analyses that you're talking about are the kinds of things that people are already interacting with you about, and that may be the answer to the question that you continue to ‑‑ you know, the Statement of Work continues to crank out this sort of --
		DR. STOTO:  "Cookie cutter approach."
		DR. HARRISON:  ‑‑ general approach.  That's difficult enough to do.
		DR. STOTO:  Right.  And it's important to do it in a consistent way all the way through.
		DR. HARRISON:  Exactly.  And then these other innovative approaches can be ‑‑ some of them you'll have the wherewithal to pull off yourself, and some you'll find partners to pull off with.
		DR. MICHALEK:  For the record ‑‑ and you already mentioned that, Dr. Harrison ‑‑ all of our data is released to the public.  There is nothing left to release; it is available on our web page. 
		DR. HARRISON:  I really apologize for even trying to temporize it in any way.
		DR. MICHALEK:  I want to make that crystal clear to anyone who is in this room, that all of it is on the web page and all of it is with the Government Printing Office.
		DR. HARRISON:  But there's always some issue in terms of releasing this data in a way that would allow identification of subjects.
		So as I recall you've looked at it in the past and been careful about how that data is available.
		DR. MICHALEK:  The names are not there ‑‑ we've protected privacy.  But all of the end points and clinical measures and laboratory results, all of that are on the web page.
`		DR. HARRISON:  All right, what about interaction models?
		DR. MICHALEK:  Well, again, this is part of our suspicion that we may be missing something.  We run what are called main effects models in all these reports:  Is dioxin related to health adjusted for body fat, age, and family history?
		Well, a piece of the model that we don't put in is, is there a change in the relation between dioxin and health with age?  In other words, is there an age by dioxin interaction?  That analysis has not been done, and that's the kind of analysis that could be done by any other researcher because all the data is on the web page.  To require SAIC to do that would enormously increase the cost of the effort and the timeline, too.
		DR. HARRISON:  You know, another thing that just crossed my mind, Joel, is that there's no rational physiological basis for what you're looking for here, so you're trying to design statistical strategies to reveal truths that you're not certain are even there.
		DR. MICHALEK:  Exactly right.
		DR. HARRISON:  So once again, I think you have to decide that you're limited at some point.
		DR. MICHALEK:  Exactly right.  In fact, the attitude of many journal referees and editors is that you're not to invoke an interaction model unless you have good a priori biological reason to do so.
		I only can identify one place where there might be a biological rationale; and that is that in the nondiabetic Ranch Handers, we see a strong dioxin effect on insulin.  We don't see it in the diabetic Ranch Handers.  There could be a biological basis for that, but that's maybe the only place in the whole study where I've ever seen anything that may have a biological rationale for an interaction.
		DR. STOTO:  I think the bottom line is the same; is that this is the same as the two previous ones. 
		DR. HARRISON:  That's really the bottom line with all this stuff.
		LTC BURNHAM:  The reason we're coming up with these ideas and presenting them is because we've had the attitude of "this might be the last chance."  "How can we make this the best exam ever?"  And so we're just brainstorming and ‑‑ if you think they're all not worth it, that's fine.
		DR. HARRISON:  No,  The issue is not whether they're not worth it; you misunderstood me if that's what you thought I said.  It's simply that it's different objectives ‑‑ as I see it, and I've already said that I'm not sure that I really understand any of this ‑‑ is that the health study is a longitudinal health survey; and as such, without what I would see as a physiologically-based hypothesis to start with, you really are constrained in what you can do with that kind of a study.
		It looks like there might be some relationships, and it would be nice to try to figure out a way now to design one last go-around that you could prove this.  But I don't think that's feasible within this context.
		I think the question should be how can you finish ‑‑  not finish this off, but how can you maintain the continuity and strengthen what you have?
		DR. STOTO:  I would answer it differently; I would say that the kind of question you bring up is an important one with respect to doing laboratory tests and so on, because it presumably is the last time we're going to see these men.  But these analyses can be done later.
		The fact that we don't include them in this Statement of Work doesn't mean they can't be done.  And I think they probably can be done better with a different arrangement.
		DR. HARRISON:  You retire from the Air Force, write a grant, and ‑‑.
		LTC BURNHAM:  But that's a big assumption, too, though.  A lot of times, if you don't do it now, it never gets done, and that's the plain truth of it.
		DR. HARRISON:  Well, that's true.
		LTC BURNHAM:  Because we have funding through '06, but that may never happen again.
		DR. HARRISON:  The other part, I think, I'll bet you that it makes a whole lot of sense, is that for some of this you're going to be a lot more efficient doing it yourself than trying to do it within the scope of work and trying to do it in all of the categories ‑‑ that's, that would be my ‑‑.
		Do you have anything to add, Paul?
		DR. CAMACHO:  No, I'm getting a little weary.  I think the argument comes down to the continuity with the past studies to match, and taking some new tests that you could analyze in the future or you could preserve that might be analyzed in the future.
		DR. HARRISON:  I agree.
		What about administering the spousal--
		DR. GOUGH:  Can I ask a question.
		Joel, have there been requests for the data?
		DR. MICHALEK:  Not since we put it on the web page.
		DR. GOUGH:  Were there requests before that?
		DR. MICHALEK:  In the past we have received Freedom of Information Act requests from the Veterans of Foreign Wars, for example, from other Vietnam veteran organizations.  And we've always handed them diskettes. 
		Now since everything is on the web page, we haven't --
		DR. HARRISON:  Do you know how many hits you got?
		DR. MICHALEK:  We keep track of the hits, but I didn't see a big shoot-up in the number of hits since we put the data up.
		DR. HARRISON:  But has the data been downloaded?
		DR. MICHALEK:  We can tell that, but we haven't checked our webmaster to see how many times a day it has been downloaded.
		DR. HARRISON:  Has it been downloaded?
		DR. MICHALEK:  I don't know.  We'll have to check and see.  It's only been up there for two weeks now.
		LTC BURNHAM:  Well, some parts of it have been up --
		DR. MICHALEK:  Right.  Some of it has been up there for about six months.
		DR. HARRISON:  Did it get archived in the various search engines?  Was that a part of your deal?
		DR. MICHALEK:  In other words, can you reach our web page from Yahoo and the others?
		DR. HARRISON:  No, I mean, normally when you have somebody make a web page for you, they actually submit your web site with the meta tags to the various search engines; Google, Yahoo ‑‑ Yahoo is Google now ‑‑ Northern Light, and so on, so that if somebody plugs dioxin in the day after your web site goes up, your web site should hit.
		DR. MICHALEK:  I don't think that's been done.
		LTC BURNHAM:  No, I believe so.  I don't know how extensively, but it has been.
		MS. YEAGER:  It does hit.
		DR. MICHALEK:  It has been done.
		DR. GOUGH:  I've been somewhat disappointed since we began, the Air Force began making these data available in 1990, that they haven't been exploited more by outside academics.
		And I think part of the reason is simply people don't know about it.  In terms of knowing about what's going on with middle-aged, largely white guys, there's nothing compares to this.  And I think it's under-used.
		I don't know what we can do or what the Air Force can do, but I certainly do think that by the year 2006, I would hope a lot of people are using it or are at least aware of it.
		DR. STOTO:  We discussed this, I think, two meetings back before you were on the committee, and discussed the idea of trying to get the word out to people who get support from NIH about the availability of this resource, presumably if people knew about it they would be able to put in RO1 applications that NIH would be willing to fund out of its own resources if people can put together a compelling argument, which I think that they certainly can.
		DR. HARRISON:  Well, remember we wrote the letter, and --
		DR. STOTO:  We wrote the letter, but that got misinterpreted as trying to get NIH to set aside money for this analysis; and I don't think that's likely to happen.
		DR. HARRISON:  But it was hoped that NIEHS would use its review capabilities to decide who should be helped.  The problem is that the Air Force has no way to review proposals; so anybody with a --
		DR. GOUGH:  I wasn't thinking about Air Force review now; I was thinking more of the general PHS review process.
		DR. HARRISON:  Yes.  So either way you look at it, is asking for money.
		DR. STOTO:  No.
		DR. HARRISON:  I mean, if you're just asking for a study section to spend a half a day ‑‑.
		DR. STOTO:  No.  No, I'm not asking for a study section.  I'm saying that there are hundreds of study sections already, and that they could perfectly well review proposals that are submitted; you know, if it's a proposal about diabetes it will go to a certain study section and so on.
		But the problem is that most investigators who have the potential for writing applications like this don't know about the resource.
		DR. MINER:  We have in fact taken some steps to increase our public output, and I've asked SAIC to give us a communications plan, including that as updating of web page and so forth.  So we're going down that road, but not fast enough.
		DR. STOTO:  Yes, I'm not sure; we'll have to see what the plan is, but I'm not sure that relates to the researchers;  People who are not working in, certainly in herbicides, or veterans but may be interested in dioxin may be interested in just longitudinal aspects of aging.
		DR. GOUGH:  That's what I would think.
		DR. STOTO:  They may not care at all about the dioxin.
		DR. HARRISON:  Let's try and do what we're ‑‑ 
		DR. GOUGH:  I'd like to see that in the minutes; we want some publicity about these datasets, and we want to see people like you using them, Bob.
		DR. HARRISON:  Those are good points, and I can't help but agree.  I don't disagree at all.  I think we just wandered just a little bit from what we were supposed to be doing first here.
		Well, the only thing left on sheet is a question, administer the spousal questionnaire.
		DR. MICHALEK:  That is a repetition of a questionnaire we gave at baseline and cycle 1 and cycle 2 and cycle 3 to the women, to the spouses and sexual partners of the men asking about their ability to conceive children.
		Not every spouse and partner has received the questionnaire.  Since we only have one more time available to contact these women, we wanted to finish that dataset and release that to the public.  That's a fairly low-level activity in terms of cost and resources.  So it's something we really want to do.
		DR. STOTO:  It wouldn't be part of the analysis of these blue books?
		DR. MICHALEK:  No, it wouldn't be part of the big report, no.  This will come later.  This will simply complete our dataset so we can write a better research paper on biotech data.
		DR. HARRISON:  Go ahead.
		DR. STOTO:  So this does fit into the category of, if you don't gather it now, you won't --
		DR. MICHALEK:  That's it, we're going to lose it forever.
		DR. HARRISON:  Right. 
		DR. MICHALEK:  There is one item left that's not on the list.
		DR. HARRISON:  Well, first of fall, we feel that that's a very sensible thing to do.
		DR. GOUGH:  Analytically it's going to be complicated, though.
		DR. MICHALEK:  We've got an analytical effort in place already to address the data with.  Debbie del Junco, University of Texas-Houston, Brenda Escanazi, UC-Berkley.
		DR. GOUGH:  But because --
		DR. HARRISON:  Well, you're going to go back and ask everybody, though?  You're not going to just ask the ones you missed the first time.
		DR. MICHALEK:  We're going to ask anyone who hasn't received it yet. 
		DR. GOUGH:  That's the issue that comes up, is that if you ask a 22-year old woman, twenty years ago about her reproductive history and you ask a 42-year old woman today--
		DR. MICHALEK:  Maybe I said that wrong; they were going to update all of that.  But whatever it is, we'll do --
		DR. GOUGH:  I think that's the analytical problem.  
		DR. HARRISON:  Well, I agree.
		DR. MICHALEK:  We should go back and try to retrieve information on any pregnancies or attempted pregnancies since the last time we gave it, which was in 1987.
		DR. HARRISON:  Well, the better way would be to just treat it as though it were --
		DR. GOUGH:  Never done.
		DR. HARRISON:  ‑‑ a new survey.
		DR. MICHALEK:  I think you're right.
		DR. GOUGH:  It needs to compare ‑‑ yes and no ‑‑ I mean old and new, once you have both of them.
		DR. MICHALEK:  I stand corrected. 
		DR. GOUGH:  We're in favor of that.
`		DR. HARRISON:  Okay, so the first recommendation is for the spousal questionnaire in a revised form to be administered to as broad a population as possible.
		I find it hard to read this thing.  Okay, so we've done statistical models, we've done covariates and interactions.
		DR. STOTO:  No, no, we haven't finished with --
		DR. HARRISON:  We haven't?  We haven't finished statistical models?
		DR. STOTO:  No, we haven't gotten into the meat of it yet.
		DR. HARRISON:  Oh.
		DR. MICHALEK:  No, this is just ‑‑ 
		[Simultaneous discussion] 
		DR. HARRISON:  I'll tell you what, in 30 minutes, we're due to have our open public session, and then our work will be done for the day.  So can we cover statistical models in the 30 minutes?
		DR. GOUGH:  Let me note the dichotomy.  Everybody except Joel and Mike say "sure." 
		(Laughter) 
		DR. STOTO:  I think we can. 
		DR. GOUGH:  Okay.
		DR. HARRISON:  Come on.  Go for it.
		DR. MICHALEK:  Let me at least mention the item that should be on the list that I forgot to put on there.  
		There was one item left, I said.  That was the item from Dr. Favata that we question the individuals about chemical exposure in the home.  I'm sorry, I forgot to put that on there.
		DR. HARRISON:  She's been trying to get you to do that since the previous cycle.  
		DR. MICHALEK:  I'd like for the record to put that on there; that was an oversight, and we intended to address that, wanted the committee to address that issue.  We would like Dr. Favata to tell us what series of questions we should ask the participants in that area; maybe she would give us a literature citation so we could inserting those questions into our in-person interview that we'll give at the next physical.  
		DR. HARRISON:  Okay, so since she's not here right now, we'll presume she'll at least be here by tomorrow, we'll make that a go issue for tomorrow. 
		DR. HARRISON:  Mike?
		DR. STOTO:  In section 3.6.1 in the subparts, there are a number of changes.  I think that they generally are not controversial, like using SAS rather than BMBDP and using body mass index versus percent fat, and so on.
		The one that I think does deserve some discussion is ‑‑ let's see, where is it.  It's section 3.6.1.2; it's at the bottom of page 23 of the one we got today.
		DR. HARRISON:  Health versus Initial?
		DR. STOTO:  Right.  And it has to do with, how do you figure out what was the level of exposure to dioxin during the time these guys were in Vietnam.  And previously if someone had a body burden of 10 ppt or less at the time of the exam, they were dropped out of the analysis.  And I think what they're proposing to do now is to include them in the analysis but not extrapolate back or extrapolate back in a flat line from the earliest measurement, if they have two measurements.
		DR. MICHALEK:  We'll just use the current measurement, basically.  We only have one value.  Suppose the guy has 9 parts per trillion in 1987.
		DR. STOTO:  Some of them have two measurements.
		DR. MICHALEK:  Well, yes, some of them do.  300 and some of the veterans had more than two.
		DR. STOTO:  And I guess that's better than leaving them out.
		DR. MICHALEK:  We agree with you.
		DR. STOTO:  I've got two things to say.  One is, an alternative would be to extrapolate back by the average half-life.
		DR. MICHALEK:  Right.
		DR. STOTO:  Because even if you start out with, even if you end up with 9, it's more likely that you had 18 so many years ago than you had --
		DR. GOUGH:  You have no idea if that's true.
		DR. HARRISON:  I was going to say, that --
		DR. GOUGH:  None at all.
		DR. HARRISON:  I have to agree with Mike.
		DR. MICHALEK:  We have data in the comparison group to suggest that an individual will fluctuate over his lifetime, between ‑‑ an interval of 0 to 10.
		DR. STOTO:  I guess I've come to the bottom line.  I would like to see an analysis to support this.  That may be right, but I'd like to ‑‑ I think it's the kind of thing that I'd like to know more about.
		DR. MICHALEK:  Okay.  I'd like to show  you, we have a paper just accepted to a journal which shows that in the comparison group.
		DR. CAMACHO:  ‑‑ the ability to go back?  You want to see something more about--?
		DR. STOTO:  No, if someone had a body burden of 20, they would extrapolate back to their about what their exposure was.
		DR. HARRISON:  Use the half life.
		DR. STOTO:  Use the half life.
		DR. HARRISON:  But if you're less than 10, they don't use the half life.
		DR. MICHALEK:  Don't extrapolate.
		DR. STOTO:  That's better than dropping them out altogether, which is what they used to do. And --
		DR. CAMACHO:  It came up last time.
		DR. HARRISON:  Comes up every time.
		DR. CAMACHO:  Ha, ha, ha.
		DR. MICHALEK:  The approach that Mike just described has already passed peer review, so to speak.  Because I presented that approach at the Dioxin Conference in California and all the guys from EPA were there and they liked it.  In fact they want to coauthor a paper in that direction.
		An extension of the ‑‑ there are two possible extensions here to address the idea here that the analysis suffers from changes in the elimination rate from one person to another.  We know that individuals who are lean will eliminate dioxin more quickly than those who are obese, and so we might have a way to adjust for that.
		And what we've done in the past, because our statistical models are not sophisticated enough to provide a bodyfat-specific elimination rate, what we do is stratify the cohort into low, medium, high by body fat or BMI when they were in Vietnam, and then within each of those strata we estimate the elimination rate.  And based on those elimination rates, which are now body fat specific, to a fairly narrow range, we estimate the initial dose in Vietnam.  There we've carried the analysis one step further to use available data to address a criticism; namely, that the initial dose in Vietnam may be wrong because of changes in body fat.
		Now that's a refinement that we can include and we will include in our datasets that we give to SAIC to carry out the analyses in the big report.  That's not something we expect SAIC to do, but it is something certainly that we can and we will do.
		Another refinement of this method is not just to use the dioxin level, but to use the amount of time since Vietnam to the present.  To accumulate the dioxin dose in the body by effectively taking what's called the area under the curve.  In that analysis you also use the elimination rate, for those that had high levels; you take full advantage of the 343 Ranch Handers that have up to four dioxin measurements so you can actually compute an area under an exponential curve.  
		Use all available information.  And we've found that when we do that, we get slightly sharper results, the way we analyze diabetes, as opposed to using the straight dioxin levels that we've been using in our reports.  However, if we go ahead and do the AUC analysis in this report, there will be no precedent for it in any of the previous reports. 
		That argues for putting the AUC analysis in as an additional model, over and above this one, but that increases cost, which could be considerable; the cost of the last report including overhead, was about $1.5 million.  So this might increase, you're going to now increase the models from four to five, that's roughly a 20 percent increase.
		So we're talking about cost constraints and time constraints here, too.
		DR. STOTO:  So does this fall into the category of things you might want to do, further analysis you might want to do that don't necessarily have to fit into the blue report?
		DR. MICHALEK:  Yes.  I would say that the body fat adjusted initial dose estimate can easily be done within the constraints of the report, simply by giving them the body fat adjusted elimination rates.  So when they do this you'll have automatically, be an adjusted analysis.  So that's our proposal.
		DR. STOTO:  I guess I agree that this proposal here is better than what's been done in the past for the blue reports.  I don't think I would want to stop there, but as long as we understand it in terms of what do we do for the blue reports, I would be happy with that.
		DR. HARRISON:  If you have a group of people whose dioxin levels ‑‑ is the less than ten the level of sensitivity of the ‑‑?
		DR. MICHALEK:  The value ten has been singled out, and some people think ‑‑ 
		DR. HARRISON:  So it's not the limit of sensitivity. 
		DR. MICHALEK:  No.  The number ten is simply the 99th percent of the comparison group.   99 percent of the comparisons have less than ten.  In round numbers.
		It just happens to be a round number, like ten. 
		DR. HARRISON:  And if you had a group of subjects with a level of ten or eight or something like that, and you assayed them again after a five year interval, the levels would be lower?
		DR. MICHALEK:  We have done that in the comparison group and we have found that ‑‑ the pieces, unfortunately you asked a question and now you opened up another area of complication.
		The dioxin levels in the comparison group are dropping.  If you look at the dioxin levels in 1987, those in 1992 and those in 1997 in the comparisons, you'll see they're coming down.  And they're coming down, following a trajectory that is parallel to a decrease that's been published in corresponding populations in Germany and other parts of Europe.
		The thinking at the EPA is that this downward trend is reflective of cleanup of industries around the world in their emissions of chemicals into the environment.  So that this is reinforcing the idea, status consistent with the hypothesis that general regulation of industry has caused a decrease in environmental pollution, and that has decreased body burdens.
		DR. STOTO:  I think that complicates it.  I think the point is --
		DR. MICHALEK:  I've asked the question and not given you the answer.
		DR. STOTO:  But I think the point is--
		DR. HARRISON:  Well, that wasn't my question. 
		DR. STOTO:  Let me see if I understand the question.
		DR. HARRISON:  My question relates to the physiologic mechanism of action of dioxin, and whether the level of 10 falls let's say an order of magnitude or more below a dissociation rate constant for dioxin age-receptor interactions.
		DR. MICHALEK:  Don't know that.  All we know is that 10 seems to be the threshold for background exposure in U.S. white males, which are the representative biocomparison group.
		DR. HARRISON:  Okay, but if I remember the argument that I heard at the EPA a couple of years ago, the EPA wants to say that any whiff of dioxin is bad, that there is a continuous dose of ‑‑ 
		AUDIENCE:  That's wrong.
		DR. HARRISON:  I believe it's wrong, don't worry.  I don't know that beliefs matter a whole lot; but one argument is that there's a continuous response all the way down until there's no dioxin left, I mean, until you whisper dioxin.  
		The other one would say that there's a level under which there can be no physiological basis for interaction.  There's even a branch of chemistry that believes that you can dilute chemicals forever.
		DR. STOTO:  I think there's a very different issue than that.
		DR. HARRISON:  This is my issue, it's not your issue.
		DR. STOTO:  I don't think anybody really knows what this threshold is, but there is a statistical issue; that is if you take people who have a level of 9 ppt, some of those people will have had 9 ppt every year in the past, and that's just their level because of where they live and stuff like that, what they eat.
		Some of these people will have had 18 ten years ago and 36 ten years before that.  When we only measure them, at the time, you know, after ‑‑ we can't distinguish those two groups.  So we're basically saying that some of these people had a level of 36 at the time they were in Vietnam, and we're lumping them in the analysis with people who had 9, at the time they were in Vietnam. 
		[Simultaneous discussion] 
		DR. HARRISON:  I want to make this something that even a statistician can relate to.
		Let's imagine that we have a doorbell.  let's imagine that that button requires a certain amount of pressure in order to push it in so the damn bell will ring.  Okay?  It doesn't matter how many fingers are on how many doorbells; if none of them are exerting sufficient pressure, then there's no bells ringing.
		DR. STOTO:  You're saying if dioxin doesn't have any health effects.
		DR. HARRISON:  What I'm saying is, we have a very good idea of how dioxin works; we have a very good idea of the molecular mechanisms of dioxin action.  And so there has to be some rational ‑‑ some rational level of dioxin that you can reasonably expect to see an effect, and that's the only question that I was asking.
		DR. STOTO:  But even if God came down and told us that 10 was the cutoff for having an effect, it doesn't mean the person didn't have 12 two years ago and 36 twenty years ago.
		DR. HARRISON:  I don't disagree with that at all.  But if 10 is already two orders of magnitude below say the dissociation rate constant for the AH receptor, then I, for one, find this to be a trivial exercise.
		DR. STOTO:  No, it's not because they may have had a substantially higher level of exposure in the past --
		DR. GOUGH:  You're talking about two different things.  You're talking about measurements and Bob's talking about effects.  Biological threshold.  And Bob's saying that the measurements below the biological threshold --
		DR. STOTO:  And I'm saying that if the measure is below the biological threshold now, it could have been substantially above it in the future.
		DR. GOUGH:  But not a hundred fold.
		VOICES ALL:  In the past. 
		(Laughter) 
		DR. HARRISON:  Okay.
		DR. MICHALEK:  There are actually three concepts here, and I think we're all talking about different things.  The reason we restrict it to people 10 parts and above is we didn't feel comfortable applying the first order elimination law to individuals who had values below 10.
		Because we believe ‑‑ this is beliefs, we're talking about beliefs.  We have beliefs.  The people below 10 are in steady state and the people above 10 may not be in steady state.  In fact, people way above 10 that we know are not in steady state, they're following the first order elimination.
		So it's simply our attempt to isolate the sub-cohort for which the first order model is applicable; and that's why we took people above 10 in the model.
		DR. HARRISON:  You know, if you want to look at a very similar action, you look at exposure to estrogens in utero and the subsequent development of vaginal cancers.
		So you have an exposure and then you have a biological event that takes place 20, 30, 40 years later.  But the level of exposure that's biologically relevant is not the level of estrogen in some woman 20 years after the fact.  That doesn't have any relevance to it; you could have castrated her at birth --
		DR. STOTO:  Right.
		DR. HARRISON:  ‑‑ and she would still develop ‑‑.
		DR. STOTO:  No, that's a good example here, because the premise behind Model 2 here is that exposure at the time that they served in Vietnam, a body burden of dioxin at the time of Vietnam is the critical thing that may or may not be related to the health.
		DR. HARRISON:  Yes, and that's biologically plausible.
		DR. STOTO:  Yes, but by taking everybody who has a level of 10 or below and presuming that they've always had a level of 10 or below, you are biasing that statistical analysis, because some of them had a level higher than 10.
		Maybe only a few, or it may not make a difference in terms of the final result --
		DR. HARRISON:  They may have just hit 10 ten years ago.
		DR. STOTO:  That's right.  That's the point.  There may not be a big bias; I don't know.  And I would like to see ‑‑ and I think from the point of view of the blue book, it's fine to do it this way, because it's an improvement over what's been done in the past.  But I think that it would be interesting to, as one of the supplementary analyses, to think "Well, suppose that a certain fraction of them had in fact" --
		DR. HARRISON:  What if you presume that they just reached 10 when they were measured?
		DR. STOTO:  And do a kind of sensitivity analysis.  What difference would that make to the outcome?
		DR. HARRISON:  Yes.  I think that's a nice idea.  I like that.
		DR. GOUGH:  Can't you do that by comparing the comparison group to the backgrounds? 
		DR. MICHALEK:  You would do that plus you'd look for dose response, with increased dioxin levels, to see if there's a continuous pattern.
		DR. GOUGH:  I want to --
		DR. HARRISON:  Go ahead.  We're still on statistics.
		DR. GOUGH:  ‑‑ this is just off the record.
		[Omitted by request]
		DR. MICHALEK:  What's the limit of detection?
		DR. GOUGH:  I don't know what the limit of detection is.
		DR. HARRISON:  No, he said background.  He said background.  Background would be something different.
		DR. GOUGH:  In the CDC study of ground troops, both the in-Vietnam and the out-of-Vietnam guys were around 5 ppt.
		DR. MICHALEK:  It looks like it's down to about 4 or less. 
		DR. GOUGH:  It's dropped three times, by a factor of 3, according to EPI.  So it's really going down.
		DR. HARRISON:  But these last drops are not the first order kinetics --
		DR. MICHALEK:  No.
		DR. HARRISON:  ‑‑ are not according to first order kinetics, and you think that they are probably due more to environmental issues than --
		DR. MICHALEK:  No.  We don't think that's first order.
		DR. HARRISON:  That's interesting; how do you --
		DR. MICHALEK:  Consistent with the idea.
		DR. STOTO:  So a level of ten is going further under the tail of the --
		DR. MICHALEK:  If you were to reassess all of the comparisons today based on the data we have now, we would think that 10 would be not the 99 percentile anymore, it might be the 100 percentile.  It might be out really farther on the tail.
		The 99 percentile today, if you reanalyze solid comparisons, might be down around 9 parts per trillion.
		DR. GOUGH:  Oh, that's not much difference.
		DR. HARRISON:  Okay.  What else on statistics?  Because we've got ‑‑ 
		[Simultaneous discussion] 
		DR. HARRISON:  Let's finish statistics, take a five minute break, and then do the public session. 
		DR. STOTO:  They can deliver their in a form other than a floppy disk this time.
		DR. HARRISON:  It was kind of interesting how there seemed to be some questions in there.
		Nothing else then, Mike?
		DR. STOTO:  No.
		DR. HARRISON:  Anybody else with comments on statistics?
		DR. HARRISON:  You're going to laugh at me for this, but I wish you would define what you mean by the term 'clean.'
		DR. MICHALEK:  Is that term in here?
		DR. HARRISON:  You know, "the contractor will clean the data, contractor will" ‑‑ and I'd like to see that defined and restricted.  Because that almost sounds like fudge.  "The contractor will fudge the data."
		DR. STOTO:  It is a commonly used term in the business, but it should be defined. 
		DR. HARRISON:  What you're really saying is, contractor will look at the input documents and reconcile discrepancies?
		LTC BURNHAM:  Quality assurance.
		DR. HARRISON:  I'm just saying spell it out a little better.
		DR. CAMACHO:  Where are you reading that?  What is that?
		DR. HARRISON:  I have it down as, down on page 20, data management activities.  But now my 20, actually ‑‑ because I printed out a section that's different than your 20.  So 3.5. 		I'm sorry; 3.5 and below.
	[Dr. Favata arrives]
		DR. HARRISON:  I'm sorry, 3.5.2.2:  Contractor shall clean the data through an ongoing process throughout the data gathering and analysis period. 
		I just thought that ‑‑ I understand what he means, I just thought it would be nice to say fundamentally what he meant.
		DR. MINER:  It's jargon; should be defined.
		DR. HARRISON:  Dr. Favata has finally ended her trek, trek through hell.
		DR. FAVATA:  Yes, it was.
		DR. HARRISON:  Glad you could make it.
		DR. FAVATA:  Thank you.
		DR. HARRISON:  We have Dr. Camacho on the telephone.  He's ill and wasn't able to travel today.   And we were just finishing up the statistical section and we were going to take a break ‑‑
		DR. FAVATA:  That's okay.
		DR. HARRISON:  ‑‑ before, then a public comment time, and if there are no more -- did you have any statistical questions, that's 3.6, that's a section I don't know if you looked at or not.  Just want to make sure.
		DR. FAVATA:  No.  I have some that ‑‑ my comments pertain to General Health and Neurology and then I have some comments about 3.3, 3.5. 
		DR. HARRISON:  All right, so why don't we take like a five minute break and then we'll do the public comments.  We have at least one person.
		If anyone else has something they would like to ‑‑ no?
		[Recess]
		DR. HARRISON:  Okay.		
		DR. MINER:  Joel, do you want to add the '91 report?
		DR. MICHALEK:  I'd just like to add to something that was mentioned before we broke.
		The idea was, Mike suggested lowering the threshold, so to speak.  To lower the bar on this 10 parts per trillion.  Well, we actually did that in 1991.  We had it in our first dioxin report.  We lowered the bar to 5 parts per trillion.  And if you go back to that report, you'll see we did so-called maximal and minimal assumptions on exposure and carried that to great lengths.
		So that report's on our web page, too, if you want to go back and browse.
		DR. STOTO:  If you can just point that, send me an e‑mail pointing it out to me.
		DR. MICHALEK:  Sure.
		DR. HARRISON:  But your point is that it didn't change the interpretation of the results?
		DR. MICHALEK:  No.  In fact, what's happened since then is there has been an evolution to simplify things based on that report.  That was a nine volume, 4,000-page report, which was carried to great lengths and created praise as well as frustration, because it was hard to read.
		So what we've done since then is tried to simplify the approach; and that's where this 10 parts per trillion cut came from, and through committee review and just like we're having today, we have moved to where we are now.  So I'll send an e‑mail to you on that.
		DR. HARRISON:  Are you back, Paul? 
		DR. CAMACHO:  All right, move out.
		DR. HARRISON:  Okay, here we go.  This is the open public session, and Dr. Gary Kayajanian is the lone public speaker for today.
	OPEN PUBLIC SESSION
		DR. KAYAJANIAN:  I published two papers on dioxin, in 1997 and 1999, which basically analyzed three studies, Caseba {ph}, the Seveso study in 1993, and the NIOSH report that accompanied the '91 publication by Finker, et al.  And I drew the general conclusion that dioxin acted as a promoter-blocker.  That is, you could see a reduction after five years of cancer incidence.
		Now because the Seveso study was just a ten year study, and because the NIOSH study had workers exposed to lots of other chemicals, the best time period in which to see the effects of the chemical acting as a promoter-blocker was five to ten years after exposure.  You have other chemicals present, but you wouldn't see their effects as cancer initiators.
		This isn't to say that promotion blocking is the only thing that dioxin does.  It's something that you can see in that window of time.  That basically has colored my view of what dioxin does.
		I had an opportunity to test some of my ideas in a paper that was published last year, and Joel Michalek was gracious enough to provide data I requested from the Right Hand study.  And there were a couple of observations probably worth relating from that paper.
		The first was that if you compared the background group and the comparison group; the background group was the Ranch Handers with 10 parts per trillion or less, when measured in '87.  If you compared cancer incidence, either non-skin cancers, total cancers other than skin, or melanomas, you found they significantly increased, roughly six-fold increase over what you would have expected from a population of men somewhat older than the Southeast Asia populations, who had never served.
		This increase was hugely significant.  If you then compared the high dose Ranch Handers to the reference population, you found a reduction.  So in effect, you have a cancer incidence level, a sixfold increase associated with the Vietnam tours of duty, and then with higher dioxin levels, a reduction of that level about a third, still significantly elevated over men who never went to Southeast Asia.
		I've tried to develop an explanation of how dioxin works.  And the model I developed generated certain unusual predictions.  And the predictions that were expected was that dioxin would have, as you increased ‑‑ a population as you increased dioxin body burden would have two cancer incidence peaks followed by two cancer incidence valleys.
		So what I ended up doing was taking all 2275, 2255 men from the comparison group and the Ranch Handers, put them together, rank ordered them least to most dioxin, and apportioned them into seven groups, least to most. One through seven, least to most.
		What you find is a cancer incidence pattern when you go from the first group to the second group.  The first group has zero level, or below 1.25, below the limit of detection.
		The second group has 1.25 to 2.50.  This represents a significant drop.
		The third group shows an increase, and that's from 1.5 to 2.5 to 2.51 to 4.0 it goes up.  
		The fourth group is from 4.01 to 8.0, and that goes up significantly.  It goes down from 8.01 to 10.  
		The final two points are from the Ranch Handers that were above 10 parts per trillion.  I didn't use the packaging that Joel used; I simply took a look at the data, and it seemed the first 60 percent of those in group six showed a significantly higher level of cancer.
		And then the final group of 224 had a significantly lower one.
		So there were five; one, two, three, four, five significant cancer incidence changes as a function of body burden.
		DR. GOUGH:  How did you make those cuts?
		DR. KAYAJANIAN:  Visually.
		DR. GOUGH:  No, but I mean some of the intervals are ‑‑ well, like there's an interval 4 to 8, and then there's an interval 8 to 10.
		DR. KAYAJANIAN:  Yes.
		DR. GOUGH:  I mean, I can make the intervals 8 to 12, and that would go away, I think.  
		DR. KAYAJANIAN:  It might.  Some of the breaks are natural breaks, between this and this, non-detects and detects.  The 10 happened to be between, included the background in the comparison group, and then there was this break because Joel had back-calculated the body burden levels to when the men came in as opposed to what they were in '87, which is what describes the first five groups.
		DR. GOUGH:  So the last point is not even the same kind of data.  That's an extrapolated --
		DR. KAYAJANIAN:  Well, let's put it this way; it may have been extrapolated data, but to be perfectly frank, had I know exactly what the '87 values were, they would have been most probably more appropriate to present.  I agree that I could cut the things and these would disappear.
		But the point is that I cut them in a way so that you would see a difference.  I don't consider that at all dishonest.  I mean, if the differences weren't there, you wouldn't see them.
		DR. GOUGH:  When I draw a line connecting points, which I could do with certainly the first ‑‑ I could draw any number of lines through those.  They're error bars or something, measurement error bars.
		DR. KAYAJANIAN:  In saying that these are significant, you take the cancer incidence, the number of cancers for however many individuals were in the group; you ask whether that's significantly different from --
		DR. GOUGH:  And so those error bars don't overlap?
		DR. KAYAJANIAN:  That's right.
		DR. STOTO:  Let the record show I'm agreeing with Mike here, having some skepticism on this.  Because I don't know about the sample sizes in the Y direction, but I know that the X direction is pretty much random noise below 10.
		DR. KAYAJANIAN:  If this is random noise, then how do you find this, and as I said--
		DR. GOUGH:  Well, you make the cuts, Gary.
		DR. KAYAJANIAN:  Where?
		DR. GOUGH:  By the way you make ‑‑ I mean, you ‑‑.
		DR. HARRISON:  The question is being asked, is ‑‑ let's take from 0 to 10.  If you were to make the intervals every two parts per trillion ‑‑ and sort the incidence by that, would you still see the same shaped curve?
		DR. KAYAJANIAN:  You probably would blur it.  Obviously sine you're doing it in two part intervals, you would certainly see this drop ‑‑ I'm simply taking your question as --
		DR. HARRISON:  If you went from 0 to 2, 2 to 4, 4 to 6.
		DR. KAYAJANIAN:  The zero stands alone.
		DR. GOUGH:  It's less than 1.25, right?
		DR. KAYAJANIAN:  Yes, it's less than 1.25.  It's sort of a natural break; it's the non-detects. 
		DR. HARRISON:  Okay.
		DR. KAYAJANIAN:  But if you were to take 1.25 say to 4, then you'd have a point in here.  It wouldn't quite be significant, this would be significant.  This would be two points, one at 4 to 6, and 6 to 8, and they both ‑‑ one would be here and the other one would be just a little less than that, and this one would stand.
		So what I'm doing is not unreasonable because I had a specific model to test, a predicted, a peak, a very early peak, which turns out to be this, and a later peak; and I expected to find two valleys; one between this and one here.
		So it wasn't totally blind and it wasn't totally unfair.  The only thing that I could probably be criticized for was splitting this into two.  And I would grant you that I split it in order to show that this was a significant drop.
		DR. HARRISON:  Okay.
		DR. KAYAJANIAN:  Now the cancers here are, just to be especially clear, they're first cancers, they're first skin cancers plus first non-skin cancers summed.  So they're not total, total cancers, but they're the best I could get out of Joel.
		DR. MICHALEK:  First diagnosis.
		DR. KAYAJANIAN:  Yes.  But if you had a skin and a non-skin, you have both.
		DR. MICHALEK:  For the record, that last point that you put out there corresponds to roughly 33 parts per trillion, 1987.
		DR. KAYAJANIAN:  Yes.
		DR. MICHALEK:  Which is very high relative to the U.S. population.
		DR. KAYAJANIAN:  Yes, I would have guessed it would have been maybe a bit higher, like 45.  I mean, you're putting this break with the middle.
		DR. MICHALEK:  It then corresponds to the cut between low and high in our reports.
		DR. KAYAJANIAN:  No, it's higher than that.
		DR. MICHALEK:  Okay, it's maybe 40.
		DR. KAYAJANIAN:  And I guess this one would be about 15 or 16.
		DR. HARRISON:  So what's the take-home lesson?
		DR. KAYAJANIAN:  The take-home lesson is that whatever conclusions you draw about dioxin at high dose are absolutely irrelevant to people in this background range.  Because you cannot extrapolate, either from these first five points as average or from this point, the zero point, to anything out here, because you have significant drops.  
		So it means, in effect, that all of EPA's high dose observations are worthless, because they're irrelevant.  I shouldn't say they're totally worthless, they'd be a value to people out here perhaps, but they're not a value if you're talking about risk assessment policy in this area.
		And if you want to reduce dioxin body burdens down to zero from here, you do so by significantly increasing cancer incidence.
		DR. HARRISON:  The other suggestion that you're making is that you're arguing for a variation in the range from 0 to 10.
		DR. KAYAJANIAN:  Yes, that's clear.
		DR. HARRISON:  And Joel has argued that less than 10 gets lumped together.  
		Am I not right?
		DR. MICHALEK:  That's what we've done in our reports.
		DR. HARRISON:  So ‑‑
		DR. KAYAJANIAN:  And in the paper that came out last year where I kept his breaks of 0 to 10 and then splitting the Ranch Handers above 10 into two groups, what you would find if you just took those numbers is that this point is not significantly higher than this, averaging, but this one is significantly lower for non-skin cancers and for melanomas, for which seer reference data are available.
		DR. GOUGH:  Are these data skin plus?
		DR. KAYAJANIAN:  Yes, they're skin plus.
		DR. GOUGH:  That's a very unusual combination.  What is it for systemic cancers?
		DR. KAYAJANIAN:  If you looked at the systemic cancers, you lose some of the --
		DR. GOUGH:  You lose some numbers.
		DR. KAYAJANIAN:  You lose some of the significance, but the important thing is, that if you start, for the comparable value here, this is significantly less than this.
		DR. HARRISON:  Is there a hormonal basis to melanomas?  I keep forgetting.  It's not a sex-based difference; men greater than women, women greater than men?
		DR. KAYAJANIAN:  Well, melanomas here constitute about 7-1/2 percent, squamous about 11-1/2.  And basal about 82.
		That's the first point, and this was in effect, a major portion of the presentation I made to EPA a couple months ago. 
		The second thing I wanted to talk about was skin cancer, and I want to talk about it not in connection with dioxin; so I'm going to be looking at the zero group, the one that didn't have any dioxin body burden measurements.
		There were 117 non-black men, white men in this group, and I looked --
		DR. MICHALEK:  These are the group with zero parts per trillion?
		DR. KAYAJANIAN:  Yes.
		[Drawing on easel]
		Now the number of man years covered in each of these intervals, the first three intervals, is almost exactly the same; and that's quite reasonable, given that in order to be included in the study you had to have a 1987 measurement.
		So there were 585 man-years for the first three of these groups.  This group, 81 and this group, 15.  I'm not really concerned about this, and --
		DR. MICHALEK:  Why don't you emphasize why you're not so interested in the high dose group.
		DR. KAYAJANIAN:  Because I want to find out what the effect of being in Vietnam was on skin cancer incidence.  So I go where there's no measurable skin cancer.
		Now normally if you look at cancer incidence tables as a function of age, you find that as the population ages you get curves that go like this.  One form or another; they just go up exponentially, they never go down.
		There are some cancers that are more like this, not many.  There were no good seer data for basal or squamous cell cancers.
		Finding a peak 16 to 20 years after the beginning of the duty tour for each of these men, and these are first skin cancers, is a surprise.  
		This increase is significant at the .01 level, more importantly this decrease is significant at the .01 level.  And you wouldn't find a curve like that unless two things were present.  The first thing is that you initiated or you prevented the blocking of initiation, roughly about the time the men began their duty tour.  And the second thing you need to have happen is either of two things:  Either the promotable skin cancer intermediate is unstable; that is, it doesn't hang around for years and years and years so it can be promoted later; or in the U.S. we have ‑‑ we're very efficient about promoting cancers.  You promote 100 percent of your cancers or close to that at your first opportunity.  You wouldn't have a curve like this without it.  
		I don't know which of those alternative explanations happens to be true, but I think one of them is.  And I think this is a very good second way of showing an increase in cancers were associated with service in Vietnam, and not associated with the dioxin.
		DR. GOUGH:  Is this simply the comparisons?
		DR. KAYAJANIAN:  This is mostly comparisons.  Of the 117 --
		DR. MICHALEK:  About 90, 80 are comparisons and 24 are Ranch Hands.
		DR. KAYAJANIAN:  Well ‑‑ well --
		DR. GOUGH:  Okay, that's enough Gary.  That's what I ‑‑.
		DR. KAYAJANIAN:  I think there were 8 of these, I think 8 of these are from the background group.
		DR. MICHALEK:  Ranch Hand.
		DR. KAYAJANIAN:  Yes.
		That's the second point, and the third has to do with prostate cancers in black men.  And for this [writing new chart] this represents a grouping by dioxin body burden.  This is the group that had none, this was the group that had between 1.25 and 4, and this was the group that had more than 4 parts per trillion.
		This is the number of black men total, and in these individual groups, this is the number of prostate cancers that were diagnosed.  And if you compare this with these together, you have a significant reduction at the .001 level.  If you compare this with this, you have a significant reduction at the .1 level; if you compare this with this, you have a significant reduction at the .004 level.
		Now let me commence a little bit.  When I went through an analysis of this to try to show the dioxin was the cause or at least significantly related to these significant reductions, I made an assumption.  And the assumption was that if we took these nine men and assumed that when service began they were 60 years old, so 30 years later, they'd be 90.
		So we would expect from each one of these men to have a chance, because they hadn't gone to Southeast Asia; a chance of 6.5, 6.6 percent of having prostate cancer.  
		So of the three prostate cancers, 9 times 6.6 percent would tell you how many prostate cancers they should have.  That hugely upper estimate was .6.  If you use that, you have a ratio of 5, and that represents a significant increase. 
		Joel shared with me, as he came in, more detailed data on when these men were born.  So the oldest man would have been 70.  So following from 40 to 70 you get roughly .15 cancers expected ‑‑ and again, that's tilting against the observation I want to make.  And in this case, .15 into 3 is 20, so it shows a 20-fold increase in cancers associated with the service in Vietnam or in Southeast Asia.
		Even assuming this, which is an extreme worst case, when you make these comparisons, 3 out of 9 as opposed to 1 out of 86, even if this group were much younger than this group, that wouldn't account for very much because all you'd be reducing is that .6 or the comparable number here.  
		So dioxin is associated with a reduction, and because you have this intermediate point, you show it goes down one.
		DR. GOUGH:  Gary, did you ever find increases in cancer when you did this analysis with other tumors?
		DR. KAYAJANIAN:  With ‑‑ 
		DR. GOUGH:  Any tumors.
		DR. KAYAJANIAN:  Well, there were increases with ‑‑ here and here. [chart]
		DR. GOUGH:  No, no, no.  I mean, you've singled out prostate.  What about --
		DR. KAYAJANIAN:  Lung?
		DR. GOUGH:  Anything.  Because I would expect, given these small numbers, you do enough of these analyses and you'll get a pattern like anything.
		DR. KAYAJANIAN:  Sure, sure.  First of all, I haven't looked at a large number of things.  With skin cancers you do see the increase.  I mean, skin cancer is clearly driving that first set of numbers.  So you do see the increase.
		And as I said, I expected to see two cancer incidence peaks; one near zero and one near this breakpoint to get you the low, the really low value.
		So yes, with skin cancers I clearly saw that.  I didn't see it with lung; and if I looked at prostate in white men it would have been pretty flat.  
		But this is just something that stood out.  It's not as if I've done 100 comparisons and I'm bringing you the one that --
		DR. GOUGH:  Yes, because I think that's what's necessary for analysis like this.  These tiny numbers, fluctuating around means--
		DR. KAYAJANIAN:  But this isn't a fluctuation.  Granted it's small, but the point is that you expect something very small here.
		DR. GOUGH:  I don't, actually, because the Ranch Hands are examined so carefully for prostate cancer, the physical examination ‑‑ you expect it to be high, as compared to the background population.  Particularly black males.
		DR. KAYAJANIAN:  Well, I understand.  I mean, these are the numbers from black males.
		DR. HARRISON:  So what he's saying is it's an ascertainment bias.
		DR. GOUGH:  I'm sure there's an ascertainment bias.
		DR. HARRISON:  That's a function of being involved in the study.
		DR. KAYAJANIAN:  If that's the case,  why don't you see these numbers higher and these numbers higher?  I understand.  I mean, if you're going to tell me for some reason these men were treated, got much better medical treatment, and so you saw them but you didn't see them here --
		DR. GOUGH:  No, I'm not going to say that at all.  All I'm saying is these are tiny numbers.  This .6 and .15 comes from the general population.  The seer population.
		DR. KAYAJANIAN:  No, it comes from the black, seer black, black men in the seer population.  And as I said, this was as old as I could ratchet the population up --
		DR. GOUGH:  Yes, I understood that.
		DR. KAYAJANIAN:  And this was much more reasonable.
		There's also another way of looking at these kinds of data.  I didn't know exactly what the age distribution was, say of the comparison group.  I couldn't tell you when everyone was born, I couldn't tell you what kind of ‑‑ how long the length of service was, but I could tell you that for say the comparison group you had the same distribution of age and service in determining skin cancers and determining lung cancers and in determining prostate cancers.
		The same population was used, so it's the same distribution.  And so what I ended up at one point doing to try to convince Joel that prostate cancers were elevated overall, was to say "Gee, if I look at the ratio of prostate cancer to non-prostate cancers, or to total cancers," total in this case being melanoma plus systemics, and I did it for lung and I did it for say bladder and kidney, and for skin, I'd expect the same ratio as I would find in a certain population grid, or close to it.
		The population which described prostate cancer was 75-79, whereas with lung it was more like 40 to 45, and for skin it was more like 35 to 39.
		So it's another way of showing that prostate cancer is elevated overall.
		So selecting this group wasn't --
		DR. GOUGH:  Why was the expected, the number I should compare to, the total of seven?
		DR. KAYAJANIAN:  Well, --
		DR. GOUGH:  I mean, if I use the upper number, .6 times 86, I'm almost ‑‑.
		DR. KAYAJANIAN:  That's what shows you that it's significantly down.
		DR. GOUGH:  That doesn't show me anything. 
		DR. KAYAJANIAN:  ‑‑ with dioxin.
		DR. GOUGH:  Shows me that you've got exactly the same incidence you'd expect --
		DR. KAYAJANIAN:  No, but this is --
		DR. GOUGH:  No, it doesn't.  There's a pattern there, but it doesn't ‑‑ anyway.
		DR. KAYAJANIAN:  If you take either of these two values, multiply it by 10 --
		DR. GOUGH:  Come on, Stoto.
		DR. KAYAJANIAN:  ‑‑ and multiply it by --
		DR. STOTO:  None of this makes any sense.
		DR. GOUGH:  Okay.
		DR. KAYAJANIAN:  ‑‑ a ratio of 86:9.
		DR. GOUGH:  Okay, that's fine.
		DR. KAYAJANIAN:  If you multiply either of these two numbers by the ratio of 86:9--
		DR. STOTO:  Can I ask a question?  Suppose this were true.  I don't understand what the relevance of it is to the Ranch Hand study.
		DR. KAYAJANIAN:  The relevance I guess is that dioxin reduces --
		DR. STOTO:  No, No, no.  We're trying to design a study and design a set of analyses, and monitor that.  Even it were true that dioxin protected against cancer --
		DR. KAYAJANIAN:  Against this cancer.
		DR. STOTO:  Even if that were true, what should we do?  Should we stop the Ranch Hand study?  No, of course not.
		DR. KAYAJANIAN:  What I would suggest to you to do is instead of using the parameters that you have been using, you rely more on length of service because that's a better reflection ‑‑ time since the beginning of service, because that's a better reflection of age --
		DR. HARRISON:  You're saying that after --
		DR. KAYAJANIAN:  ‑‑ and so all the talks --
		DR. HARRISON:  ‑‑ five years after exposure to dioxin is when all the action starts.
		DR. KAYAJANIAN:  No.  In this case it's not, and I'll tell you why it's not.
		DR. HARRISON:  Okay.
		DR. KAYAJANIAN:  You need to have a background of cancers to reduce.  This is a small study, and the first 15 years you don't have very much expected cancers, so there's not much to reduce.  When you're able to see a reduction in cancers, is when they occur as a result of being in Vietnam.
		So for the skin cancers, it's 16 to 20 years you get this peak in the zero group, and then you see a reduction when you move out.  And if you want to do it for the non-skin, you look 16 to 30, and you see the reduction.
		DR. HARRISON:  Okay, so that's --
		DR. KAYAJANIAN:  What I'm saying is that the parameters you're using are not the best ones.
		DR. HARRISON:  So that's one thing to consider.  We've only got about ten more minutes.  
		DR. KAYAJANIAN:  I'll take any question you want.
		DR. HARRISON:  No, I just want to make sure that you had finished what you --
		DR. KAYAJANIAN:  I came to make three points, I made the three points.
		DR. HARRISON:  Okay.  I didn't mean to stifle ‑‑ 
		DR. KAYAJANIAN:  And I would certainly concede any argument as to the relevance of this, the second one dealing with skin cancers, to what the effect of dioxin is.
		I guess the point I want to make here and emphasize is that it's not the dioxin that's doing the damage with respect to cancer; it's having been in Vietnam or Southeast Asia for two to three years.  And that's caused roughly a sixfold increase in a lot of cancers.  Probably moreso in the case of prostate.
		DR. MICHALEK:  Two points to make following this is first, if there is an effect of being in Vietnam, we would totally miss it in this study, because we have Vietnam veterans who are controls and we have Vietnam veterans who are an exposed group.  
		So a pure Vietnam effect would be totally missed.  That's one point.
		Secondly, the analysis that I proposed earlier, the area under the curve, does accommodate a measure of time since exposure in the model; and it supports the idea that accommodating that body burden of time seems to sharpen our resolve; it's consistent with what he just said.
		And thirdly, I have checked the cancer rates, melanoma against the seer rates, and there is roughly a fivefold increase in both groups relative to the seer population.  But that analysis itself is open to criticism just like you suggested.  But that needs to be argued out as to whether that's recall or not, the so-called ascertainment bias, that we got a very carefully monitored group, and whether that has anything to do with elevating the risk or the ascertainment of cancer.  That all needs to be discussed.
		That's basically it.  And by the way, all the data that he's using is on our web page. 
		(Laughter) 
		DR. HARRISON:  The nice part about science is that people are going to examine it from every perspective, even unexpected perspectives, and that's their traction of science.
		DR. MICHALEK:  I always enjoy hearing from Gary.
		The other thing to know, for the record, is that all the cancers that he has talked about have been verified two and three hundred percent against medical record review.  These cancers are real, they have been diagnosed, and we have documents to prove it.
		DR. HARRISON:  300 percent verification.  That's --
		LTC BURNHAM:  That's 100 percent, three times. 
		(Laughter) 
		DR. KAYAJANIAN:  It's like the vote count in Florida.
		DR. STOTO:  How many of the cancers were diagnosed at their clinical exams, the Ranch Hands?
		DR. MICHALEK:  Very few.  In fact, because there were no invasive procedures at Scripps for cancer.  And I have to check to see the skin cancer; that would be the one that would be the most likely diagnosis at Scripps.  We'll have to check that.
		DR. HARRISON:  So you're saying then, for instance, the prostate cancer data should not then ‑‑ well, that's not true, because even --
		DR. MINER:  We're doing PSA.
		DR. MICHALEK:  You want to know the source of the diagnoses, and we can tell you that.
		DR. HARRISON:  You have prostate specific antigen; not only that, but the mere fact that every five years these men are contacted and recruited to participate in a health study means that in the interval they are a little more health-aware than the average bear, and if they're not, their doctors damn well are, because they don't want to be embarrassed by having you go out to Scripps and find something that they don't already know about.
		DR. STOTO:  And that applies to controls as well as the Ranch Hands?
		DR. MICHALEK:  Yes.
		DR. HARRISON:  There is still a very reasonable ascertainment issue.
		DR. MICHALEK:  We call them in between physicals to remind them to go see their doctors.  We're on the phone with them all the time, all 2,300 of them.  So they get a constant telephone follow-up from us, plus they get letters from Scripps telling them what their abnormalities are, and they are told to take that letter to their family doctor.
		So yes, they're watched pretty closely.
		DR. HARRISON:  Do you have an actual person call them, or do you use one of --
		DR. MICHALEK:  Our staff.
		DR. HARRISON:  So you don't use one of these recorded --
		DR. MICHALEK:  No.
		DR. KAYAJANIAN:  The ascertainment issue surely shouldn't apply if you're worrying about better medical care.  It shouldn't apply across the study; you know, we would apply in comparison with outside groups.
		DR. HARRISON:  Agreed.
		DR. KAYAJANIAN:  You don't want to overuse the argument.
		DR. MICHALEK:  That's true.
		DR. HARRISON:  Well, thank you very much. 
		MR. WEIDMAN:  I'm Rick Weidman, Vietnam Veterans of America.
		DR. HARRISON:  Welcome.
		MR. WEIDMAN:  It's not easy getting in here. 
		(Laughter) 
		DR. CAMACHO:  Hi, Rick.
		MR. WEIDMAN:  Hello, Dr. Camacho.
		DR. CAMACHO:  How are you doing.
		MR. WEIDMAN:  Good.
		DR. HARRISON: Sounds like you're coming out of the pits there every now and then, Paul.
		So what do we want to do?  It's 10 minutes to 4.  
		DR. STOTO:  Do we have the option of moving forward and doing some of the stuff for tomorrow?
		DR. HARRISON:  No, not for tomorrow; we're not finished with today.  We've got, we did statistical models.  We haven't done covariates and interactions, we haven't done analytical planning, general category ‑‑ I mean, we haven't done any of that stuff.
		So do we want to try to press on for maybe another half hour?
		DR. CAMACHO:  Can I ask a question?
		DR. HARRISON:  Of course.
		DR. CAMACHO:  It's about, I was asked to look at 3641. and on, right?
		DR. HARRISON:  Uh-huh.
		DR. CAMACHO:  Anyway, you've got a linear model and then it says then that binary variables via logistics regression.  I'm just double-checking, you're using the logistic regression to smooth out the variables and get a straight line?
		DR. HARRISON:  Are you asking Joel?
		DR. CAMACHO:  I guess so.  I'm referring to what ‑‑ the first document that we were sent, via e‑mail.  And it's 3.6.4.1.1.  
		DR. HARRISON:  It says:  These four variables shall be analyzed adjusting for age, race, military occupation?
		DR. CAMACHO:  Yes, and then it goes to the body fat, the sedimentation rate ‑‑ I wish somebody would go over that again.  Why is that so important?  But it's more a case of fat analyzed variables via a general linear model, and then it says:  As binary variables via logistic regression.
		And the point of their logistics
going to logarithms, is to what, achieve a straight line?
		DR. STOTO:  No, that's the appropriate method when you have a dichotomous dependent variable.  When the Y variable is dichotomous.  Either they have the condition or they don't, because you're talking about the risk of getting those ‑‑.
		DR. CAMACHO:  How important is it to have some notion of the true model that's governing the relationship?  I mean, we're talking about what we don't know and trying to look at some variables.  I don't want to throw a big ringing in the thing because I'm not sure what I'm talking about.
		I know that you can pick ‑‑ what is that reciprocal Ys, you can pick a number of different things.  And is it because it's the standard and it makes the data smooth and you get a straight line so you can look at the regression?
		DR. STOTO:  No, it's not a matter of linearity, it's a matter of the data structure.
		DR. HARRISON:  So if you're black or non-black, if you're --
		DR. CAMACHO:  And that's why you're using it?
		DR. HARRISON:  Yes.
		DR. CAMACHO:  For that reason.
		DR. HARRISON:  Yes.  
		DR. STOTO:  You can think about whether you want to put some different curvature on the Xs, but I don't think there's any reason to think that you would want to do that.  But when you have a discrete Y with only two values, you pretty much have to use a model like this.  
		DR. CAMACHO:  All right.  That'll answer it.  I was off on the wrong tangent, then.
		DR. HARRISON:  So even something like drinking history gets dichotomized?
		DR. STOTO:  No, this is a dependent variable.  Either they have diabetes or they don't or they have heart disease or they don't.
		DR. HARRISON:  Now since we're on this, this is probably not the appropriate place, but I have no idea why we're still doing sed rates. 
		DR. MICHALEK:  It's not, it's been moved to hematology.
		DR. HARRISON:  I still don't know why we're doing it at all.
		DR. GOUGH:  Dr. Camp.
		DR. FAVATA:  Wanted it?  To continue.
		DR. GOUGH:  Yes, he was very adamant.  It was just ‑‑ over and over and over again he said that it's a general indication of --
		DR. HARRISON:  I can't argue with anybody that old. 
		(Laughter) 
		MR. WEIDMAN:  He may be old, but he'll get you ‑‑ 
		(Laughter) 
		DR. HARRISON:  Okay.  Well, did you have anything else right now, Paul?
		DR. CAMACHO:  No.  Let's progress.
		DR. HARRISON:  So what about covariates and interactions?  That is 3.6.2.
		Any comments on that?
		DR. STOTO:  There are really no changes in that.
		DR. HARRISON:  What about analytical planning, 3.6.3?
		DR. STOTO:  I discussed that already; that they're going to use SAS and not have everything on floppies.  Perfectly reasonable.
		DR. FAVATA:  I have some questions and points to raise, Bob.  One is, and I apologize for my tardiness and I know that this has been brought up before; but the question is the use of the residential and occupational history regarding chemical exposures post the Vietnam experience.
		The issue is that if we only consider the Vietnam experience to be the source of dioxin exposure, and health problems are surfacing right now, we may be inappropriately attributing it to a latent effect; and that may  not be the case.
		I think that these are very important to include in every analysis.  Regarding the residential; Joel, during our October 1999 meeting, and this was from the minutes, page 9 of that meeting, you noted that the EPA has a database of counties in the U.S. which are rank-ordered by a dioxin exposure.  And we also have the complete residential history of all the veterans in a very detailed fashion.
		So can we therefore access this EPA data and give ourselves the benefit of understanding what their dioxin exposure has been residentially?
		DR. MICHALEK:  Yes, we can, and we can get the data from the EPA on associating residence with background levels of dioxin exposure.  They have that data.
		DR. HARRISON:  So that was Dr. Favata's residential issue.
		DR. MICHALEK:  Yes, and that's one of the ideas I forgot.
		DR. HARRISON:  Not the in-house exposure --
		DR. FAVATA:  Not within the walls of their house.
		DR. HARRISON:  ‑‑ but exposure by zip code or ‑‑.
		DR. MICHALEK:  I thought you were questioning the exposures to chemicals in the household, and you had a series of questions you wanted us to ask them about that.  But we can get the EPA data; the answer is yes.
		DR. FAVATA:  I think that looking at the indoor environment, I really don't think as a group that's going to be a significant exposure to have an effect on this data, and I think that what is most important is from a residential standpoint that we look at their geographic location and see if that has any effect.
		DR. STOTO:  But given that we have measures of dioxin for these people, is that better than ‑‑ what's the point of having the residential measures of dioxin.
		DR. HARRISON:  It might have changed the disappearance rate unexpectedly.  You don't have enough points to be sure about that.  You might be looking at a 10 that should have gone to a 5 and is still a 10.
		DR. FAVATA:  And the other thing is that you have an individual with a certain level, you have different rates of elimination; that may be impacted on, we don't know what at this point.  So I think, why not utilize that in addition?
		Also, regarding their occupational history, in a previous document, and I'm sorry I can't find this ‑‑ that there is a standard coding system.  What is that?  What is the standard coding system used?
		DR. MICHALEK:  For what.
		DR. FAVATA:  For occupational history.
		DR. MICHALEK:  There is a ‑‑ do you know the name of that coding system? 
		[Simultaneous discussion] 
		MR. WEIDMAN:  There's Standard Industry Code, SIC.
		DR. FAVATA:  SIC?
		MR. WEIDMAN:  And the actual occupation is, dictionary of occupational titles was what was formerly used.  They just switched over at Department of Labor to a different system, but it's still coded, every occupation in America.
		DR. MICHALEK:  Exactly.  We have a database of all jobs ever held, start and stop dates, in all positions coded according to the system that you just described.  We have not made a full effort to relate those occupational exposures to dioxin levels.  That's something that should be done eventually.
		DR. FAVATA:  I think that that would be important.
		DR. HARRISON:  How are you going to use that, now?  How are you suggesting that they use it?
		DR. FAVATA:  Well, number one, I'm not sure in the SIC codes, whether they ‑‑ I really need to look at that to see how they break out chemical exposure in those. 
		DR. STOTO:  Not well.
		DR. FAVATA:  Then that may be a problem if that's --
		DR. HARRISON:  You'd have to infer it from the occupations.  You'd have to --
		DR. CAMACHO:  A standard book breaks those ‑‑ I think that you have an industrial category as a group, industrial category and then occupational groups.  It breaks down to at least five or six digits.  
		DR. STOTO:  But it could tell you that somebody is in the chemical industry --
		DR. CAMACHO:  Yes.
		DR. STOTO:  ‑‑ but it won't tell you what chemicals were made or whether they work in the factory or in the office or anything like that.
		DR. CAMACHO:  Yes, I believe so.  It gets finer than the usual numbers that we see in a table.  I know if you look in the book, it goes down a couple more digits, put it that way.  I don't have one in front of me.
		DR. HARRISON:  But the problem is that you're still only referring to occupation, and the occupation ‑‑ 
		DR. CAMACHO:  That doesn't necessarily tell you that he worked with it.
		DR. STOTO:  It's not even occupation, it's the nature of the industry that he worked in and not what the job he had was.
		DR. FAVATA:  We asked the questions in the neurology section, and we specifically addressed metals, what was in quotes was insecticides and degreasers.  
		Can't we take that information, since we've already asked it, and then use that as a covariate?  Or ask those --
		DR. MICHALEK:  Yes.  In other chapters, right.
		MR. WEIDMAN:  I guess I'm curious, Doctor, why you particularly would want that, because am I correct in this, that our understanding is that nobody knows what body burden for what period of time causes what toxic, adverse health effects.
		Am I correct in that?
		DR. FAVATA:  You mean in general?
		MR. WEIDMAN:  In general.  Once it's above the threshold.
		DR. FAVATA:  In dioxin, you're speaking of?
		MR. WEIDMAN:  Yes, ma'am.
		DR. FAVATA:  I think that you're correct in saying that.
		MR. WEIDMAN:  So that if someone lived in Piscataway, New Jersey which has a high dioxin residential rank and worked in the federal chemical agency, it still would not be a counter-indicator as to whether or not the origin to the maladies which that individual suffered, in fact were incurred by the initial exposure in Vietnam.  
		Am I correct in that?
		DR. HARRISON:  I think you're coming at it from the wrong angle.  We're making the assumption that we're not sure what happens, and we're trying to examine various measures of exposure to dioxin and look at various health measures and see if they correlate in any way; making no presumption that there should be a relationship.
		So in essence, we keep asking ourselves, is there anything else we can measure to try and correlate with health effects?
		MR. WEIDMAN:  Well, I think what you're suggesting is needed.
		DR. HARRISON:  For example, in Vietnam one of correlations was historical exposure ‑‑ not in Vietnam, but one of the correlations that's been used in studies is historical exposure.  Another one is actual blood dioxin levels, and another one might be whether or not there was continued exposure to dioxin in some form once back Stateside.
		Joel has one famous guy who worked on power transformers, and his dioxin levels rose after he returned to the United States.
		So you try looking at different exposure parameters to see if any of them provide you with any better insight into whether there's a relationship or not.
		MR. WEIDMAN:  It's something that clearly we're interested in, too, in the veterans community at large.  I had talked with the Iowan, the current committee that just completed their biannual review.  And they have urged them to recommend that there be additional studies in the United States of U.S. veterans and not just of Air Force personnel, but a cross-section of people.
		And particularly to focus on doing studies of domestic exposure in those counties that you were referring to, Doctor, where we know there's been high exposure of the population in general.  And that studies of the population in general in those areas with doing a veteran's identifier, that's never been done.
		It hasn't been done at Times Beach or Northeast Arkansas or any of the places that we know were so highly exposed to figure out, is there a cumulative effect?  In other words, don't come out and test from this population, but from the broad base of the population with a veteran's identifier or a veteran or progeny of a veteran, an identifier, to see whether or not there's something that leaps generations.  Into the next generation or even the grandchildren.
		That is within the purview of this committee, as I read 102-4 --
		DR. HARRISON:  No.
		DR. GOUGH:  Not at all.
		DR. HARRISON:  No.
		MR. WEIDMAN:  ‑‑ to make recommendations for further research.
		DR. HARRISON:  Well, it may be within the purview of this committee, but this committee's agenda at this meeting is to review the Statement of Work or scope of work, whichever one it's called, and to make recommendations for, to finalize that scope of work for the Air Force Health Study.
		I think you're correct that we're kind of free people, so we can look at this and say that we need other studies.  I agree with you wholeheartedly, but within the ‑‑ if you would like to make some additional proposals, I'll be happy to consider us stopping us right now and reopening the public comment session or, if you're going to be around tomorrow, we can talk about arranging it then so that you get a chance to fully express what you feel we should be considering.
		MR. WEIDMAN:  That would be very kind sir.  I'll come back tomorrow.
		DR. HARRISON:  Is that acceptable?
		DR. GOUGH:  Sure.
		LTC BURNHAM:  It's part of the agenda.  On Wednesday.
		DR. HARRISON:  It is?  We've got public again tomorrow?
		LTC BURNHAM:  Well, no, no.  Study disposition.
		DR. HARRISON:  Oh, okay.
		DR. GOUGH:  I have a specific question.  The dioxin registry that NIOSH has, does NIOSH have comparable registries for people in heavy metals or electroplating or anything like that?  Does anyone know?
		DR. MICHALEK:  There might be ASDR.  Do you know?
		MR. COENE:  I know they have some.  They've done a cadmium, they've done --
		DR. GOUGH:  But they have inventories ‑‑ the trouble is the numbers, we have so few people, it's probably not worth it.
		MR. COENE:  They've got some cohort studies in some of the heavy metals.
		DR. GOUGH:  But they know everybody in the country who is working with dioxin.
		DR. HARRISON:  What point are we on now and how well are we staying on it?
		DR. STOTO:  I think the relevance of this is for 3.6.1.5, which has to do with adjustments in the statistical models.  When you do an analysis adjusted for, and this is about occupation and body mass index and so on.  And then additional things depending on which outcome you're looking at, as described elsewhere.
		So I guess one question here should be whether there's any additional information that we want to adjust for of this sort, either everywhere or in some particular analyses.  And I guess that I think that what we should be looking at is other things in the occupational environment or the home environment or whatever that we can measure that might be related to the outcome.  And that the question about other sources of dioxin is kind of a second order consideration given that we have a measure of dioxin, a body measure.  And I think it's worth looking at those things, but I don't think they're the main analysis.
		DR. HARRISON:  Are you saying that this area-by-area correlation is nice if it can be done, but you don't consider it central?  Is that what you're saying?
		DR. STOTO:  No, no; I think that it makes sense to always adjust for body mass index and to always adjust for occupation, as is suggested here.  And then depending on the outcome, what we know about the risk factors for that outcome, we want to adjust for other things.  So that all makes sense.
		DR. HARRISON:  What other things do we want to adjust for?
		DR. STOTO:  Well, if it's heart disease you want to adjust for ‑‑ I don't know whether they have exercise or diet or things like that; but those aren't risk factors for other outcomes.
		The question is whether there are some general environmental measures other than this military occupation that are worth thinking about or adjusting for always, or even most of the time, or something like that.
		DR. HARRISON:  The cancer rates are adjusted for obesity, right?
		DR. STOTO:  Well, they're all adjusted for BMI.  
		DR. HARRISON:  That's all analyses.
		DR. STOTO:  Yes.
		I don't know whether there are good enough data that I'd want to say we should do it on these other things, that we should want to use it all the time.
		DR. HARRISON:  You know, the reason I thought the area analysis might have made sense is it might affect the persistence of dioxin levels.  If that's been taken care of by measuring dioxin levels, then I --
		DR. STOTO:  I've been pushing generally that we need to think more about how dioxin persists over time, but I'm happy to have that done in these special analyses that the Air Force group does, rather than in the blue book.
		Actually, we've been making a distinction here between, the scope of work has to do with the big standardized analysis that the contractor will do, the blue books; and we've recognized that Joel's group can and in fact has been doing other more sophisticated analyses that they publish in journals.
		So I think that your idea is a good one to look at, but I'm not sure there are ideas for the blue book.
		DR. HARRISON:  And one reason would be that you'd either want to go back and do all the prior health study years so that there was some longitudinal comparison, or you'd have a stand-alone analysis, which is really the kind of thing that Joel and his group, and his collaborators have been publishing as they got to it.
		I guess that's the --
		DR. STOTO:  That's part of it, yes.
		DR. HARRISON:  Yes.
		DR. FAVATA:  Well, if we have that information anyway, we ask those questions regarding occupation.  Then ‑‑ I think that it's foolish not to use it in this analysis.
		I don't know, how ‑‑ what are the logistics of ‑‑?
		DR. MICHALEK:  I'm not rebelling against your point, and I agree.  I think it's certainly within ‑‑ it's feasible to do that in a blue book.  Because remember in the big blue book we're doing everything unadjusted and then adjusted.  So we always have a track record compared to previous reports on the unadjusted analyses.
		And based on, let's face it, 15 years' worth of analysis, we've never seen any wild changes after adjustment.  You know, like the picture suddenly became clear and everything was supposed to clear ‑‑ Wow, you know, like we're really on the track because we put a covariate in the model.  That has never happened.
		DR. GOUGH:   I agree.  I agree with Elissa, although I don't generally favor adding on analyses.  We collected these data.
		DR. MICHALEK:  Why not use them.
		DR. GOUGH:  Why not use them.  And particularly they bear ‑‑ a common confounder.
		DR. HARRISON:  Let's just think about this for a moment, though.  Do you want to just use where the person's living now?
		DR. GOUGH:  No, no.  I'm talking about the interview.  I'm talking about the interview that's in the neurology session about, "have you ever worked with?"
		DR. HARRISON:  Oh.
		DR. GOUGH:  That's what I was talking about.
		DR. HARRISON:  Oh, I'm sorry.  I'm a day late and a dollar short.
		DR. STOTO:  We've actually been talking about a number of different thing ‑‑ 
		(Laughter) 
		-- but I like that proposal as well.
		DR. HARRISON:  Okay, in the neurology interview.  Okay, all right.  That's a separate question.
		DR. GOUGH:  Really?  You're losing your grip, we were talking about more than one thing, Bob.
		DR. STOTO:  We were talking about those covariates, but using them across the board, right?
		DR. HARRISON:  The thing that I was concerned about was the area analysis, because I could see as you thought about it, you'd want an average time that a person spent in each area.  You know, you'd have to sort that out as well as not just at a single point in time; and Joel was talking earlier about in the matching analyses that's a complicated programming kind of question that would not be easily done by--.
		DR. MICHALEK:  Let's follow this thought through for a second more about the residential location versus the EPA databases on environmental levels.
		DR. FAVATA:  Bob does raise a good point as far as the duration of time that they served.
		DR. MICHALEK:  We have the entire residential history in our dataset; the start and stop date of every residence by longitude, latitude and zip code.  It's all there, right back to birth, I think.
		Now if I went to EPA and said "Well, I'm going to accumulate, county-by-county, by taking the time spent in a given county times the dose for that county and adding them all up, they would cringe."  And the reason they'll cringe is that number one, their dataset is pieced together from many different small studies, from many different sources, from soils, from animals, from whatever; and they would see that as way, perhaps, an overextension of the intended purpose of their analysis.
		And then they would also object that "Well, that may be what the U.S. looked like in 1992, it doesn't mean that's what it looked like in 1982."  So they would be very, probably very uneasy with this kind of approach.
		I'm talking about Linda Birnbaum, Bruce Rhoded and Mike DeVito at EPA.
		DR. STOTO:  But it's a very different argument for the kind of other exposures that you collect in your questionnaire.
		DR. GOUGH:  Occupation.
		DR. MICHALEK:  Yes, let's talk about that for a second, too.  It's very easy for us to get a little bit too overconfident about these covariates.  When we say, "Have you ever been exposed to heavy metals?  Yes or No."  A lot of guys say what?  What's a heavy metal? 
		The NORC interviewer, she can't elaborate.  She's not a chemist, she's not an occupational-environmental engineer, she just reads the question.  And he'll answer yes or no.  "Were you ever exposed to degreasing chemicals?"  Well, a guy who works in a factory who has worked with cars or equipment might know what she's talking about, but otherwise they don't know what you're talking about.  
		And so you've got a simple binary response, yes or no, to a question that may not have been understood in the first place.  This is very soft data.  Anyone who works in the field knows this.  However, this is the only study in the world that has this data.  So you might say "Okay, well, we've got it, let's use it."  Well, we do use it.  We use it in neuro, we use it in cancer --
		DR. GOUGH:  Well, if it's good enough for neurology, why isn't it good enough for everything else? 
		DR. MICHALEK:  I was trying to emphasize a point, and I guess I've made my point, so.
		DR. STOTO:  There's more to it than that.  There are hypotheses and there is evidence that these things might be associated with cancer and with neurological effects, but is there any evidence that degreasing chemicals are associated with heart disease?  No.
		DR. MICHALEK:  See, that's another thing.
		DR. STOTO:  The only one ‑‑ 
		DR. HARRISON:  Is there any evidence that drinking wine is associated with heart disease?
		DR. STOTO:  Yes.
		DR. HARRISON:  How long ago was that figured out?
		DR. STOTO:  Recently.  I understand --
		DR. HARRISON:  I happen to think it's the solvent action of the alcohol, myself.
		DR. STOTO:  Well, it's always possible that there's some mechanism out there, or association that we don't understand.  But generally just throwing in possible covariates just because there might be something there is not a good thing to do.
		For them to be helpful, they have to have an association with the outcome.
		DR. MICHALEK:  Just to be some biological plausibility.
		DR. GOUGH:  Ten years ago there was no biological plausibility between dioxin and diabetes.
		DR. HARRISON:  I was just thinking a little earlier here today, I thought you were raising your eyebrow and talking about statistical stuff, and not really liking my argument for biology -- when I was talking about dioxin levels and everything you were saying "Who cares about the biological, it's the statistics that count." 
		(Laughter) 
		DR. FAVATA:  Joel, I realize the limitations that you're discussing regarding the particular interviewer and their lack of ability to perhaps explain it, or the subject's ability to understand it.  But I agree with Mike, also, if we're using it in neurology and feel confident in that; or should we even use it in that, if we don't have confidence in the information that we're getting.
		DR. MICHALEK:  I think we should come down on the side of using it.
		DR. CAMACHO:  Is it possible to have a short list like a prompt list in the questionnaire, like an example list?
		DR. FAVATA:  Would that be helpful to the interviewer?
		DR. CAMACHO:  Yes.
		DR. HARRISON:  It probably would be helpful for a lot of the questions, because it would standardize what kind of elaborations you could make.
		DR. CAMACHO:  Now that you said standardized, are all the interviewers given training?
		DR. MICHALEK:  Yes.
		DR. HARRISON:  Yes.
		DR. FAVATA:  And what is that training?  What is the training. 
		DR. CAMACHO:  Maybe that's an absurd idea, a prompt list as an example.
		DR. MICHALEK:  They are given prompt lists, as I recall, in certain areas but not others.  In the area of contraception, for example:  Have you ever used any contraception?  And they'll give a list of 'such as' and there will be a list of several kinds.
		MS. YEAGER:  I think there is one for heavy metals.
		DR. HARRISON:  There is?  Okay, then there may be lists for other chemical exposures, too.
		DR. GRUBBS:  For the record, these interviewers are not supposed to elaborate beyond their training.
		DR. HARRISON:  We understand that.
		DR. GRUBBS:  The standard approach.
		DR. HARRISON:  We understand that.
		DR. GRUBBS:  It has nothing to do with the skill of the interviewer, at all.
		DR. HARRISON:  But if there were a prompt list, then again ‑‑ 
		DR. GRUBBS:  It's part of the protocol, it's part of the procedure.
		DR. MICHALEK:  We have such prompt lists; I just don't have them at my fingertips at this point.
		DR. HARRISON:  Okay.  Yes?
		DR. FAVATA:  Regarding the residential, how old is that EPA data?
		DR. MICHALEK:  I would guess about ten years, but I'll have to check.
		DR. HARRISON:  The point that I thought was more telling is that it's cobbled together; it is not done ‑‑ it's not like the EPA did a soil sample analysis in every zip code or anything like that.
		DR. FAVATA:  It's cumulative over a battery of times.
		DR. MICHALEK:  I believe you'll find it comes from various studies, all kinds of sources.  And it's modeled. There's a modeling.
		DR. HARRISON:  You know, one thing is that in biology there's an awful lot of bad data.  I mean, that just ‑‑ that's the essence of biology.  As long as you acknowledge that it's got a big variation.
		DR. STOTO:  I'm not objecting to the quality of these data; I'm trying to think through the logic of including variables of this sort.  There were a number of different kinds we've been talking about here in the analysis.
		And I think that if we got halfway decent data that would give some indication about industrial exposure or other occupational exposure to a chemical that was suspected of being associated with the outcome, then we should use it.
		By the my concern is that other than for cancer or neurological things, I don't know ‑‑ maybe there's some evidence I don't know about, that these kinds of things are associated with the outcomes.
		DR. FAVATA:  Well, if you look at liver disease, you could have because of solvent exposure.
		DR. STOTO:  Okay.  So that's the kind of thinking that ‑‑ 
		DR. HARRISON:  Especially a solvent plus an alcohol.
		DR. STOTO:  Okay.
		DR. FAVATA:  I think that there are a lot of health endpoints that they would affect.
		DR. MICHALEK:  Another area that we've explored in journal articles are exposures to various prescription drugs, and what they might have to do with the endpoint.  In our latest neurology paper, we exclude individuals that have had certain chemotherapies, for example, because it was known by our collaborator that taking such medication is associated with a peripheral neuropathy in some people.  So we need to do an exclusion.
		So that whole area has not been fully explored in the study.  The use of prescription medication --
		DR. HARRISON:  But see there are two separate things here.  We're talking about, again, inclusion of data in the longitudinal analysis in the blue book.
		You can go do an article on neuropathy and you can futz around and throw people out, and as long as you can convince the reviewers, that's your little red wagon, that's not a problem.
		The question is, should the regional dioxin exposure database be used to see if it clarifies any relationships within the areas that are being studied?  And it kind of sounds almost like it should, even though it's an imperfect database.
		DR. STOTO:  I think that even if the data were good, I don't think that the logic makes sense there, given that we have individual level measures of dioxin.
		DR. HARRISON:  But if you're looking at area under the curve, if you have area under the curve and you've got a zero dioxin environment and you've got a first degree curve--
		DR. STOTO:  But we're not talking about area under the curve for needs analysis here in the blue book.
		DR. HARRISON:  Well, I keep hear Joel keep talking about area under the curve.  I'm not sure how he intends to include it; but the point is, obviously, that ‑‑ if he raised the general environment level, then you're going to affect the area under the curve.
		DR. STOTO:  I agree that in a sophisticated analysis, that you could take it into account that it could be helpful.  But in the models that we're talking about for the blue book, it doesn't seem to me to fit.
		DR. HARRISON:  "If it don't fit, must have quit."
		DR. STOTO:  Well, from the point of view of a skeptic might say "Well, you're missing an effect" because it could be that some of your group was living in a very heavily polluted area and another part of your group wasn't, and so that may have biased your results towards finding nothing because you didn't account for that disparity in environmental exposures.
		DR. MICHALEK:  But if people were living in a heavy polluted area, they would have high blood dioxins.
		DR. STOTO:  but if people were living 
		DR. MICHALEK:  Well, true.
		DR. GOUGH:  Actually, it's very hard to ‑‑ in a general population exposure to generate a high dioxin level.
		DR. STOTO:  Then it doesn't matter.
		DR. GOUGH:  I know.  That's what bothers me, is that it's --
		DR. HARRISON:  Let's ask the question another way.  You don't think that it will be very helpful.  Do you think it's wrong?
		DR. FAVATA:  What is "it" that we're talking about?
		DR. HARRISON:  Using the regional adjustment, using that as a, adding that as a covariate.  Do you think it's wrong or do you think it's just not very ‑‑.
		DR. STOTO:  The problem is you have a Y variable which is a disease.  You have an X variable which is either a dioxin or being in the Ranch Hand group versus the control ‑‑ that's the primary exposure we're trying to study.  Then you have some Z variables you're trying to adjust for like body mass index and so on.
		DR. HARRISON:  Or another Z --
		DR. STOTO:  Well, it's not clear whether we're throwing in an X or a Z.  That's my problem, because it's a dioxin measure ‑‑ if in fact the relationship is due to dioxin, if living in the area ‑‑ if you lived in Times Beach and you got a lot of dioxin that way, and it caused diabetes, that showed that there is a relationship between ‑‑ it adds to the strength of the relationship.  You don't want to take that away, you want to capitalize on that.
		So I guess that it would tend to take away from the relationship between diabetes and outcome.
		DR. HARRISON:  Well, maybe in the executive summary of the minutes of this meeting, it can be said that the committee was divided in its assessment of whether this would add value to the analysis of the 2002 data.
		Is that fair enough?  I want to move us off of this and onto something else, is what I'm trying to do.
		DR. FAVATA:  After hearing what Joel said as far as the EPA data, it really doesn't sound strong enough to go forward and use that.
		DR. HARRISON:  The committee is not divided.  The committee doesn't think it's a good idea.
		DR. GOUGH:  But we considered it.  I think it's worth noting.
		DR. HARRISON:  Yes.  We considered the heck out of it.
		DR. STOTO:  I have become convinced, though, about the value of using the questionnaire about occupation and --
		DR. GOUGH:  Yes, I would like to see that.
		DR. STOTO:  Because that really is adding another Z, because it's ‑‑ 
		VOICE:  (inaudible) 
		DR. STOTO:  ‑‑ yes, and it's because it's exposure to other things that are primarily --
		LTC BURNHAM:  It reminded me of this when you mentioned that we have the dioxin levels.  The plan is not to do it in '02.
		DR. HARRISON:  I've got that noted down here.
`		LTC BURNHAM:  So I don't know if you want to discuss that or not.  But when you said "Well, we have a level so it really would wash with where they live, that may have an impact on the fact that we're not doing it again in '02.
		DR. HARRISON:  Yes, but most of the area data is older than your dioxin data.
`		LTC BURNHAM:  The other thing that I just remember is, I don't know what your plan is, but when you do give us suggestions ‑‑ I don't know if we need to iron out the specifics here; maybe that would be best, or if you want us to get with an individual person after the meeting.  But again we're trying to iron out this statement of work, and so it's tough for us to say to SAIC, "And oh, by the way, you need to throw in some stuff about where they live."  
		You need, we need to really word down to the specifics right now; we need to tell them exactly what we want.
		DR. HARRISON:  Well, and I think you all need to help us out in the sense of, if we think that we've made a recommendation and it's not clear, it doesn't contain enough ‑‑ it's not granular enough, then you've got to pull our chain before we get away.
		DR. STOTO:  And I think that in some cases, it may make sense --
		DR. HARRISON:  To go individual.
		DR. STOTO:  To go individual.
		DR. HARRISON:  What I'll try to do is, if it looks like that would be the best way to work, I'll try to move it there so that we can keep on with our agenda, which is falling further and further behind.
		I had noticed, though, I'm glad you mentioned that.  I had down here serum dioxin draw, page 12:  Will there be none this cycle?  If so, why not delete it?   I mean, you've got all this stuff in there about dioxin, but if I read it right, you said there are going to be zero samples.
		DR. MICHALEK:  No, no.  First of all, 99 percent of the study subjects have at least one dioxin measurement already.  We just meant that we weren't going to do ‑‑ the only people that will get a dioxin level measurement this time are those that don't already have one.
		DR. HARRISON:  The contractor shall draw serum following the protocol ‑‑ on up to zero participants.
		DR. MICHALEK:  That's a misprint, should be up to 40 participants.
		DR. STOTO:  That makes a big difference.
		DR. GOUGH:  Good catch.
		DR. MICHALEK:  Sorry.  What page was that?

		DR. HARRISON:  Well, now that you're looking at it, it may be that the crossbar in the 4 and the crossbar in the X-out ‑‑ it's 3.2.1.8 9.  I think you're right, I think it is 40.  Okay, all right.
		So where are we now?  General Category Analyses.  It's right at 4:30.  Do we want to do the General Health data, and listen to any other general comments and then maybe ‑‑ call it quits?  Yes.
`		DR. FAVATA:  I have actually a couple more points before the general health.  
		DR. HARRISON:  Okay, go ahead.
		DR. FAVATA:  One is regarding Lab QC; I think that that's important to revisit.  But can you explain this tri-level controls?  And also when are the samples collected?
		DR. MICHALEK:  The patient samples or the control samples?
		DR. FAVATA:  The control samples.  It says under 3.2.4.6.6, the contractor shall initially run sample of each tri-level control for 20 days prior to the first physical exam.
		DR. MICHALEK:  The purpose of that tri-level control is to establish by means of quality control charts that the laboratory methodology is in control; namely that the laboratory instruments are measuring what they're supposed to measure.
		So that for example in the area of cholesterol there will be a manufactured control that they will get from the company that makes the lab kit for cholesterol that will provide a specimen with supposedly exactly 100 milligrams per deciliter of cholesterol, and that when they run that specimen through their instrument, they had better get something close to 100.
		So they will see these repeated assays of these manufactured controls, and those will also be charted and will get that from Scripps, and we can watch the control of that instrument, low, medium, high.  And we do that in many different lab panels.  We do it in liver, we do it in lipids, we do it in urology and we do it in many different ways.
		In this respect, this study is probably unprecedented in that as the men are walking through the clinic, we at Brooks Air Force Base are visually watching in real time the instrumental accuracy of the laboratory at Scripps that's measuring the specimens in the men.
		DR. HARRISON:  I don't understand how that differs from what the lab has to do anyway.
		DR. MICHALEK:  It isn't; it's over and above. 
		DR. HARRISON:  It's not over and above.  The lab is required --
		DR. MICHALEK:  They're required to do that, yes. 
		DR. HARRISON:  Every day they have to run their controls and they've got to have values that are both above and below the expected values.
		DR. MICHALEK:  Exactly right.  But we as the ‑‑ we want to see it, and we do see it, and we get deliveries periodically from the lab so that we can watch to assure ourselves that there's no trend out of bounds and there are no trends in the data, and there's nothing in the data to suggest that there may be a change in the instrumentation or a change in the batch that might cause --
		DR. HARRISON:  I'm just asking, this implies that they're running a separate QC when all you really should be asking them for is to fax you a copy of their QC.
		DR. MICHALEK:  In effect most--
		DR. HARRISON:  You're paying them.
		DR. MICHALEK:  Yes, we're paying them to do a research level quality laboratory job, and we are monitoring to the nth degree the output of that process.  We're monitoring on a daily basis the values of these manufactured controls and the values from the men themselves.
		We worry about changes in batch, we worry about trends with time, we worry about everything and we watch it on a daily basis.
		DR. GRUBBS:  I think more the point is, they want the lab to use the standard data; they want to see it.  They want to see it every month or every three months. 
		DR. MICHALEK:  Every day.
		DR. GRUBBS:  We had a real issue with alkaline phosphatases last time, we had to clarify it; but it was because it was Joel had seen the data and saw something that was foreign to him, and we went through and explained it.  But it was mainly to see the data.  It's important to do, but the added requirement is please provide us this data so we can look at it, too.
		DR. MICHALEK:  Sometimes it can happen, for example, that the batch will change on the lab kit, and that can cause a change in the response by a small percentage.  We want to accommodate that in the analysis.
		DR. HARRISON:  that's one of the comments that I had; I can't find it now, but you said you were going to run 20 samples for each one, and I was wondering where you came up with that, it seemed like such a small number; it's 3.2.4.6.4.
		DR. MICHALEK:  The idea there is to establish the quality control chart parameters prior to the men walking into the clinic.
		DR. HARRISON:  This is where ‑‑ if you do have to change lots, I'm saying that if you do have to change lots, I'm not sure that 20 samples is enough.  And I'm just asking, where did you come up with that number?
		DR. MICHALEK:  That number was prescribed a long time ago; probably 1984 and has been reviewed ever since by this committee.  And if you think that number should be increased, say so.
		DR. HARRISON:  I don't know what the number should be, and I suspect that the number should be different for each test, depending on the coefficient of variation and inter-assay variation for the test.  And I'm saying that if there's anyplace that you might put your statistical expertise to use, it would be there.
		In that regard, I'm also not clear how you came up with the acceptable coefficient of variations for the lab values that you have listed here.  You don't list all of the lab values, but the total testosterone for instance, levels in men should be something from 300-something to 1200 and something.  The free testosterone, on the other hand, goes from something like .5 to 2.5; yet you've got a coefficient of variation of 10 in both cases here.
		DR. MICHALEK:  Well, we can revisit the c.v.s.  Those most likely came from a textbook.  We can check those.
		DR. HARRISON:  You have the same coefficient of variation for ACTH as you have for insulin.  That's got to be crazy.  ACTH has a half life of five minutes in blood.  I'll bet you a jelly donut that 90 percent of the ACTHs that you're getting aren't worth nothing and serum insulin, on the other hand, is extremely stable.  Nowadays you can sniff it.
		So again, I think those coefficients of variation don't seem to have the correct relationships with each other.  I'd expect ACTHs to be higher.
		DR. GRUBBS:  Again, we had talked about this issue a couple years ago and our agreement was that this should be in a biomedical plan, should be specified by the lab according to current methodologies and procedures as to what their c.v. is, and then approved or disapproved by the Air Force.
		DR. HARRISON:  Okay.
`		DR. GRUBBS:  So yes, that section should be revised.
		DR. HARRISON:  All right, so that section should be revised.
		DR. STOTO:  I was just noting, now that this has been called to my attention, that in one section you talk about 20 specimens, in another place you talk about 20 days.  Another place you talk about 20 sampling days.
		VOICE:  Somebody likes 20.
		DR. STOTO:  I mean, are these things all supposed to be the same?  Probably not.
		DR. MICHALEK:  I suspect, a long time ago, this was taken from a textbook, but we'll have to revisit that issue, as well as the c.v.s.  And we will.
		DR. FAVATA:  I'll leave my diabetic question, but I have a question regarding 3.5.3, out of range variable review.  And B in that section notes that ‑‑ B.  My question is, who was carrying out this review; specifically the assessment of whether a value is compatible with the patient's clinical status, and what clinical information is available to them if, say if medical records are not supplied or they're incomplete.
		So who does this, to decide whether it's clinically compatible?
		DR. MICHALEK:  that was a medical doctor at SAIC, I forgot the name.  
		Dr. John Whiteman.
		And the answer is, doesn't he have available the entire patient folder? 
		VOICE:  Yes.
		DR. HARRISON:  He's the person that you refer to in another place as the diagnostician or something?
		DR. MICHALEK:  The diagnostician is a physician at Scripps Clinic.  Dr. Whiteman is the physician at SAIC.
		DR. CAMACHO:  The out of range variable review.
		DR. HARRISON:  Yes.  So  you just need to make explicit who's doing that?
		DR. MICHALEK:  Is that your recommendation?
		DR. HARRISON:  Well, apparently, you know who's doing it.
		DR. MICHALEK:  Right.
		DR. HARRISON:  It just would be nice if it were in the Statement of Work.  Not nice, it would be desirable for it to be within the Statement of Work.
		DR. MINER:  The scope of work, though, we put things in there often that says:  "Contractor, we want you to do this" and they come back to us with a biomedical test plan specifically on how they're going to do it.
		DR. OGERSHOK:  Right.  A lot of this would be in their approach.
		DR. MICHALEK:  It's actually the bid, what we call the proposal from the company that the government buys.  Is that a good way to put it?  So that's the document you ultimately want to see, too.  This is what we're asking for, then you're going to see what it is they bid and what they propose.
		MS. YEAGER:  And that's where we propose Dr. Whiteman.
		DR. MINER:  But your comments are very valid; that when they come back with our ‑‑
		DR. OGERSHOK:  Wait a minute.  The proposal, a proposal has got to be compliant with the Statement of Work.  Otherwise it is unacceptable.  There is a provision, in at least a couple points, to refine or to fill in the details of the Statement of Work.  We have a biomedical test plan which has been mentioned, which takes us through the biomedical procedures; everything that goes on in the laboratory, the urine collection, the analytical methods, certifications of personnel, all kinds of stuff like that.
		There's also, to harken back to a previous discussion, we have a statistical analysis plan that refines what's in the Statement of Work.
		The proposal, I think, is kind of intermediate to this process.  The real key documents are the Statement of Work and the plans to implement that Statement of Work.
		DR. MINER:  As we evaluate your biomedical test plan, then our comments are very appropriate about who's doing what.
		DR. STOTO:  I have a different question about that paragraph.  It says the contractor shall record out of range variables.  Does that mean that it just notes them and doesn't fix them, or?
		DR. MICHALEK:  We don't change any data.  If an individual has --
		DR. HARRISON:  What you're saying is there's nothing there saying that you're going to act on it; it's just saying you're going to record it.
		DR. MINER:  We wanted a separate, out-of-range report that addresses every single out-of-range variable and whether that's clinically feasible or not.
		DR. HARRISON:  This is to make sure that your data is correct.  This has nothing to do with taking care of the patient.
		DR. OGERSHOK:  That exercise is a two-step procedure.  The first, out-of-range, is a statistical procedure to go through and just sift out unusually high values.  The medical adjudicator reviews that information and the patient folder to say could this be a real measurement?  Is this thing too big to be believable, or could it be this big?
		DR. STOTO:  So this relates to the data cleaning, but it's not clear from this document how it does.
		DR. HARRISON:  Well, now that you say it, it's pretty clear.  A doctor looks at this and says:  "Wait a minute, this guy's bilirubin is reported as 20, but he's not jaundiced."  So the bilirubin is wrong.
		DR. STOTO:  And what do they do?  Do they go back and look at the folder and see if they made a mistake transcribing it, or?
		MR. OWENS:  We haven't had any material number ‑‑ any number of variables that come out of that, measurements that comes out of that process as being that "this is just unacceptable."  But if that happened, that's what we would recommend to the Air Force.
		Is that not --?
		DR. MICHALEK:  I think, Maurice, to back up a step further.  Isn't it true that at Scripps Clinic, if they see a value of beyond a certain range, don't they automatically do a retest?
		MR. OWENS:  Yes.
		DR. MICHALEK:  So the answer to your question is that ‑‑ actually, they have emergency values.
		DR. MINER:  I was going to say, panic values.
		DR. MICHALEK:  Panic values, at Scripps Clinic, that they act on.
		DR. MINER:  This is a statistical thing; there's also the patient consideration, that if a high value of something is found, very high blood glucose, out of sight.  They are emergency values, they are attended to right then.  Values that are diagnostically either too high or too low in the outbriefing, the diagnostic outbriefing that the individual gets.
		Those are documented and a letter sent from Scripps for follow up, so the individual gets care.  It's not just a statistical thing.
		DR. STOTO:  But I'm concerned about the statistical aspect of it.
		DR. MINER:  I know, but these are--
		DR. STOTO:  These guys deserve care, I won't deny that.
		But I'm trying to understand the relationship between this, 3.5.3, and the data cleaning which is simply --
		DR. MICHALEK:  It's part of the data cleaning.
		MR. OWENS:  It's part of the data cleaning.
		DR. OGERSHOK:  There's another paragraph later ‑‑.
		DR. STOTO:  I thought the data cleaning was earlier.
		DR. HARRISON:  No, data cleaning is right up there at Cumulative Data.  Look right up above it, 3.5.2.2.
		So it's all in the same general area.
		DR. CAMACHO:  Can I insert something?
		DR. HARRISON:  Insert away.
		DR. CAMACHO:  By the way, the one just above 3.5.2.3, the size of that data dictionary for the nonresponse; these are tailored to each question and I surmise when you get a new answer that you didn't think about, you're going to add a code?
		DR. MICHALEK:  Yes.
		DR. HARRISON:  Yes.
		You don't like that?
		DR. CAMACHO:  Well, it's nice to go through and think of all the kinds of codes, possibilities beforehand.  I mean -- for that matter, I never thought of asking this:  Is there any kind of a little pretest in this questionnaire?
		DR. MICHALEK:  Yes.
		DR. STOTO:  Well, they haven't been doing it for 15 years. 
		DR. MICHALEK:  Prior to the start of physical, there were ten individuals who are given the questionnaire and the physical in a pretest, or actually in a test.  And I'm one of them.  Some of them are in this room.  The investigators, the contractors, and some military.
		DR. CAMACHO:  Very well. 
		MR. WEIDMAN:  I have two questions.  One is, Joel, did you pass every time? 
		(Laughter) 
		MR. WEIDMAN:  The second question is, part of the purpose of doing this is to complete the sixth round with some reliable evidence and conclusions that can't be drawn and hopefully published by the folks that are working on it currently from the Air Force.  That's one goal.
		The second goal, that's a larger goal, is that this is the only longitudinal study that we know of, of Vietnam veterans who were exposed in Vietnam.  And therefore it carries on beyond as a public trust and record that can be mined by researchers all over the country and will be, for years to come.
		DR. CAMACHO:  Now we're getting into that "what happens after the study closes in 2006" problem?
		MR. WEIDMAN:  Well, no, I'm getting at something that's happening right now, because you mention that the only time that everybody who has not had a blood serum dioxin screen somewhere upwards or less than 40 people are going to have it now, and no one's going to be retested on the dioxin screen at this point.
		There is no more, to the public and I can assure you to the Congress and to the organized veterans community, no more important variable to have a good lock on and to compare with to previous samplings than the blood dioxin serum as you go through the sixth cycle.
		So I guess what we would urge you to think about and the committee to think about is to do a universal screening, because this is the last shot in the barrel you're going to get with this group of people.
		And to not do it at this point will raise question after question after question, not only in 2006, but up to 2016, and in the future "Why the heck when they had them all there didn't they test them for the most important variable, which was the level of dioxin of the body burden at least at the time that they went through it to be able compare to the earlier cycles."
		So that's both a question and a very strong recommendation.
		DR. HARRISON:  I think Joel's got a good answer to that.
		DR. MICHALEK:  Well, I agree.
		DR. HARRISON:  Joel.
		DR. MICHALEK:  Not only that, you can develop a good case that you should be measuring all the other congeners of dioxin, PCBs, and there's a full panel I think of 35 chemical congeners that should be measured, and a summary measure called the TEQ, computed for each individual.  We're not budgeted to do that.  I think it's important scientifically, personally, but we're not budgeted to do that.  And if you are able to address the budget issue, then I think I agree with you.
		DR. HARRISON:  Let me ask ‑‑ I thought you were going to say something else.
		DR. GOUGH:  Me, too.
		(Laughter) 
		MR. WEIDMAN:  That's an important issue.  What would it cost?
		DR. GOUGH:  A thousand dollars a person.
		DR. MICHALEK:  I think to do the full panel, the estimate from CDC is roughly $700-$800 times 2300 people.  So it's going to be about $2 million.
		MR. WEIDMAN:  So if that $2 million was available to you, you believe it would be scientifically valid.
		DR. MICHALEK:  I do, personally; but you'd have ask the committee.
		DR. HARRISON:  The answer that I thought, is that I thought that you had ‑‑ first of all, you've pretty firmly established the half life of dioxin.
		DR. MICHALEK:  Yes.
		DR. HARRISON:  You have two data points on the majority of the patients participating in the study, or at least a substantial number of them. 
		DR. MICHALEK:  We have up to four data points on 343 Ranch Hand veterans.  We have one data point on everybody else.
		DR. HARRISON:  So I thought the judgment that you had made, and I guess I should ask now, is knowing the half life and having the data points, do you feel that you can confidently assess their ‑‑ so now you have a batch of people who are down at baseline so you can't really extrapolate the baseline value back.  You've got everybody else who is at above baseline, you can extrapolate them back.  Measuring again doesn't help you, because they're going to be either lower or at background.
		So in terms of estimating initial exposure, it seems to me your work is done.
		DR. MICHALEK:  If your goal is to estimate the decay rate, there's very little to be gained from a fifth measurement in that cohort of 300 men.  But that's not the issue here.
		DR. STOTO:  I think the issue is the ones where you have only one measurement.  If you believe that there are important differences from man to man in terms of the decay rate that may be related to BMI and obviously it would have related to the risk for diabetes and so on, you may want to do more sophisticated analyses, and you'd be better off having a second measure on as many people as possible.
		So one to think about is, of the people who currently have only one --
		DR. HARRISON:  That's above baseline.
		DR. MICHALEK:  No, regardless of its value.
		DR. STOTO:   I was going to say that that's the fall-back position; but I'd prefer to do it for everybody.
		DR. HARRISON:  Okay.
		DR. STOTO:  Who only has measure.
		DR. HARRISON:  So you'd like to have two measurements on everyone?
		DR. STOTO:  I'd like to have two measurements on everybody.
		DR. HARRISON:  I think that's very reasonable.
		DR. MICHALEK:  Well, 99 percent of them have at least one.
		DR. HARRISON:  Yes, but we want two.
		DR. MICHALEK:  Right, I want two also.  I mean, as a scientist I can always tell you that additional data will never hurt.  It can only help.  Plus there's the issue of the TEQ, which is considered in toxicological circles as the measure of exposure that we should have measured anyway.
		DR. GOUGH:  No, but with the dioxin in 2,4,5 T was largely 2378 TCDD.  The others are inconsequential.  So in terms of measuring what the dioxin exposure was in Vietnam, I think 2378 TCDD is fine.  I know what EPA says, of course.
		DR. STOTO:  I agree, this is a study about the kind of dioxin that was in Agent Orange.
		DR. HARRISON:  So if we want you to do it, are you going to be able to ‑‑ can you do a second measurement on those ‑‑ what would that be, 1600 individuals?
		DR. MICHALEK:  2,300.
		DR. GOUGH:  No, no --
		DR. HARRISON:  You've got 300 that you've already got four or five measurements on.
		DR. MICHALEK:  Well, it depends on what your goal is.  If your goal is to measure another dioxin level, fine.  You can probably get by with 1600.  But if your goal is to measure TEQ --
		DR. HARRISON:  No.  What we're saying is, for those individuals who have a single dioxin measurement there should be a second one.
		DR. MICHALEK:  Okay, that would mean all of the controls and about 500 of the Ranch Handers.  There's about 1500-1600 people.  Times about $1,000 apiece.  $1.6 million.
		DR. HARRISON:  So that's ‑‑ Does everybody agree?
		DR. STOTO:  Well, it's not a thousand.  You said $700-$800, and that was for the full TEQ.  So it would be more like $500.
		DR. MICHALEK:  No, that's not true.
		DR. HARRISON:  Don't get evasive --
		DR. MICHALEK:  Let's be more realistic.
		MR. WEIDMAN:  Would the $700 or $800 include both the dioxin and the TEQ?
		DR. HARRISON:  No, that's just ‑‑
		MR. WEIDMAN:  Joel, would that $700 to $800 per pop out of CDC, would that include both the dioxin and the TEQ?
		DR. MICHALEK:  Yes.
		MR. WEIDMAN:  So it would be the whole shooting match?  So you could separate out the dioxin --
		DR. MICHALEK:  Exactly.
		MR. WEIDMAN:  And have the markers for 2,45T.
		DR. MICHALEK:  Dioxin plus all the others.
		DR. GRUBBS:  My biggest question is, on comparisons also?  That's where I think you get the least amount of benefit for that.
		DR. MICHALEK:  Well, that's just the opposite of some opinion from my people.
		DR. HARRISON:  What Mike is saying, and I'm embarrassed to agree, is that it would be desirable, to draw a line you need two points.  So if you're going to draw it flat or whatever, it's still two points.  So everybody needs to have two points.  That's not a bad idea at all. 
		Now if it turns out that there's really incredible budget problems, then I think no one would criticize you for saying "Well, everyone below X cutoff won't get repeated."  That's a fall-back position.
		DR. STOTO:  Particularly if you're going to analyze the data by the way that you suggested here anyway.
		LTC BURNHAM:  Getting everybody would handle the geography question, also, if they're getting other sources of dioxin.
		DR. STOTO:  You already have one measure on everybody; the issue is the change over time.
		DR. FAVATA:  How many more people are there?  
		DR. MICHALEK:  About 2200, 2300 total that will come to the next physical.
		DR. FAVATA:  So is it worth it to pursue having the entire group done again?
		DR. MICHALEK:  I think so. 
		DR. FAVATA:  So that down the line ‑‑ is there a pop?
		DR. MICHALEK:  First of all, this is your last chance, supposedly.  If you decide to do only 1600 of the 2300 and if you find a trend within those 1600, you're going to be awfully sorry you didn't do the rest of them.
		DR. FAVATA:  Right.
		DR. GOUGH:  Hopefully you won't find a trend on two points when you've got four and five points on everybody else.
		DR. MICHALEK:  I said 'if.'
		DR. GOUGH:  Well, I know.
		DR. HARRISON:  Okay.  
		DR. MICHALEK:  But this is a major point, and I feel glad it's on the table.  Should we do the TEQ?  To do that, I think scientifically the answer is yes, and we need to do everyone, and I'm telling you we don't have the money to do it.  If we did have the money, then I would vote in favor of doing it.
		DR. HARRISON:  I was very convinced by what Mike said.  He seemed to be pretty ‑‑ this Mike, the older Mike ‑‑ 
		(Laughter) 
		DR. HARRISON:  He seemed to be pretty convinced that the TCDD contaminant was clear, and there wouldn't be additional information to be gotten from doing the panel.
		DR. GOUGH:  The only thing you would learn, I think, if you did the panel, is that if somebody had been exposed, somebody outside of the Ranch Hand experience, in some mixed chemical environment where he's exposed to the pentas and the octas and so forth, you'd know that.  But I don't think it makes any difference.
		MR. WEIDMAN:  I want to harken back, if I could, speaking from the point of view of somebody in my organization that worked hard for that ' 91 law.  The issue is, something happened in Vietnam --
		DR. GOUGH:  No, the question is, did something happen in Vietnam?
		MR. WEIDMAN:  Well, all right.  Did something happen in Vietnam.  Not just due to 2,45T but in terms of total toxin exposure --
		DR. GOUGH:  No.  This is a herbicide study.
		DR. HARRISON:  No, actually, you can't do that.  You missed this earlier when we were talking about it, because the comparisons also come from Vietnam.  So if something globally happened in Vietnam, there's nothing to compare to, it should have happened to both groups.
		So the only real comparison that's being made is between exposure to Agent Orange and lack of exposure to Agent Orange; and even that's screwed up because --
		MR. WEIDMAN:  Because everybody was exposed in Vietnam.
		DR. HARRISON:  Everybody was exposed either to Agent Orange or agent whatever, some of the other herbicides were as well; Agent Orange was used in Army compounds, so it's still unclean.  But you can't make it a Vietnam study without having a control group that wasn't in Vietnam.
		LTC BURNHAM:  But for another $2 million, we could ‑‑ just kidding.
		MR. WEIDMAN:  But if you had the data there with the TEQ, you can take this data and match it up with a cohort group that did not serve in Vietnam but who did serve in military service during the Vietnam era, and essential have the same, you know, be able to do those kinds of groups --
		DR. STOTO:  That's a whole another study.
		MR. WEIDMAN:  I'm not saying it's this study.  I'm saying your responsibility does not end when this study ends in 2006 with this dataset.
		DR. HARRISON:  And on that note, I think that's going to be an excellent part of the discussion that I'm looking forward to hearing tomorrow.  But I think our work should be done for the day. 
		[Simultaneous discussion] 
		DR. HARRISON:  Wait a minute now.  Tomorrow we start at 8:30, we're going to go from 8:30 to roughly 11:30 continuing our review of the SOW; at 11:30 we're going to have public session number two.
		Is that acceptable?
		DR. GOUGH:  Sure.
		DR. HARRISON:  Paul?
		DR. CAMACHO:  Yes.
		DR. HARRISON:  Thanks a lot.
		DR. CAMACHO:  All right.
		DR. HARRISON:  Are you going to try to come up tonight, or are we going to call you again tomorrow?
		DR. CAMACHO:  I wouldn't ‑‑ is it more important to be there, do you think, or do you lose ‑‑ some quality is obviously lost.  What would you like me to do?
		DR. HARRISON:  I would much rather have you here, if you can be here without ‑‑ if you can get permission from your physician, it would be nice for you to be here.  But I don't want you killing yourself.
		DR. CAMACHO:  Let me check some planes and stuff, and if I can make it I might try to do it.  
		DR. HARRISON:  It's up to you, and to get you and Dr. Favata in the same meeting at the same time is going to be the capstone of my career. 
		(Laughter) 
		DR. HARRISON:  We'll talk to you tomorrow.  One way or the other.
		DR. CAMACHO:  One way or the other.
		[Whereupon at 4:53 p.m., the meeting recessed, to reconvene at 8:30 a.m., the following day.]

	RANCH HAND ADVISORY COMMITTEE

	Department of Health and Human Services

	Tuesday, January 23, 2001

	Day II

	Meeting

	 Parklawn Conference Center
	Conference Room K
	Parklawn Building
	5600 Fishers Lane
	Rockville, Maryland

	ATTENDANCE
Committee:
Robert W. Harrison, M.D., Univ of Rochester, Chairman
Michael A. Stoto, Ph.D., George Washington University
Michael Gough, M.D., Consultant
Elissa Favata, M.D., Robert Wood Johnson Med School
Paul R. Camacho, Ph.D., Univ of Massachusetts-Boston
Ronald F. Coene, P.E., Consultant [former staff]
Leonard M. Schechtman, NCTR, staff
Barbara Jewell, NCTR, staff
Attendees:
LTC Karen A. Fox, M.D., Brooks Air Force Base 
LTC Bruce Burnham, Chief of Population Research
Dr. Joel Michalek, Principal Investigator
Richard Ogershok, U.S. Air Force
Dr. Judson Miner, Program Management Support
Manuel A. Blanca, Program Management Support
Meghan Yeager, SAIC
William Grubbs, SAIC
Maurice Owens, SAIC
David Banks, SAIC
Robert Newman, House Sub on Nat'l Security and VA
Mary Lambert, DHHS
Bill Chism, EPA
Rick Weidman, VVA

	C O N T E N T S	

Review and Discussion of the SOW for the 6th Cycle of the AF Health Study  (Continued)

	Clinical Category Analyses (Continued)
		General Health Data	214
		Neoplasia Data	236
		Neurological Data	254
		Psychological Data	269
		Gastrointestinal Data	277
		Dermatologic Data	288
		Cardiovascular Data	290
		Immunologic data	299
		Hematological Data	303
		Renal Data	310
		Endocrinological Data	310
		Immunological Data	349
		Pulmonary Function Data	352
		
Open Public Session	356

	Discussion of Dioxin Study Disposition	394
	Section 3.7 	465
	Addendum A General Physical Examination	498
	Agenda and Future Meeting Dates	507
	Discussion of Report Writing	517

	P R O C E E D I N G S
	[8:55 a.m.]
		DR. HARRISON:  Shall we try and start where we left off yesterday?  
		DR. GOUGH:  I have a problem, a minor problem.  
		When you did the spousal questionnaire, originally, every answer was followed up for medical evaluation, wasn't it?
		DR. MICHALEK:  The spousal questionnaire --
		DR. GOUGH:  On reproductive health?
		DR. MICHALEK:  Yes.  On anything to do with the children, yes, they were followed up by medical record review.
		DR. GOUGH:  Are we opening the door to that again?
		DR. MICHALEK:  No, because what we've asked them to do here is tell us:  Is there a period of time where you tried to have a baby and weren't able to have a baby?  And they tell us the dates.  And we get that information from the mother and from the father.  The purpose of this is simply a paper on fertility.
		DR. GOUGH:  Okay, all right.
		DR. MICHALEK:  We've already published the papers on the children.
		DR. GOUGH:  I was concerned, because I remember it took so long to do that.
		DR. MICHALEK:  No.  That's another ‑‑.
		DR. GOUGH:  Okay.
		DR. HARRISON:  All right, now I'm not exactly sure where we left off last night.  I think we were somewhere around General Health Data?
		DR. FAVATA:  I just had a few comments on that. 
		DR. HARRISON:  General Health Data is 3.6.4.
		MR. COENE:  And I think Paul had already talked about his comments.  He got some clarification yesterday.  He was the other reviewer on that section.
		DR. HARRISON:  Okay. 
		All right, Dr. Favata?
		DR. FAVATA:  Really, it's very limited; one is just an editorial, line 6 down at 3.6.4.1.1, to remove erythrocyte sedimentation rate.
		DR. MICHALEK:  I'm sorry, where is this now?
		DR. FAVATA:  In 1.1, Joel.
		DR. HARRISON:  Oh, the sixth line down.
		DR. GOUGH:  3641.
		DR. FAVATA:  The only question I have is, what is the significance of the issue of a participant's self-perception compared to bla-bla-bla, being adjusted for hostility?  Why was hostility chosen, and the question is, how are you going to measure for that?
		DR. MICHALEK:  Those are two good questions; I don't have an answer.  Except that early on in the study someone thought that personality type was an important covariate.  Well, since then, we've stopped measuring personality type and replaced that with a measure of hostility as recommended by I believe someone on this committee, and we've tasked the contractor with finding a good measure of hostility.
		So that's really all there is to say.  If you think this is not an appropriate adjustment, then that's important.
		DR. FAVATA:  I guess my question is, why was that particular personality trait or personality problem noted, and how do you actually measure for that?
		DR. MICHALEK:  There are probably a series of questions in the literature that people use to assess hostility.  Someone's going to have to do a literature review on that, on how to measure hostility.
		As to why we would adjust for hostility or personality type, the intuition I have is simply the demeanor of the individual; you know, he could be --
		DR. HARRISON:  This represents a departure, though.  I mean it was personality type before and now it's hostility.  So --
		DR. MICHALEK:  Yes.  The reason we're in this problem is that the instrument we've used to measure personality type is no longer applicable to this group.  Because the scenarios in the questions refer to employment.  Most of these men are retired, and actually they've become very irritated, many of them, at taking this Jenkins questionnaire.
		So merely by administering the questionnaire we're making them hostile, or we're changing their personality type.  And we've examples of them just ‑‑ you know, doing diagonal patterns down the page on the multiple choice responses; they're not responding in a reasonable way to the questionnaire.  So we're going to drop the Jenkins, which means we do not have a clear measure of personality type at this physical.
		We were told that ‑‑ someone told us, and I've seen it in the literature, that the appropriate covariate would be a measure of hostility, but we're talking cardiovascular endpoints here.   And the question posed at the time we talked about this was "If we're not going to measure personality type, what covariate or corresponding covariate would we use for cardiovascular endpoints?"  And the answer was "hostility."
		Well, I simply replaced personality type with hostility in this section; may not be appropriate?
		DR. FAVATA:  Why not anxiety?  Or.
		DR. MICHALEK:  Yes.  We have anxiety.
		DR. STOTO:  In the past has the personality type ever made a difference when you adjusted for it?
		DR. MICHALEK:  Probably not.
		DR. HARRISON:  Certainly it's said to make a difference.  I mean, in terms of cardiovascular disease and so on.  
		DR. STOTO:  This is the General Health section.
		DR. HARRISON:  I don't know that there's any evidence of personality type changes.  
		DR. MICHALEK:  Well, if you want to use past measures of personality type, you're going to miss about 10 percent of the group.  You know, they're going to have about 10 percent of the people come this time that didn't come last time.
		DR. HARRISON:  They haven't been any time?
		DR. MICHALEK:  Well, I don't know; what percent ‑‑
		DR. GRUBBS:  I'm not sure that --
		DR. MICHALEK:  We're going to lose a few percent.
		DR. GRUBBS:  Relating to that question, we looked at '87 classification of personality types versus 1992, on the same subjects, and about 25 percent switch from A to B in terms of their answers to their questions, which was real interesting to us.
		DR. HARRISON:  But you're also talking about men that have already gotten into the situation that Joel is talking about, where the questions aren't relevant.  If you had an '82 test or something, you'd really almost have to go back to there.
		DR. STOTO:  That may be the most relevant.
		DR. HARRISON:  And may be the least generally available, too.
		DR. MICHALEK:  I think the more general question is, should we do any adjustment at all?  Maybe this is a question for Paul, because these are kind of socioeconomic types of things and personality types.  I don't know.
		MR. OWENS:  I have a comment.  In going back over the history of using the Jenkins for personality type, the Jenkins test  is going out of favor and very few people use it, and it was weakened; and we came into, we were having difficulty accessing the test, and we always asked the question, "Well, what other measure of personality type could we use?"  And the questions would come up, "Well, what do you want to do with it?"  You know, the second level questions would come to play, and the answers really ‑‑ really didn't have the answers or we went back to, "Well, we used the Jenkins before."
		So that led us to gravitate towards the Jenkins test for the purpose of continuity.  But if we put the Jenkins test aside and go for a new measure, that's going to open up whole new ground, and unless we know where we're going, it's going to be difficult ‑‑.
		DR. HARRISON:  I'm suggesting that we retain this for discussion when Paul gets here, and ask the question of whether there should be any personality assessment in this round.
		DR. GOUGH:  Can we ask the Air Force to let us know if the adjustment did make a difference or not?
		DR. MICHALEK:  We can get an answer to that in a few minutes, as soon as I get to the phone.
		DR. GOUGH:  Okay.  Why don't we do that, too?
		DR. MINER:  I've got the report here on disc, if you want to --
		DR. MICHALEK:  Oh, yes.  We've got the report on disc, or anyone who can get to the Internet will see the report on the web page.  But since you have it on disk.
		DR. STOTO:  Why don't we look at it during the break or something.
		DR. GOUGH:  Well, they can set it up; we don't need to look at it.
		DR. HARRISON:  While Joel is looking for that, let's go on.
		What else?
		DR. FAVATA:  There's nothing else.
		DR. GOUGH:  I have a question on the section.
		DR. HARRISON:  Go ahead.
		DR. GOUGH:  On 3641a, the comparisons made to other people of the same age, are these the other patients in Scripps?
		DR. MICHALEK:  No, this is an instruction to the doctor.  This the physician answering:  Compared to other people of the same sex and age, would you say this man is older than or younger than --
		DR. GOUGH:  Okay.  So it's very subjective.
		DR. MICHALEK:  Yes, it's subjective.
		DR. HARRISON:  Before we go any ‑‑ is that all for General Health Data.
		DR. MICHALEK:  I'm sorry, this is the self-perception. 
		DR. HARRISON:  If that's all on General Health Data, I realize I've got a couple of things I want to ask about that don't fall into any of these categories; and I just want to make sure that I don't forget.
		Where are we with IRB approval, both the Scripps IRB and whatever you all use.  Are we able to get a copy of that for our records that --
		DR. MICHALEK:  The answer is Yes.  What will happen is, the sequence of events will go like this.  Out of this meeting will come a set of opinions, and we will use that, your opinions to revise the Statement of Work.  And after we revise the Statement of Work and we're pretty much settled on what we're going to do at Scripps, then I will approach the IRB.  And the IRB will want to know, what are we doing this time that we didn't do last time?  And conversely, what have we stopped doing this time that we did last time, and why?
		And after that presentation and I obtain IRB approval for the current Statement of Work, at the same time I'll present to them consent forms.  That's the other piece that they have to approve. 
		There's usually an editing process on the consent forms that may go on for two or three months. 
		After we've received formal IRB approval for the study and for the consent forms, then if you'd like I can communicate those to you.
		DR. HARRISON:  I think we should have that.
`		DR. MICHALEK:  For the record.
		DR. HARRISON:  The other two things that I had down here was, could we have a complete list of the previous contractors and subcontractors?  That is, for the 19 --whatever it was.
		DR. MICHALEK:  '97
		DR. HARRISON:  '97.
		DR. MICHALEK:  Sure.  A complete list of contractors.
		DR. HARRISON:  And the list of the specialists, medical specialists used in preparing the various chapters?
		DR. MICHALEK:  Okay, you've put your finger on something new, actually.  We will get you those lists.
		DR. HARRISON:  Which part is new?
		DR. MICHALEK:  What's new is that last time we had a single physician who did all of the interpretations and discussions, summary paragraphs across all the chapters.  But this time we're going to have specialists in each chapter write the overall interpretations.
		DR. HARRISON:  That's one of the reasons I was curious, because I've been dissatisfied with the chapters; and somewhere in here I've got a notation that, wherever you spell out that you're going to use specialists, I wanted to ask you if you could change that to say that you'd use experts.
		DR. MICHALEK:  Okay.
		DR. HARRISON:  The point being that a fellow right out of his endocrine fellowship may not write the kind of balanced review of the endocrine chapter that would satisfy me.
		DR. MICHALEK:  Okay.
		DR. STOTO:  Better than one doc writing the whole thing.  
		DR. HARRISON:  I was amazed.  
		A couple other things that I wanted to must make sure ‑‑ you've got in there that there's a, you've got a toll-free number for people to contact.  Is that accessible 24 hours?
		DR. MICHALEK:  No.
		DR. HARRISON:  I think that would probably facilitate things; and you also have that there's a number for the family to contact the Ranch Handers when they're out being studied, and I think it would be a nice gesture if they were able to make free calls for that, and it probably won't cost you that much.  It would be good --
		DR. MICHALEK:  You mean free calls to their family while they're at Scripps?
		DR. HARRISON:  In other words if mama wants to call up daddy and see how he's doing, she should be able to call an 800 number and be connected to him, and not have to pay three dollars long distance.
		DR. MICHALEK:  We'll have to price that out and see.
		DR. HARRISON:  Do you have a problem that, for some of the ‑‑ you have two groups of examinees in per week, if you do it like you used to.  Do you have a problem with them not filling, some people canceling at the last minute?
		DR. MICHALEK:  Yes; NORC is very good at that.  They're our schedulers, and they keep up with it.
		DR. HARRISON:  I was just wondering, do they keep a list of people who are ‑‑ you know, like every time I go on the plane and they want to know if anyone is willing to be bumped, somebody always jumps up because there's always somebody who's really very flexible.  You might keep a sub-list of very flexible people who could come at the drop of a hat; they could help fill out your groups.
		DR. OGERSHOK:  They have a system that they use like that, and --
		DR. HARRISON:  That's fine.  If that's done, that's fine.  I'm just trying to ‑‑.
		DR. OGERSHOK:  They've had all kinds of problems that way, though, when people will say they'll come and don't show up.
		DR. HARRISON:  And I guess this wasn't quite in the General Health section; it was before that.  The herbicide exposure question asks if they ever intentionally drank the herbicide, determine how many missions they were on; but they also used the herbicide as a degreaser, right?  So you want to also know if they washed with the herbicide.
		DR. MICHALEK:  We have already questioned the enlisted in great detail about that.  The questions that are there are primarily focused at the flyers, the officers.
		The questions about using it as a hand cleaner have already been summarized and published.
		DR. STOTO:  I read in the paper yesterday that Colin Powell does his own plumbing.
		DR. MICHALEK:  Great.
		DR. STOTO:  So maybe officers used this stuff for things, too.
		DR. HARRISON:  Could have been.  I don't understand what the term severity of diabetes means.
		DR. MICHALEK:  That is a label that may not be appropriate.  The values of that variable are, no ‑‑ diet control, medications--
		DR. HARRISON:  Well, there's severity of diabetes and there's current level of control.
		DR. MICHALEK:  Level of control might be a better name for it.
		DR. HARRISON:  Well, first of all, as I said, I don't understand what severity of diabetes really means.  I don't think that insulin-requiring diabetes is more severe than diabetes that's treated with oral medication, and not intrinsically.
		I don't know that ‑‑ you have objective assessments of control in the endocrine chapter; I don't know that you want a very subjective measure, assessment of control as a part of a diabetic question.
		So for the diabetic questions, I would ‑‑ now, maybe you meant to ask the type of diabetes, just to get rid of the Type Is.
		DR. MICHALEK:  We already know only there's only one Type I in the whole study.
		DR. HARRISON:  So that's --
		DR. MICHALEK:  It was a question about level of control.  Is that a better name for it?
		DR. HARRISON:  I don't especially ‑‑.
		DR. STOTO:  How is this used.
		DR. MICHALEK:  It is a variable that has four levels.  1 was called no control, 2 was called diet, 3 was called medication, 4 was called insulin.  What you name that thing, I don't know, but what would you call that?
		DR. HARRISON:  I couldn't use it in terms assessing what kind of diabetes the person had.
		DR. STOTO:  How is it currently used?
		DR. MICHALEK:  Well, it's been published; it's in our paper on diabetes and dioxin --
		DR. STOTO:  As an outcome variable?
		DR. MICHALEK:  ‑‑ as an outcome variable, and it trends with dioxin.
		DR. STOTO:  But you've got better measures of diabetes than that.
		DR. HARRISON:  If everyone was being taken care of by a uniform protocol in terms of treatment of the diabetes, then I would think that has some relevance.  But some of us use oral medication for a long, long time.  Others of us use insulin fairly quickly, others of us use insulin very poorly and not well, you know, we don't actually treat the diabetes even though we're giving them insulin.
		DR. MICHALEK:  So you're saying we shouldn't even measure this?
		DR. HARRISON:  I'm saying that the measure of control of diabetes, probably the best measure you have is the glycosylated hemoglobin.
		DR. MICHALEK:  And that's one of our laboratory outcomes.
		DR. HARRISON:  Yes, that's a direct measurement.
		DR. MICHALEK:  So we should drop this variable from the report?
		DR. HARRISON:  Yes, I would.
		DR. STOTO:  Is that a question that's filled out by the men or by their medical review, or?
		DR. MICHALEK:  That's a question, the answers are determined by us by reviewing medical records.
		DR. HARRISON:  I guess, Mike, the things I'm looking for are things that I think would not elicit an argument from other endocrinologists, and if they save a little bit of time here, then we can use it in other places.
		DR. STOTO:  But that's why question is relevant.  They're not asking that of the men.
		DR. MICHALEK:  We're reviewing medical records.
		DR. STOTO:  Record reviewers are doing that.
		DR. MICHALEK:  Record reviewers are telling us.
		DR. HARRISON:  I'd like them reviewing something else.  Wouldn't you?
		DR. STOTO:  I guess that they have to look at those --
		DR. MICHALEK:  They're looking at them anyway.
		DR. STOTO:  They have to look at that part of the record for other reasons, and it's just kind of a summary measure.
		DR. GOUGH:  But it's from very different sources with very different standards of care, what does it tell you?  That's the question.
		DR. STOTO:  I think that there's a real question about whether it should be included in the analysis.  I think that you can do a better job with the analysis.
		But if the guys are reviewing the record and are getting a lot of information out, does it hurt to get one more little summary thing?  I don't think it hurts to ask them to do it.  It doesn't involve new records.  I don't feel very strongly about that.
		DR. HARRISON:  I wouldn't ask something that I wasn't going to use, and I wouldn't ask something that I'd feel embarrassed to be using.
		DR. STOTO:  But you're asking the people who do the record review, not the men.
		DR. HARRISON:  What I'm saying is, I wouldn't ‑‑ I'm making up a table; I wouldn't add something in the table that I wouldn't want my colleagues to think I was going to use in some way.
		DR. STOTO:  I don't think it should go in the publication.  I guess the question is, does that help in just making sure the people are doing a complete review, or something like that ‑‑ may help our quality control purposes.
		Maybe not.  I don't think it hurts too much.
		DR. HARRISON:  I agree that there's no great harm done either way with this.  Either way.  
		These are just kinds of things I saw as I was reading through, Joel.  In the medical authorization request, that's 3.3.3.2, it just says that:  Participant can't recall the addresses of the doctors, and the contractor shall question the participant as to whether this information can be obtained after his departure from the examination site ‑‑ ya-da, ya-da, ya-da.
		Wouldn't it be simpler, because most guys know the names of their doctor, and they know what town the doctor's in.  Wouldn't it be simpler to have a clerk call information and get the name and address right then rather than going back and forth?
		DR. MICHALEK:  I don't think so, because this is a two and a half hour interview, and they're asked about 
the different medical conditions.  There's a great volume of material that has to be received for that to be done, for that to work.
		DR. HARRISON:  If you don't think it can be done, that's fine.
		DR. MINER:  We actually ask them to bring the names of their physicians with them.
		DR. HARRISON:  I am just saying, a guy says, "Well, you know, he's Dr. Winthrop in Edwards, but I don't know his address or phone number."
		DR. STOTO:  Are there directories that they might have on ‑‑ matched analysis
		DR. HARRISON:  Well, we have directories that could be used for that.
		I don't consider this to be anything to really ‑‑ I'm just reading through the terms, and ‑‑.
		Okay, I'm up to page 26 now.  
		So, Neoplasia Data. 
		DR. GOUGH:  That's me.  I just have a couple of questions.
		Besides PSA, is there any other routine test or standard test for prostate?
		DR. HARRISON:  There's no standard test.
		DR. FAVATA:  And that's not even without flaw.
		DR. GOUGH:  Oh, I know that.  I know that.  But it's a concern ‑‑ because dioxin is also a concern in older men, and I just wonder if there's something else that should be done for prostate.
		DR. HARRISON:  Well, you could always look at the repeat element in the first exon.
		You know, the molecular basis for the race-based difference in prostate cancer incidence and incidence of BPH is thought to be an expansion of a repeat element in the first exon of the androgen receptor.
		DR. GOUGH:  I did not know that.
		DR. HARRISON:  And what happens is, if you get a very long repeat element, you get a neuromuscular disorder called Kennedy Syndrome.  If you get a little bit shorter element than that, you get a normal person who's Asian; and if you get a shorter element, you get a normal person who's white and an even shorter one gives you a normal person who's black but who has the most ‑‑ who gets the most bang from  his testosterone buck.
		In other words, the receptor translocates more readily.  What this expansion effects is receptor translocation into the nucleus after exposure to androgens.
		So if you actually wanted to look at a propensity for prostate enlargement in cancer in this large group, then very simple; you'd take some white cells, extract the DNA, do a PCR across this region, run it on a gel and measure its length.  And guys at the NIH and U of R do that all the time.  But it's not a standard --
		DR. GOUGH:   Well, it is?
		DR. HARRISON:  It's not predictive; it's correlative.
		DR. MICHALEK:  Is it expensive?
		DR. HARRISON:  No.  Actually, it's pretty cheap.  I mean, PCR is very cheap.  
		DR. MICHALEK:  Can you give us a methods paper on that?
		DR. HARRISON:  I will.  Be happy to.
		DR. MICHALEK:  Mail a citation to me.
		DR. GOUGH:  From the standpoint of what you just described, it would also provide a database, with 2000 men.
		DR. HARRISON:  Oh, this has been done.  I don't think 2000 men would be ‑‑.
		DR. GOUGH:  Then my nice question for the clinicians, both of you, is are there other cancers ‑‑ I mean, I know all cancer incidence goes up with increasing age, but are there any in 60-year old men that we should ‑‑ I mean, prostate comes to my mind as one that we should really look at carefully.  Are there others that we should at this stage?
		DR. MICHALEK:  Other what?
		DR. GOUGH:  Other cancers.
		DR. FAVATA:  You need to --
		DR. HARRISON:  In other words, should something be appearing now that ‑‑ is there something we should be alert to?
		DR. GOUGH:  Yes.  I mean, I just know everything's going to go up. 
		DR. FAVATA:   Colorectal, we were looking to that already; but I don't think there's anything that we're not looking for.
		DR. GOUGH:  I had a couple editorial questions.
		On these long tables, 3.6.4.2.!!, is there a difference between ‑‑ are malignant skin neoplasms different from malignant neoplasms, the eye, face, head and neck ‑‑ head and neck?  The cancers they had that are different than the skin cancers.
		Okay, that's fine.  I didn't want there to be a redundancy.  Then on paragraph 3.6.4.2.1, are you really doing this thing about skin reaction at this stage?  Covariants were adjusted out for skin neoplasm?
		DR. MICHALEK:  Good point.  Those are strong covariates, by the way, for skin cancer.
		DR. GOUGH:  Oh, I know that.  But the skin reaction after two hours of Sunday after first --
		DR. MICHALEK:  They are questioned about that, as I understand it, on the questionnaire, and use those responses here as covariates.  
		DR. GOUGH:  That should ‑‑ if that's a question, that's fine.   No, if it's a question, I guess it's fine, but I just didn't imagine you had time built in to have a guy sit under a heat ‑‑ for two hours.
		DR. MICHALEK:  No
		DR. GOUGH:  And it looks very specific, and it's not very specific.
		DR. MICHALEK:  What do you mean.
		DR. GOUGH:  Well, it looks like this is part of the clinical exam, and it's not; it's a matter of ‑‑ questioning people.
		DR. MICHALEK:  Well, the only piece that's specific is the hair color.  Actually we have some different samples of hair, and they hold it up next to --
		DR. GOUGH:  But Joel, your hair's going to ‑‑ it will have changed over the last twenty years.
		DR. MICHALEK:  Yes, it's changing already.
		DR. HARRISON:  Or even front to back.
		DR. MICHALEK:  Less brown and more and more gray.
		DR. STOTO:  What do they say, what the hair used to be, or what it is now?
		DR. MICHALEK:  Good.  This is a problem.  Here you have 70-year old men and you're trying assess susceptibility to skin cancer.
		DR. GOUGH:  If they're blonds, they probably had skin cancer, so.
		DR. MINER:  We have skin color charts.
		DR. MICHALEK:  That's true; we have skin color charts.
		DR. GOUGH:  I just want ‑‑ because I couldn't imagine you doing a two-hour exposure to sun.
		DR. MICHALEK:  No.
		DR. GOUGH:  Then on 36424, the black
participants, you don't need the first only in that sentence.
		DR. MICHALEK:  good point.  
		DR. HARRISON:  In fact, I think the sentence sort of bordered on silly.  It's saying it's zero we're not going to do the analysis.
		DR. MICHALEK:  Well, that's just another attempt to do it the best we can, to exclude those 4 percent who are black to increase our ability to detect an effect in the remainder, and so on.
		DR. GOUGH:  No, I understand.
		DR. HARRISON:  So you're trying to exclude black people, huh?
		DR. MICHALEK:  Only, if they behave as they should, they won't have skin cancer, fortunately for them.  And we hope that's the case.  And that's all.  Just another little attempt to tighten up the statistical analysis; that's all.
		DR. STOTO:  Suppose they're half black or a quarter black?
		DR. GOUGH:  Well, there's no question in this country.
		DR. MICHALEK:  Exactly right.
		DR. HARRISON:  In this country, you're black.  
		DR. STOTO:  But you may be a bigger risk for skin cancer if you are ‑‑ 
		DR. GOUGH:  If you're lighter, of course.
		I have a ‑‑ I have one more question.
		DR. HARRISON:  Go ahead.  Yes, sir.
		DR. GOUGH:  You clinicians, you just --
		DR. HARRISON:  We're overly aggressive; that's true.
		DR. GOUGH:  And domineering.
		DR. HARRISON:  I was once told I had the personality of a surgeon but none of the ability. 
		(Laughter) 
		DR. GOUGH:  Back to 36421, the last sentence, a strategy for categorizing listed covariates will be provided by the offeror.
		DR. MICHALEK:  Right.
		DR. GOUGH:  Who is the offeror?
		DR. MICHALEK:  That will be SAIC and Bill Grubbs and company.
		DR. HARRISON:  Who's also called the contractor in other places.
		DR. MICHALEK:  Well, good point.  We can do a search and replace on that.  
		DR. MICHALEK:  Some of this language goes way back to 1982.  It's carried along.
		DR. GOUGH:  Okay and ‑‑ oh, I would like to ‑‑ maybe not in the blue book, but sometime I would like to see a table for each exam of the hypotheses that came out about possible relationships or associations with dioxin, for everything.   Because like the pulses, the abnormal pulses --
		DR. MICHALEK:  Across all cycles?
		DR. GOUGH:  Yes. Just so we can see what has remained consistent, what's drifted away.
		LTC BURNHAM:  You want a chart of each year, and then the abnormalities ‑‑ 
		DR. MICHALEK:  For every endpoint.
		DR. GOUGH:  No --
		DR. MICHALEK:  Actually, we have that.
		DR. GOUGH:  That would be really interesting to see.
		DR. MICHALEK:  Those are called longitudinal analyses.
		DR. HARRISON:  Tell me again what it is you're asking for?
		DR. GOUGH:  The pulses, the abnormal leg pulses; they came up in the very first examination.  I think they weren't there in the second examination; isn't that right?
		DR. MICHALEK:  Yes.  Back then we didn't have dioxin then.  We measured them by physician's palpation, and then we ‑‑ I can't remember whether they went away.
		DR. MINER:  They went away.
		DR. MICHALEK:  Then we went back to a doppler method for testing, and then they came back again.
		DR. STOTO:  So when you say they were there and went away, it means they were significant.
		DR. MICHALEK:  Yes.
		DR. GOUGH:  They were abnormal.
		DR. MICHALEK:  There was a significant difference in the groups.
		DR. GOUGH:  Then there wasn't, then they came back.
		DR. HARRISON:  But you're asking for the hypotheses.
		DR. GOUGH:  I think from that first examination our hypothesis would be that Ranch Hands are more likely to have abnormal pulses.
		DR. HARRISON:  So you want to know every hypothesis that was generated --
		DR. GOUGH:  Yes, I do.
		DR. HARRISON:  ‑‑ in which cycle it was generated --
		DR. GOUGH:  Yes.
		DR. HARRISON:  ‑‑ and what the final disposition or what the most recent disposition was.
		DR. GOUGH:  Yes.
		DR. STOTO:  That sounds like it would be good as a kind of summary of the whole process, not necessarily the blue book for --
		DR. GOUGH:  No, I don't think it belongs in the blue book, but I think at the end we'd like to see it.
		DR. HARRISON:  Well, you know ‑‑
		LTC BURNHAM:  I think it would be good in the blue book, a final blue book.
		DR. GOUGH:  One big, fat blue book.
		DR. HARRISON:  Wouldn't you also, though, if you were looking at something like that and you saw that pulses had had some significance, lost some significance, you might look more closely at the pulse question and ask whether there's anything that should be sharpened there to --
		DR. STOTO:  That's true.  Or could be sharpened.
		DR. HARRISON:  Yes.  So that's still not a blue book issue, but it says that it would be nice to --
		DR. STOTO:  Come to think of it, the blue books do say "in the past we found so-and-so."  That's part of the introduction.
		DR. GOUGH:  You generally make a comparison between this exam and the previous one.
		DR. HARRISON:  Basically what you're saying is, everything that ever got flagged, like in a flow sheet, saying this was flagged and disproven, this was flagged and disproven, this is flagged and still bumping along.
		That's not a bad planning tool.
		DR. GOUGH:  The bad planning part of it, though, as Joel just mentioned, is that the criteria for assigning abnormalities changes.
		DR. HARRISON:  But that's okay.
		DR. STOTO:  Put it in the story you're telling them.
		DR. HARRISON:  Yes.  I wouldn't try to go back and normalize everything --
		DR. GOUGH:  Oh, no, no.  Absolutely no.
		DR. HARRISON:  ‑‑ I would just take it as it is.
		DR. FAVATA:  Have the physician- examiners changed throughout this entire study?
		MR. OWENS:  Somewhat. 
		[Simultaneous discussion] 
		DR. FAVATA:  Each time there's been a different ‑‑ 
		MR. OWENS:  Some are the same, but in general --
		DR. FAVATA:  That may be a problem, lack of standardization.
		DR. HARRISON:  So we have a recommendation that will be pending until Paul gets here to do --
		DR. MICHALEK:  Personality type.
		DR. HARRISON:  No, no, I got the personality test down, but this is to prepare a chart of all hypotheses ‑‑.
		DR. MICHALEK:  You want a longitudinal summary of the entire study?
		DR. GOUGH:  Yes.
		DR. STOTO:  I wouldn't use longitudinal, because that suggests following individual through.
		DR. HARRISON:  Well, and I wouldn't want the entire study.  I'm just saying, I think you're saying, what are the things after the first cycle that you thought you found.
		DR. GOUGH:  Yes.  That stirred some interest.
		DR. HARRISON:  And keep them, then for the rest of the time.  What are the things in the second study that you thought you found, and keep them until the end, along with whatever dispositions occurred at each subsequent study?
		DR. MICHALEK:  Well, we have done that, and we can summarize all that for you.
		DR. HARRISON:  Yes.
		DR. GOUGH:  That would be good.
		DR. HARRISON:  I think that would be very nice.
		DR. GOUGH:  Those are all my comments.
@		DR. HARRISON:  Okay.  Neoplasia Data.
		DR. STOTO:  I think neurological is next.
		DR. GOUGH:  Wait, one other thing.  I had this as a general question: Is there any attempt to verify smoking and alcohol history?
		DR. MICHALEK:  Smoking and alcohol are elicited by a detailed questionnaire; "tell me about your smoking during the past five years."  Well, from year 1997 to '98 I was smoking a pack a day, and then I changed from, to two packs a day" and they tell us the time intervals, and tell us how much.  We're taking their opinion for it, of course.  We're not--
		DR. GOUGH:  Well, it's not ‑‑ I don't think it's really an issue between the Comparisons and Ranch Hands, which would be the same kid of bias.  But I just wondered ‑‑ so there's no effort.  
		But what if you have a guy who says "I don't drink" and he has cirrhosis?  Does that pop up?
		DR. HARRISON:  But that's possible.
		DR. MICHALEK:  A guy that has alcohol-liver cirrhosis?  
		Yes, that's possible.  We're just taking their opinion.
		DR. HARRISON:  Could have even been taking testosterone, get peliotic hepatitis with that if you take an oral testosterone.
		DR. MICHALEK:  We do have the entire record of medications, of prescription meds.  I don't believe we're making full use of that.  We've not made full use of that.  We've used it, but there's not been a full blown attempt to study that data.
		DR. GOUGH:  Well, it comes up because in the mortality part, which is very early on, there's an excess of digestive disease, mortality among ranch hand enlisted, and you say they're related to alcohol.
		DR. MICHALEK:  Well, we looked at those, and many of those were alcoholic-related liver conditions.  So we presumed that they were alcohol-related conditions.
@		DR. HARRISON:  Okay, neurological.
		DR. FAVATA:  One quick question just back to general.  Were there only two races throughout the study?  It just says: Race shall be dichotomized as black and non-black.  Are there any other races?
		DR. MICHALEK:  Yes, if you study the data, you'll see there are some men with Hispanic surnames, for example.  We did a detailed questionnaire on ethnicity, a couple of cycles back.
		DR. HARRISON:  Is Hispanic surname an ethnic group or a race?
		DR. MICHALEK:  I don't know.   But we asked about the ethnicity of the father and the mother and the religion and all of that, and what you get yourself into is a very complicated mess.
		DR. STOTO:  Officially Hispanic is not a race.
		DR. HARRISON:  Not only that, but there are white Hispanics and there are Indian Hispanics for sure; there are even black Hispanics for that matter.  But Asians.
		DR. MICHALEK:  I don't know if we have any Asians or not.
		DR. HARRISON:  Neurological. 
		DR. FAVATA:  Neuro.  Number one, relates to 3.6.4.3.b, Physical Examination.
		DR. HARRISON:  You're not going to bring this up, are you?
		DR. FAVATA:  Yes, I am.  Because this is important.  I had reviewed this section before and had made this point before, and I think it is important that we are testing appropriately, and it was in regard to the neck range of motion.  That is not a cranial nerve.  That does not relate to cranial nerve function.
		 If we are testing for the accessory nerve, it is not forward extension and flexion of the neck; and I went to the Neurologic chapter and that is what was tested.  So that really should be stricken from ‑‑ it should not be included by any means in the tests for cranial nerve functioning.  
		DR. MICHALEK:  Should it be in this chapter at all?  
		DR. FAVATA:  Neck range of motion.
		DR. GRUBBS:  Based on your recommendation at the October '99 meeting, what you suggest was done.  It was taken out of the analysis, neck range of motion.  It was not part of the cranial nerve function, and the appropriate cranial nerve was looked for, so.
		DR. FAVATA:  It was reported in the chapter, though.  It talked about the flexion and extension of the head under the section of cranial nerve functioning.
		DR. GRUBBS:  What version?
		DR. HARRISON:  You're saying that it's still in the exam, but it's not being ‑‑ it's not being analyzed.  
		DR. GRUBBS:  It's not being analyzed as ‑‑ the cranial nerve function.
		DR. HARRISON:  Dr. Favata is saying it shouldn't even be in the exam, under Neurological, because it indicates that we don't know what neurological is.
		DR. FAVATA:  And are you certain that it isn't, because why would it be noted in this ‑‑ Joel, I'm not sure who sent this; if it was Ron's office or you.
		DR. MICHALEK:  I did.
		DR. FAVATA:  But this was the chapter on neurologic assessment.
		DR. MICHALEK:  From the '97 study.
		DR. FAVATA:  Right.
		DR. MICHALEK:  And is neck range of motion there in that chapter?
		DR. FAVATA:  It's noted in that section on cranial nerves.
		DR. MINER:  That was current I think through June, and this happened --
		DR. MICHALEK:  But I copied that from the web page.
		LTC BURNHAM:  I thought we sent them most current report.
		DR. HARRISON:  Well, let's put it like this: it seems like everybody agrees that this should go.
		DR. MICHALEK:  You want to remove it from the chapter.
		DR. HARRISON:  So let's just --
		DR. MICHALEK:  Drop it.
		DR. HARRISON:  Assure that we'll --
		DR. STOTO:  You want the chapter removed from the exam, or both?
		DR. HARRISON:  Both.
		DR. OGERSHOK:  Both.
		LTC BURNHAM:  Well, there may be a function for something other --
		DR. HARRISON:  I was going to ask.  Now, it is nice to be able to note somewhere in the physical examination that the range of motion is appropriate.  
		Is there anyplace ‑‑ and what we don't have here ‑‑ it doesn't say anywhere in here it's neuromuscular or neuromuscular-skeletal.
		DR. STOTO:  Has there ever been any suspicion that this is --
		DR. FAVATA:  Well, it notes muscle status.  So I think that's the point where they're testing muscle strength.
		DR. HARRISON:  I guess the question to ask them is, the question was being asked "Should range of motion of the neck be thrown out completely from the exam?"  And I was saying "Well, range of motion is something that's noted in most physical exams, at least physical exams that I do, and one of the problems ‑‑ the problem with it here is that there's not an appropriate place ‑‑ maybe it could be noted under General Health Data?
		DR. FAVATA:  I think it should be a part of this exam, of the neuro section.
		DR. HARRISON:  You do?
		DR. FAVATA:  Yes. 
		VOICE:  It's just not a measure of accessory nerve. 
		VOICE:  Yes, it's just out of the cranial nerve.
		DR. HARRISON:  So you want it to be -- where do you want it to be?
		DR. FAVATA:  It should probably be under muscle status.  Motor function.
		DR. MICHALEK:  So move it down to the next place, under Muscle Status?
		DR. FAVATA:  Uh-huh.
		LTC BURNHAM:  Do we need another test?
		DR. FAVATA:  Do you disagree?  Because I don't see any better place to put it.
		DR. HARRISON:  No, actually I was just having trouble finding muscle status.
		DR. FAVATA:  I also want to note that we should clearly be testing for the 11th cranial nerve in the appropriate way.
		DR. HARRISON:  Which is?
		DR. FAVATA:  Well, basically you're testing for the motor function of the trapezius and sternocleidal mastoid muscles.  So you're opposing someone's head as they're laterally rotating and you're palpating the muscle as you're doing that and shrugging the shoulders and palpating the trapezius; it's standard.
		The other is, how is hearing, the cochlear nerve assessed?  It's not included in the list of cranial nerve function tests.
		DR. MICHALEK:  I know.
		DR. FAVATA:  We have balance for vestibular but we don't have cochlear nerve.  So hearing should be assessed.
		DR. MINER:  As I remember, we used a tuning fork.
		DR. FAVATA:  Yes.  Weber and Renie.  Lateralization, put it on and see if it lateralizes to either ear, and the Renie, and then you take it off and you see if they hear it.
		DR. HARRISON:  So that's not included in the physical exam; it should be listed.
		DR. FAVATA:  It should be.  We're not covering the 8th cranial nerve.
		DR. MICHALEK:  The 8th cranial nerve.
		DR. FAVATA:  Yes.  Fully.  There are two components; vestibular and cochlear, and we're not covering the cochlear nerve.
		DR. MICHALEK:  Okay.
		DR. FAVATA:  This regards the ‑‑ and this is another point I think that we've talked about before.  Physical exam as noted in the ''97 neuro assessment, peripheral nerve status; there's a concern in that the patellar, Achilles and biceps reflexes are being coded as normal even if very active or sluggish.  And that's inappropriate, that should be ‑‑ it should be graded, actually, of None, and that relates, zero relates to your peripheral neuropathy.  Sluggish may relate to your peripheral neuropathy, too, so there's a concern that that's seen as normal.  2+ should be normal and 3 to 4+ should be very active. 
		So it should be coded differently, and it does bear out in prediction of disease.
		DR. MICHALEK:  So that, summarize for me, which of these variables are we talking about?
		DR. FAVATA:  This is reflexes, under peripheral nerve status; patellar Achilles biceps.
		DR. MICHALEK:  So you're saying.
		DR. FAVATA:  Should not be listed as normal.  It should be a graded scale.
		DR. HARRISON:  Should not be a dichotomous scale.
		DR. FAVATA:  Correct.
		DR. MICHALEK:  Is there some language here under the text that says otherwise?
		DR. GRUBBS:  3 6 4 3 1, second paragraph.
		DR. MICHALEK:  So that sentence needs to be revised. 
		Then 3 6 4 3 1, second paragraph, first sentence should be revised.  Is that true?
		DR. FAVATA:  Is that all binary variables?  Okay, shall be recorded as normal or abnormal.
		DR. HARRISON:  The sentence starts:  Patellar, biceps and Achilles.
		DR. FAVATA:  Okay, that's what needs to be revised, yes.
		DR. MICHALEK:  And how would you revise that sentence?
		DR. GOUGH:  Graded?
		DR. FAVATA:  Shall be presented --
		DR. HARRISON:  4+ is clonus, isn't it?
		DR. FAVATA:  3 to 4 people say is very active; I don't know.  I think people usually say clonus when it is.
		DR. HARRISON:  Okay.
		DR. FAVATA:  Shall be presented in an ordinal fashion with ‑‑ absent equalling zero, sluggish equalling one, normal equalling two.  And very active, it's usually three to four.  And if you're dealing with clinicians, that's the way they usually write it.
		DR. MICHALEK:  Okay.  It might already be that way on the exam form.  But if it's not, we can take care of it. 
		DR. FAVATA:  Okay.  The other issue is regarding diabetics and diabetic questions.  I didn't note it yesterday, but ‑‑ and Bob, I look to you for this information.  I think we should include the duration of diabetes in order to further evaluate the relationship between diabetes and peripheral neuropathy. 
		Isn't it usually decades before you see some peripheral neuropathy?
		DR. HARRISON:  It could be a lot sooner.
		DR. FAVATA:  Really?
		DR. HARRISON:  Yes.  But certainly years.  I wouldn't ‑‑ to say decades is to say that you expect to see it after 20 years.  I'm not surprised to see neuropathy after 10 years.
		DR. FAVATA:  However, wouldn't that be a helpful question in sorting out ‑‑ 
		DR. HARRISON:  Duration would be helpful.
		DR. FAVATA:  ‑‑ this issue of attributing your peripheral neuropathy potentially to your diabetes?  So that should be included.  Actually, that pertains to 3.3.2.3, the diabetic questions.  Note in there the date of diagnosis.
		DR. HARRISON:  Also, though, you've got that in this section under Covariates.  So you probably want to add it or consider it as a covariate.
		DR. FAVATA:  Also my question is, the criteria that are defined here, that have just been inserted, I'm not quibbling with them, but what is the source for that criteria?
		DR. MICHALEK:  Dr. James Albers, University of Michigan, Department of Neurology.  He's the coauthor of our paper in submission on this subject.  So I want to repeat the analyses using the same criteria we used in our published paper, which ‑‑ these are the criteria. 
		And based on those criteria, I think I sent you all a copy of that paper.  We found a significant trend; risk with increased dioxin, with or without adjustment for diabetes.
		DR. FAVATA:  Okay.
		DR. HARRISON:  So this is the vibrator guy?
		DR. MICHALEK:  No, that's Alezo at Albert Einstein College of Medicine.  He's the vibrator guy.  Albers is the electrophysiological guy.  He wants us to measure nerve conductions.
		DR. FAVATA:  I like the inclusion of the, or the use of the electrodiagnostic testing and the assessment of vibrotactile responses.  I think that that would really help us with defining peripheral neuropathy.
		Just another comment on the covariates; I think that they're comprehensive, particularly with the '97 additional questions regarding metals, vibrating tools.
		DR. MICHALEK:  Which reminds me ‑‑.
		DR. HARRISON:  What was that?
		DR. FAVATA:  I'm not sure if I read it in here ‑‑ yes, it's 3.6.4.3.4.  Can we expand insecticide to pesticide?
		DR. MICHALEK:  Uh-huh.
		DR. FAVATA:  And can we annotate that and the questioning so it would be helpful ‑‑ as you noted yesterday, an individual may not know what a degreaser is.  Can we say "such as toluene, acetone, and benzene"?
		DR. MICHALEK:  Yes; we have something for you on that.  For example, we ask about heavy metals:  Any other heavy metals, such as chromium, nickel or copper?  So the interviewer does provide prompts.
		DR. FAVATA:  Okay.
		DR. MICHALEK:  So, yes.  The same with pesticides and solvents.  Yes.
		We'll make sure that takes place.
		DR. FAVATA:  I don't have anything else.
		DR. MICHALEK:  Okay.
		Dr. Stoto?
		DR. STOTO:  All those things occurred to me, but I ‑‑ 
		(Laughter) 
		DR. STOTO:  ‑‑ I don't have anything beyond that.
		DR. HARRISON:  I'm sitting here in awe, you know.  Where does she get all this stuff from?
		DR. STOTO:  I really don't have much to add to this whole section here.
		DR. HARRISON:  That reminds me, no one here would know my mentor, Grant Little, who established the dexamethasone suppression test, the mateer-pone {ph} stimulation test, and was the chairman of medicine and head of the Endocrine Division at Vanderbilt.
		And one day we were talking and he said that well, he was a Mormon from American Fork, Utah.  And he said "Well, I've never really aspired to be the first person to publish in a field.  I've always aspired to be the last."  
		(Laughter) 
		So every now and then, there's someone who, when they finish their review, there's really nothing left to say and we just move on to psychological data.
		DR. GOUGH:  Paul.
		DR. HARRISON:  Paul's a psychology person?
		DR. GOUGH:  I am, too.  Paul certainly knows a lot more than I do.
		DR. HARRISON:  You want to wait for Paul?
		DR. GOUGH:  No, because I have very little to say.
		There is an association between either being a Ranch Hander with dioxin exposure and short-term memory.
		DR. MICHALEK:  Yes.
		DR. GOUGH:  And on the list of things you're going to do here, is there any follow up for that?  Is there any investigation of that?
		DR. MICHALEK:  That's the new text on the page in the second part of the variable list there.  It says Wexler Memory Scale.
		DR. GOUGH:  Yes.
		DR. MICHALEK:  That's the same instrument we gave at baseline in 1982.  So we're going to give it again at 2002 so we'll have paired measurements on about 2,000 people.
		DR. GOUGH:  Well, is that it?  Is there anything else that should be done?  Again, this is a very specific hypothesis come out of this.
		DR. MICHALEK:  Well, the advise we got from CDC was to give exactly the same version of the Wexler that we gave at Cycle 1, because there had been many other Wexlers out there since then.  
		DR. GOUGH:  I can understand that.
		DR. MICHALEK:  And not to use any of the other versions.  That's the extent of the advice we got at this point.
		Now if we see a continued, if this finding holds up, there's going to be a lot of interest in pursuing this.
		DR. GOUGH:  I'm asking, is there anything besides a Wexler that --
		DR. HARRISON:  That measures short-term memory.
		DR. GOUGH:  Yes, but ‑‑ sort of another test for it.
		DR. MICHALEK:  We've asked the question, and the advice we're getting is to do this, and confirm what we've seen already before we launch into something else.
		DR. GOUGH:  But you won't be able to launch into anything else.
		DR. MICHALEK:  Well, someone else will, maybe.
		DR. HARRISON:  That sounds like a very limited answer.  That answer sounds like the kind of answer I've heard before from psychologists that you know, every test is ‑‑ I forget the word now, but it's verified.  So you're using it against --
		DR. MICHALEK:  Take one step at a time, yes.
		DR. HARRISON:  But what we've been talking about is that this is the one last throw of the dice here.
		DR. MICHALEK:  Right.
		DR. HARRISON:  And I think what Mike is asking is, is this the only role that you've got?
		DR. MICHALEK:  Well, I think that's a great idea.  This is an area where --
		DR. HARRISON:  Let's table that and ask Paul when he gets here.  I think that's an excellent question.
		DR. MICHALEK:  Which opens up the whole SEL90R.  You know, we're in a position with psych ‑‑ the first part of this, the first 16 variables there come from the SEL90.  I think the whole area of psychology needs a new look.  In other words, we keep doing the SEL90R because we know what else to do.  We gave it last time, we gave it the time before; if you could provide a fresh look at psych, I think we'd all benefit from that.
		DR. HARRISON:  Well, it certainly would be additive, though.  Because you wouldn't want to drop out anything unless you could just show that it really wasn't working.
		DR. MICHALEK:  If you had a good reason for doing that.
		DR. GOUGH:  Would somebody at the National Institute of Mental Health, could you approach somebody there about it?
		DR. MICHALEK:  I'd need a name, I'd need a contact.  I need somebody who ‑‑ to talk to.
		DR. GOUGH:  Would you trust talking to a psychologist who will talk to me?
		DR. MICHALEK:  Sure.
		(Laughter) 
		DR. STOTO:  Have you looked into something like the SF36?  
		DR. STOTO:  Well, it's the short form, it's a questionnaire developed at Rand, and now by a group at Tufts.  John Ware is the key guy.  It's a general health status questionnaire; it includes a mental functioning and a social role functioning and so on.  It's used quite widely now, and it seems to be a pretty good measure in terms of limiting reliability.
		DR. MICHALEK:  Of psychological things?
		DR. STOTO:  Of general health status, and it has I think it's eight different scales, subscales.
		DR. MICHALEK:  That seems to be a different subject.  I'm not opposed to it, but I though we were talking psych.
		DR. STOTO:  Well, no; part of it is psych, is mental health, but it also covers some other things as well.  So it might fit into the general health better than here, but I didn't think about it at that point, though; it just occurred to me now.
		DR. HARRISON:  If you had a very specific question about short-term memory.
		What would you --
		DR. STOTO:  This doesn't deal with the memory question; but this is a more general thing.  I'm not saying the memory isn't important.  But I think it's worth thinking about.
		DR. MICHALEK:  This has been mentioned before, the SF36.
		DR. STOTO:  They've got a web site.
		DR. MICHALEK:  Oh, they do?
		DR. STOTO:  www.sf-36.org.
		DR. HARRISON:  Well, we're now at --
		DR. GOUGH:  I have one other thing.  This is just a comment.  3 6 4 4 3, covariants.  That's such a jumble of outcome measurements and propensities and --
		DR. MICHALEK:  That, too, needs a fresh look.  The whole idea of covariate adjustments, the whole section I think needs new eyes to look at it.
		DR. GOUGH:  I don't know what that means.
		DR. STOTO:  Have we been finding things in the psychology area generally?
		DR. MICHALEK:  Yes.  Actually, having a child under thea gentlemen of 18 in the house seems to be correlated with depression. 
		(Laughter) 
		DR. HARRISON:  And anxiety in the parents.
		LTC BURNHAM:  Yes, there's a test for anxiety.
		DR. HARRISON:  And low intelligence.
		DR. MICHALEK:  Many of these covariates are, I believe.  I'll have to check that.  We have the report right here, so during our break I can answer that.
		DR. STOTO:  But have we been finding differences between the Ranch Hands and the controls --
		DR. MICHALEK:  Probably not.
		DR. STOTO:  ‑‑ in psychological things.
		DR. HARRISON:  Let me --
		DR. STOTO:  Maybe because the right questions haven't been asked.
		DR. GOUGH:  Except for the short-term memory.
		DR. HARRISON:  Let me make following observation:  We are now an hour and a half into our second day and we are now just finishing the first chapter that we were supposed to have started this morning at 8:30.  And I think we need to demonstrate a little more efficiency.
		DR. STOTO:  Why don't we wait until Paul gets here to continue this one?
		LTC BURNHAM:  Be efficient.
		DR. HARRISON:  My suggestion exactly.
		So we'll revisit psych when Paul gets here.
		GI Data.  
		I only had two questions in the whole GI section.  One question, which I think we probably talked about before; and that is the use of laboratory normals versus using the comparisons as the normals.  And Mike keeps telling me why we don't need to do that.
		It seems to me with a big control group like this, your normals would be the control group, not a bunch of teenagers that Scripps gets to come in and donate blood.
		DR. STOTO:  I'm trying to remember what the issue is about there.  These are dichotomous variables; either it's above normal or not.
		DR. MICHALEK:  We've already noted, Mike, that we can be misled by using the Scripps abnormal range.  Many times I think the Scripps normal range will be taken from a package insert from a lab kit.
		Sometimes those normal ranges are so -- they don't produce a very sensitive test for abnormality, a good example being insulin.  We used the Scripps normal cut point for insulin last time in our big report, and we totally missed an effect.  By using the upper 2-1/2 percentile of the comparison group we revealed an effect, an adverse effect on nondiabetic Ranch Handers.
		DR. STOTO:  So you are doing that now?
		DR. MICHALEK:  Yes, we are using the normal-abnormal cut points as the upper and lower 2-1/2 percentiles of the comparison group.  Not always, but we need to reconsider every single one of these variables from that point of view.
		DR. HARRISON:  You're starting to sound like that guy yesterday.
		DR. GOUGH:  Gary Kayajanian.
		DR. HARRISON:  Yes.  I mean, you change your analysis to --
		DR. MICHALEK:  No, actually we messed up.  In all prior reports we had been using the upper and lower 2-1/2 percentiles.  But in the Cycle 5 report, for some reason --
		DR. GRUBBS:  We've been using Scripps throughout.
		DR. MICHALEK:  We used Scripps.  Well what happened was, Scripps changed their cut point.
		DR. HARRISON:  Now the way a lab usually does this is the lab gets a kit and a range is published in that kit.  The lab then has to run a certain number of samples, depending on certain criteria, to confirm that its range is the same as the range presented in the kit.  If it can't confirm that, it's supposed to change it.
		DR. MICHALEK:  Well, sometimes ‑‑ getting back to the study ‑‑ it can happen that by using the laboratory cut point you can find that 40 percent of the men in the comparison group are abnormal, using that particular cut point.
		DR. HARRISON:  What I'm saying is that if you take the package insert and you compare that range to the comparison group --
		DR. MICHALEK:  That has to be done, yes.
		DR. HARRISON:  ‑‑ and it doesn't match, then you certainly have to change it. 
		DR. MICHALEK:  Right.  That has to be done.
		DR. STOTO:  Do these things have continuous values?
		DR. MICHALEK:  Yes.  They're all analyzed both as continuous and discrete. 
		DR. STOTO:  To me, that's the way to  handle, is to analyze them as continuous variables.  There's more information there.
		DR. HARRISON:  Okay, is that what you mean when you say, I've got it highlighted here:  Continuous variables shall be transformed to normality as appropriate?
		DR. MICHALEK:  Yes, because some of them are highly skewed; they have exponential distributions rather than normal and so it's not appropriate to test on the mean.
		DR. HARRISON:  As someone who is naive about this, I --
		DR. STOTO:  I think that's part of it, but I think that the general part is that rather than them fuss about the cut point and decide whether the guy's normal or abnormal, you basically say "Let's look at the average between the control and ‑‑"
		DR. HARRISON:  Well, the reason I brought it up here is it says:  All laboratory variables except bilirubin, et cetera.
		3.6.4.5.1.  All laboratory except certain laboratory data shall be analyzed twice, once with the dependent variable maintained as continuously distributed and again as a dependent variable dichotomized as normal or abnormal.
		And it was the dichotomization that I was querying, how that would be accomplished.
		DR. STOTO:  Right.  I understand.  I guess my point is that if they can do it as continuous, I don't care so much about how they do dichotomous.  I think it's a better analysis.
		DR. HARRISON:  Okay.  Second paragraph, 3.6.4.5.2, participants whose blood contained hepatitis-B antigen shall be excluded from analysis of current hepatomegaly.
		Does that mean that if they were positive at any point?  Because I think sometimes you can be positive and then negative, can you not?  In other words, someone who was hepatitis-B positive in 1987 may not be hepatitis-B positive today.  Is that?
		DR. GRUBBS:  It's based on the measurement for the last report at the '97 exam.  Nothing has gone back from '92 or '87.
		LTC BURNHAM:  Is this surface antigen?
		DR. GRUBBS:  Surface antigen is, correct me if I'm wrong, it's current hepatitis, where say antibodies or a history of? 
		DR. HARRISON:  All right, so this is surface antigen, okay.  Or hepatitis-C antibodies.
		Okay. I understand now. 
		I did not have anything else on the GI system.
		DR. FAVATA:  I had one question regarding covariates.  Why was that changed, regarding alcohol use?  Was the data too cumbersome, asking it the way it was previously asked?
		DR. MICHALEK:  Where are you referring to?
		DR. FAVATA:  This is .5.3.  Covariates for adjusted analysis.
		DR. MICHALEK:  Which sentence?
		DR. FAVATA:  You were excluding current alcohol use, average number of drinks per day during the two weeks prior to the physical exam.
		DR. MICHALEK:  You mean I crossed it out?
		DR. FAVATA:  Yes.  And then you changed that to 'current drinking.'
		DR. MICHALEK:  Yes.  What we're trying to do there is imitate what will be published in the Anals of Epidemiology.  We have a paper on this which is just accepted.
		The idea was to use current drinking, measures of current drinking when analyzing laboratory results, and to use historical drinking when analyzing clinical outcomes, such as hepatomegaly.
		DR. HARRISON:  So drink-years represents your historical and whether you had a drink --
		DR. MICHALEK:  Current drinking means right now.
		DR. HARRISON:  ‑‑ and whether you had a drink yesterday is your lab stuff.
		DR. MICHALEK:  Right.
		DR. GRUBBS:  So, Joel, for the history is it both current and past?  It seems to read that way.
		DR. MICHALEK:  You mean for the clinical piece?
		DR. GRUBBS:  Just analysis of hepatic disease history shall also include.  Also meaning current and history there?  I'm questioning the 'also' there.
		DR. MICHALEK:  Drinking history as a covariate.
		DR. GRUBBS:  Yes, the first sentence.  I'm looking at the last sentence.
		DR. MICHALEK:  Is that the sentence you're referring to? 
		DR. GRUBBS:  Right, the adjusted analysis of past disease history shall also include --
		DR. MICHALEK:  So probably we should stirke the 'also'.
		DR. GRUBBS:  So you don't want current as a part of --
		DR. MICHALEK:  I don't think 'current' should be there.  If you're trying to imitate our paper.  But I'll have to check that.
		DR. FAVATA:  Was the previous information helpful if you had an individual with a lab abnormality, a liver function test abnormality to explain clinically in those two weeks prior whether that would have impacted upon that particular finding?  I just didn't know whether that provided more comprehensive information clinically.
		DR. MICHALEK:  What sentence are you referring to?
		DR. FAVATA:  What was stricken before, the question included the average number of drinks per day during the two weeks prior to the physical examination. 
		DR. HARRISON:  Sounds like a pretty good definition of current drinking.
		DR. MICHALEK:  You're questioning why we struck that out?
		DR. FAVATA:  Yes.
		DR. MICHALEK:  All right.
		DR. HARRISON:  Put it another way:  haven't you now made current drinking a much vaguer quality?
		DR. FAVATA:  It seems to be offering less information.
		DR. MICHALEK:  I think what happened here was I ‑‑ the first sentence was supposed to introduce global covariates that are in all analyses; race, military occupation.  Then degreasing chemicals.  Then this whole paragraph needs to be fixed, because it doesn't communicate what I just said, that the measures of current drinking, which will include the one you just said, within the last two weeks, should be covariates for the lab variables.  And historical drinking should be for the clinical.  So I'll fix this paragraph.
		DR. HARRISON:  Yes, but Joel what she's also saying is that ‑‑ maybe you're saying the same thing now, but the way it is now it just asks for current drinking.  So yes, I had a drink in the last week, so I'm a current drinker.  Yes, I had 20 drinks in the last week.
		DR. MICHALEK:  Yes, we have average number of drinks per ‑‑ yes.  So that's better date.   Yes, I agree.  So I will fix this.
		DR. HARRISON:  Okay.  
		It seems like I remember from somewhere that alcoholic cirrhosis has a strong genetic pattern; you either have it or you don't.  And in fact, it's unusual enough that -- the buy in Pittsburgh was transplanting alcoholic cirrhosis patients who were still drinking, because if you got a new liver, the chances were 1 in 500 or something that you would get one that was sensitive to alcohol?
		Because if that's the case, all of the alcohol-induced lab changes have probably already been picked up.
		DR. FAVATA:  Predetermined, too.
		DR. HARRISON:  Yes, and picked up.  I mean, they were drinkers in the last cycle, their values were abnormal or not abnormal.
		I know I've been told that; I just don't know from looking at primary events that it's true.
		Okay, Dermatologic data.  Who did that?
		DR. FAVATA:  I have a comment.
		MR. COENE:  It wasn't assigned.  Let me say that.  
		DR. FAVATA:  3.6.4.6.1, line 2, 3.  It's:  Location of acne shall be coded as all intersections.  What does that mean?
		DR. HARRISON:  I saw that, too.
		DR. FAVATA:  Does this further explain --
		DR. HARRISON:  4th and Vine.
		DR. GRUBBS:  Dr. Favata, I think that means eyes, ears temples, eyes and ears, eyes and temples, ears and temples, eyes, ears and temples ‑‑ seven different categorizations there.
		DR. STOTO:  That's set theory, you're talking about intersections.
		DR. MICHALEK:  Algebraic.
		DR. GRUBBS:  Yes.
		DR. FAVATA:  If we're looking for chloracne, the other characteristic place of location for the chloracne would be periumbilical and scrotal.  So those should be included.
		DR. STOTO:  I think you want to use, instead of intersections, combinations is a more appropriate word.
		DR. GRUBBS:  I'd agree.
		LTC BURNHAM:  Do you see chloracne this far out?  Is it a chronic ‑‑?
		DR. FAVATA:  I think it's yet to be determined.
		DR. GOUGH:  Some of the industrially-exposed people in the late '40s had chloracne 35 years after their exposure.  But we've never seen any, so there's a difference here.
		LTC BURNHAM:  Did they also have it acutely?
		DR. GOUGH:  Oh, yes.  Oh, yes.
		LTC BURNHAM:  And it just stayed, or it went away and --?
		DR. GOUGH:  Well, it diminishes.  It goes slowly away.
		LTC BURNHAM:  Then it comes back, 35 years later?
		DR. GOUGH:  No, no; just the number of temples decreases, but there's still this characteristic pattern, a sideglass pattern, as I recall.  There's a bunch of papers by Crowe, an English dermatologist.
		DR. HARRISON:  Anything else on dermatology?
		Cardiovascular.
		DR. GOUGH:  Unfortunately, that's me.
		DR. STOTO:  Me, too.  Two non‑clinicians.
		DR. HARRISON:  Well, you guys go ahead.
		DR. STOTO:  A couple of things to note.  There is the addition of a new test, a carotic intima media thickness, which I recall has been discussed, and they've got some findings on that.  Looks like it's a sensible thing.
		And then percent body fat as a covariate has been replaced by BMI, which again I think makes sense; and then here's where personality type has been replaced by hostility.  So we're back to the same discussion we had this morning, and maybe we'd better wait until --
		DR. HARRISON:  Until our hostile expert gets here.
		DR. STOTO:  Right.
		DR. MINER:  He's got an answer; it's one that made the difference.
		DR. GRUBBS:  In general health, it was marginally significant with sedimentation rate.
		DR. GOUGH:  With what?
		DR. GRUBBS:  Personality type.
		DR. MICHALEK:  Personality type was marginally significantly associated with sedimentation rate.
		DR. HARRISON:  But the least most significant test you all run.
		DR. MICHALEK:  And the least most significant psych variable.
		DR. HARRISON:  I'm going to seize in another minute here.  
		DR. STOTO:  Why don't we wait until Paul gets here to talk about this one, too.
		DR. HARRISON:  Okay.  There is one thing, though, that I would like to ask about the carotid thickness.  I accept that that's a widely used epidemiologic measure of atherosclerosis; it's the only variable that I know of that they've agreed to so far in the show trial for the effects of weight loss that the NIH is running.
		What you don't have in here is the protocol, and particularly important to me in the protocol is how blinded the readers are.  What should be done is the carotic wall thickness should be ‑‑ it's an ultrasound exam. You record the ultrasound, you send the tapes off to the reader somewhere who's blinded as to ‑‑ you can even send off dummy tapes that allow you to calibrate how they read the things, for obvious reasons.
		DR. STOTO:  That's a more general question.  When the physicians are doing these clinical exams, do they know --
		DR. HARRISON:  No, they don't.  They're not --
		DR. MICHALEK:  The protocol is in addendum G on page 90.
		DR. HARRISON:  See, mine stops at D. 
		Well, wait a minute.  
		DR. STOTO:  It's actually page 91 of the new one.
		DR. HARRISON:  I thought you said G.
		DR. STOTO:  This is addendum G, begins at page 91 of this --
		DR. HARRISON:  My 91 is Addendum D ‑‑ here we go.  It's labeled D, and it's G.  All right.
		DR. MICHALEK:  So you're asking about the blindedness of the IMT technician.
		DR. MINER:  And the reader.
		DR. MICHALEK:  And the reader. 
		DR. HARRISON:  And there's no ‑‑ there's no description of the protocol of the reading.
		DR. MICHALEK:  I believe the ‑‑ correct me if I'm wrong.  The fellow lies on a couch.  A nurse or technician will apply the instrument to the neck.  She will calibrate on a screen, and she'll resolve the signal on a screen.  You lay there and say nothing for about 10 or 15 minutes while she does that, and then she stops and you get up and leave.
		Then later on, offsite, the data is analyzed.  And all that's known to the analyzer is the case number, and the case number is not assigned to a name or a group number; it's totally blinded.
		Did I say that right?
		DR. HARRISON:  What it says in the protocol here is ‑‑ it just refers to a reader and cardiologist, who will review the scans within two weeks of collection and provide feedback to project sonographers, a deterioration in acquisition technique.
		I'm not a sonographer, but I know that sonographers can find what they're looking for.  I know that.  I've been sonographed.  That's generally true.  So the blindedness of the sonographer and the blindness of the reader should be assured in ‑‑.
		DR. MICHALEK:  The men are instructed not to speak to the ‑‑ and the examiners are instructed not to question.
		DR. HARRISON:  Okay.
		DR. MINER:  And we ask them on their outbriefing --
		DR. MICHALEK:  To report.
		DR. MINER:  ‑‑ if anyone asked about their status.
		DR. HARRISON:  Did anyone probe them.
		DR. MICHALEK:  Right.
		DR. GOUGH:  I have a couple of questions for you and Elissa.
		Is it, on 3 6 4 6 1, my question is, is this a general definition of abnormality?  Leg pulses shall be defined abnormal if any of these things is abnormal and shall be defined normal, if all these pulses are normal?
		DR. MICHALEK:  This is a made-up variable called quote, "leg pulses"; we made this up ourselves in 1982.
		DR. GOUGH:  What I'm going to open up now is a real Pandora's box.  What of these things have clinical significance?  As I recall from last time, this carotid intermediary thickness doesn't have any demonstrated clinical significance.
		DR. MICHALEK:  I didn't know that.
		DR. HARRISON:  I'm not sure that's--
		DR. GOUGH:  Well, I may mis-remember.  But what does it mean to have, if you group all these leg pulses together and you find any one of them is abnormal, then you say this person has abnormal leg pulses, what does that mean in terms of anything?
		DR. MICHALEK:  This was a statistical construct to address sparse data in 1982.  Every single one of those, the pulse at the knee, the pulse at the angle, the pulse in the thigh, there were very few abnormalities.  And so this was an attempt in 1982 to combine the data ‑‑ this is called lumping.  We lumped these together so we could have enough points so we could analyze.
		Now if you think we should drop this, then --
		DR. GOUGH:  I don't know, I'm not a clinician.  I'm just wondering because --
		DR. MICHALEK:  It's a stretch.
		DR. HARRISON:  I think it might help.  And the reason it might help --
		DR. GOUGH:  What, to lump together?
		DR. HARRISON:  Well, to have them.  Yes, and lump together is probably not unreasonable because diabetes is a medium vessel, small vessel disease.  So that one of the abnormalities that you'll see will be abnormalities in pulses.  And they may be abnormalities in the dorsalis peadis/, posterior tibialis ‑‑.
		DR. STOTO:  So it makes more sense to lump these than to lump all cancers, for instance?
		DR. HARRISON:  Yes.  I think so.
		DR. STOTO:  You'd expect different pulses to have the same cause.
		DR. FAVATA:  I don't think you lose anything by lumping.
		DR. GOUGH:  Okay, all right. 
		LTC FOX:  What is abnormal and what's normal?
		DR. MICHALEK:  Well, the physician makes a judgment as to whether the pulse is diminished, absent, or present.
		LTC FOX:  That's what I was asking; diminished, absent or present.
		DR. MICHALEK:  It's a physician's judgment.
		DR. HARRISON:  Or asymmetrical.
		LTC FOX:  Asymmetrical.
		DR. MICHALEK:  That's right.
		DR. HARRISON:  Is it explicated that way in the examination form?
		DR. MICHALEK:  It's on the exam form that way.
		DR. HARRISON:  Okay.  All right. 
		Immunologic data. 
		DR. GOUGH:  I have one more.  I was a reviewer on this one.  36465.
		DR. HARRISON:  36465.
		DR. GOUGH:  Due to the large number of covariates, blah-blah-blah.  Only one variable from each of the following sets shall be selected for the use of a covariate.  Lifetime cigarette smoking or current cigarette smoking.  Lifetime alcohol history or current alcohol use.  Those are very different things.
		DR. GRUBBS:  Joel, I think that was dropped, and should be dropped for this.
		DR. MICHALEK:  So this whole paragraph should go?
		DR. HARRISON:  I'm just curious, though.  Let me ask you, are you saying that cigarette smoking, alcohol use, cholesterol, low HDL and family history of heart disease are all correlated?  Is that what you had concluded earlier?  
		Due to the large number of covariates and certain covariates being highly correlated,
		DR. STOTO:  I think they're correlated within those groups, is the point.
		DR. MICHALEK:  Some of these might be correlated with each other.
		DR. HARRISON:  I could see where smoking and alcohol history probably would match and probably correlate quite well.
		DR. GOUGH:  But I don't think that if  you ask a question about current cigarette smoking of a guy who's quit smoking last week, that gives you the information you need for this.
		DR. HARRISON:  I'm not disagreeing with you.  But you're saying that's been dropped?
		DR. MICHALEK:  The whole paragraph should go.
		DR. GRUBBS:  In the age of the slower computer, it really took up a lot of resources to grind through all these ‑‑ I think there were close to 15 covariates in the whole cardiovascular section.  
		DR. STOTO:  You still have problem of multicollinearity in these things, which you need to be careful about.
		DR. GRUBBS:  Yes.  Sure.
		DR. STOTO:  How do you deal with that?
		DR. GRUBBS:  Well, if I'm not mistaken, multicollinearity will affect the coefficients, but within each other, and you may not get a significant effect where you might see it in a fully adjusted model.
		However, we use just main effects models with no steppings.  So they're in the model regardless, and we're not looking really at the significance of the coefficients in the model, per se; just really on the dioxin or the group.
		DR. STOTO:  I think that's generally appropriate.  I guess the problem you could have is if you have two of these covariates that are very highly correlated.  I mean, you could have numerical problems.
		DR. GRUBBS:  Right; it's not that bad.
		DR. STOTO:  So you check for that kind of thing to happen, okay.
		DR. GRUBBS:  Yes.
		DR. HARRISON:  You know, sometimes --
		DR. STOTO:  You understand all that, right? 
		(Laughter) 
		DR. HARRISON:  It's in code --
		DR. STOTO:  That was a technical point.
		DR. GRUBBS:  Was it the right answer?
		DR. STOTO:  It's not like they haven't been technical points about some of the clinical measures, though.
		DR. HARRISON:  Any other comments on the cardiovascular section?
		No?
		Moving on, then, to the Hematology section.
		DR. FAVATA:  Let's do Heme, that's quick.
		DR. HARRISON:  Prothrombintine should be under Liver.  ESR should be eliminated.
		DR. MICHALEK:  Wait a minute, now.  Last time you said we should move ESR from General Health to Hematology, and now you're saying that it should be just thrown out.
		DR. HARRISON:  Yes, I am.  I don't claim to be consistent, but I'm never in doubt.
		DR. MICHALEK:  You're throwing away some findings when you do that.
		DR. HARRISON:  If you exclude the liver tests for temps over 100, you should exclude pro‑time for temps over 100.  Because as far as I'm concerned, pro‑time is a liver function test.
		DR. MICHALEK:  So we're going to move prothrombintime to the gastro chapter, and you still think we should drop ESR completely from the report?
		DR. FAVATA:  I know that it's so general we don't know what this test means anymore; and we still do use it as a general indicator of inflammation.  The rheumatologists use it.  I don't think we should get rid of it, Bob; I think we should keep it.
		DR. HARRISON:  Okay, that's fine.  That's fine.  I don't even want to try and defend my suggestion.  If there's one person who feels it should be kept, I withdraw my suggestion.  My last question was, how will changes in the platelet counts be analyzed differently from the other values?  
		3.6.4.7.4 says:  Changes in the mean platelet count from '82 to 2002 for cycle 5 shall be analyzed.  I mean, it's sitting there all by itself, like you're doing something extraordinary.  Something to be proud of.
		DR. HARRISON:  Only because platelet count, for some reason in 1982 was singled out as worthy of longitudinal analysis, and that language has been carried along ever since.  So if you think we should analyze something else longitudinally; or actually the suggestion was we analyze everything longitudinally from since '82.
		DR. HARRISON:  That wasn't his suggestion, though.  
		DR. GOUGH:  No, it's when  you see something.   This is really a hypothetical ‑‑ to use terms that we use.  This is almost a hypothesis-generating study originally.  And you have generated some hypotheses, so follow them up.
		DR. MICHALEK:  We have analyzed these other variables longitudinally, but not in the big report.  We did in an article which has been accepted to a journal.
		DR. HARRISON:  But what you're saying is that something funny was seen in the platelet count in '82, and you've been following it ever since?
		DR. MICHALEK:  Yes.
		I don't remember the findings, though.
		DR. STOTO:  No, no.  I think that what I heard you say doesn't come across here, and that is that most of the variables are looked at, you know, the current value versus the disease status now.  But some of them, including platelet count, has been looked at, changes in platelet count over time being associated with --
		DR. MICHALEK:  And herbicides. 
		DR. STOTO:  So the dependent variable was changes in platelet count.
		Now what are you saying has changed here?  What's the change?
		DR. HARRISON:  So what you're saying is that in the high dioxin group versus the low dioxin group, platelet counts here ‑‑ 
		DR. MICHALEK:  I forgot; they're either decreased or they're increased.  I forgot.
		DR. HARRISON:  Yes.
		DR. MICHALEK:  But there's significant change in platelet count.  That will be published soon.
		DR. STOTO:  So what's the change that's being proposed here?
		DR. MICHALEK:  Only to change the year, from 1997 to the year 2002. 
		DR. STOTO:  But no, assess for dioxin associations.
		DR. MICHALEK:  Oh, that's just some reduction in words.  I just wanted to make ‑‑ based on discussions we had with the previous committee, I want to downplay the emphasis on dioxin.  This is a study of herbicides, and dioxin is a contaminant, and so that's why I took out the phrase 'dioxin'.  They're still going to analyze using all the statistical models we've talked about.  That's all.
		DR. HARRISON:  Okay.  What do you think about prothrombintime?  Is it a liver test or a ‑‑ 
		DR. FAVATA:  I think that it's clearly indicative of your liver function.  However, it's normally presented in hematologic data.  I don't have a strong feeling either way, Bob.
		DR. HARRISON:  You are leaving today, right?
		DR. FAVATA:  Yes.
		DR. HARRISON:  Okay.  Well, and the reason for excluding analysis of liver function test for temperatures greater than 100 degrees ‑‑ 
		DR. MICHALEK:  Excluded from analysis of prothrombintine.
		DR. HARRISON:  Well, I'm not sure why the LFTs are ‑‑ I'm not sure why that restriction is in.  Participants whose blood contains hepatitis-B surface antigen, that makes sense; or hepatitis-B antibodies, that makes sense, or participants with a body temperature greater than 100 degrees, shall be excluded from analysis of all Cycle 6 laboratory variables.
		DR. MICHALEK:  Where are you reading now?
		DR. HARRISON:  I'm back in the GI chapter, 3.6.4.5.2.
		DR. MICHALEK:  Right.
		DR. STOTO:  How many people have fevers when they're doing this exam?
		DR. GRUBBS:  There was one last time.
		DR. MICHALEK:  One.
		DR. STOTO:  I mean, is it ‑‑ 
		DR. GRUBBS:  I think there might have been eight at baseline. 
		DR. STOTO:  I mean, wouldn't it make sense to wait until the guy's fever resolves before you do the exam?
		DR. HARRISON:  Well, you don't know that he's got a fever until he gets there and has his physical.  
		DR. STOTO:  Yes, but I suspect that most people who have a fever ‑‑ you wait a day or two, it'll get better, or not, and then it's something serious.  I'm not a physician, obviously.
		DR. HARRISON:  I don't think it's a real major issue.  A) I think of pro‑time, as I said, and then B) I thought if you were going to say that fever affects liver function tests, then you've got to say that fever affects the pro‑time.  I think that part is consistent.
		Any other comments on hematological?
		Okay, it's 10:30.  Is anyone in favor of taking a break, or shall we just keep going?  		DR. GOUGH:  Well, I'm going to excuse myself if we don't take a break.
		DR. HARRISON:  Okay, let's take as quick a break as we can.
		[Recess]
		DR. HARRISON:  Okay.  All right, Renal data.
		Anyone have any comments on Renal Data? 
		[No response.] 
		No.  Endocrine Function. 
	Okay.  I have Dr. Osei's comments; Dr. Kwame Osei is chief of Endocrine at Ohio State.
		[Handout]  
		And I'll just read what he says.  He says:  Include a family history of diabetes.  
		I suspect that's in the general --
		DR. MICHALEK:  I'm sorry, that is a covariate, may not have been put on the next page.  We are adjusting for that.  I'll make a note of it, though. 
		DR. HARRISON:  And Kwame suggested in addition to the laboratory data, laboratory tests listed, C peptide pro insulin, luteinic acid carboxylase antibodies, and urine microalbuminuria.
		Do you have any comments or questions about that, Joel?
		DR. MICHALEK:  We have analyzed these in the past.  They ran in Cycle 4, the C peptides and pro insulin, don't remember the other two.
		DR. HARRISON:  I don't think you ever did luteinic acid carboxylase antibodies.
		DR. MICHALEK:  No.
		DR. HARRISON:  And I don't think you ever did urine microalbumin.  Urine microalbumin is an indicator of medium vessel damage from diabetes, it's one way of thinking of it.  It will be kind of interesting because it's another test of diabetes severity, if you will.  Better test of severity than some of the things we've talked about.
		DR. MICHALEK:  Tell me about the method.  What about the 24 hour piece?  You have to hold your urine for 24 hours?
		DR. HARRISON:  No, you have to collect your urine for 24 hours.
		DR. MICHALEK:  Oh.  Repeated urine collection, in other words, for a 24 hour period?
		DR. HARRISON:  Generally what you do is give the guy a jug and ask him to try and remember to --
		DR. MICHALEK:  Always in the same jug, or always --
		DR. HARRISON:  Always in the same jug.
		DR. MICHALEK:  Just keep filling up the jug.
		DR. MINER:  Here we go again.
		DR. MICHALEK:  We used to do that.
		DR. HARRISON:  What was the problem?
		DR. MINER:  They didn't like it.
		DR. MICHALEK:  Well, in the past we had logistical problems, but --
		DR. GOUGH:  The first one's a spot urine, so that's not a --
		DR. HARRISON:  Well, the problem, though, with what Kwame suggested here is that in the kind of three day cycle that I think you all general do the exams in ‑‑ Well, first of all, you're talking about how many?  
		DR. MICHALEK:  22.
		DR. HARRISON:  Actually, we're going to get back to this in a second.  How many diabetics are you talking about?
		DR. MICHALEK:  About a hundred and ‑‑ out of the 2,300, about 300.  400 diagnosed.
		DR. HARRISON:  Since you're looking at a diabetes lesion, it doesn't make sense to do them in all 2000 subjects.  You might want to do them in the 400 subjects ‑‑ this might be a place where you'd do a matched analysis, where you do the comparisons that match to those diabetic patients in terms of age, race, and so on.
		DR. MICHALEK:  Does this require that you have to like stay in your own telephone room for 24 hours to collect every single drop of urine?
		DR. HARRISON:  Well, you have to take your jug with you.
		DR. MICHALEK:  You have to carry it around with you.
		DR. HARRISON:  Yes. 
		VOICE:  Carry it around to rest rooms.
		DR. HARRISON:  I guess the only thing I was going to say is that I'm not sure that you wouldn't just go ahead and do the 24-hour collection on all of the patients with an abnormal glucose --
		DR. MICHALEK:  That have a history of diabetes, in other words.
		DR. HARRISON:  Or that have an abnormal glucose test.
		DR. MICHALEK:  We won't know the abnormal glucose until the middle of the first day, right?  Because they have a fasting glucose in the morning and if they're not known to be diabetic, they'll have a two hour postprandial, so we know ‑‑ will we know the glucose that day, or would we not know it until the next morning?
		DR. HARRISON:  So you'd be starting the collection on the morning of the second day and finishing it --
		DR. MICHALEK:  The morning of the first day, I believe, is the glucose.  Is that right?
		DR. MINER:  Right.
		DR. HARRISON:  Yes, but you'd be starting the urine collection on the morning of the second day.
		DR. MINER:  For those that had a high --
		DR. MICHALEK:  Yes.  So we wouldn't start that until morning the morning of the second day, and so it could theoretically have it by the morning of the third day, the last day.
		DR. HARRISON:  You'd have to examine the practicality of that versus the practicality of just doing everybody, which --
		DR. MICHALEK:  We don't want to do that.  That's a large volume of urine in 24.
		DR. HARRISON:  Well, of course what the lab does is the lab takes an aliquot of that, measures the total volume, takes an aliquot, throws the rest away, and does the microalbumin assay on the small aliquot.  
		DR. MICHALEK:  Would there be any value for us to save the remaining urine?
		DR. HARRISON:  No.  You know, there's always stuff you can do with urine.  
		DR. MICHALEK:  We have urine saved from previous cycles.
		DR. HARRISON:  Kwame also suggests a Wasip ratio.
		DR. MICHALEK:  We have that.  We have the waste measurements; I'm sure we have the --
		DR. HARRISON:  No, actually I noted that you have waste but you don't have HIF.  Now there's actually a guy named Picinet will argue that you can just use the waste measurements, that there's some cutoff that can be used for men and women and greater than that indicates ‑‑ 
		DR. STOTO:  If you're going to be measuring waste, why not just get their measurement?
		DR. HARRISON:  Well, one of the problems is, where are the HIFs?  You know, so you really need to have an actual definition of what you're measuring.
		DR. FAVATA:  What does it indicate?
		DR. HARRISON:  It's a sign of abdominal adiposity.  
		So we're looking at some serious abdominal adiposity here, and that ‑‑ well, you know what that means.  That bears on the incidence of atherosclerotic, basically atherosclerotic disease and coronary disease.
		DR. STOTO:  But aren't there standard protocols for measuring HIF?
		DR. HARRISON:  Yes, there are.  I'm just saying that they should be used.  Kwame wants to do bioelectrical impedance for total body fat and lean muscle mass.  That's his suggestion.  Thyroid antibodies.  You've got thyroid antibodies down here; I don't understand.  And that was it for endocrine.
		LTC BURNHAM:  We're going to have the recommendations of the committee?
		DR. HARRISON:  Well, I'm reading Kwame's recommendations, since he's not here.  I'm going to go through my recommendations and then I ‑‑ you know, then we'll discuss it and see what we as a committee agree are the recommendations, if that makes any sense.
		DR. MICHALEK:  Now the antimicrosomal, is that a spelling error?
		DR. HARRISON:  Should be antimicrosomal.
		DR. MICHALEK:  That is included in the Immunology chapter, as I recall.
		DR. HARRISON:  You have antithyroid antibodies here as number seven.
		DR. MICHALEK:  Oh, you're right; we do have that.
		DR. GRUBBS:  Yes, and in Immunology, there's an A&A thyroid microsomal antibody, under the lipids panel I believe it is.
		DR. HARRISON:  Okay.
		DR. MICHALEK:  So the only things that are new here are the HIF measurement ‑‑ oh, there's two lab measurements, the HIF measurement and the impedance.
		DR. HARRISON:  Well, really, yes.  1 and 2 you've done before but didn't have in for this time; and then two lab measurements you didn't.
		Now before we fixate completely on this, I think you can get rid of glycated hemoglobin.  That's number 22 in the revised list of lab data.  Because on number 15 you've got hemoglobin A1C.  You're doing the same, you've got the same test listed twice, essentially.
		DR. MICHALEK:  I'm sorry; I didn't know that.
		DR. HARRISON:  I think you can get rid of number 12; that's the fasting urinary glucose.
		DR. STOTO:  Because the serum glucose is better?
		DR. HARRISON:  Serum glucose is far better, depending on whether someone has had a certain level of hypoglycemia, the urinary threshold varies so the fact that you've got glucose in your urine doesn't really tell you anything.
		LTC BURNHAM:  That's probably a holdover.
		DR. HARRISON:  I don't even remember this being in here.  I'm kind of ‑‑.
		DR. MICHALEK:  We've been doing that at every cycle, the fasting urinary --
		DR. GOUGH:  How did you miss it?
		DR. HARRISON:  Sure you have.  You have a total T4 and a T3 uptake.  Now I know what you're going to say, but I'll go ahead and say it anyway.  A lot of hormones circulate bound to protein, and the part that's bound is biologically irrelevant.  It's only the free hormone that's relevant.  
		And there are facile assays nowadays to measure the free thyroid hormone.  So if it is not an issue of continuity, the more appropriate assay of the thyroid hormone level would be a free T4.  And there's antibodies now that can tell the difference between whether the T4 is bound to hormone or not.  So I would do that.
		In that same context, I'm not really sure; if I were looking for a place to save money, I wouldn't do the total testosterone, I'd just do the free testosterone, if I could get a price for it.  Now the problem is whether you can ‑‑ most labs try to give you both of them at the same time.  And the last thing ‑‑ well, no.  It wasn't clear to me when the non-fasting serum insulin was going to be drawn, and why?
		DR. MICHALEK:  Wasn't it done after the two hour?  It was done with the same blood that they used to get the two hour glucose.
		DR. HARRISON:  But it's going to be measured at the two hour time point.  Why?
		DR. MICHALEK:  That's history.  I don't know why; it was decided that way in 1982.  But that's the way it's been done since the beginning of the study.
		DR. HARRISON:  Okay.  In that context, I probably wouldn't ‑‑ 
		DR. MINER:  So make a recommendation. 
		DR. HARRISON:  Well, the problem with the single measurement of the serum insulin is that ‑‑ I'm not sure that's very helpful. 
		DR. MICHALEK:  Well, we're doing the glucose clamp on 30 matched pairs in Arkansas as we speak, Dr. Phil Kern.
		DR. HARRISON:  So that's probably a lot more informative than this.  
		I still wish that in terms of defining patients as being diabetic that you would either use the World Health Organization criteria or the American Diabetes Association criteria.  I don't think this 200 cut point is either.  I think that's your cut point.
		DR. MICHALEK:  Noted.  
		DR. HARRISON:  The rest of the world defines diabetes.  In fact, I don't even know, Joel, that ‑‑ you know, there's no such thing now as "a touch of diabetes."  There's no such thing as prediabetes.  Those definitions have been erased from all of the health organizations. Your two hour postprandial is greater than the cut point, and that's it.
		LTC BURNHAM:  160?
		DR. HARRISON:  No, it's 140, I think.
		DR. MICHALEK:  For a two hour postprandial?
		DR. HARRISON:  Yes.  And then in one of your paragraphs on variables, you trichotomize the postprandial glucose so you're actually looking at it ‑‑ you know, you're actually separating out people who are greater than 140.  And I'm not sure why you're doing that.
		DR. MICHALEK:  Okay.  Where is that?
		DR. HARRISON:  That's 8.1, the last three lines.  I'd like to keep that in and I'd like to see you rethink your cut point in the early part of the paragraph where you're seeing a two hour postprandial of at least 200 milligrams per deciliter.  
		DR. MICHALEK:  So you're saying we should just drop that 200 criteria altogether?
		DR. HARRISON:  I'm saying that I would either define it by the World Health Organization criteria or the American Diabetes Association criteria.  
		DR. STOTO:  If I understand this, what it does is it tells you whether they have greater than 140, and then it looks to see whether there are people who have, in addition to that, greater than 200.  Is that --
		DR. HARRISON:  I'm not sure that helps.  
		DR. STOTO:  The alternative is to look at it in a continuous measure, which ‑‑.  I guess if you're going to use a discrete you should use 140, and also use due to continuous.
		DR. HARRISON:  Let me think about this for a second.  The reason that you're doing the two hour postprandial is to pick up new patients with diabetes.  Those are patients whose blood glucoses are greater than 140.  If the blood glucose is greater than 200, it makes no more difference; they're all diabetic.
		So to use this word that I'm just learning, it's a dichotomous result.
		DR. STOTO:  I think that that makes sense, particularly if you're also going to look at it as a continuous variable, because you may pick up something there.  You don't have much to pick up --
		LTC BURNHAM:  Why would we want to look at it continuously?
		DR. HARRISON:  Yes, I'm not sure ‑‑.
		DR. STOTO:  I think that if you found a dose response relationship, that the people who had more dioxin exposure had higher levels of serum glucose.
		DR. HARRISON:  You know the problem with that, though?  If you fast for three days, not even fast, but if you diet for three days before you come out there to have your labs done, you're going to make your two hour postprandial worse. 
		DR. STOTO:  But the controls in the Ranch Hands will do the same thing.
		DR. HARRISON:  Maybe.  Maybe you're worried; maybe you do think you have a touch of sugar, and you don't want it to show, so you watch your diet for a few days.  That's a spurious argument.
		DR. STOTO:  I think it's worth looking at both, looking at the official definition --
		DR. HARRISON:  I don't mind it being looked at as a continuous variable.  I'm not really truly opposed to that.  The only thing I would like again looked at is using an organization's reference for the definition of diabetes rather than a made-up one.
		DR. STOTO:  I think as long as you're going to do the continuous, there's no gain to be looking at the trichotomous versus the dichotomous.
		DR. HARRISON:  Agreed.
		DR. MICHALEK:  Actually, this used to be called impaired; there's the word there.  In the old days, 140-200 was called impaired.  I guess that language is no longer --
		DR. HARRISON:  that language was even old then.  There's another place where it says "With the exception of the fasting and nonfasting insulin, cut points will be determined by the contractor's medical laboratory reference values."
		And again, that's ‑‑ as long as it's understood that you're verifying those values against the --
		DR. MICHALEK:  Against the percentiles of the comparison group.
		DR. HARRISON:  Comparison groups.
		LTC BURNHAM:  What's the difference between WHO and ADA?
		DR. HARRISON:  I think there is a difference, and I'm sorry to say, I didn't look it up before I came here.  There is some small difference between the two.
		LTC BURNHAM:  But the big thing is using 140 instead of 200.
		DR. HARRISON:  Yes.  200 is way out of line.
		DR. MICHALEK:  For your information, in 1998, we responded to a series of questions from the National Academy on this very subject, to reanalyze the study using ADA criteria.  We did that.  We found the same results that we found using the existing definition, and that's all summarized in a document that we sent to the NAS.
		DR. HARRISON:  I didn't think it was going to make a difference, I just find it embarrassing.
		DR. MICHALEK:  Well, this is history, this is legacy.
		DR. HARRISON:  And in fact, you know, I think it's really interesting that the IOM had to get you to do this. 
		DR. MICHALEK:  Well, very few studies have this long follow-up with extensive repeated physicals, and we're trying to track one report with another, and we don't like to change our definition along the way, our case definition.
		DR. HARRISON:  I agree.
		DR. MICHALEK:  If you do that, then you can't compare reports any more.  So you're always in this quandary. 
		LTC BURNHAM:  But this is particularly significant, because even though the percentages ‑‑ the ratio may stay the same, the level of diabetes that we see in our group could change.
		DR. HARRISON:  It should make a difference, yes.
		DR. STOTO:  So you're suggesting there may be --
		DR. MICHALEK:  You said it didn't.
		DR. STOTO:  ‑‑ it helps to keep the 200 level, and just for continuity purposes.
		DR. HARRISON:  It still meant there was a difference.
		DR. GOUGH:  Yes, but --
		DR. HARRISON:  But if you look at the total number, you know, instead of saying our incidence, we only have 400 diabetics, you're saying we've got 600 or whatever.
		DR. GRUBBS:  Dr. Harrison?
		DR. HARRISON:  Yes?
		DR. GRUBBS:  If somebody was diagnosed as diabetic in 1982 and somebody was diagnosed as diabetic today, or last year, would his physician have a different criteria such that when you're searching medical records --
		DR. HARRISON:  Probably.
		DR. GRUBBS:  ‑‑ back in '82 he's a diabetic ‑‑ or not a diabetic anymore?
		DR. HARRISON:  I mean even today searching medical records, you're going to find those kinds of differences.  I mean, what doctors put down in their medical records are frequently very guarded.  You don't want to screw up somebody's medical insurance until you really have to.  So even though you've got a two hour postprandial in there and you sit down and you tell Joe that he needs to lose some weight, you don't code in your records that this person has diabetes.
		There's going to be a lot of those inconsistencies.
So the question is, what is, to our best knowledge, what's the correct definition, it seems to me.
		DR. STOTO:  Well, I think that Joel introduces a different wrinkle; is that there is some value to continuity.  So if we ‑‑ maybe it could be done with, rather than trichotomized, just two different cut points.  Say just for historical purposes we've done 200 all along, let's show what that defines, and now we think we know how to do it better, let's look at 140, and even better yet, let's look at the continuous. 
		DR. HARRISON:  I've got one other thing to say, and then we can go back over this and see what we've agreed on.   And that is, I don't think that you have to exclude participants with orchiectomies from the analysis of total and free testosterone.  I think you have to exclude participants with bilateral orchiectomies.
		DR. MICHALEK:  What paragraph is that?
		DR. HARRISON:  8.3.  
		DR. MICHALEK:  Bilateral.
		DR. HARRISON:  Oh, maybe about eight lines down, participants with orchiectomies shall be excluded from analysis ‑‑.  I think the one gonad will do.  The --
		DR. STOTO:  Are there many people who have this?
		DR. MICHALEK:  A few.
		DR. HARRISON:  Yes.  You might have had a torsion, there are various things where you could have, could wind up lopsided.
		The other thing is, FSH and LH should be treated like testosterone in terms of, the last sentence says:  No exclusions will be made for the analysis of FSH and LH.  But if you do have someone with bilateral orchiectomies, then their LH/FSH may well be abnormal as well.  Even if they're on replacement testosterone.
		DR. GRUBBS:  Should covariates for these two be treated like testosterone also?
		DR. HARRISON:  Yes. 
		So let's go back over this now and see what we're going to recommend.  
		I think Kwame's suggestions for added labs are very reasonable, particularly since this is an area that has been thought to yield differences, we can pound away at it as much as we'd like.  
		I would like to add to the suggested test changes the free T4, and the only reason that ‑‑ but I would also say that if you felt that this was again a continuity issue, that I'd feel less argumentative about the free T4 than I am about the two hour postprandial cut point.
		DR. STOTO:  When you say add the free T4, do you mean drop the other two?  Thyroid?
		DR. HARRISON:  Yes; that's what I would do.  But again if the continuity is an issue, ‑‑ because the free T3 is going to be a separate test.
		DR. STOTO:  Have you found anything in the thyroid?
		DR. MICHALEK:  There are hints, yes.  Prior studies of the relation with dioxin.  It's being worked right now on paper.
		DR. HARRISON:  You know, you might even be better off with ‑‑ well, you don't have --Yes, but you can still do the comparisons, so you might be better off with the free T4.
		DR. MICHALEK:  Total and free or just the free?
		DR. HARRISON:  Well, the free is the biologically relevant measurement.
		DR. MICHALEK:  True.
		DR. STOTO:  So in other words, you're saying that we've been measuring these things because that was what was available in the past.  There's a hint of something maybe going on, let's focus in using a better measure.
		DR. HARRISON:  The other thing that's not said here is that you can combine the T3 uptake and the T4 in what some people call the T7 or T12, or whatever you use --
		DR. MICHALEK:  Thyroxin index.  Is that different?
		DR. HARRISON:  Yes.  You use it to construct --
		DR. MICHALEK:  A variable.
		DR. HARRISON:  ‑‑ to construct an index.  And if that's what you're using, then the free T4, the direct free T4 assay may actually give you even cleaner information.
		DR. MICHALEK:  Okay.
		DR. HARRISON:  So the recommendation is to add the free T4, with or without deletion of the T3 uptake in T4.  But if I had to choose, I would delete the two in favor of the free T4.
		Fasting urinary glucose, that can be deleted.  That can just go.
		And glycated hemoglobin can be deleted because it's a redundant test.
		So those are the recommendations?  
		And you're going to do the waist-hip ratio, you've agreed to that; you're going to do the hip measurement.  
		You know, the bioelectrical impedance would not be that hard to do.
		DR. MICHALEK:  How is that done?
		DR. HARRISON:  Well, there's real simple ways and then there's harder ways.  There are instruments.  I'm not real familiar.  The only one I've ever actually seen is the one that Brookstone sells that you hold in your two hands like that, and measures body fat.  
		The ones that are used, though, in studies are not much more complicated than that.
		[Telephone interruption; Dr. Camacho arriving.]  
		DR. HARRISON:  Joel, I don't recall if you have ever had any more direct measurement of body fat.  It's always been a calculated value, hasn't it?
		DR. MICHALEK:  Right.
		DR. GOUGH:  I thought you weighed, floated people.
		DR. MICHALEK:  We tried that once.  I remember having taken that test, in the water.
		DR. MINER:  That was offered for a few, but was not done much more.  We looked at it to see how difficult logistically it was to do, and it was too much trouble.
		DR. OGERSHOK:  It was too much trouble to do on a mass basis.  It was offered as part of an executive health test.
		DR. HARRISON:  Can we leave it at this; that's something that you can look into? 
		DR. OGERSHOK:  Yes.
		DR. HARRISON:  And I think you'll find that it's relatively facile to do.
		DR. STOTO:  What does that measure?
		DR. HARRISON:  It measures percent body fat.  
		DR. STOTO:  Okay.
		DR. HARRISON:  It has an algorithm that is based on the different conductance of muscle and fat.
		DR. STOTO:  So the issue is, is it that much better than BMI?
		DR. HARRISON:  Yes.
		LTC BURNHAM:  Didn't you say all the studies are using BMI now?  Joel?
		DR. MICHALEK:  Well, it's used a lot.  People are --
		DR. HARRISON:  Body mass index is used almost universally.  But the reason that it's used universally is that it's very easy to weigh someone and determine how tall they are.
		If you ask what's used to verify the body mass index, probably bioelectrical impedance is the next most accurate test that's widely used.  The gold standard would be the floating.  The other gold standard, which is only available in about three places, is a scintillation counter large enough to hold a person, that looks at potassium isotope ratios; and those are left over from the Second World War-type big lab.
		DR. MINER:  I was going to say, there were a couple chambers at Brooks for that.
		DR. STOTO:  The purpose of this BMI for fat content is just a covariate all the way through, right?
		DR. MICHALEK:  Well, it's an endpoint in general health, but it's also a covariate.
		DR. HARRISON:  I just thought of another reason, though, why you might want to look at this.  Because there are two instances where the body mass index fools you.  We'll have an example of one of those instances next Sunday, because we'll watch a herd of Neanderthal mesomorphs, whose body mass indexes will indicate that all of them or almost all of them are obese, but who will have less than 5 percent body fat.
		Very highly developed professional athletes.  That's one group.  The other group is the sarcopenic female.  That is the woman who maintains a normal weight by not eating very much but who doesn't exercise, who has very little physical activity, and actually has a higher percent body fat than expected because she's got no muscle.
		And because this is an aging group, you may wind up in the same situation with aging Ranch Hand population.  So actually, I think it makes sense to look at some other independent way of assessing whether the body mass index in this older group might require a little bit of change.  I apologize to any ladies about the sarcopenic comment, but it's just muscle. 
		I think you should look into it.
		DR. MINER:  On the urine microalbumin, does that have to be a 24 hour collection?  Could it be a 12 hour?
		DR. HARRISON:  It can either be ‑‑ the accurate collection is the 24-hour collection.  The screening collection is the spot urine, random urine.  
		LTC BURNHAM:  Now, we could sell it as a valuable test for them; because that's a very good test for diabetics to have, in that many of them probably never have had.
		DR. HARRISON:  May not have had.  In fact, the American Diabetes Association, I think, recommends that you have one every, I believe every six months.
		[Dr. Camacho arrives.]
		LTC BURNHAM:  Are we ready to break for lunch? 
		(Laughter) 
		DR. CAMACHO:  I got on the plane at 6:40 a.m.
		DR. HARRISON:  You've borne up under these --
		DR. CAMACHO:  I got up at 4 o'clock; I could have driven here.  
		DR. HARRISON:  Well, we're just finishing the discussion on the Endocrine chapter, or Endocrine section?
		DR. MICHALEK:  Does it make sense to give this 24-hour urine test to non-diabetics?
		DR. HARRISON:  No.
		DR. MICHALEK:  Doesn't.  Okay. 
		LTC FOX:  Do you need to refrigerate the 24-hour urine?
		DR. HARRISON:  I don't know.
		DR. MINER:  When we collected before for the ‑‑ there was a preservative that was in the jugs.  But I also remember for the diabetics at that time it took sometimes two, three or four jugs, to do the 24-hour collection.
		DR. HARRISON:  You mean they had poly urine?
		DR. MINER:  Yes, they did.  Then we went to a 12-hour collection, and they tolerated that much, much better than the 24-hour.  But there still was some logistical problem associated with all that activity.
		DR. HARRISON:  Maybe the way to think about this is, I was criticizing you earlier for having the term 'severity of diabetes' in.  But if there is a measure of severity of diabetes, it'll be things like the glycosylated hemoglobin, the urine microalbumin, changes in peripheral pulses, neurological changes.
		And now you can ‑‑ the spot urine will be easily, easily assessed as either normal or abnormal.  The 24-hour urine will be more quantitative, and might give you more continuous data.
		DR. STOTO:  I would ask whether you pick up, whether there's additional information in this 24 thing you wouldn't get with all the measures that you have here.
		DR. HARRISON:  It would be ‑‑ either spot or 24 hour?
		DR. STOTO:  No; 24 hour.
		DR. HARRISON:  No.  I think what --
		DR. STOTO:  Given that you have all these other measures, do you get any other information by doing the 24-hour?
		LTC BURNHAM:  Doesn't that ‑‑ kidney damage?
		DR. HARRISON:  Well, you don't have another test that shows whether the kidneys are damaged.
		DR. STOTO:  Okay so that's a ‑‑ 
		DR. HARRISON:  It correlates well with the vascular changes. and there are a lot of vascular changes that you might, evidence of vascular changes, including the neuropathy, which has a vascular component to it.
		DR. STOTO:  But there could conceivably--
		DR. HARRISON:  This would be the only kidney test.  And if you --
		DR. MICHALEK:  So we should consider doing this in the diabetics.  Got a recommendation?
		DR. MINER:  Yes.  Again, I go back to ‑‑ If we could get to the 90th percentile of goodness out of a test for the 12 hour collection.  The guys don't like to carry the jugs when they go out to eat; I mean there are some real ‑‑ 
		[Simultaneous discussion] 
		DR. HARRISON:  Yes.  You know, I don't know if there's a diurnal variation in protein excretion through the kidney.  I would almost favor either doing it on the spot, which people who are generally known, or doing it as a 24-hour.  But I think it would be very helpful to do.
		DR. STOTO:  Does the spot pick up the kidney damage? 
		DR. HARRISON:  Yes.  The spot is a yes/no kind of ‑‑.
		DR. STOTO:  Yes.
		DR. MICHALEK:  Are we already doing that in the renal section?
		DR. HARRISON:  No.
		DR. MICHALEK:  We're not?
		DR. HARRISON:  No.  
		DR. STOTO:  The one thing that's missing from the other measures is the kidney damage, and the spot gives you some indication of that.  I guess I would wonder if it's really worth it to get these guys to carry the thing around.
		DR. HARRISON:  Half a loaf ‑‑ yes.
		LTC BURNHAM:  My son is diabetic, and we just finished doing this a month or so ago.  And they told us that we were supposed to keep it in the refrigerator.
		DR. HARRISON:  Okay, that I didn't remember.
		LTC BURNHAM:  That's another problem, because I don't think there are refrigerators in all the rooms there. 
		VOICE:  No, there are not.
		DR. HARRISON:  Sounds like we're going more ‑‑.
		DR. MICHALEK:  What is the technical name for the spot urine test that we could add to the renal section.  What do I call it?
		DR. HARRISON:  It would still be microalbumin; spot microalbumin.
		DR. MINER:  What percentage would you expect to be abnormal then on the diabetics?
		DR. HARRISON:  I don't know what percentage.  But remember also, one of the things that we don't know is why this difference is present.  For many years there's been the argument that diabetic complications are not due to the glucose, but are due to associated metabolic defects that ‑‑ of which an elevated glucose is merely one.  Nowadays, the general consensus is that diabetic complications are, "that it's the sugar, stupid" you know, and nothing else.  
		But in this group, we're looking at an effect of dioxin, we have no idea why the dioxin, why this effect is correlated with dioxin, and hence we have no idea whether the complications associated with it are going to occur at the same rate, because they have the same basis, or whether there really is some different basis.
		DR. MINER:  I asked because if we could do the spot tests and then if that was positive, follow up with 24,  It might cut down on some of the ‑‑   Actually, that was the recommendation.
		DR. HARRISON:  Well, if that's practical to do, I think that's the best of both worlds, by far.
		DR. STOTO:  So most of the diabetics with have a negative spot test?
		DR. MINER:  Or a lot of them.
		DR. HARRISON:  A lot of them will have a negative ‑‑ a lot of them whose diabetes is of short duration, ten years or less let's just say as a guess, whose diabetes has been well-controlled, whose glucose levels have not been very elevated.
		DR. STOTO:  So of the 400 or so who might be diabetic, the 200 or 100 or so might have needed the 24-hour.
		DR. HARRISON:  Yes.  Even less.
		LTC FOX:  Didn't you also have to control for certain blood pressure lowering medications?
		DR. HARRISON:  Not that I'm aware of, but that may be.
		LTC FOX:  I've picked up from reading lately that some of the blood pressure medications are affecting that, albumin.
		DR. HARRISON:  What you've been reading is that ace inhibitors are protective.  And so a lot of ‑‑ 
		DR. STOTO:  But that would be something you would do in the analysis?
		LTC FOX:  Right, in the analysis, that you would have to take into consideration.
		DR. HARRISON:  Well, yes, I guess you would have to.  Would we know which?
		LTC BURNHAM:  We know everything.
		LTC FOX:  Joel was making a comment that he hasn't done much with the medication issue, and that is one area that I --
		DR. HARRISON:  You're right.  Yes.
		Ace inhibitors are protective, the dose response curve has shifted to the right for African-Americans, further complicating matters.
		DR. STOTO:  But none of this says you shouldn't collect the data?
		DR. HARRISON:  No, no.  Not at all.
		Okay, so what else do we have in the Endocrine chapter?
		Bilateral orchiectomies are the only ones that count.  LH and FSH gets treated like testosterone.
		DR. MICHALEK:  Then family history of diabetes should be in the list of covariates. 
		VOICE:  It is.
		DR. HARRISON:  It's there already; okay.  
		DR. FAVATA:  May I make one addition to renal?
		DR. HARRISON:  yes.
		DR. FAVATA:  Looking at the tests in the analysis of renal function, we're not looking at tubular function at all; we're looking at glomerularis, urinary protein should be large molecular weight proteins, and a lot of toxins affect the tubules.  We should have a urinary Beta‑2 microglobulin in there.
		DR. HARRISON:  Anything else?
		Okay, Immunology.
		DR. STOTO:  As far as I can tell no changes in immunology, proposed.
		DR. FAVATA:  I have a question on the covariates.  Why we changed it in GI, the current alcohol current alcohol use, this is 9.3.  We changed it in GI but didn't change it here, not to say that I want to give up this information --
		DR. MICHALEK:  The change in GI reflects the referee reports on a paper we submitted; and Immunology has recently published in the American Journal of Epidemiology following this plan, and I received no critique on our use of covariates in that journal.  So they left it alone.
		DR. STOTO:  That doesn't mean --
		DR. MICHALEK:  Yes, it doesn't mean it's right or wrong, I'm just telling you that's what happened.
		DR. STOTO:  Isn't there some value in consistency across the different ‑‑?
		DR. MICHALEK:  Seemed to be.
		DR. HARRISON:  So maybe we can make a general recommendation that you should strive for consistency.
		DR. MICHALEK:  This is consistent with Irene Check's advice.  
		DR. GRUBBS:  I do have one comment; batch to batch variation.  It's really not --
		DR. MICHALEK:  I'm sorry.  Drop batch-to-batch variation.  Batch-to-batch.
		DR. HARRISON:  Well, what you were saying is --
		DR. FAVATA:  I would like some consistency, but I would like the --
		DR. HARRISON:  You like the additional data that this gauged.  So I think what you do for a referee is one thing, but going back to the GI data, this has more information in it; so it would seem logical to retain this.  You could always go back and shift it to say "Yes, they were drinking" or "No, they weren't drinking."  But this gives you some more quantitative data.
		DR. MICHALEK:  What we're going to end up doing is fixing the gastro --
		DR. HARRISON:  Yes, exactly.
		DR. MICHALEK:  ‑‑ to imitate this.
		DR. HARRISON:  That's what I was ‑‑ isn't that what you understand?
		DR. FAVATA:  Uh-huh. 
		DR. HARRISON:  Anything else?
		[Mr. Weidman arrives]
		DR. HARRISON:  Pulmonary.  Kwame said that it was unclear whether DLCO will be done in the participants. 
		DR. MICHALEK:  What is that?
		DR. FAVATA:  It's diffusing capacity.
		DR. HARRISON:  So why is he ‑‑?
		DR. FAVATA:  I guess the issue is that we're not addressing the issue of interstitial disease, when we're not assessing it additionally with this test.
		DR. HARRISON:  So Kwame is saying that you don't have full evaluation of pulmonary function.  You have how hard they can blow, but you don't have how well oxygen and carbon dioxide move back and forth across the alveoli.
		Now, since Kwame is not here to defend himself, why does he think that that needs to be included?
		LTC FOX:  Is there a change in the PFT ‑‑ without seeing a significant change?
		DR. MICHALEK:  What was the question?
		DR. HARRISON:  Is there a significant change in the pulmonary function studies, have significant changes been seen in pulmonary function studies?  I would have guessed yes; I mean, these are servicemen.  They smoke more than the average, they should have more emphysema than the average.
		DR. MICHALEK:  The question is, is there a significant change over time in the groups.  Is that the question?
		LTC FOX:  Is there a difference in the dioxin group --
		DR. MICHALEK:  We have seen very little effect of exposure on any of these variables, in pulmonary.
		DR. FAVATA:  However, we haven't been checking that.  We haven't evaluated DLCO.   
		DR. STOTO:  Is that a whole new test, or is that another reading that can be done?
		DR. FAVATA:  It can be part of your pulmonary function studies.  But it is an additional test.  I don't think it would be that much ‑‑ 
		DR. MICHALEK:  Is it a blood measurement?
		DR. FAVATA:  No, no.  It should be part of your pulmonary function studies.
		DR. GOUGH:  There's nothing in the current set of tests that provides the same information?
		DR. FAVATA:  No, there isn't.
		DR. MICHALEK:  What's the full name of DLCO?
		DR. HARRISON:  Well --
		DR. FAVATA:  I don't know what the L is, but it's diffusing something or --
		DR. HARRISON:  I'll go out on a limb here and say that I don't think that needs to be done.  I mean certainly at this late date.
		DR. STOTO:  So if you saw a hint of some other aspects of pulmonary showing up, maybe you would.
		DR. FAVATA:  No chest X-ray, interstitial disease.
		DR. HARRISON:  I think I will leave Pulmonary as it is.  Do I hear any great howls of protest?
		Here's what I suggest that we do.  We're at pulmonary.  Well, we said that we ‑‑ I said yesterday that we'd stop at 11:30 for public comment.  We really have no other systems to cover.  There are some other verbiage here that I've got a couple of comments to make.
		DR. GOUGH:  We have to return to psych.
		DR. HARRISON:  We have to return to psych, but what I'm suggesting is, let's do the public comment, go to lunch, come back refreshed and have at it.  Is that agreeable to everyone? 
		VOICE:  So moved.
		DR. HARRISON:  So we've got Mr. Weidman, who is representing --
		Mr. WEIDMAN:  Vietnam Veterans of America. 
		DR. HARRISON:  We've got Mr. Weidman, who is representing ‑‑ 
		MR. WEIDMAN:  Vietnam Veterans of America, sir.
		DR. HARRISON:  Vietnam Veterans of America.  Thank you, sir.  The floor is yours.  We're running a little behind, but that's okay.
	OPEN PUBLIC SESSION
		MR. WEIDMAN:  Thank you very much.  I have that for the record, and I'll give one to the gentleman preparing a transcript, and any other drunk on the street who really wants one.
		First, let me say that I want to thank each of the individual members of committee, some of you who have been on this committee for a long time, for your service and your yeo-person efforts, as it were.
		I would be remiss if I didn't express some dissatisfaction, if you will, with the service given to this committee by FDA.  We will be approaching the new Secretary of HHS, Tommy Thompson, asking that support for this committee be moved from FDA to someplace that's actually going to support the committee.
		The reason you have me here today, as opposed to our first string, Dr. Linda Schwartz and George Claxton, is because we didn't get the notice except inadvertently on Friday, through a member of this committee.  And neither did the other VSOs, veteran service organizations.   This is a problem that has been recurrent, every time we've asked that it be fixed and thought that it was fixed, it wasn't fixed; the meeting a year ago in August, we found out about from General Accounting Office interviewers quite by happenstance.  It's just a constant recurrent problem.
		If you're going to have a public sunshine law meeting, then have a sunshine law meeting that is advertised in such a way that the people who really are the constituency which you are providing service to by all of your extraordinary efforts; not just by coming to these meetings but in between time, when I know all of you devote an enormous amount of time and energy and dedication to trying to make this the best possible study, and to provide the kind of input that excludes folks.
		And therefore, a lot of your good work becomes suspect of the Advisory Committee simply because the sunshine steps to make sure that the meetings take place in the sunshine were not taken, and therefore your public, if you will, your constituency ‑‑ which you really have two constituencies, one is the scientific community and you're upholding the integrity, from a scientific point of view; and the other is the men and women who were exposed to Agent Orange and other toxins in Vietnam.  And obviously your third constituency is the public at large, to make sure that the overall needs are properly met.
		So I would be remiss if I did not touch upon that, and I will apologize.  I talked briefly to Dr. Schwartz this morning, who had been out of town, and she sent her warmest to you, Chairman Harrison, and to all of you good folks, and asked specifically that all the members of the committee keep a sharp eye on the broken down former Marine masquerading as Dr. Paul R. Camacho ‑‑ 
		(Laughter) 
		‑‑ and make sure that he doesn't get into trouble over the next day and a half here, and that all of the folks from Yale, from University of Massachusetts and other academic institutions in New England would be grateful if you would try to keep Camacho from making too much of a scene.
		The second thing is --
		DR. STOTO:  Before you get off that one, I don't know whether you were here for the discussion of the Minutes yesterday.  I don't think you were.  Because the committee felt very similarly about the level of support that's available from HHS in the preparation of the minutes.  And we felt that there really needed to be a greater level of support so that better quality minutes were done, which is in everybody's best interest.
		MR. WEIDMAN:  Well, it's not only better quality minutes, it's making sure those minutes are publicized, if I may.
		DR. STOTO:  Sure.
		MR. WEIDMAN:  We had requested and got in zip form, which it turns out we didn't have the capability on our system to ‑‑ 
		DR. STOTO:  I just think it adds to the point that you made about need for better support.
		MR. WEIDMAN:  You folks have tried like the Dickens to do your job and not been supported, either with money to have enough meetings, right along; certainly not as many as members of this committee in the past would have wished; and secondly, the way in which the meetings are handled only give rise to suspicion where there doesn't necessarily need to be any, and calls your good efforts and your genuine service into not having the kind of salutary effect that the Congress envisioned when this advisory committee was indeed created to the Ranch Hand study.
		And I think that that's unfortunate and I don't know the schedule of the meetings for the next year, or actually it will be another five years here, but for those meetings in Washington and making sure that the Secretary of Health and Human Services exhibits the kind of commitment to this committee that has been so sorely lacking in the past, we will do our best.
		Governor Thompson has ‑‑ is not a veteran, but has a tremendous track record to veterans in his service as Governor of Wisconsin.  Wisconsin has far and away the best state services to veterans in the nation.  That's because he's taken a personal interest in it, and has provided both resources and wholesale political assiduous support for enhanced services to veterans.
		So we're quite confident that we'll be able to get in to see him, and that I think it's likely that he'll be able to respond or will respond, number one; and number two, we've already had discussions with folks on the Hill about re-enhancing the veterans function at HHS in general, and to Ranch Hands specifically.
		So I just wanted to let you all know that so you didn't think that somehow that was a slap at any of you who serve on this committee, because it's not.  It's, we're frustrated because we believe that the members of this committee who have donated their time have not been served well by the way in which HHS and FDA have served you, in terms of, you name it.  
		To have the meeting in Washington, D.C. but to have it here makes no sense if in fact you're really interested in having the public attend.  It's hard to get to and it's difficult to get in the building if you're not on the list ahead of time.  And I want to thank you, Ms. Jewell, for putting me on the list this morning.  It was, instead of 25 minutes getting in the building, it was about 3 minutes getting in the building, so I'm grateful for that.
		So it's not that people are ugly, it's just a question of organizational commitment to be able to showcase the extraordinary talent that is in this room in such a way that the veterans community has much more confidence in the overall study.
		DR. HARRISON:  Where should we have held the meeting?
		MR. WEIDMAN:  I would suggest someplace in town.  And in the future, if it's moved from FDA and it's moved downtown, someplace like the Hubert Humphrey Building would be appropriate and you'd have a lot more participation from people in the peanut gallery, if you will, sitting in.  You would also have reporters from Stars and Stripes and perhaps general press; but they're not going to come out to Rockville, bluntly, unless it's an earth-shattering announcement; and if there were, it wouldn't be released out here anyway.  So it's just not going to happen.
		So the only veterans publication that has covered this committee in the past has been VVA.  The other veterans service organizations find out about this from us, when we inadvertently find out when the darned meetings are.  So it just, it diminishes your extraordinary efforts as opposed to magnifying and showcasing your extraordinary efforts and the expertise that all of you have brought to the table to try and assist Joel to make this the best study possible.
		I don't want to dwell too long on that, but I think you understand where we're coming from; and I want to just move on to another topic.
		The second topic is, and this is ‑‑ we had a commitment, we thought, and of course Dr. Michalek testified under oath that the rest of the databases, all of the databases would be available by the end of the year.  That's not happened yet, as far as we know.
		DR. MICHALEK:  Everything's on the web site.
		DR. HARRISON:  Yes, we just didn't; we haven't told you yet, but ‑‑ 
		MR. WEIDMAN:  Well, once again, I talked to Linda this morning and she didn't know it.
		DR. HARRISON:  Let the record show that, as Chairman of the Advisory Committee, I didn't know that it was on the website either.  But that was just a few weeks ago.
		MR. WEIDMAN:  One of the things I might suggest might be in order, Dr. Harrison, is a motion by the committee to make sure that some kind of press release and notification happens of Congressman Shay's office, of Lane Evans, of others ‑‑ Senator Daschle, we certainly will give them an informal heads-up.  But that's not the same as you folks taking steps as a committee to report to one of the constituencies you serve.
		DR. STOTO:  I saw a draft of the press release.
		DR. MICHALEK:  We wrote a press release and released it, the last dataset was put on the web page on the 29th of December; and on that day we sent a press release to Washington.
		MR. WEIDMAN:  To?
		DR. MICHALEK:  To TES GI, the public affairs office at the Surgeon General on Bolling Air Force Base.
		MR. WEIDMAN:  And they did what with it?
		DR. MICHALEK:  Well, they have their own process.
		LTC BURNHAM:  Coordinating it.
		DR. MICHALEK:  Coordinating it.
		MR. WEIDMAN:  So it's aging like fine cheese.
		DR. MICHALEK:  So it hasn't come out yet, in other words.
		LTC BURNHAM:  The last I heard, just before we left, was Donna finalized it and put it out.  
		Now again, we have no control over ‑‑ we did a press release after the third --
		DR. GRUBBS:  About September.
		LTC BURNHAM:  After we released the first four; just to say we're on schedule, and absolutely no one, no news agency picked it up.
		DR. HARRISON:  You know, it seems to me it that there are two questions being asked here.  But they're kind of related.  Actually, one request that, or one suggestion that was made to the committee was that the committee request that several officers and several VA organizations again request that those organizations be notified well in advance of our meeting dates.
		That doesn't seem to be a real arduous task; maybe there's ‑‑ maybe there are administrative issues that have to deal with that.  And it seems to me that some members of the committee have questioned the location of the meeting here at 5600 Fisher's Lane, Parklawn Building.  And as I recall, we met once down at the Hubert Humphrey Building, and really had more attendance than ‑‑
		MS. JEWELL:  No, we didn't.
		DR. HARRISON:  Okay, maybe I'm mis-remembering.  But at any rate, let me just --
		MR. WEIDMAN:  But if you do both, if you have it at the Hubert Humphrey Building and you give adequate warning ahead of time so that folks can get the word out and people can arrange their schedules, you will have people.
		DR. HARRISON:  Of course one of the things we can do is the committee ‑‑ we're a bunch of scientists here, we can test this hypothesis.  We can ask that this arrangement be made.  If it's feasible to be made then it will, and then we'll see what the outcome is.  According to Ron and Barbara, we've been down there once without attendance, but perhaps without adequate forewarning.
		MS. JEWELL:  We've also been in a hotel in D.C.  If you remember.
		DR. STOTO:  I recall being in the peanut gallery at least once in the Humphrey Building.
		DR. HARRISON:  But my suggestion is, that that sounds like a reasonable suggestion.  Does the committee feel the same way?  Paul, you just spent a half hour trying to get into the building yourself.
		MR. WEIDMAN:  That's because he had a profile from the FBI at the front desk.
		DR. CAMACHO:  I thought the last time we met that they were ‑‑ I thought the last time the committee met, in San Antonio, it was sort of understood that we were going to send notices to the VSOs.
		DR. GOUGH:  I drafted a letter for Bob.
		MR. COENE:  I don't know how much the Chairman wants to put on the record here, and also for Rick.
		DR. HARRISON:  I mean, if it's something that I didn't do, then let's go ahead and put it on the record.
		MR. COENE:  No, no, no.   The fact, and in all due respect to the new Secretary, 18 months ago we recommended that this committee be elevated and put into the very office that you're talking about.  The individual, who's not here today for reasons that we don't understand, but she ‑‑ Col Caldwell is the new liaison, isn't here today.  She's going to be here this afternoon.  I pose maybe that some of this discussion be postponed, because she needs to hear this.  
		The fact of the matter is, she was notified.  She was given the list of the organizations to contact.  That didn't get done.  It didn't get done last fall because the office was vacated, and the Office of the Secretary chose not to give it any priority.  It is a problem that you, I guess, and I would have to recommend that you do have that audience with the new Secretary.
		DR. STOTO:  That's exactly the way to handle it. 
		MR. COENE:  Because at this point in time, it hasn't changed and we ‑‑ you know, we're frustrated ourselves.
		DR. HARRISON:  What you're saying is that your protocol requires that you forward this information to --
		MS. JEWELL:  Run it by them, and they do the VSOs, exactly.
		DR. HARRISON:  Okay.  And you're saying that has been forwarded.  You're assuring us that it's been forwarded and that it died in that office.
		MR. COENE:  And I'm concerned, Rick, that you're making this recommendation, and you, when you get all done, are going to have this ‑‑ what happened with the Air Force's press release on the dataset.  It gets up into that higher echelon down there, and their priorities and the things on their plate, it doesn't get done.
		And you're right, we've  pushed this wet noodle of support for the last ten years, and am fully aware of it.  I hope that you're right, that you're right, that you're going to see some more support from the current administration in that office.  But I know what's happened to that office, they've just shrunk it.  There's no staff.
		The fact that we had it in this building out here is so that Barbara and I and now Len had resources in the building.  When we move down into a hotel or into HHS, the resources to support this, the simple things like xeroxing, are not available.  So we made with the minimum resources, people resources, we stayed close to the physical resources that we knew and had at hand, and we balance that.  That is the bottom line.  And I wish you all luck in elevating this in the Secretary's office, because that's obviously what we've got.
		I give you a history over the last ten years, two times, three times I had to defend the existence of the committee, to do away with the committee completely.  And even the Secretary at one point had to override GSA, who ultimately compiles the total list of advisory committees.  
		It's not just in the Department; but this committee and the number of the committees that the federal government is to have is not support.  
		DR. HARRISON:  That historical perspective is I think always helpful to me, and I suspect it's helpful to you, too.
		MR. COENE:  You've really got a battle.  I'll be honest with you, I don't think the solution is to move it up there.  We thought CDC was the appropriate place, and I'll put that on the record, too; CDC was assigned their responsibility as their fair share of ‑‑ because it had been at NIH, it had been at FDA; CDC, one of the agencies of HHS, it was their turn to ‑‑ because it's uncompensated.  It's unfunded, okay?  It's unfunded.
		DR. HARRISON:  It's an orphan committee.
		MR. COENE:  And CDC said No.  It's unbelievable, the track record.  If you did a case study on just trying to make this work.  It's, I think ‑‑ I put that on the record only because a year from now or whenever, or now ‑‑ three months from now, where there's support.
		DR. MICHALEK:  I thought we had settled all this at the Shays hearing.  Remember?  You were grilled by Mr. Shays.
		MR. COENE:  Oh, I know.
		DR. MICHALEK:  Was there no outcome to that hearing?  Was there any sequelae --
		MR. COENE:  Well, no.
		MR. WEIDMAN:  In defense of Ron, we have --
		DR. MICHALEK:  Yes or no, was there any sequelae to the Shays hearing?
		Nothing, huh?
		MR. WEIDMAN:  Pete Mazella retired, and that was the sum total of the support out of the HHS building, was Pete himself.  And we have gone through eight years of an extraordinarily bright woman as Secretary of HHS who could not spell the V word, and was not interested in the V word.  And it may turn out that past performance and commitment will not count in future performance with the current Secretary, the new Secretary, but we think that unlikely.
		And it's amazing how reasonable people can be in those middle and upper echelons when their attention is focused by the boss.
		DR. STOTO:  And this is the exact time to ask, too.
		MR. WEIDMAN:  And if it's not done immediately, and even if it is done immediately, we have been working on legislation, because it's not just this committee that we need a veteran's office within HHS, it has to Rehabilitation Services Administration, with lots of other things that there needs to be a strong veterans office that provides an omnibus person and service function within the Health and Human Services and the various entities within that comprise Health and Human Services Department.  Which is the, I guess after VA it's the second largest.  Or excuse me, after DoD, in the federal government.  I mean, it's a huge agency, or a huge department made up of many, many agencies, many of whom not only don't talk to each other, don't want to talk to each other; and I think that's a fair summation, and I see from some knowing smiles around the room that that's a perception that squares with the perception of some veteran hands in the audience, because it takes the boss's commitment from the top and/or a mandate with oversight function to get people focused and keep them focused on the mission.
		The upshot of all of that is, and I want to stress, reiterate something that I believe I covered before ‑‑ it was not a shot at Len and it wasn't a shot at Barbara or Ron, what I had to say.  The problem is that the overall support of this committee has been lacking, and is not provided the kind of cotton-batting and spotlight functions that should be for a committee of this caliber.  In other words, the Secretary ought to be doing everything possible to make it A) easy for your work, facilitate your work, draw heavily on your expertise as much as possible within the limits of your time, and not within the limits of an artificially-imposed budget; and to do so in such a way that it spotlights your public service but magnifies the impact of every hour that you put into this effort.  And we will do our best, from Vietnam Veterans of America, and I'm quite confident we'll be joined by other veterans service organizations, the American Legion and others, in that effort to make sure that for the remainder of the time of this project that that in fact occurs one way or the other.
		And Joel, I should have asked you directly yesterday, and I apologize for presuming that because we hadn't heard anything about it that you hadn't been able to make that commitment, but I'm delighted to hear that you did and I shouldn't be surprised that you did; and we will do our darndest to get out our own press release since the Air Force doesn't seem to want to trumpet the fact that this data is available and do everything that we can, working with our good friends on the Hill to get the information out within the academic and research circles as well as within the veterans community that it's there, and start to go ahead and mine the data.  That will be a significant function.
		I'm sure that, once again had we had notice, that both Linda and George would have been here with many specific comments having to do with the Statement of Work.  And I would ask leave, Mr. Chairman, if they can submit something in writing to you.  I know you have to make a decision this weekend, but those may be ‑‑ we'll submit them to you and with a copy to Joel, that may prove to be helpful as you move forward, because as you write the Statement of Work and actually try and take all the notes from this meeting, there will be some editing process, I would assume, and the SOW will be sent out to committee members for final review.  
		And so would by our leave sir, would like to ask if we could come up with such comments.
		DR. HARRISON:  Any comments that you all have would be welcomed by me.  I don't know what Joel's deadline, editing deadline is, but I suspect that it's measured in weeks rather than months.  And that might be kept in mind.
		MR. WEIDMAN:  I also think that one of the things, just to share a bit more perspective, and this is not specifically having to do with the Statement of Work, and I know we're overtime so I'll try and make this brief.
		What has happened in the past is a combination of lack of support from the Department as a whole for this committee, and of various and sundry entities for the Ranch Hand study per se, coupled with a lack of other studies.
		Now, has put an inordinate burden on Joel and on the Ranch Hand researchers, and therefore by extension, upon this committee.  What I mean by that is this:  Too much is expected from the results of this committee without enough support to get where you need to get, even within the limitations of the sample size and the fact that this speaks only to Air Force personnel and not to ground pounders such as Camacho and myself.
		And that's a sticky wicket; we need those additional studies.  We're keenly aware that we need those additional studies, and we will be redoubling the efforts.  We did in fact get ‑‑ and we have been working closely with the State Department and with Senator Daschle and others, and Lane Evans, and Pete Peterson, our ambassador to Vietnam.  And the first negotiating session has in fact taken place between the Vietnamese and U.S. scientists, led by the National Institute for Environmental Health Sciences, and with CDC representatives, EPA representatives, et cetera.  It happened at the end of November in Southeast Asia to begin the process towards working towards a protocol to do research in Vietnam, with both U.S. scientists and Vietnamese scientists.  And that's an important step.
		But we need more domestic studies of U.S. veterans that cuts across sections, which will frankly relieve some of the pressure on y'all, number one.  But number two, the most significant thing ‑‑ one of the major and of the most significant things about the Ranch Hand study will be that database and the blue book as Joel calls it, both of the adjusted and the unadjusted data.  And as a veritable mother lode, if you will, of data that is much more extensive than exists anyplace else.
		And even though it is a small sample size, noplace else  has that kind of longitudinal data in this depth.  And therefore, it can be mixed and matched, if you will, with data from elsewhere to do comparison studies between Air Force personnel to match it up with Air Force personnel who served during the Vietnam era but who did not serve in Vietnam.  And therefore, at least do some kinds of further research and publishable studies based on this data that will be, has now been made available to folks and on the last protocol.
		So that on that protocol is any and everything that looks promising and that looks operational, whether it be ‑‑ I wouldn't take a stand because I just frankly am not nearly enough of an expert on it, on the pulmonary function or whatever it may be; is that when in doubt, we would urge you to include it as long as it does not throw a monkey wrench in to the overall progress in order to get it on the record, if you will.  Particularly in terms of replication of things.  And if there isn't money for things but you think that it needs to be done, we would encourage you to go ahead and put it into the Statement of Work and then let the green eyeshade people take it out instead of being intimidated to not put it into your statement as scientists about what needs to be included based on what the green eyeshade boys tell you.  If that makes any sense.
		And so I would encourage you to approach it from that public trust and that scientific trust basis and let the budgeteers and the new secretary of the Air Force say "Oh, no, we don't want to do it right."  So that would be the sum gist of my comments.
		DR. STOTO:  Did we make a decision yesterday about the dioxin measurements?
		DR. HARRISON:  Well, yes, we actually did.  But one of the comments that I would make is that, you said that a group from NIEHS and CDC met with Vietnamese officials about performing studies in this general area.  And I may be naive in this, but I think of the Air Force study and I think of the people who have performed the Air Force study, Joel and others, as having more expertise in this particular type of study than anyone else that I know of.
		On the other hand, we can't hardly get anybody from NIEHS to participate in the committee.  So I don't know why they're over in Vietnam getting ready to set up a new study, without at least using this group as their advisors.  And I've seen the same thing happen with the VA Chemical Corps study, set up not optimally at all, and often without regard to lessons that have been learned from this study.
		DR. STOTO:  I was going to ask, what has happened?  At one point we were advising that group as well, and I haven't heard.
		DR. HARRISON:  They only ‑‑ I don't know.
		MR. COENE:  He was invited to participate; he being the project officer, Dr. Kahn, but they had nothing to report.  They also were made aware that we thought we would possibly have another meeting of this committee and we'll talk about that more tomorrow.  Later on this spring, and that he might at that time be prepared to report the progress on their study.  But they --
		MS. JEWELL:  They were invited to San Antonio.
		MR. COENE:  Yes, they were invited to San Antonio, too; and they chose not to participate at that point.  They didn't have anything to bring before the committee.
		DR. HARRISON:  Well, that means that they're off doing their own thing.		
		MR. COENE:  I know what they're doing, but that's another matter.  That's a resource issue, too, and it's the Persian Gulf stuff that their limited epidemiological staff is focused on that.
		DR. HARRISON:  That's one other thing that I ‑‑ I don't know if I mentioned this, I think I mentioned it to Mike, but I'm not sure I mentioned it in general.  That is, it seems to me that while it may not be within our designated purview, then we might at least, not this morning but maybe this afternoon, discuss briefly how much better this study could have been done if there had been a prospective plan in place for assessing environmental hazards during wartime.
		If you had to do that, what would be the kind of information that you'd want to, you'd want the Armed Forces to have on its personnel in order to assess something that you may not be -- you know, depleted uranium.  I think it was Mike Gough that mentioned the uniformed services don't even know where the men were in Vietnam.  In many cases, they don't even know who was there.
		DR. GOUGH:  You're exaggerating the second part.  
		DR. HARRISON:  Okay, all right.  Don't know where they were, and that being a bit of information that would be terribly useful, for almost anything.  
		So in addition to analyzing the present problem ‑‑ which includes not just Vietnam but the Persian Gulf War and the European limited conflict --
		DR. GOUGH:  Peacekeeping.
		DR. HARRISON:  Which would be only limited if you and I aren't being shot at.
		MR. WEIDMAN:  Only limited if you're not under fire.
		DR. HARRISON:  Exactly.  But prospective consideration, prospective planning.   Now surely there must be someone doing this somewhere.
		MR. WEIDMAN:  A lot of thinking has gone on our part and with friends on the Hill.  And sometime during the 107th Congress we would anticipate that there will be two separate bills introduced.  One is to create a National Institute of Veterans Health as part of NIH, that would gather a lot of what has happened to veterans of every generation, and research and reporting on that, in an entity that is not fiscally liable for those actions.  And NIH would be the place; in other words, not DoD and not VA, because there are all kinds of pecuniary impacts on the study, and you need to free it from that in order to have an objective viewpoint based on the science.
		The other recommendation that we have made to numerous folks and have had discussions time and again has to do with creation of a National Institute of Military Medicine.  And the same thing for predeployment, to study what is going to likely be the impact of various weapons systems and other mechanisms on a large scale on our own people, as well as on the civilian population.
		DR. HARRISON:  Well, you've got a military medical school.
		MR. WEIDMAN:  UHUHS is not really set up to do it, and it would have to be separate from that, in our view.  We've talked with folks over there, we've talked with numerous physicians who are very familiar with that institutions, and it would be giving them a mission that they're really not set up to meet.  And therefore although they would be there in consultation and they could draw on the expertise, but a National Institute of Military Medicine that is housed at NIEHS could draw on many resources in the Greater Washington Area including Bethesda Naval, National Medical Center at Bethesda, and Walter Reed, and some of the top physicians from the Uniformed Services.
		But it really has to be independent of the services in order for people to have confidence in their findings, either for predeployment or for postdeployment, look-back if you will, and recommendations for the future based on what happened in Korea, to  the veterans who were exposed to radiation, to the Vietnam veterans who were exposed to the toxicological soup, or to Gulf War veterans and many things to which some of them somewhere or all of them may have been exposed, whether it be serin gas, heavy metals, from the oil well fires or depleted uranium or whatever the case may be.
		The problem with all of these things is many people had so many multiple exposures we're never going to tease out exactly what was the triggering agent that would elevate the rates of certain diseases.  We propose to ‑‑ the acting secretary ‑‑ well, then Secretary West entered a petition having to do with in-country effect, based on the fact that you're probably never going to be able to tease out what was that silver bullet that caused X, Y and Z elevation in terms of adverse health effects in veterans who served in Vietnam.
		I'll give you just a mundane example:  Central cereus retinopathies, which is ‑‑ I'm sure most of you know, the physicians anyway ‑‑ is a leaching of plasma through the back of the eyeball that causes bubbles under the retina.  It is the one eye disease that is connected and related to stress, to acute stress.  Well, you know, for some people who've done dioxin research, they believe that central cereus retinopathy is due to the exposure to Agent Orange, to 2,45T.
		Well, you're talking about the same folks.  How are you ever going to be able to tease out what was the silver bullet that did it?  And in the end, does it necessarily matter for some purposes anyway, having to do with access to health care and to compensation.
		What we were suggesting to Secretary West was, and will be coming back around the horn to the new secretary, Tony Principie, is that if you establish a baseline of people who served in a combat theater of operations, whether it be Bosnia or Vietnam theater of operations, or wherever the case may be, or Southwest Asia for the Gulf War vets, and you have an elevated level of whatever.  In other words, establish a baseline of health right across the board, comparing to the cohort group of the civilian population.  And anytime you have a blip you do the same thing that is done generally in the industrial medicine model; is you move to compensate and to treat insofar as you're able to at the same time that you have ongoing research to try and tease out better treatments based on what in fact might have been the causal agent.
		So those are the three steps that are not done for the men and women who serve in the military.  That happens very quickly in a Monsanto plant, I can assure you, and those of you who are familiar with and I see a smile in the back there from the designated responsible adult from SAIC, that this is in fact what happens at an industrial plant.  Because they know that if they don't move quickly like that, that they're going to have a liability that won't quit.  But we have a little thing called the Ferris doctrine where Paul and I can't sue the government for damage done to us during the military service.  On the theory that the benefits and health care system is set up and will meet all those needs; and therefore the Supreme Court has upheld that we cannot sue.
		So this young lieutenant colonel here, if something happens to him in military service, he can't turn around and sue the Air Force or the Secretary of Defense for the damage done to him in military service on the theory that the military will take care of its own through our extensive service of veterans health.
		Sometimes that's true and sometimes that ain't true.  So it's ‑‑ we believe that in the future that's the way to go, and end all of the slogan ‑‑ firing slogans at one another over entrenched positions over each separate element having to do with Agent Orange -- each disease whether it be diabetes, whether it be you name it, that we need to move to essentially look at things from a macro level right across the board and then move forward.
		That does not negate, in any manner, shape, or form that value of what you folks have been doing and will do over the next five years in the Ranch Hand study, nor any of the other particular studies having to do with Agent Orange or any other aspect of it.  What it does is put an overlay on that that moves forward to provide the assistance to the men and women who have been harmed by virtue of military service to country when they need it, not 15 years down the line but now, when they and their families need it.
		DR. HARRISON:  Okay.  Joel?
		DR. MICHALEK:  I only ask that you stick around, because I have some slides to show on the disposition of the study, and you should probably see those slides.
		MR. WEIDMAN:  Okay.  Will that be right after lunch?
		DR. HARRISON:  We can change that around if that will suit you better.
		When will Caldwell --
		MS. JEWELL:  There's a Gulf War conference or something with a conflict, and that's where she was yesterday and this morning.
		DR. HARRISON:  So we're not sure.
		MS. JEWELL:  She said after lunch, so I would guess 1 or 1:30.
		DR. HARRISON:  So that might bring all the parties together at the same time.  
		Why don't we break now.  Let's not rush lunch; let's be back here at 1:30. 
		Whereupon, at 12:24 p.m., the meeting recessed for lunch, to reconvene at 1:30 p.m., this same day. 

	A F T E R N O O N   S E S S I O N
	[1:35 p.m.]
		DR. HARRISON:  Paul, we still have psychology to do, because there are some questions about it that we thought you could help answer; and we've been trying to make a list of recommendations, so we have some things that we need to go back and ask you to agree to so that we have a quorum voted on that, in that order.  
		Once we've done those things, then we'll go through whatever else is remaining on the agenda.
		So Joel, go ahead.
	DISPOSITION OF THE AIR FORCE HEALTH STUDY
		DR. MICHALEK:  Briefly put, we are concerned about what to do with the study, from many different points of view.  The immediate concern, which we've expressed at previous meetings, are the disposition of 51,000 biological specimens collected from these men since 1982, and they reside in these freezers in our building at Brooks Air Force Base.
		These were all collected under informed consent, and include ‑‑ I have a chart here to show ‑‑ they include serum, urine, semen and a few specimens of body fat but not much, and there you see across the top, you see the years of collection.
		Last year, Dr. Harrison wrote a letter to Donna Shalala recommending that a peer review panel be set up at NIH to solicit proposals to address the Agent Orange question with these specimens, which was the intent of the protocol, and the informed consent we received from the study subjects.
		A subsequent letter was sent to Ken Olden at NIEHS, not very strongly, directing him to set up such a committee.  Ken Olden responded back to me saying that he's received such correspondence, but no funding, and that was the end of it.  And that correspondence and activity stopped sometime in June last year; never heard a word since.
		That's why we need Rick Weidman here, because he may be able to exert some influence on this process.  The point being that this material was collected under informed consent, number one; number two, it is irreplaceable.  Once you use it up, it's gone forever.  And there is the unique biological specimen database for Vietnam veterans that sits in those freezers.
		We also had, we're using those up as we speak, 313 Adipose tissue specimens which are being analyzed by Dr. Fumio Matsamura, University of California - Davis, and we recently shipped him 100 of those specimens; we're going to have a meeting with him I believe next month.
		DR. FAVATA:  Joel, what is he studying?
		DR. MICHALEK:  He's studying the diabetic intermediaries such as glucose transporters and biological parameters that I cannot recite, but he can.  If you'd like to hear that, I guess we could arrange maybe at a future meeting to have Dr. Matsamura summarize his work.
		I have a copy of his protocol, if you'd like to have it.  We can e‑mail that, or send that out to everyone.
		DR. CAMACHO:  Yes, run that to us.
		DR. MICHALEK:  Let's back up.
		MR. COENE:  Let's see that intro thing again.
		DR. MICHALEK:  Rick Weidman.  [Mr. Weidman returns]
		DR. HARRISON:  Rick, look on your seat over there.
		MR. WEIDMAN:  Thank you.
		DR. CAMACHO:  Rick, this is for you.
		DR. MICHALEK:  This is especially for you, Rick Weidman.
		MR. WEIDMAN:  Are you commenting on my disposition, Joel?
		(Laughter) 
		DR. MICHALEK:  I'm commenting you and the VVA and the whole world, really.  
		We, as executors of this study, are concerned about its disposition; in particular concerned about this study at large, but we're also concerned primarily, right now today, about these specimens that were collected under informed consent from the outset of the study in 1982.
		We have 51,000 biological specimens collected under informed consent from these men, beginning with the first physical in 1982, for the express purpose of answering the Agent Orange question.  They remain in our freezers as Brooks Air Force Base.
		Last year, Dr. Harrison ‑‑ and this was discussed at the committee ‑‑ decided that Dr. Harrison would write a letter to Donna Shalala, which he did, suggesting that NIH set up a peer review panel with appropriate funding authority to receive proposals from the scientific community in the United States or elsewhere to answer the Agent Orange question with these specimens.
		A correspondence was sent from Shalala's office to Ken Olden at NIEHS, suggesting ‑‑ and I can get you copies of these letters -- suggesting that this be done.  Soon thereafter, a letter from Ken Olden was sent to me saying that he had received such correspondence but no funding.  And that's where the processed stopped.  It stopped sometime around the middle of last year.
		I bring this up because we who have experience with administering and soliciting research know that even in the best of circumstances, I believe that if this were to start today you would not see results until maybe five years from now.  So five years from now will put us at the end of our study.  This is not optimal from the point of view of the use of these resources to delay this much further so that the results of these analyses, if they are ever done, would come in after we all leave.  There would be no one here to synthesize the results, if that happened, there would be no way to assemble it all together and ask whether these results have to do with what we found in our reports.
		So from the point of view of technical optimality and scientific efficiency, and there are so many other things, it would be a really good idea to launch this effort as soon as possible so that the results can be realized before the study ends.  Another reason is, that if you wait much longer and decide we're going to do this, but "We'll do it sometime in the future, say the year 2005," now you're talking about results that won't come in until roughly the year 2010, which may be too late for all the Vietnam veterans.
		You see, we're at a critical point here in terms of getting these specimens used in the way they were intended to be used.  Now it can be argued ‑‑ here's the rest of the summary.  We have 313 adipose tissue specimens that are being analyzed as we speak at the University of California-Davis, to study glucose transporters and other chemical intermediaries and dioxin as they relate to diabetes.
		At the time we did these slides, we had some specimens still outstanding at CDC; I'm not sure that's the case anymore.  Small number of adipose tissues.
		So that the rhetorical question is, should these specimens be used for their intended purpose before the study ends, simply put?  There's my guess:  Four to five years.  If you believe this should be done and it's going to start now, today, I believe that's what we're going to be, four to five years from now you will see results.
		Later may be too late for the veterans.  You put this off much longer, I think it's clear to all of us or many of us in the room, you're not going to see the results in time to help anyone who was in Vietnam.
		There are many hypotheses outstanding in the study; many questions to be answered.  
		DR. HARRISON:  I think there's another point that you might be missing there, too, Joel, just to interrupt.  And that is that the effects of dioxin are very species-dependent.  So you can't reliably test a hypothesis in a rat to prove a relationship in man, at least that's my impression.  Nor can you prospectively administer dioxin to human subjects in order to test a hypothesis.
		So the inadvertent presence of these samples are again difficult if not impossible to replace, because, for those two reasons.
		DR. MICHALEK:  That's right.  They are unique.  This is the only biological specimen bank on Vietnam veterans, let alone exposed Vietnam veterans, because for every one of those specimens we know the dioxin level.  And we know the dioxin level multiple times, for about 350 Ranch Handers, their specimens in the freezers.  This is an irreplaceable and unique dataset that's sitting in the freezers and the question that's begged here is, what should be done with these specimens?  And should they be used for their intended purpose before the study ends?
		LTC BURNHAM:  You could mention what happened to the West Point study.
		DR. MICHALEK:  Of course.  We have an example of another study that literally fell through the cracks and was just, specimens allowed to thaw in the freezer, and become spoiled simply because the funding was cut off.  It can happen.
		A scenario that we've seen happen in other studies is that the funding is ended on a given day, and at that point literally the staff walks out of the office, and it's over.  There isn't even enough money to keep the electricity going to keep the refrigerators and freezers going.
		You see what you've got here are 22 institutional freezers that must be kept at -70 degrees, there can be no power failure, there can be no mistake; and every one of those specimens is tied to a consent form and that's tied to a patient record. 
		In other words, there is a chain of custody here and there are logistical issues associated with simply maintaining the specimens without even using them for anything.  They have to be kept under lock and key, they have to be kept linked to the folders and the consent forms, and I believe they're all bar coded and labeled with case numbers so we can connect them.
		This is a major issue, in other words.  It's important  and needs to be addressed, needs to be discussed.  And in that connection, I received an e‑mail from Paul Camacho a few weeks ago that he attempted to talk to a staffer at the House Veterans Affairs committee.
		Do you want to make a remark about that?
		DR. CAMACHO:  Yes, Darryl.  I asked him about, I brought up to Darryl that we had these issues about, how are we going to dispose of the study?  He got excited, and he said "They're out there" he goes "Out there, there are very specific rules.  These were set out.  There's very specific things they absolutely by law have to do."  But he couldn't, he said "I can't tell you where that is right now."  But he was referring to some rules, regs, somewhere, something in the law about all federal studies and where the --
		DR. HARRISON:  All federal studies?
		DR. CAMACHO:  Well, that's what he was implying.  Federal studies where the disposition of this is supposed to go.
		I didn't know what he was talking about at all in that, but he was adamant that something --
		DR. STOTO:  Maybe it's this.
		MR. WEIDMAN:  Mary Ellen McCarthy will be here tomorrow morning, and I would urge you and encourage the committee --
		DR. HARRISON:  We may not be here tomorrow morning.
		DR. MICHALEK:  We might quit today.  But I'm going to be here tomorrow morning.
		MR. WEIDMAN:  You might want to call her, then, and let her know that.
		DR. GOUGH:  I have a couple questions.  First of all, I don't know what the limitations are on the use of these samples.  You have this word 'intended purpose' there.  It is an intended purpose to find somewhere?
		DR. MICHALEK:  They were collected to provide collateral information to the physical exam data that we're talking about today.
		DR. GOUGH:  Okay, so do we need a legal opinion about how broad that intended purpose definition can be expanded in case, say somebody applies to NIH, gets research funding to use these samples?
		DR. MICHALEK:  For what purpose?
		DR. GOUGH:  Well, that's just it. 
		DR. MICHALEK:  As soon as you entertain that idea that these samples could be used for any other purpose than Agent Orange, is that what you're saying?
		DR. GOUGH:  I can say Agent Orange and I can make Agent Orange a tiny little part of a bigger research project.
		DR. MICHALEK:  That's why there has to be a gatekeeper; there has to be a panel.  There has to be someone responsible.
		DR. HARRISON:  Wait a minute.
		DR. STOTO:  No, no.  I don't think we know the answer to this.  I don't know the answer to this; I think that Mike is right, that we need some consultation from people --
		DR. MICHALEK:  I have consulted with the IRB at our facility.
		DR. GOUGH:  I think it's a --
		DR. STOTO:  A broader question than that.
		DR. HARRISON:  Yes, but in point of fact, your facility's IRB does have the right of making that determination.  They're not going to be overruled by some other institution's IRB.  So to that extent I understand what you're saying, but I'd like for us to make sure we don't get too excited, because we do have time to solve this problem; and we can discuss it.
		DR. CAMACHO:  In terms of funding, was there something that's been lost way back when when they originally appropriated money and oh, authorized, when they originally authorized this study piece that indicated that the appropriated funding, the disposition was to be included in any game plan?  In other words, they would say to you "We've already paid for you guys to dispose of this study.  It's supposed to be locked in your budget."
		DR. MICHALEK:  Good point.  Someone might say that.
		DR. GOUGH:  There's never been a congressional authorization for the study, has there?  It's just been appropriations, because the Air Force --
		DR. OGERSHOK:  There's been public laws issued where the study would continue, there's been public laws --
		DR. GOUGH:  All right, because I remember there was an Air Force initiative.
		DR. HARRISON:  Let me ask a question as chair here, about what it is that we're trying to discuss right now.  As a member of a scientific advisory body, are we discussing the desirability of retaining these samples and someone organizing a mechanism for their further use, or are we trying to decipher what laws apply?  What is the purpose of this discussion?
		DR. CAMACHO:  I thought we were talking about the disposition of all these study materials, the samples.  In other words, how do we close this study?  It's like a computer program, I can close it properly or I can yank the plug and shut the machine down.
		DR. HARRISON:  Let me review something.  Joel mentioned that I wrote a letter, and I wrote a letter at the direction of the committee.  And the substance of the letter was that the committee felt that the Air Force had demonstrated a relationship between herbicide exposure and diabetes.  As I recall, I don't have the letter in front of me, but that's what I think we wrote.
		And we said, we felt that that information should be, that correlated information should be followed up by studies intended to understand what possible relationship there might be between herbicide exposure and diabetes.  And the samples that are a part of the Agent Orange study are an important resource for people who think about these kinds of problems.
		So we wanted that information made public and we wanted somehow there to be some collaboration between the Air Force and an appropriate ‑‑ the problem that the Air Force has is they have neither the money nor the review capability to determine if one idea is just crazy or of it's just innovative.
		So my point is that we've already said that we think that these samples are important.  We've already said that we think collaboration is needed with other appropriate agencies; that's a part of this committee's, if you will, judgment about what the disposition of the samples in the study should be.
		So what's the question?
		DR. MICHALEK:  I guess the purpose of these slides is to inform you that there has been no action based on your committee's decision, and to remind you that this is still an issue.
		DR. HARRISON:  Okay.  All right.
		LTC BURNHAM:  Let me read something real quick out of NAS update of '98.  It says: 
		Section 7 of the law, that public law, calls for the establishment of a system for the collection and storage of voluntarily contributed samples of blood and tissue of veterans who served in Vietnam.
		Balancing the strengths and weaknesses of stored biological samples and clinical data for research purposes, the committee feels that systems of the sort have scientific value, but only to the extent they are components of specific well-designed studies.  In the absence of a clear study design to guide such activities, and without resolution of important design, quality control and ethical issues regarding tissue banks, the committee does not recommend the establishment at this time of the clinical data and tissue archiving systems described in the law.
In other words, they want us to have an idea of what to do with these things.
		DR. STOTO:  That's a very important point, because the Ranch Hand is the one ‑‑ there's an exception mentioned there, that there needs to be a study plan, and in the Ranch Hand in fact, there is a study plan.  So --
		DR. GOUGH:  This was done the way it was --
		DR. HARRISON:  I'm treating this as a public discussion rather than a committee discussion.
		MR. WEIDMAN:  I guess I had a question for Joel.
		Did you actually talk with Dr. Olden?
		DR. MICHALEK:  No, I have not.  I simply received a letter from him.
		MR. WEIDMAN:  That said they didn't have any --
		DR. MICHALEK:  They said they didn't have money.
		DR. HARRISON:  I will say, though, that I know Ken personally, and I placed three calls to him within around the same period of time and didn't get an answer, didn't get a return phone call.
		MR. WEIDMAN:  Well, I'm seeing him tomorrow; that's why I'm asking him the question.
		DR. HARRISON:  You can tell him I said that.
		MR. WEIDMAN:  How much do you estimate it will cost or have you talked with Portier or any of those guys about how much it would cost, Joel?
		DR. MICHALEK:  Well, Dr. Harrison put an estimate in his letter.  I forgot the number.
		DR. HARRISON:  I don't remember either.
		DR. MICHALEK:  We're talking 40 funded proposals at a cost of what?
		DR. HARRISON:  A million, 1.2 each or something like that.
		DR. MICHALEK:  $40 million.
		DR. STOTO:  I think that we chose the wrong way to go last time when we did that.  And actually, I knew about this stuff that Joel handed out, the 102-4, but I had forgotten all about it.  And there really are three sections that are potentially relevant here.  7 and 8 I think is the most relevant, and 9.  But the 8 one says that the VA should have a whole series of studies going on, about the health effects on Vietnam veterans, and explicitly says they need to consult with the National Academy of Sciences about the conduct of those studies.  And the tissue samples could be one of them, and the IOM recommended against that, except for things like the Ranch Hand study.
		I think that we need to be talking to the VA about convening a group from the Institute of Medicine to think about the disposition of these studies.
		LTC BURNHAM:  Why don't you finish your slides, because this is part of the bigger --
		DR. MICHALEK:  Okay.  Well, of course the larger issue is what will happen to the study in the year 2006?  Are we talking about a scenario such as the West Point study where they literally pull the plug and material is destroyed and wasted and lost, or are we talking about something else?  Or what are we talking about?
		Certainly scientifically there are going to be many open questions remaining in the year 2006.  Every position, as we could understand it as you see from our notes, it could be debated.  One would be just to stop the study completely.  A skeptic would say "Well, we've spent enough public money on this.  Let's do something else with our tax dollars."  Another would be, "Well, there are many open questions remaining and there's a big resource here and it shouldn't be wasted, and we've just reached the point of technical optimality where we have scanned all of our records into a system that we can point and click and reach any document.  We can do great things with the existing database, and that should continue.
		So there are many pros and cons, and it can be argued both ways, and that debate should begin, in our estimation, should begin soon.  And should take place until the day comes in the year 2006 when we all leave.  
		There are many issues.  Funding, of course, what's the performing organization?  Who's going to do it if it is to be done beyond 2006?  Who's going to be responsible for the patient folders containing approximately 8 million documents on the children, on the wives, their sexual partners, other sexual partners and themselves.  Who's going to be responsible for the specimens?  What is the chain of custody and what are the rules regarding informed consent?  All that has to be worked out.
		Even if the study is not going to actually stop dead in its tracks in the year 2006, exactly what will be done with all this material?  Is it going to be burned, is it going to be handed back to the study subjects?  That all has to be worked out and discussed in a slow and thoughtful way over the next five years and not done hastily in the last few months.  Because in my experience, what can happen in the last few months is that the staff will start quitting; they're all looking for new jobs, and the place will contract.  We're already going to lose a lot of staff in the later years because our scanning will be finished.  And as soon as the funding stops, at that point we have no control whatsoever about what happens.
		So the point is to put a lot of thought into this and exert as much control as we have so that the outcome is something we can all live with in the year 2006.
		Did I miss anything?
		DR. HARRISON:  No, you didn't.  Go on.
		DR. STOTO:  I think one point that needs to be clear, somewhere in here, in these issues here, is that there's value in these data to understand more about Vietnam veterans.  What might have happened to Vietnam veterans.  There's value in these data for people interested in the effects of dioxin, separate from whatever happened to Vietnam veterans, and there's also value to people interested in the aging process, in white men, having nothing to do with dioxin or Vietnam veterans.
		DR. HARRISON:  But the problem is those samples were not collected --
		DR. STOTO:  Clearly you need to look at the issues involved with using it for other purposes.  I don't know that these problems are insurmountable; they may be, but I think that we need to have someone who really understands those issues look at them.
		The guy reaction of the guy who runs the IRB at Brooks will say "Oh, no."  But I think that the VA might see the value beyond that; and in fact the law gives them some authority here.
		I think that if people at NIH understood the value of this beyond the specifics of the Vietnam veterans, they may find it very interesting, too, and it's a way that the Ranch Hand veterans can contribute to society, take advantage of what's happened to them --
		DR. HARRISON:  Make another contribution.
		DR. STOTO:  Make another contribution, that's right.
		DR. HARRISON:  You know, the Food and Drug Administration is responsible for overseeing ethical clinical research in this country.  It has, if I understand it correctly, a major office in that area.
		DR. STOTO:  I think the key office is the Office of Protection from Research Risk, is what it's called.
		MR. COENE:  There are two titles.  There's Title 45 and there's Title 21.  FDA is Title 21 and covers clinical research.  Title 45 is everything else. 
		DR. HARRISON:  My point is there's an Food and Drug Administration resource that we should be able to tap into to--
		DR. STOTO:  I think that the other HHS resource is the one that's more appropriate for this.
		MR. COENE:  Yes, it is.  This is not clinical research, and FDA's is just ‑‑ it's HSRB activities, Human Subjects Review activities, is limited to those studies involved in clinical studies for new product approval.
		There's another part of the law, Section 45 of the code, that has to do with everything else that goes on with human subjects, and that's administered by the Department.  And that's the level that would play out here.
		DR. STOTO:  Yes.
		DR. HARRISON:  I would much rather see us approach it that way than to try and approach it through and interpretation of the law.  I would like us not to be in a position in justifying what could be considered unethical behavior by citing a law that says that we can do it.  
		DR. STOTO:  I think we need to look into it.  I don't know what can be done and what can't be done; but --
		DR. HARRISON:  I think that could be one of the functions of our FDA support; we're going to be talking sometime later about the next meeting, would be to request an opinion and request someone to appear personally and discuss with the committee and the Air Force just what the ethics of this are.
		DR. STOTO:  I think Section 8 of the law suggests or perhaps commands that we work with the VA on this.
		DR. HARRISON:  I don't care who we work with, as long as we work with someone who has --
		DR. STOTO:  Well, the thing about the VA --
		DR. HARRISON:  ‑‑ the appropriate --
		DR. STOTO:  They're more likely to put up the money to do the work.
		DR. HARRISON:  There are two issues, one is money and the other is ethics.  And I would like ‑‑ I want as much ethical coverage as we can get.  I'd like as much ethical discussion as we can get; and from whatever sources we can get it.  If we can get Billy Graham or his son to come and talk about it, I'd just as soon then.
		DR. STOTO:  But I think the VA is more likely to give us the resources to even bring the ethics people in.
		DR. HARRISON:  That's fine; that's something that Len and cohorts can work out.
		You had something you wanted to say?
		LTC BURNHAM:  I talked to the chairman of our IRB before we left about this, and he said that as long as we have done what we ‑‑ stuck with our protocol, you could actually ethically and with the IRB, you couldn't throw them away.  Of course that's not what we ‑‑ but that's an alternative.
		Another alternative is that another agency does the research, within our protocol about Agent Orange, and as long as Joel is a co-investigator, you don't really need a new consent form.  But if you look at any other research protocols or another agency does the research, then you need a new consent form.
		And then I asked him, "Well, should we get" --
		DR. HARRISON:  You've already told me this.  And --
		LTC BURNHAM:  What I'm leading up to the last point is--
		DR. HARRISON:  Okay, because we're supposed to be offering you advice, not your IRB person telling us what should be done.
		LTC BURNHAM:  Well, I thought they had impact on each other.  The last thing is, I asked him "Well, should we try to get a new consent form at this next exam?"  And he didn't know.
		DR. HARRISON:  Well, first of all, I would say that you cannot get consent on samples that have already been given.  I know that.
		DR. STOTO:  I don't know that that's true.
		DR. HARRISON:  Because an essential part of the consent process is the lack of coercion.  The fact that you already have the sample is coercive. 
		MR. WEIDMAN:  It's accurate; there have been court test cases on that.
		DR. STOTO:  But does that prohibit the new use of these things?  Can you get consent about new uses of these?
		DR. HARRISON:  Yes, it does.  The only way you can get out of this is for somebody to say that you can broaden the definition of ‑‑ I don't know.  That's why I'm saying that we need to ‑‑ 
		[Simultaneous discussion] 
		DR. HARRISON:  The issue of coercion is ‑‑ whew.
		DR. GOUGH:  These can't be passed on to anybody; then we just pull the plug.
		DR. CAMACHO:  But that in itself is unethical, as far as I'm concerned.  Let's bring in some legal counsel --
		DR. HARRISON:  Let's find out the answer is.  That's what I'm suggesting.  Or at least what the counsel is.
		DR. GOUGH:  That's a first step.  Before we know that, we can't do anything.  We can't recommend anything, we can't advise anything.  
		DR. STOTO:  I think it's not an easy thing to do.  I think it needs some very careful thought, get the right people involved, and ‑‑.
		DR. HARRISON:  Can I ask, if we agree that these are extremely valuable samples, we agree that these are unique samples, we agree that it would be a waste to do anything other than to use them in the most intelligent way possible.  But we also agree that there's an ethical consideration and a practical consideration.
		Can we ethically use it?  How can we ethically use the samples, and where can we find resources to use the samples with?
		DR. STOTO:  And we have to balance all these things.
		DR. HARRISON:  Yes.  And for all those, we don't have the answers in this room.
		LTC BURNHAM:  Maybe the VA could ask the NAS to answer both of these questions; the endgame and also what to do with the specimens now.
		DR. HARRISON:  I'm open to any suggestion.
		Let's do it this way:  Who wants to make, as a committee member, a straightforward suggestion of what should be done next?
		DR. STOTO:  I would suggest that we contact the VA, we as the committee, contact the VA and say that we're aware of their responsibility under Section 8 of the law, and that we know about something that we think that they should at least get their consideration, and that they consider consulting with the National Academy of Sciences as the law calls for, to discuss some of the practical and the ethical and the legal and the financial issues involved, as well as the scientific issues involved in doing this.
		DR. HARRISON:  Okay, does anyone else in the committee agree with ‑‑ like in a second for this approach?
		DR. CAMACHO:  I would agree with that.  We should be casting out our questions now, whether it's before the Veterans Affairs committee and all this, we should get some people ‑‑ by airing the argument instead of clutching it inside, airing the argument we'll find people that will support "No, this is unethical."  "Yes, it's ethical."  "This is what we should do."
		We'll get better parameters by going out and getting other input.
		DR. STOTO:  What I'm trying to avoid is the Secretary of HHS telling Ken Olden to do it, and then he says --
		DR. HARRISON:  And then Ken saying "I don't have the money"; yes.  Whenever somebody tells you to do something and they don't give you any money, they're not telling you to do anything.
		DR. STOTO:  Right.
		DR. HARRISON:  That's pretty obvious.
		DR. STOTO:  We can't blame Dr. Olden.
		DR. HARRISON:  No, not at all.
		DR. STOTO:  But the other thing about this is that, not only does the VA have the authority to do this, they've got the interest.
		DR. HARRISON:  But they don't have the money.
		DR. CAMACHO:  Money is a down the road trick.
		DR. HARRISON:  I understand.
		DR. STOTO:  I'm not saying they need the money to archive the samples.  They can have the money to convene a workshop under the auspices of the National Academy of Sciences.
		DR. HARRISON:  Can I get your agreement to one other ‑‑ I'm sorry.  Now we've got two people down here.
		Do you want to say something?
		MR. COENE:  I think at least your proposal is to approach the VA.
		DR. HARRISON:  Right.
		MR. COENE:  Your responsibility is to the Secretary.  You'd probably need to go to ‑‑ you'd recommend to the Secretary that she communicate with the VA.  That's the charter of this committee.
		VOICE:  The Secretary is 'he' now.
		MR. COENE:  Sorry.
		DR. STOTO:  We can work that channel.
		DR. HARRISON:  Well, if a letter is going to come from this committee, then we need to make sure that we know where we're sending it.  So protocol says it goes to the HHS Secretary.
		MR. WEIDMAN:  Joel, when you said $40 million, are you talking about $8 million for five years?
		DR. MICHALEK:  We were talking about a number of proposals to be carried out over a relatively short period.  We didn't put a time limit on it.
		DR. HARRISON:  If you did a Request for Proposal, if NIEHS published a Request for Proposals that said that there's 50 some million samples, a mixture of this, that and the other; the following clinical data is already available, request proposals to study the mechanism of action of the increased incidence of diabetes secondary to herbicide exposure.
		All of us in academic medicine would be trying to figure out how we could write a proposal to get funded under this, and it would have to be reviewed, so you'd have probably ‑‑ 50 different study sections would have one or more grant proposals from this; and out of those, we were presuming a certain number of grants to be funded, and we were figuring that a five year proposal runs total cost somewhere around $1.2 million.
		And those are all just ‑‑ very puffy figures.  Obviously very puffy figures.
		LTC BURNHAM:  I thought it was 20 grants.
		DR. HARRISON:  My point is, who cares?  You know, when you actually get down to doing the RFA, people who are much keener than us in terms of the appropriate cost are going to, having a much better idea of what the actual cost is going to be; but that's an order of magnitude.  It's not going to be $400 million, and it's not going to be $4 million.
		MR. WEIDMAN:  It's unfortunate that ‑‑ and I know you've touched on this before -- but it's unfortunate that this contacting the VA didn't happen after the San Antonio meeting, because the head of VA Research is here.  The VA, after what happened in West Los Angeles, has tightened up and has all sorts of safeguards, particularly with ‑‑ at this point when it comes to any research with human subjects, they're like Caesar's wife:  purer than pure and appearing to be purer than pure.  
		How long that will last is anybody's guess, but that's the way they are right now.  But the head of research is solid, and it would have been good to have him here at this meeting, and I don't know if it's possible to get him over for tomorrow morning or not.  But the real question is, is that chain of custody, is VA even potentially willing to do so?  I'm not sure that they would be, because of the inherent conflict of interest that the results of any study then come back from NAS to the Secretary of Veterans Administration.
		I don't know if I'm making any sense on that.
		DR. STOTO:  Well, they don't necessarily have to do the studies or pay for the studies in the long run.  What I think they ought to have an interest in doing is organizing an activity this year to think about this issue, and to sort of lay out the possibilities and evaluate the possibilities.  In fact, Section 8 says they've got the responsibility.
		MR. WEIDMAN:  Tony would be open to that kind of thing, I'm quite certain, and would work with Secretary Thompson.
		DR. HARRISON:  So what we are proposing to do is to submit a letter.  We'll do it the way we did it the last time, a draft goes out by e‑mail and people get to jabber over it, to point out that this is an impending problem of major proportions; that it's our understanding ‑‑ this is pointing out to the secretary, that it's our understanding that serious scientific and ethical considerations are present and need to be dealt with in the widest forum possible; that there appears to be a legal mechanism in place to provide that type of advice through the public law, whatever it is and section, whatever it is.  And that as a committee, we urgently propose that the Secretary act on this and request the VA to coordinate a sufficient number of meetings to determine what should be done.  That's a rough kind of idea.
		DR. STOTO:  I'd be happy to volunteer to help to talk about this with the National Academy of Sciences; and if it would be helpful, with the VA folks.
		DR. HARRISON:  I think that would be a good idea.  The other thing that I would like to ask if it's acceptable to the committee; as I recall, the last bit of correspondence was also copied to a number of interested parties.  This is a public thing.
		DR. FAVATA:  I think we need to raise the awareness of the scientific community of the availability of these specimens.  How do we do that?  It's kind of a backwards fashion.  I think that clearly we need the ethical, legal and scientific guidance and we need to have a time line to move this forward.  We don't really need to bring it to closure, but we need to move it along faster, and I think a time line is important. for us to achieve that.
		But I think making the scientific community aware of the presence of these specimens might stimulate a backward reaction; and an investigator could have an interest and then find funding instead of us finding the funding and then get --
		DR. HARRISON:  You know, I mentioned to Ron a month or so ago, I got asked ‑‑ I don't know why, but I got asked a little while back by the editor of Environmental Perspectives to write a review.  He asked me on what subject I wanted to write on, and I wonder if it wouldn't be interesting to sort of write a review saying, "This is an example of what can be done in a well-organized, well-thought-out study, that certain things have been found" and almost kind of a puff piece sort of thing, but --
		DR. STOTO:  And the data are available on the web and more might be available on these samples and so on.  
		DR. HARRISON:  I don't have to ask your permission to write something like that, but if anyone had a reason to think that it was not a good idea, I'd like to hear it.
		DR. CAMACHO:  We're writing to --
		DR. HARRISON:  We're talking about two things; letter to the Secretary of HHS --
		DR. CAMACHO:  Which brings this problem to the front --
		DR. HARRISON:  And suggests a possible --
		DR. CAMACHO:  Couple of alternatives.
		DR. HARRISON:  ‑‑ way of approaching it, through the VA.
		DR. CAMACHO:  Okay, and that's one thing.
		DR. FAVATA:  How do we seek guidance?  That's the other thing.
		DR. HARRISON:  No, that's all ‑‑ 
		DR. FAVATA:  That's it?
		DR. HARRISON:  Yes, so the VA and NAS will hopefully --
		DR. STOTO:  That letter has to be addressed to Secretary Thompson, for protocol reasons, but it probably should be copied to Secretary Principi, and that's the more important. 
		DR. GOUGH:  Can you do that?
		DR. HARRISON:  Yes.  Well, I can do that.
		DR. CAMACHO:   We do it and get yelled at later. 
		(Laughter) 
		DR. HARRISON:  Better to beg forgiveness than ask permission.
		But also, as I said, letters will be copied to some of the interested parties; some of the VA organizations.  And those letters will be --
		DR. STOTO:   And the cc's will be more important than the addressee, perhaps.
		DR. HARRISON:  Well, perhaps.
		LTC BURNHAM:  In this letter, we're also going to mention 2006.  Right?  Because that's connected.
		DR. CAMACHO:  That's our premise.
		DR. HARRISON:  In this letter we're not going to mention anything.  Because --
		LTC BURNHAM:  "You'are."  
		DR. HARRISON:  "We're" going to mention something.  You'd get in trouble if you started mentioning this stuff.
		LTC BURNHAM:  That's our whole point, is that we want a disinterested -- because the Air Force's position is, we don't want to do research.  Not in this room, but the big guys that drop bombs, they don't want to do research, they want out of this.  And so, and since our financial cycle is five years, we really need --
		VOICE:  To talk about it now.
		LTC BURNHAM:  What's going to happen in '06 is ‑‑ is CDC going to do this?  
		DR. HARRISON:  Actually, that will bring up another interesting question, and that has to do with the timing of our next meeting.  And I don't know how we're going to get to that.  But I think we're settled for right now.
		DR. MICHALEK:  Can I just flick through the last couple slides?
		DR. HARRISON:  If you insist. 
		[Slide]
		DR. MICHALEK:  This is Section 8 of the law; I urge you to read that.  The language is in there about VA, consulting with the National Academy about these kinds of issues.  And here we are ‑‑ we thought we'd be the next step just to get your opinion, and then I'm going to present an overview to the House Veterans Affairs Committee later this year, and perhaps by then we'll have something more to say.
		DR. HARRISON:  When is that scheduled?
		DR. MICHALEK:  It's not scheduled yet; the last time we made a presentation to them, they expressed the opinion that they'd like to hear an update from us every year.  So maybe a month or two from now we might arrange another presentation, giving them an overview; and this would be part of the presentation.
		DR. STOTO:  Knowing that that's coming up, it ought to get people's attention to this letter.
		DR. HARRISON:  Well, yes.  We were wondering if there was any advantage in us meeting just prior to that presentation.
		MR. WEIDMAN:  Joel, that meeting was a briefing for staff; it wasn't an open ‑‑.
		DR. MICHALEK:  That's right, it was just staff.  A House briefing and separately a Senate.
		DR. STOTO:  I would just say in the letter to the Secretary of HHS that Joel is required to ‑‑ Joel has been invited by the House committee to talk about next steps and so on.
		DR. GOUGH:  And he's asked us for advice.
		DR. STOTO:  Right.  
		DR. GOUGH:  We need theirs.
		DR. STOTO:  Yes.
-		DR. GOUGH:  This is just a timing thing, but when we get around to publicizing this, I think we should make a real effort to reach the professional clinical societies as well as the NIH, because I think we may miss people, just by going through the government.
		You know, put notices in the newsletters that the data are available, bla-blah-blah.
		DR. HARRISON:  Well, that's why I asked Joel yesterday how the web site had been managed and whether the website had been submitted to the search engines, because if you're in academic medicine like I am, you're sniffing around everywhere you find to see if you can find some money. 
		DR. GOUGH:  But the first key word should be money. 
		(Laughter) 
		DR. HARRISON:  You know, every now and then I put something like "diabetes" into Google, you know, to see what comes up.  There's got to be some way to raise the ‑‑.
		DR. MICHALEK:  I agree.
		DR. HARRISON:  Okay.  Anything else --
		MR. WEIDMAN:  One of the ways is, I don't know whether Joel can do it or not, but it is not unusual for the veterans organizations to have, in the veterans websites, to have hotlinks back and forth.
		DR. MICHALEK:  We have hot links to your website from ours.
		MR. WEIDMAN:  To our website, right.  Do you have them to them all?
		DR. MICHALEK:  The major ones; to VFW, yours, and ‑‑.
		DR. STOTO:  I think that's helpful, but it's really the non-veterans community that might have a lot more ideas about what to do about this.
		DR. HARRISON:  Do you know what would make a lot of sense, Joel, what I've suggested that we might also consider doing?  And that is, what would you think of the idea of sending a letter to the, the way the American Diabetes Association is organized, there is a nonprofessional head and there's a professional head.  It's kind of ‑‑ I'm never quite sure exactly how it works.
		What if we send a similar kind of toned letter, saying that these are important findings that have been made, the committee feels that they represent new information about the possible etiology of Type 2 diabetes, and we would like to invite an ADA representative to the next meeting of the Advisory Committee, as a spectator, and we would like your ideas about how this work might be brought forward.
		Did you ever read Eric Hoffer's The True Believer?  These are true believers.  And if you tell them that there's something new about diabetes, a whole horde is going to come sniffing down here.  And they've got research funds.  You actually might wind up, with the ADA, trying to develop a line of support for this.
		DR. FAVATA:  Not to diminish the importance of the finding of diabetes, but wouldn't we be guiding the future research that way, toward that path in and of itself?
		DR. HARRISON:  Yes, absolutely.
		DR. FAVATA:  But then in doing so, are we excluding some other important research?
		DR. HARRISON:  There are not that many true believers around.
		DR. GOUGH:  Well, FASEB must have a lot of true believers.
		DR. CAMACHO:  I don't think we're narrowing things, though.  We're searching for widest possible announcement power here, and advice here.
		DR. STOTO:  You know there are a couple things you can do here.  One is you can focus on the outcomes where there is some interest, like diabetes.  Or you can focus on the exposure to dioxin and their environmental health and occupational health, groups that have been interested in that.  
		DR. HARRISON:  Does one diminish the other?
		DR. STOTO:  No.  I think you can do both of those; and the third one, I would say, is epidemiologists who are interested in doing, analyzing long term studies.
		DR. HARRISON:  Your point about this being a long term study and the study of aging, I think those are excellent points.
		DR. STOTO:  Gerontologists make a fourth one.
		DR. HARRISON:  Those are excellent points.  
		There's no closure on that, though.  We've already decided what we're going to do.  The letter is going to HHS with copies to everybody ‑‑
		DR. STOTO:  I guess I would maybe not promote the other ones at this moment, because there's so much up in the air about what might be available.  Even what's available now is valuable, but we may only have, you know, may want to go out to these groups one time and maybe want to get a bit of sense --
		DR. HARRISON:  That's fine with me.  So for right now, our response to the question of disposition is a letter indicating that an urgent need to make decisions on this, and that's it.  That's our response.
		DR. GOUGH:  And our suggestions about the procedure, VA through --
		DR. HARRISON:  Yes, all that's already included.
		Okay?  Questions?  
		Anything else?
- 		DR. HARRISON:  Let's try and finish what we were supposed to be doing.
		Paul, at each cycle there have been findings that generated hypothesis that then either got strengthened as each new cycle came up or may have even fallen by the wayside, as it didn't hold up.  A suggestion was made that there should be essentially a chart, not in the blue book, necessarily, but in helping us work on this, that has all of the hypotheses from Cycle 1, 2, 3, forward, sort of like a timeline saying "this was a hypothesis, it's still active, it's not active, it was dropped after Cycle 4," and so on.
		Can we get you to just say that you agree that that's a good idea?
		DR. CAMACHO:  Sure.  It's a good idea.  Hey.
		DR. HARRISON:  Let's see.  
		Did you have any GI review comments to make?  It was acceptable.  
		DR. CAMACHO:  Yes, plus I told you, I'm better off in other areas.
		DR. HARRISON:  Okay, for the psychological question, we needed your comments, and I needed to tell you that questions were also raised ‑‑ I'll tell you in a second.
		DR. GOUGH:  I can't find it now.
		DR. HARRISON:  What are you looking for?
		DR. GOUGH:  Psychological.
		DR. HARRISON:  It's right after Neurological.
		DR. CAMACHO:  How about a number?
		DR. GRUBBS:  3644.
		DR. HARRISON:  And there's a specific question, Paul, and that is: short-term memory has been said to be one of the affected variables, and the question was raised, if there weren't better or additional tests of short-term memory, that ought to be considered for inclusion in this cycle.
		DR. GOUGH:  In addition to the Wexler.
		DR. CAMACHO:  That's the kind of thing you'd have to look up.  We need a decision now, right?
		DR. HARRISON:  No; in fact if you'd be more comfortable talking with a colleague or looking something up and giving Bill a call, that would be perfectly all right.
		DR. CAMACHO:  What's my timeline?
		DR. MICHALEK:  A month.
		DR. CAMACHO:  Fine.  So that's from 3644 to --
		DR. HARRISON:  Well, analysis of psychological data.  Do you have any other comments to make about that?  That was one of your review areas.  If you don't, then that's fine.
		DR. CAMACHO:  Let me get to you within the month.
		DR. HARRISON:  Joel, that drinks per day thing, is it a covariate in every section?
		DR. MICHALEK:  No. 
		DR. HARRISON:  I just saw it again in Psychological here.  What you've agreed is that you're going to normalize that back to the more detailed way of expressing the drinking, right?
		DR. MICHALEK:  I think we are interested in both current drinking --
		DR. HARRISON:  Right.  Drinks per day and drink-years.
		DR. MICHALEK:  ‑‑ and drink history, both.  In looking at this data.
		DR. HARRISON:  I'm just checking one more time.  Instead of just whether they had a drink yesterday --
		DR. MICHALEK:  Oh, you want the average in the last 12 days?
		DR. HARRISON:  Number of drinks per day during the two weeks prior to the physical exam.
		DR. MICHALEK:  Right.  I'll put that in.
		DR. STOTO:  It's there now.
		DR. HARRISON:  Mike, if you remember what happened was, that in the GI section he had changed it to just "current drinking, yes or no."
		DR. STOTO:  But in this section it's drinks per day.
		DR. HARRISON:  Yes, but we had discussed, and I'm just reiterating is that everywhere where drinking is analyzed, we want it analyzed at this more precise level; and then if he wants to simplify it for an editor or for a reviewer, that's a different thing. 
		DR. HARRISON:  Anything else, Paul, on your psychology?
		DR. FAVATA:  You wanted to ask Paul about the last issue on general and the adjustment for hostility.
		DR. HARRISON:  Oh, yes.  
		Speaking of hostility, Paul ‑‑ the discussion we got into is that ‑‑ they started off with separating the subjects into type A and type B personalities.  They did a psychological test that included jobs.  Most of these people, and how they reacted in their jobs, most of these people are now retired and they're getting irritated at being asked irrelevant questions.
		So they had changed it to, instead of type A and type B personalities to just an expression of whether or not the person was hostile.  
		DR. MICHALEK:  Or a quantitative measure of hostility.
		DR. FAVATA:  Was that for the reason of bearing out on the cardiovascular?  But why choose hostility?  Why not choose anxiety?  I'm not saying that either of them should be chosen.  Why adjust it for anything?  You have a measure of hostility on your psych testing.
		DR. MICHALEK:  It's possible, all we need to do is take a hostility scale off of the ‑‑ Is there a hostility scale on the SCL90?
		DR. GRUBBS:  Yes, there is.
		DR. FAVATA:  Yes, that's included in that.
		DR. MICHALEK:  Then maybe that's the answer.  The hostility idea was expressed at the last committee meeting.  I wrote it down.
		DR. FAVATA:  I remember that discussion, and I think that I was the one that was reviewing it, and I don't remember hostility being suggested, but what is the need for the assessment of one's perception of their health?  How is that important?
		DR. MICHALEK:  I'm not sure that's ‑‑ that's an item of discussion.  I can't justify the use of that covariate through any knowledge base of my own.  It would have to be someone like you or someone else to advocate that.  I'm no advocate for that.
		DR. HARRISON:  You really were using that in terms of selecting comparisons.  You wanted comparisons that matched in every way, and including ‑‑ I thought as part of the selection they had to feel as good as the Ranch Handers.
		DR. MICHALEK:  True, they had to have the same perception of health or approximately the same as the guy that refused to come, that's true.  But that's not the purpose of the hostility or personality type.
		DR. HARRISON:  No.  Everything is getting mixed together here.
		DR. STOTO:  General health is a dependent variable, is it not, under --
		DR. FAVATA:  Yes, it is.
		DR. STOTO:  ‑‑ under general health.  General health itself is one of the dependent variables there.
		DR. MICHALEK:  Wait a minute.  Hostility.  Hostility does not have to be included.  That's the first question.  Hostility is now going to be just taken if necessary from a scale on whatever that exam is.
		DR. FAVATA:  Right.
		DR. HARRISON:  Okay, that's taken care of.
		DR. FAVATA:  Done.  We don't need to adjust it for anything.
		DR. HARRISON:  So then there's the perception of health.  You're raising that as a separate issue now.
		DR. FAVATA:  Yes.
		DR. HARRISON:  Why do we need a perception of health?
		DR. MICHALEK:  Well, perception of health is an endpoint in the study.
		DR. HARRISON:  And maybe the best answer is that we've always had a perception of health, and it is not a big deal.  
		DR. STOTO:  And we also talked about the possibility of incorporating a more general ‑‑ something like the SF36, to get at self-assessed health.
		DR. HARRISON:  Right, but then we would be adding a new questionnaire at the last cycle.
		DR. STOTO:  Right.  I'm not saying we should do it; I think we should look into that possibility.
		DR. MICHALEK:  What I hear you saying is that the use of a hostility as a covariate in the analysis of general health, perception of health, is not necessary.  And I accept that, that's your opinion, and we'll just scratch it from the Statement of Work.
		DR. HARRISON:  Okay, so the only work that Paul is left with is the short term question of is there another ‑‑.
		DR. GRUBBS:  I have a question.
		DR. HARRISON:  The other reason this was being raised is because short-term memory is one of the things that's been found.  And yet there's only way of testing it within this psychological section, and this Mike was saying "Well, if that's something that's been found, shouldn't there be" ‑‑?
		DR. CAMACHO:  Other tests.
		DR. HARRISON:  Yes.
		DR. GOUGH:  If there is one.
		The other thing, Paul, is this paragraph here, which just seems to me to be ‑‑ I brought it up with Joel about, how do you think the mixture of their dependent or independent variables, their codependent variables and things; and Joel said this needs attention.
		DR. CAMACHO:  See where the problem is ‑‑ you've got page 32?
		DR. GOUGH:  Well, it's probably on your 33.
		Here it is.  You've got it.  It's back there.
		Could you look at that and could you consult with your friends and find out if this is a reasonable listing and ‑‑ it's such a conglomeration of stuff.
		DR. CAMACHO:  This one.
		DR. GOUGH:  Yes.
		DR. CAMACHO:  36?
		DR. MICHALEK:  36443.
		DR. GOUGH:  Maybe actually that's the way psychology is.
		DR. MICHALEK:  And actually 36442, excluding AIDS-positive patients from this analysis.
		DR. HARRISON:  Well, their perception of health is probably different. 
		DR. GOUGH:  If you could shed some light on that.
		DR. HARRISON:  Yes.
		DR. GRUBBS:  Dr. Harrison, a question on personality type.  It's used as a covariate in three chapters: General Health, Cardiovascular, Endocrine.  I think the main driver of personality type was this covariate adjustment factor for cardiovascular.
		We searched the covariate associations.  Anything that's significant shows more abnormalities in type B participants than type A participants, throughout.  Maybe it's a fault of how they're filling it out, or whatever.
		Should personality type or some surrogate, whether it's  hostility or impatience or whatever, should that even be used as a covariate for cardiovascular anymore?
		DR. STOTO:  It seems to me we have an opportunity to look at something new, which is the component of the SL- whatever it is.
		DR. GRUBBS:  Is hostility an appropriate covariate for cardiovascular?
		DR. STOTO:  I think it's a well-known ‑‑ psychological factors like that are well-known to be associated with cardiovascular outcomes.  Right?
		DR. HARRISON:  I guess the first point is that you can't use the old test.  That's really not us telling you ‑‑
		DR. GRUBBS:  Yes, it's impractical.
		DR. HARRISON:  ‑‑ you're telling us that guys are playing games with it now.  So it's out.  What you'd propose to do instead was to add another hostility assessment, but yet it turns out there's a hostility assessment within the exam that's being given.  So you don't really need to add, if hostility is what you're going to use, there are ‑‑ my understanding is that there weren't any other tests to separate into type As and type Bs, so now the only question that remains is, when you do the analysis, are you still going to use ‑‑ are you going to use the hostility section from this as a covariate?
		And what Mike is saying is that you haven't used it before, so actually you got a good chance to add something new to the study.
		DR. GRUBBS:  And it's an appropriate covariate.
		DR. MICHALEK:  It's appropriate for cardio.  Is it appropriate for endocrine?
		DR. GRUBBS:  It was done on thyroid.
		DR. MICHALEK:  Your face says no.
		DR. GRUBBS:  No.
		DR. MICHALEK:  Should not be.
		So drop it from endocrine, but kept it in cardio, and keep it in general health.
		DR. GRUBBS:  Good.
		DR. HARRISON:  Where are strokes?  Cardiovascular?
		DR. GRUBBS:  Yes.
		MR. WEIDMAN:  I guess I'm a little puzzled over here on a number of things.  One is that --
		DR. HARRISON:  After this, though, we need to try and stick with our --
		MR. WEIDMAN:  This has to do with, you already know that heart conditions are secondary to PTSD in chronic acute stress and are already rated as such by VA, and although it may or may not be strictly stress, it may be effects on the endocrine system that lead to that and the triggering of the chronic acute stresses of firing over and over again of the adrenal gland, which may be related back to the thyroid and the parathyroid gland.
		How would you tease out all of that in the tests that you do for the covariables, I guess is my question.
		DR. HARRISON:  Well, there are some things I don't think you can tease out.  I think that the psychological tests themselves are probably better at identifying men who are stressed than any of the hormonal levels that we're going to find.  If that's the question that you're asking.
		MR. WEIDMAN:  I guess, I mean there are many reasons why people would be hostile, as an example.  And hostility at this point, I mean some people are just hostile towards the Air Force, you know, who have served in --
		DR. STOTO:  Hostility is not the dependent variable here.  Hostility is the adjustment variable.  If it so happens that the controls are more hostile than the ‑‑ if the Ranch Hands are more hostile than the controls, that may be responsible for a higher level of cardiovascular problems in the Ranch Hand group.  And you want to make sure that if you find a bigger difference, it's not attributable to --
		MR. WEIDMAN:  Oh, I see.  So it's just comparison between those two.
		DR. STOTO:  It's to help even out the groups.
		DR. HARRISON:  You know, the problem with this type of a study is that there is no hypothesis to start with.  If you knew at the beginning that, if your hypothesis was that exposure to dioxin causes more myocardial infarctions, then you can focus on that and you can do whatever you want.  But when the study began, you didn't know what you were going to find.
		In fact, I spent the first few years on this committee being beaten to death over something called a checkmark pattern that essentially meant that if you analyze enough people ‑‑ well, this is how I would interpret it ‑‑ if you analyze enough people with enough tests, you wind up with differences.  You know, not because there are differences but because things happen.  That's one of the realities of life.
		MR. WEIDMAN:  Mr. Chairman, thank you.  We'll submit written things, and I appreciate all of your efforts.
		DR. HARRISON:  It's been a pleasure having you.  You're not going to stick around and see the last part of this sausage turned out?
		MR. WEIDMAN:  I'm going to go get ready for my meeting with Dr. Olden on Thursday and with Tony Principi in Thursday.  So thank you for arming me further.
		DR. HARRISON:  If you can remember, please tell him hello for me.
		MR. WEIDMAN:  I will, indeed.
		DR. CAMACHO:  Did you say you informed somebody about this meeting and they were coming here tomorrow?
		MR. WEIDMAN:  I didn't inform her, but Mary Ellen McCarthy was planning to come here tomorrow.  If you're not going to meet tomorrow, I'd urge you to call her.
		DR. HARRISON:  Well, --
		MS. JEWELL:  Bob, we have no choice.  It's a Federal Register notice and our meeting goes through noon tomorrow, and we have to meet tomorrow.
		DR. HARRISON:  Okay.  That's no big deal.  I'll be here tomorrow.
		DR. MICHALEK:  I'll be here, too.
		DR. HARRISON:  Not a problem.
		MR. WEIDMAN:  Thank you.
		DR. HARRISON:  Take care.
		MR. WEIDMAN:  Is it possible, that in addition to those letters that have already been sent to Dr. Olden and others, and to Secretary Shalala that the prospective letter could be routed in our direction?
		DR. HARRISON:  That's what I was saying.
		MR. WEIDMAN:  We'd be grateful, sir.  Thank you.
		Take care now.
		[Mr. Weidman leaves the meeting.]
		DR. HARRISON:  Okay, where are we here now?
		DR. CAMACHO:  Are you ready for Mike?
		A couple of questions.  I got this today, when I walked in the door.  I had some pre-s, but then we had some CD trouble, when I e-mailed her.
		The Psychological Battery is 3.2.2, and it goes on a bit about what they're going to do.  And then it's way down in 364 you're asking me to look at.  I just want to make sure I'm not off on a wild goose chase here.  3 2 2 is related to this 3 6 4; it's got to be.  Right?  I mean, you're not doing these things out of the blue. 
		DR. GRUBBS:  3 2 2 talks about the conduct of the exams; 3 6 4 is in the Statistical Analysis section.
		DR. CAMACHO:  So this is the plan to collect the data; this is the plan to analyze that data.
		DR. MICHALEK:  That's right.
		DR. CAMACHO:  Okay.  And you're asking me to comment on this so I have to look at this as well.
		DR. MICHALEK:  Yes.  Whatever you decide will influence what goes in this 3 2 2 paragraph.
		DR. CAMACHO:  Okay.
		DR. MICHALEK:  You might decide to administer another questionnaire, so we would say so here.  
		DR. CAMACHO:  All right.   Because, pardon me, but I just came on the committee and I got ‑‑ the whole history of this is a non ‑‑ I don't have any history on it.
		DR. MICHALEK:  Right.
		[Discussion about hotels.]
		DR. HARRISON:  Paul do you get anything else?
		DR. CAMACHO:  I know.  I'm going to look at 3 2 2 for the deaths, the methodology of collecting the data and comment on 3 6 4 4 about the analysis techniques of the data, and you're back to him within four to six weeks.
		DR. HARRISON:  Okay so we're not going to discuss that any more now.  
		So now we have a discussion ‑‑ and we're not going to have the discussion of dioxin and debates, we're going to have a discussion of report writing?
		DR. MICHALEK:  Yes.
		DR. HARRISON:  What we have left is discussion of report writing, and agenda, and future meeting dates.
		DR. STOTO:  We didn't do section 3.7 yet.
		LTC BURNHAM:  7, and addendum A.  Those are two.
		DR. HARRISON:  Oh, I'm sorry.  Well, wait a minute.
		DR. STOTO:  I have a very insightful comment on 3 7.
		DR. HARRISON:  You're right, I am sorry.  Here we go.
		Somebody start off.
		DR. STOTO:  On page 45 of the new version of this, section 3.7.3, they talk about the summary tables.  And remember, at some previous meeting some of us had some good ideas about how they should be presented in clinically meaningful terms.  Like saying, you know, that there's a so-and-so increase in hemoglobin a1C and so on, not just whether they're statistically significant.  And it was decided at that time that it was too late to do that.  Well, now it's time, I think, that we should work that into this paragraph here that says a summary table should be presented in terms of clinically meaningful effect sizes.
		DR. MICHALEK:  So the idea would be to annotate the findings that are biologically plausible, or clinically meaningful?
		DR. STOTO:  No.  Whichever ones that would have made the summary table before in terms of statistical significance, that you report not only the p-value but also whatever --
		DR. MICHALEK:  Direction.
		DR. STOTO:  No.
		DR. MINER:  And clinical relevance.
		DR. STOTO:  You know, it depends on what variable it is.  If it's a continuous variable, you report the difference in the mean of the outcome.
		DR. HARRISON:  Mike, you're talking about 7.3, right?
		DR. STOTO:  Yes.
		DR. HARRISON:  Can you read it the way you think it should be written?
		DR. MICHALEK:  It says right there, 3 7 3, p-values together with corresponding group means and percent of normal.
		DR. GRUBBS:  Dr. Stoto, I think possibly your sense said that the relative risk was 1.5, and it was significant.  You'd want to see the 1.5 rather than p=0.001.
		DR. STOTO:  That's right, that's part of it.  Or if it's a continuous variable --
		DR. GRUBBS:  You'd like to see the effect, the difference--
		DR. STOTO:  Right. You know, these guys differ ‑‑
		DR. GRUBBS:  Increase of 3 grams.
		DR. STOTO:  10 millimeters of mercury, or something like that.
		These are values that are given in ‑‑ whatever values are given earlier in analysis, they just need to be carried over to the summary table.
		DR. HARRISON:  The reason I'm asking because I -- this is the kind of stuff that I get very confused about.  And you know exactly what it is that you would like, what you're trying to say, and it helps me to have you presented in complete sentences, you know.
		DR. STOTO:  I would say that the second sentence there --
		DR. HARRISON:  Main effect p-values.  Let me take that sentence, let me give you a replacement for that sentence.
		DR. HARRISON:  All right.
-		DR. STOTO:  I would say the results should be presented in terms of clinically-meaningful effect sizes, and p-values.
		DR. GOUGH:  What does "clinically-meaning" ‑‑?
		DR. STOTO:  Well, I was going to say, you could add "such as relative risks or difference in group means or regression slopes or something like that.
		DR. HARRISON:  So what you're saying is, you not only want them to say that the difference between Ranch Hand and comparison was significant, p=.005, but you want to say relative risk for this particular finding was 1.5. 
		DR. STOTO:  If it's a dichotomous value, the clinical and meaningful thing was a relative risk.  If it's a continuous variable, then it would be the group means.  If it's a kind of regression analysis, it would be a slope; it would say "How much more does this go up when you increase the X by so-and-so?"
		But whatever you used and was reported in the earlier tables --
		DR. HARRISON:  You want it in the summary table.
		DR. STOTO:  I want in the summary table.  Now new analyses.
		DR. GRUBBS:  Or the significant ones.
		DR. STOTO:  Right.  So the effects that go into the summary table are the same; just a little bit more information about those effects.
		DR. HARRISON:  So a little more detail in the summary.
		DR. STOTO:  I wouldn't say detail, I would say more information.  Because you're not talking about more ‑‑ I'm not saying put the interactions in the summary or anything like that; it's just a little more information.
		DR. HARRISON:  Mike?
		DR. GOUGH:  I had some related question.  I would like to see, for all the things, point out the significance between the Ranch Hands, the difference between the Ranch Hands and controls.
		DR. HARRISON:  In the summary table, now?
		DR. GOUGH:   In the summary table.  Then whether or not the measured effect is outside the normal range of values, is it of any clinical significance in the judgment of somebody, and what are the levels that a physician will have to see before he would refer the patient to a specialist, prescribe medication or suggest alterations in diet or life‑style.
		I would like to see this put on some sort of clinical indicator basis.  That's a lot of work.
		DR. STOTO:  I think needs to be discussed, but it's a complicated issue.
		Like for instance, if you did a very large study that showed that you can lower blood pressure by 2 millimeters of mercury, 2 millimeters of mercury doesn't make a difference to any given individual.
		DR. GOUGH:  But clinically it makes a difference to the person.
		DR. STOTO:  No, it doesn't.
		DR. GOUGH:  Your prescription will say ‑‑ 
		DR. HARRISON:  Not 2.  He's saying --
		DR. STOTO:  2 millimeters is within the measurement area.
		DR. HARRISON:  He's deliberately choosing something that's --
		DR. GOUGH:  All right.  You mean there are error measurements in this stuff?
		DR. STOTO:  But if everybody in the population lowered their blood pressure by 2 millimeters of mercury, they would have a noticeable effect on cardiovascular mortality.
		DR. HARRISON:  If the truth be known, you probably would need several million subjects in each group in order to show that.
		DR. STOTO:  Right.  But this is a point; that there's a difference between what's meaningful for an individual and what's meaningful in terms of a population.
		DR. HARRISON:  One of the questions that Mike asked resonates with me, and that is that you can see differences between groups when both groups are normal.  And that's a point that I think gets forgotten sometimes.  
		DR. STOTO:  I think that that kind of ‑‑ my suggestion would give you the information you need to think about that, but wouldn't be in a position of dismissing things that might be important on a population basis.
		DR. GOUGH:  I don't care about population.  I think this is --
		DR. HARRISON:  You weren't saying to exclude anything; you were saying you wanted it extended.  You were saying that he's extended --
		DR. GOUGH:  I wanted it to be related to what it means to an individual.
		DR. STOTO:  I don't think that's the right perspective for analyzing an epidemiological study.
		DR. HARRISON:  Yeah.  I --
		DR. GOUGH:  I do.
		DR. HARRISON:  Okay, well --
		DR. STOTO:  That information is in the report as it has been done in the past.
		DR. GOUGH:  It's very, very hard to find that information.
		DR. HARRISON:  So there's two levels that you're talking about here.  One level, it seems to me, points out that there are population differences that are seen that all occur within what we think of as a normal range.  And you can argue there whether there's any physiological relevance there.
		But then you're asking, "Well, even if I show a population difference, is it sufficiently different that a physician would worry about it?"
		DR. GOUGH:  No, there it was not the population difference, but say ‑‑ yes.  
		DR. HARRISON:  Because you know ‑‑ if we take the diabetics, those patients who have a two hour postprandial greater than 140, their physicians don't worry about that.  
		DR. GOUGH:  Yes.
		DR. STOTO:  So this is not an issue for the dichotomous variables; it's an issue for the continuous variables.  
		DR. HARRISON:  That's true.
		DR. STOTO:  And I think that if we said "Oh, well, we find a difference of so-and-so in a1C hemoglobin" but for an individual that would be meaningless, that would tend to dismiss the whole thing when that was inappropriate.
		DR. MICHALEK:  What you really want to know is were the results of the dichotomized continuous variables, what was the percent abnormal?  So you have a percent, the number of abnormally high glucoses, for example.  That has real clinical meaning.
		DR. HARRISON:  Right.  You don't need to know how high, just that they are high.
		DR. MICHALEK:  And that's already in the report.
		DR. HARRISON:  Let me ask you this, Mike:  Why should this study, with 2000 and some men in it, covering 20 years of experience, try and determine whether a value is significant ‑‑ try to determine in its report whether a value has significance for an individual.  They're already reporting this stuff back to the primary care physician.  So if they find anything, the airman is being taken care of.
		DR. GOUGH:  Yes.
		DR. HARRISON:  What do you see reporting it in that way would serve?
		DR. GOUGH:  What I see is ‑‑ if this study ever gets a lot of public attention again, there'll be newspaper reports saying they were elevated levels of so-and-so.  And I would like for it to be right there, whether or not those elevated levels might have clinical significance or whether or not they're within the range of  normal values.  That's all.  And I think that's important for the individual, too.
		DR. STOTO:  The range of normal values is something that applies to individuals, not to population studies.  
		DR. GOUGH:  Excuse me?
		DR. STOTO:  The range of normal values is something that applies to individuals, not to population studies.
		DR. GOUGH:  It's what's tolerated as acceptable among the population, isn't it?
		DR. STOTO:  No.  The range of normal values for blood pressure is 30-40 millimeters of mercury, something like that.  Okay?  If you found a 2 millimeter difference that you can show was statistical significant, on average, that would make a big difference to the population.  And to say it all, 2 millimeters is within the 40 millimeter range.
		DR. GOUGH:  In this report it says normal blood pressures are 90 over 140 or below.  If you find a lot of blood pressure variation, whether it's high in one group or another, but it's all ‑‑ it's occurring, where the average in these two groups is below 90 over 140, I don't think that's a significant result in that group.
		DR. STOTO:  Well, it is.  It could be statistically significant, and that's what's in the report.
		DR. GOUGH:  What does it mean?
		DR. STOTO:  It means that dioxin is associated with this health outcome.
		DR. HARRISON:  If one group's average diastolic pressure is 85, and the other group's average diastolic pressure is 89, on a population basis that will show increased strokes, increased myocardial infarction, increased incidence of renal failure.
		On the other hand, if you go into the clinic and they use one of those automated blood pressure cuffs on you, you can get about a 4 millimeter mercury difference in an individual measurement.  If you're in a parking lot and you walk up a ramp or two before you go into the doctor's office, you can get a 4 millimeter difference in mercury measurement.
		If what you're after is to present these data or have a presentation of these data that would serve the purpose for the popular press, if this were to get out, that's not something that has to be included in the blue book.  The popular press isn't going to look at the blue book anyway, with all due respect.
		DR. GOUGH:  No.
		DR. STOTO:  And I think that if you do what they've already been doing plus what we suggested just a moment ago, the information will be there for someone to make a judgment about that.
		DR. HARRISON:  I would like to see him include, or I'd at least like to see the notation made of whether the variations are still within the normal range.
		DR. MICHALEK:  That's not appropriate, and I think Mike has already expressed that opinion.
		DR. STOTO:  Normal range has to do with individuals.  It would be inappropriate to talk about population averages in those terms.
		DR. MINER:  We've gone round and round --
		DR. HARRISON:  Actually, you know something, I'm ‑‑ my sleep deprivation is starting to get to me.  Really.  I'm sorry, I didn't mean that, I take it back.
		DR. MICHALEK:  A summary that might be of use would be to summarize how many of those letters we give to our study subjects.  After they leave the clinic, we send them a letter saying "These measurements were abnormal.  Go see your doctor right away."  We send them these letters to spell out all their abnormalities and give them advice about seeing their family doctor.
		DR. GOUGH:  That would be very useful --
		DR. MICHALEK:  Now, those letters, we can summarize in the document; tell how many we sent and for what reasons.
		DR. STOTO:  And how many of the controls, too.
		DR. MICHALEK:  Same thing; Ranch Hand and control.  Would that help?
		DR. GOUGH:  Yes.
		DR. MINER:  The piece we're missing, I think, though, is ‑‑ that we've gone round and round about, is a subclinical effect.
		DR. MICHALEK:  Exactly.  We see things statistically that we've never seen in an individual.
		DR. GOUGH:  Well, I've just been told that there's no such thing as subclinical effect.
		DR. HARRISON:  No, no.  On a population basis ‑‑ that's why I'm sitting here embarrassed.  On a population basis, of course.
		DR. CAMACHO:  But why did you say here's this whole pool of Ranch Hand people, they're units of analysis, each one of them; and we can't make an inference to the group as a population?
		DR. STOTO:  No, I didn't mean to say that.
		DR. CAMACHO:  All right.  See, that's where ‑‑ and you said you went round and round.  That made my head go round and round.
		DR. HARRISON:  We're talking about sub --
		DR. MINER:  No, it was how to display a difference in the means on a continuous measurement when both were, let's say, within the normal range.  Should we just blow that off and say "Well, that's within the normal range, it doesn't mean anything"?  Or are we missing an important piece that might be a subclinical effect?
		DR. HARRISON:  Actually, though, within which normal range, though?  Are you talking about within the lab's normal range, or are you talking about within the normal range that you can define for the comparison group?
		DR. STOTO:  I think that --
		DR. HARRISON:  Because if you're showing a statistical difference, that's saying then that that's not within the normal range.
		DR. MICHALEK:  Let's put it this way, if the Ranch Hand mean were outside the normal range, you would have at least 60 to 70 percent of the Ranch Handers abnormal.  In other words, it is not appropriate to argue that these data are useless or not informative, because the means are within a normal range yet.
		DR. GOUGH:  I'm not saying they're useless.
		DR. STOTO:  I think that the subclinical confuses it, because when there's a small difference in the mean, that means that there's an increased proportion of the people who have the condition, however defined.  And that proportion is important, because ‑‑ maybe it's 3 people, maybe it's 30 people, have this condition, more than you would expect.
		DR. HARRISON:  But let's --
		DR. STOTO:  That's not meaningless to those people; it's--
		DR. GOUGH:  No.
		DR. CAMACHO:  So what you're saying is the control group has a curve that looks like this, and ours, while it's still in the mean, is shifted more by so many points.  
		DR. STOTO:  Mike, can I draw something on the board here?
		DR. CAMACHO:  Fine, because if that's the case then I would say that you're right.  If Group B is within the normal range but they're at the very high end of it, ‑‑ is at the high end of this normal range, and Group A means yes.
		DR. MICHALEK:  That's right.
		DR. STOTO:  This is Ranch Hand and the other one is controls.  So if you say the difference of the averages is pretty small, and that's well within the normal range, the difference of the averages.  But if you make a cutoff over here, there's many more people in the Ranch Hand than the control.
		It's the kind of variable that you measure with a continuous measure; you know, the statistics have to do with this, but there may not be a natural cutoff, but whatever cutoff you choose out here in the tail there's more people with the condition than --
		DR. HARRISON:  Now Mike, if you were to draw another standard curve that was wider --
		DR. CAMACHO:  You mean broader?
		DR. HARRISON:  [Going to easel]  Let's suppose that because of the way life works, this is the normal.  That's what comes with the kit to the lab and so on, okay?  Because this is what I think some of us are talking about.
		So in this case, both of these are within the normal ‑‑ normal for the United States population, but if you define normal by the comparison group, then there's no confusion; they're abnormal in both cases.  In other words --
		DR. GOUGH:  You mean both ‑‑?
		DR. HARRISON:  In other words, this is abnormal because normal range has been redefined by the range of the comparison group.  If we accept the contractor's laboratory normal range, we may think that we're talking about stuff that's just fluctuating --
		DR. STOTO:  But that has to do with a discrete analysis.
		DR. HARRISON:  No, this is a continuous analysis, right?
		DR. STOTO:  But you would only use normal range from either source when you have a discrete analysis.  Where you first say, "Does this person have an abnormal value?"  And then say "Is there a greater proportion of people with abnormal values in the Ranch Hand as compared to the control?"
		DR. HARRISON:  If you take the serum calcium, serum calcium in most labs runs from like 8-1/2 to 10-1/2 whatever, milliequivalents per deciliter.
		DR. STOTO:  Okay.
		DR. HARRISON:  If you were to analyze the comparison group, let's just say for example it would turn out that the normal range for the comparison group was from 9 to 10.2.
		DR. STOTO:  Well, see, there's two ways to analyze a laboratory value like that.  One is, you say "What proportion of the people have high levels?"  And high could be define different ways depending on what you decide is the normal population.
		And then --
		DR. HARRISON:  No, what you do is you measure all these calciums, you plot them on here, and what falls between whatever it is, 97.5 is normal, and what falls outside of that is abnormal.  That's the way most laboratory values are defined.
		DR. STOTO:  But the way that it's going to be done here, if I understand it, is you figure out what's high, what number is high, and there's a number of ways we discuss of doing it.  But then you say, "Are more people high in the Ranch Hands than in the controls?"  
		DR. HARRISON:  I didn't think that was how we said we were going to do it.  I thought --
		DR. STOTO:  And that corresponds to this, and you might be saying "Well, maybe this should be set over there rather than here," but in any case, that's a discrete analysis, and then you just report the proportion for --
		DR. HARRISON:  See, the thing that's worrying me is that when a laboratory gives you a normal range, they've got the entire population that they're talking about.  We're talking about a subset of the normal population, because none of these guys are younger than what --
		LTC BURNHAM:  Average is 60.
		DR. HARRISON:  So you can't use the SGOT, the SGPT, you can't use any of those values just out of hand from the --
		DR. STOTO:  I understand that, and we deal with that--
		DR. MICHALEK:  We already talked about that.
		DR. STOTO:  We already talked about that, but that's dealt with in terms of defining what the cutoff value should be.
		DR. HARRISON:  Those are defined by the comparison group.  		DR. STOTO:  We talked about doing it both ways, and I'm happy with either one.
		DR. HARRISON:  Okay.
		DR. HARRISON:  But they both result in, either people are above it or below it.  They result in a discrete outcome.
		DR. GOUGH:  And then you tell me that none of these numbers have any significance, right?
		DR. STOTO:  No, I never said that.  
		DR. GOUGH:  Well, what I was saying is that there may be a number whereby above it a physician would pay attention, below it a physician wouldn't.
		DR. STOTO:  Right.
		DR. GOUGH:  You draw just such a thing on a curve.
		DR. HARRISON:  Let me actually make a suggestion here, that's actually not mine, but I won't reveal the source because he might be stoned.
		This is one of the areas that elicited some of the more heated comments, has elicited some of the more heated comments in past meetings.  Am I not correct?
		DR. GOUGH:  Oh, yes, that's correct.
		DR. HARRISON:  And yet there really is very little change in it.  And the committee has suggested stuff before.  I mean, you're listening to it all over again here. 
		I think we need a rewrite.  I think instead of us trying to go word by word through say the summary tables here, I think what we should say is, "We think you need to rewrite this and send it back to us."
		DR. STOTO:  Well, the issue about what to use for the cutoffs is dealt with someplace else other than paragraph 3.7.3.
		DR. HARRISON:  I'm not disagreeing with that; you say it's in there, and ‑‑ okay.  But this ‑‑ still, how this gets presented is something that has ‑‑ in fact, didn't Landrigen have concerns about it as well and ‑‑?
		DR. MICHALEK:  Let me try to --
		DR. HARRISON:  What I'm suggesting is --
		DR. MICHALEK:  ‑‑ you would like a rewrite.  We'll do a rewrite and I'll e-mail it to all.
		DR. HARRISON:  Make it a little more explicit, too.
		DR. MICHALEK:  There's a fundamental conflict here that we've touched on many times.  The conflict goes like this:  We as statisticians and epidemiologists are trying to test the hypothesis that two means are the same.  Fundamentally that's the hypothesis we want to test.  
		Or else, we want to test the hypothesis that two proportions of disease are the same in two groups.  And we do that by testing the hypothesis that the relative risk is one.  Okay, that's what we do.  That's all we do in this 3,000 page report, is we test hypotheses.  We are not in the business of deciding whether a particular individual is sick and whether he should go see his doctor.  That's a different line of thought, and that's all handled through correspondence with our study subjects.
		There's a fundamental conflict there between testing hypotheses and drawing inference about parameters and populations, and making decisions about individuals.  They're two fundamentally different ideas, okay?  
		DR. HARRISON:  I don't think there's any disagreement about that.
		DR. MICHALEK:  They're not saying that either one should be done; they're both done in the study.  The report is summarizing statistical summaries of these analyses of association.
		DR. HARRISON:  I'm getting back to the suggestion that Mike kicked off --
		DR. MICHALEK:  Which is?
		DR. HARRISON:  ‑‑ about changes in the --
		DR. MICHALEK:  Effects side.  Show me the change.  I agree.
		LTC BURNHAM:  Is that the only way you want it to be rewritten?   We need some guidance.
		DR. HARRISON:  You guys have had guidelines.
		DR. MICHALEK:  I understand what Mike is saying; I made a note of the change, and I'm going to change it in the text.
		And you will see that in the revision, which will come in a few weeks.
		DR. HARRISON:  Yes, Paul?
		DR. CAMACHO:  3 1, the statement of opinion.  I take it those are end notes?  Or they're just collected up there.
		DR. GOUGH:  3.7.
		DR. CAMACHO:  Yes, 3.7.3.1, Statements of Opinion.
		DR. MICHALEK:  Statements of Opinion --
		DR. CAMACHO:  I'm writing along, I know your syntax and the language and everything, and I'm writing along and whether I use a certain adjective or adverb has all this ‑‑ so at the end of that sentence you're saying we're going to get bang, an endnote number, if he's implying an opinion or he's leading to an opinion; and then that's what you're saying here, right?  Is that what you're saying?  And then at the end of each chapter.
		I mean, are they going to just sit out there?  They're going to be refer to special sections, end.
		DR. MICHALEK:  A discussion section, that's where the opinion will go.  We will make no value judgments about the findings until we get to discussion, then we exercise value judgments, all in one place, separate from the data.
		DR. STOTO:  But it will be part of the text but clearly labeled.
		DR. MICHALEK:  Yes.  It will be labeled Opinion or Discussion.
		DR. CAMACHO:  And you're telling the story all over again from the opinion side.
		DR. MICHALEK:  Right.  Just like in an article.
		DR. CAMACHO:  It's not an endnote.
		DR. MICHALEK:  It's written as in an article.
		DR. CAMACHO:  Okay.
		DR. MICHALEK:  Introduction, Methods, Results, Discussion.
		DR. HARRISON:  And just to back up one more, the clinical discussion, you've already mentioned it once; but you're saying explicitly now the contractor is going to provide 12 experts.  That should be interesting. 
		[Simultaneous discussion] 
		LTC BURNHAM:  And a medical editor.
		DR. MICHALEK:  And a medical editor smoothing out the writing.
		DR. HARRISON:  Well, rather than ‑‑ it almost stands to reason that you're going to have a pulmonologist write the pulmonary chapter; but the point we were making was that it shouldn't just be someone who is just a pulmonologist, it should be someone with demonstrated expertise.  That would mean to me that you want someone who is published and who has shown ability to get his or her writing through review.
-		What about these other associations between covariates and exposure group or dioxin.  Tabular results of all ‑‑ tabular summaries of all results.  I mean, when these things start coming out, you guys are going to spend two days wrangling over how this stuff is presented.  
		There's no other comments to be made on this by the committee?  By the statistical experts?
		DR. STOTO:  I understand that has to do with things like the association between BMI and cardiovascular illness, which is not the focus of this study.  
		DR. HARRISON:  But a covariate issue.
		DR. STOTO:  These are covariates; these are not exposure or outcome.  These are things that --
		DR. HARRISON:  Okay, what about Ranch Hand initial dioxin analysis summaries?  Summaries shall contain: A) continuous, B) binary, 2, polychotomus?
		LTC BURNHAM:  Polychotomus.
		DR. HARRISON:  Polychotomus.
		LTC BURNHAM:  Excellent, good, fair, poor.  There.
		DR. HARRISON:  A country boy from Mississippi can't hardly even talk in this ‑‑.
		DR. HARRISON:  It's another new word for you; you learned dichotomous.
		VOICE:  Trichotomous.
		DR. MINER:  Just wait until tomorrow.
		DR. STOTO:  I think that this whole thing here basically says they're going to do it the way they've been doing it, at least in the previous study --
		DR. MICHALEK:  Unless you tell us something different, yes.
		DR. STOTO:  ‑‑ and we didn't have general problems with that the last time around.
		DR. GRUBBS:  That's the road map, if you will, for the 171 page Appendix G that gets every number, seemingly, in the report, summarized in one appendix.  And that just specifies what should be done.  Included in that appendix.
		DR. GOUGH:  But you are going to redo 3.7.3?
		DR. MICHALEK:  Yes.
		DR. HARRISON:  3.9.1.  I think you all should start using eTickets.  Seriously, that's transportation.
		You don't want to be delivering these tickets to these guys, do you?
		MS. JEWELL:  They want us to use eTickets, and I'd be glad to send you them, but if you want to make a change at the last minute, you're not going to be able to do it.  We've had our travelers stuck because they have to stand in line and go to the original electronic issuing person, get a piece of paper to allow them to go someplace else to re-book themselves.
		DR. STOTO:  You can't change airlines.
		MS. JEWELL:  Exactly.  I'd be glad to do electronic; it's a lot easier.  
		DR. MINER:  It was still applicable.
		DR. HARRISON:  I was wondering why you were getting off down there ‑‑ 
		(Laughter) 
		DR. HARRISON:  Okay.  Does anybody -- Oh.
		Addendum A, General Physical Examination.  No. 8.
		What are PBs per minute?
		DR. MICHALEK:  Premature beats?  Or --
		DR. FAVATA:  Where's, is that related to your respiratory rate?
		DR. HARRISON:  No, no.  You're telling me that these are premature beats per minute?  That are assessed in the physical exam?
		DR. CAMACHO:  Where are you? 
		VOICE:  Sixties.
		DR. HARRISON:  Addendum A, General Physical Examination.  No. 8 says PBs per minute.
		DR. MICHALEK:  We will find out, and we will spell it out.
		DR. HARRISON:  Addendum A.
		DR. MICHALEK:  The first addendum.
		DR. GOUGH:  What table is it, Joel?
		DR. MICHALEK:  It's in Table 2.
		DR. HARRISON:  I hear a suggestion that there should be a glossary.
		DR. MICHALEK:  Or else no abbreviations at all.
		DR. HARRISON:  Yes, that sounds ‑‑ so we agree that, one or the other.
		DR. MICHALEK:  Right.
		DR. HARRISON:  On the EKG --
		MR. COENE:  The glossary still would be a good idea only because you will probably use the abbreviations somewhere else.
		DR. HARRISON:  Or you can always define clean.
		DR. MICHALEK:  A glossary.  We'll add a glossary.
		DR. HARRISON:  Under Addendum A, Item 6, electrocardiogram, where it says follow the last sentence, it says follow the mounted tracing and rhythm strip if obtained, to the diagnostician.   I just suggest that you should indicate that you're trying to follow the reading from the cardiologist as well.  Or if those are going to be back in time.
		DR. MINER:  That's not the one.
		DR. HARRISON:  Am I reading off the wrong one?
		DR. MINER:  You may be looking at a slightly older version.
		DR. GOUGH:  This is the one we got yesterday.
		DR. HARRISON:  No, no, this is one I did at home.
		DR. MICHALEK:  That's what mine says.
		DR. MINER:  Then you edited the wrong one.
		DR. MICHALEK:  No, I didn't touch that section.
		DR. FAVATA:  What section are we on?
		DR. HARRISON:  I'm on addendum A, Item 6, electrocardiogram, and all I'm just saying is, they say they're going to send the tracing to the diagnostician.  Earlier they say they're going to have the tracing read.  Somewhere they said they were going to have this read. 
		DR. FAVATA:  Yes, will be interpreted by the cardiologist.
		DR. HARRISON:  And I'm just saying that the tracing and the reading should go to the diagnostician.  That's kind of nickel and dime stuff.
		DR. MICHALEK:  Tracing and the interpretation.
		DR. HARRISON:  And the interpretation.
		No. 11, doppler testing of peripheral pulses.  Procedure will be conducted after a minimum of four hours' abstinence from smoking.  Isn't it customary to have abstinence for a certain time from caffeinated beverages as well?
		DR. MICHALEK:  We apparently have two or three different versions of this.  Do your versions say anything about abstinence from caffeine, on the doppler?   
		Bill Grubbs.
		DR. GRUBBS:  I'm looking.
		DR. STOTO:  The part about the travel here says that you have to give coffee to the wise but only water to the men.
		DR. MICHALEK:  No caffeine?
		DR. HARRISON:  So it's just as soon that they are caffeine-free for their three day ‑‑ I can't believe that.
		DR. MICHALEK:  Oh, no.  I think it just doesn't say anything; that's all.  It says nothing.
		DR. HARRISON:  Well, you know, it says they can't smoke, and I'm just wondering why it doesn't say they can't have --
		DR. MICHALEK:  That could be an oversight on our part.
		There's no mention of caffeine?
		DR. MINER:  Not in either of the versions we have.  But  I don't know if that's the --
		DR. MICHALEK:  Are you suggesting that we should abstain from --
		DR. HARRISON:  Yes.
		DR. MICHALEK:  For four hours?
		DR. HARRISON:  I think that affects the pulses as much as smoking, or more.
		DR. STOTO:  For four hours before that test?
		DR. MICHALEK:  Four hours is sufficient?
		DR. HARRISON:  I think four hours probably is.
		DR. STOTO:  And Doppler, as well?
		DR. HARRISON:  Well, actually I was referring to the Doppler.
		DR. MICHALEK:  What about EKGs?
		DR. HARRISON:  Okay, EKG it says, abstinence from smoking, food, and liquid intake.  Unless you're going to chew on instant coffee.
		We already talked about measurement of height and weight.  You want the measurement of the hip.  And I think that's really defined as just the hip at its widest.
		If you all are going to draw dioxins again, and I guess this is probably the same protocol you have been doing all the time; but it's probably a good idea to label that bag when you're starting to use it, not at the end.  I mean, if people get distracted or something --
		DR. MICHALEK:  Yes, there's some text I forgot to edit right there.
		DR. HARRISON:  There's 4.1 --
		DR. MICHALEK:  Section 14.
		DR. HARRISON:  Addendum B.
		DR. MICHALEK:  Oh, I'm backing up to Section 14, Laboratory Procedures.  There's a paragraph in there about 650 for dioxin --
		DR. GOUGH:  I wondered about that.
		DR. MICHALEK:  It's not going to be 650.
		Now you were on Addendum B.
		DR. HARRISON:  Although Addendum B, 4.1 in the procedure, after ‑‑ basically it's saying that you draw the blood, you clamp the tubing, and then you label the bag. 
		DR. MICHALEK:  We would probably label the bag first.
		DR. HARRISON:  I would say that surely it's somewhat--
		MR. OWENS:  We have state laws that govern the protocol, in California, and it's done according to that.  It's labeling first.
		DR. HARRISON:  Okay.  I would agree with the state law.
		DR. GOUGH:  Will there be electricity during most of these exams? 
		(Laughter) 
		DR. MICHALEK:  Let's hope so.
		DR. HARRISON:  For some reason, I have a note ‑‑ I have a note that you need a better description of your computer, and the modem is missing from the specs.
		DR. MICHALEK:  We will edit that computer description. 
		DR. HARRISON:  I guess the thing that I ‑‑ first of all, I don't know what ADPE is.
		DR. MICHALEK:  That's old-fashioned Automated Data Processing ‑‑ that's 1970s technology.  We'll drop that.
		DR. HARRISON:  At any rate ‑‑ it doesn't matter a whole lot, but you did say that you were going to need a modem and I could see where you'd want a modem to get back and forth to Brooks.  And we just didn't have it down here and I just --
		DR. MICHALEK:  We'll fix that.
		DR. STOTO:  Or were you going to do it over the Internet.
		DR. MICHALEK:  We need the Internet connection.
		DR. HARRISON:  Well, either that or you need a network connection; one way or another.  A network card.
		Anybody else have anything?
		DR. FAVATA:  Just respiratory rate on general physical exam. 
		DR. MICHALEK:  Where is that?
		DR. FAVATA:  Page 60.
		DR. MICHALEK:  Respiratory rates?
		DR. FAVATA:  Yes.
		DR. MICHALEK:  Are you saying that should be added or?
		DR. FAVATA:  I don't see it there, it should be added.
		DR. HARRISON:  Is there any difference in the temperature you get with that little ear thing?  Isn't that the same temperature you get orally?
		DR. FAVATA:  I imagine they've done studies.
		DR. HARRISON:  Okay, Agenda and Future Meeting Dates.
		What is the committee's will?
		DR. GOUGH:  I have a question to Joel about the addenda.  A number of places in the last couple days you've said "I'm going to take care of that" or "I'll rewrite that."  When should we expect that and when do you have to have it back?
		DR. MICHALEK:  Four weeks.
		DR. GOUGH:  The turnaround?
		DR. CAMACHO:  Oh, you want it from me in four weeks.
		DR. MICHALEK:  Well, no.  We want something from you in four weeks.  When do you think we should --
		DR. MINER:  The RFP is supposed to go out on the 2nd of March, is that right?
		VOICE:  That's six weeks.
		DR. MICHALEK:  So our deadline is it has to go out, so to speak, on the 2d of March.  That means we have to have a revision -- we have to have something pretty much firmed up within four weeks.  It means I have to receive feedback from Paul Camacho, I have to put all these changes in that you suggested, and get it all cleaned up; and what I could do after I get your feedback is put that in and then send the whole thing back to the committee.  And then we're going to need a quick turnaround from you within two weeks.
		DR. STOTO:  When you do that, would you highlight the changes that have been made since this draft?
		DR. MICHALEK:  Sure.
		MR. COENE:  Just one set of changes at this point.
		DR. STOTO:  I'd say everything that's been changed up until now; treat that as fixed.
		MR. COENE:  Except --
		DR. STOTO:  The things that were discussed at this meeting, and you said you would change.  Highlight those.
		LTC BURNHAM:  That changes Paul's deadline.
		DR. MICHALEK:  So anything Paul gives me will be in a different color font.
		DR. CAMACHO:  I'm going to try to ‑‑ you're not expecting anything dramatic unless I check with my friends and somebody trips over somebody, somebody says something.  Bing.  So I'll try to do it within three weeks.
		DR. HARRISON:  You're talking about the Psych section, right?
		DR. CAMACHO:  Yes.
		DR. HARRISON:  So nobody's going to disagree with Paul about the Psych section.  So there's no sense in making it different from the rest of the --
		DR. CAMACHO:  I just want to check with a couple of people.
		DR. HARRISON:  I understand.  But I don't see where we're going to --
		LTC BURNHAM:  So if we sent next version out within two weeks; and we got it back within two weeks of that, then we'd have it in a month.
		DR. HARRISON:  Well, why don't we ‑‑ why don't you send it out with one of those ‑‑ well, how do we want to do this?  We want everyone to send suggestions back directly to the Air Force?
		DR. MICHALEK:  You've already given us.  You mean on the next revision?
		DR. HARRISON:  In other words, what we're saying is, maybe something got misunderstood and missed in the translation.
		DR. MICHALEK:  Right.  So the attitude could be "Well, here it is, are there any objections?"
		DR. STOTO:  Ideally we should do that through the staff.  But is there going to be a staff?
		MR. COENE:  Barbara and Len.
		DR. GOUGH:  You mean send it to them before we're gone?
		DR. STOTO:  Yes.
		DR. HARRISON:  So --
		DR. STOTO:  Or at least copy them.
		DR. GOUGH:  Yes.  I agree.
		DR. HARRISON:  So we're going to ‑‑ you're going to send a corrected copy back to staff in two weeks.
		DR. MICHALEK:  Yes.
		DR. HARRISON:  Staff is going to then Fedex some more CD-ROMs out to us with a two week deadline.  If we find something that we don't like, we get back to you.
		DR. MICHALEK:  And if you say nothing, that's mean's it's approved.
		DR. HARRISON:  If you say nothing --
		DR. MICHALEK:  That's it.
		DR. HARRISON:  It means that everything is just hunky-dory.
		DR. MICHALEK:  It's a done deal.
		LTC BURNHAM:  And whoever wants hard copy should tell Len now rather than ‑‑ you know, if you had CD problems or --
		DR. HARRISON:  Well, I'm not sure those weren't problems with the ‑‑ I don't know.
		DR. MICHALEK:  We think it was a problem with our CD cutter, our CD burner.  That's why, we think that was what happened.
		DR. HARRISON:  Well, mine wasn't readable, either.
		DR. MICHALEK:  Understood.  We can get around that. 
		DR. HARRISON:  I'm not sure that it's any big deal to just send it as an attachment.
		DR. GOUGH:  That's how I got mine.
		DR. HARRISON:  Because it's not huge.
		DR. MICHALEK:  No.
		MR. COENE:  It's 2 meg.  Some e-mail --
		DR. MICHALEK:  Won't take that big a file?  I could split it up into two files.  I could put the main statement of work and all the addendums as a separate file.  That gets it down to 1 meg.
		MR. SCHECHTMAN:  You can make two attachments to one e-mail.
		DR. STOTO:  No, that may have the same problem.
		MR. SCHECHTMAN:  Then have two separate e‑mail messages; Part A and Part B.
		And then everybody can use Microsoft Word?
		DR. HARRISON:  yes.
		MR. SCHECHTMAN:  It's a common format.
		DR. HARRISON:  Why don't you do this?  If you're going to send them directly, why don't you send them directly and why don't you send a separate e‑mail message saying "I just send you your file, let me know if you didn't get it."
		DR. MICHALEK:  For that I need a complete and current list of everyone on the committee and all their e‑mail addresses.  I do not have that.
		MR. COENE:  It's on the Internet; it's on our web site.
		VOICE:  Turnabout ‑‑ 
		(Laughter) 
		DR. STOTO:  Where is the web site?
		MR. COENE:  It's nctr.fda.gov, and you go in there and there's a thing about committees, and you'll find both committees and you'll find the committee makeup.
		LTC BURNHAM:  We're just sending them to Len, though, Joel.
		DR. HARRISON:  No,  He's going to send them directly.
		DR. MICHALEK:  I'm just repeating back what he told me.
		DR. HARRISON:  That's what I was suggesting.  If you're going to be sending CD-ROMs and the CD-ROMs are going to ‑‑ that might make sense, but if it's e‑mail messages, I don't see why e‑mail messages have to come here to go, come to me.
		MR. SCHECHTMAN:  Everybody, plus us, will all be included on the e‑mail message, right?  
		DR. MICHALEK:  Right.
		MR. SCHECHTMAN:  Then everybody will wire back their comments to you.  That would be the most efficient way as a reply to that e‑mail document.  Then you'll include all those comments, adjustments, changes, and finalize it.
		DR. STOTO:  I think that we need to copy you.
		DR. HARRISON:  I'm ‑‑ yes, I ‑‑.
		MR. SCHECHTMAN:  Right; cc everything for the record, to us.
		DR. HARRISON:  Just because some of us are forgetful and some of us aren't here, make sure in your message that you spell out what we're supposed to do.  Reply to all, da-da-da, all that sort of stuff.
		DR. STOTO:  What are we going to do now, and tomorrow?
		DR. HARRISON:  Well, the question of the timeline for report writing has come up, and Mr. Grubbs wanted to say something about that.  That is part of our agenda here.
		DR. GRUBBS:  The Air Force asked me to just briefly give an overview of how we put together these blue books or the entire report.
		DR. MINER:  Wait a minute.  We lost --
		DR. MICHALEK:  Should we stop or should we wait?
		DR. MINER:  Wait.
		DR. HARRISON:  Well, we've lost two-fifths of the committee here.
		DR. MINER:  Well, this was a big area of contention last time, and we want to give adequate time for --
		DR. HARRISON:  Well, I agree.  
		DR. MICHALEK:  How about a five minute break?
		DR. HARRISON:  Well, yes.
		[Recess]
		DR. HARRISON:  You can go ahead.
	DISCUSSION OF REPORT WRITING
		DR. GRUBBS:  The Air Force asked me to give a brief summary of our report writing process, the blue books, if you will, and how do we go about accumulating all these blue books.  It resulted in about an 1800 page report.
		So I've got a basic layout here; it's not exact for all 20 chapters or some huge Gantt chart there, but I'd like to go over that.  And this is also reviving the review of the report for the '97 report, and also giving the new members some idea of the process it goes through.
		In '97 we put together the report of 20 chapters, 10 of which were clinical.  It was 1,790 pages in length.  The clinical chapters, there are ten of that we've gone through today, they were from 57 to 235 pages in length, gastrointestinal, if you'll remember, was the big one there.  
		We had six appendices.  In each analysis, we did four statistical models, both an adjusted and an unadjusted analysis, and there were a total of 266 endpoints.  So when you put all the things together, this is an overview of what you came up with.
		DR. STOTO:  Things like diabetes, where you measure it a couple ways and some continuous, some discrete, that's --
		DR. GRUBBS:  That's Two.  That's two endpoints.
		DR. STOTO:  Well, it's more than two for diabetes, because it's --
		DR. GRUBBS:  Diabetics are very different.  Right.  Any analysis, 
		DR. STOTO:  Ten or twelve.
		DR. GRUBBS:  ‑‑ really any table, if you will ‑‑.
		[Slide] 
		Just to quickly go through the different chapters, these 20 chapters, the first column here and through the covariate associations we call, if you will, the up-front chapters.  They're not the clinical chapters.  They give an overview of the questionnaire methodology, the physical exam methodology, a summary of which participants attended by group, and reasons for refusal.  Joel can comment, he's important in the bias, examining the bias of the participants coming to the study.  Quality control methods, the statistical methods section and covariate associations.
		Then we started ‑‑ that went through Chapter 8, I believe, and then Chapter 9 was the general health assessment.  We stepped through ten clinical chapters; the committee reviewed all of them, but the majority of the time was spent on the clinical chapters, starting with General Health.
		General Health, Neoplasia and Neurology/Psychology, Gastrointestinal, Cardiovascular, Hematology, Endocrine, Immunology, Pulmonary.  This time there will be two additional chapters that were done in 1992, the Dermatology and the Renal, for a total of twelve clinical chapters.
		At the end there is a Conclusions chapter, which summarizes the results found across all the clinical chapters.  There was a one-page Future Directions; Future Directions may be how do we dispose of the data or transfer the data, this being the last follow up; and then appendices that went along with it.  Summary tables, the Addendum A and Addendum B that you just looked over, they were part of the report.  The Examiner's Handbook, copies of forms, things like that.
		[Slide] 
		Each clinical chapter typically would include the following:  A review of the literature, then we'd summarize previous Air Force Heath Study results in the next section.  We'd put which endpoints were to be analyzed, the statistical methods that we used.  We would go through and do this statistical analysis:  We'd have a clinical discussion of the findings, a statistical summary, and we've talked about summary tables of the findings, and then an overall conclusion.
		So those are some of the general big sections you'll see in a chapter.
		[Slide]
		To put together a report of this magnitude in a ‑‑ I don't want to say fairly short time, but a limited time, what we have to do to get this going is get chapters going simultaneous.  I may have three analysts working for me, working on three different chapters.  They may be in different stages.  Last time I started one of my analysts off on the gastrointestinal chapter right at the very beginning.  We didn't get everything done until April or May of the next year; it was just so big.
		So we'll have these chapters staged, and they'll be going in stages and delivered to the Air Force in stages for their review.  We call this the rolling report.  At the last cycle we delivered two drafts of each chapter, and each appendix before, we even got to the draft final report.  And that process took 13 months.  It started on 26 August '98 and went through 26 September '99.  Add five years to each of those and you get a general time frame of when it's going to be happening this time, 2003, 2004.
		There's multiple chapters going on at once, there's many functions within the chapters going on at once, and what we've done here is lay out a chart, if you will.  I just did three chapters here and I just said "Okay, three medium-sized clinical chapters" and this is just a bogey, if you will, as to the process that we'd use.  
		First chapter, we might start building the analysis database ‑‑ might take us a couple weeks.  Then six weeks or so to analyze the chapter, have them go through our editor, another couple weeks; give it one final review before we deliver draft one to the Air Force.  Then give the Air Force two, three weeks to review it, that's the comments; and then get their comments back, resolve them, and deliver draft two, which might take another two to three weeks there.
		As you can see, I laid that out for the first chapter, but you're seeing the second and third chapter going on simultaneously.  So one chapter might be in editing and the other we might be starting to build the analysis database.
		I personally put my hands on each of the chapters; I don't do all of the analysis for the chapter, but I read over everything before it's sent to the Air Force, and I can be reading multiple chapters within the same week, at different stages there.
		[Chart] 
		So we call this our rolling schedule.  I laid it out here for three chapters; you can imagine it for 20.  I've got that over eight or nine months, but tried to visualize that, 20 chapters over a period of 13 months.
		One of the main purposes of this is we need to involve the committee and get your review also.  In cycles before 1997 we had only delivered one draft to the Air Force.  We delivered draft one to the Air Force, we got comments, and we resolved comments and then we put it off to the side; we didn't deliver a second draft back.  They would get that in the draft final report.
		What we found last time, and it served a number of purposes; but I think it helped the advisory committee to see the Air Force's comments incorporated before you all even saw the report; and that's why we did a second draft.
		So the first appropriate time for the Air Force, for the Advisory Committee to get involved would be after this delivery of draft two.  I say that from a formal standpoint; the time for the Advisory Committee to get involved, we're doing it of course yesterday and today in terms of getting your comments in the statement of work.  
		So we have a document and a road map and a direction to go in.  And that's why I'm very interested in these discussions here, to know what the statement of work is going to look like for three years down the road here.  
		But one of the options for the Committee is to get involved right after the second draft here, on each of the chapters.  Now again, imagine this with 20 chapters culminating in a draft final report, 13 months past when we start.  That it would be another opportunity for the Advisory Committee to get involved is, okay you've got the draft chapters and now you've got all the draft chapters, you've got the entire report, or what it's going to look like.
		There were some comments last time that "Well, to make a final assessment on gastrointestinal, I may need to see the endocrine chapter, or some chapters interrelate, or I might come up with some ideas as to well, could we look at the relationship between cardiovascular and diabetes, for example.  So that's a point to be made for seeing all the chapters, and then making a final assessment. 
		What I'm here to emphasize is, speaking for SAIC, we can do it however it needs to be done, but we need to know when the Advisory Committee primarily would like to become involved in the process so we can lay out the schedule, the overall schedule as to ‑‑ really comes down to the endgame; how do we take it from the draft final report to the final report?
		For example, if the committee agrees that they can make their comments on the General Health chapter after draft two, getting back to the Air Force getting back to us when we do the draft three, if you will ‑‑ that's one option to do, and then we're stacking those up as we come to the draft final report.
		If the committee decides "Well, I need to see the entire report and I can't make a definitive comment until the draft final report comes out" that's another option.  However, that adds more time at the end of the report between the draft and the final, in case additional analysis needs to be done or things need to be reworked.
		So SAIC has done it, worked with the Air Force both ways in this, and mainly we wanted to lay out the process and say "Here are opportunities for the Advisory Committee to review" and had some discussion on that.
		DR. STOTO:  Can I make a suggestion on that?  This has been very helpful.  I think it would work the best if there were three meetings; one where we reviewed about half of the chapters, draft two.  Another one where we reviewed the other half of the chapters, draft two, recognizing that the first batch may be more weighted toward the front of the book stuff, and so on.  And then a third meeting where we reviewed your response to our first comments and how the overall thing fits together.
		DR. HARRISON:  As I recall, the problem and the complaints from the last cycle was that the time frame was compressed enough so that we got a lot of draft one's, I think.  And we found ourselves correcting stuff that was then ‑‑ it was almost like the Statement of Work business this time, where you  had two drafts out and that was problem.
		Is it feasible within this schedule to have the three meetings like Mike suggests?  Is that doable?  
		The other issue is, there has to be a certain time elapsed from the delivery of the chapters to when we meet so there's opportunity for us to actually do our review, so we actually have to build that in.
		DR. GRUBBS:  That's correct.  If there was a meeting scheduled right here, this chapter might not make it into that, but previous ones would, for example.
		DR. HARRISON:  Right. Right.
		DR. GRUBBS:  That's correct.
		DR. HARRISON:  So is that --
		DR. GRUBBS:  And if I may add, I believe that was the intent back for the '97 study.  The timing just didn't work out.  I think there had been an attempt to schedule meetings in May or June and August to the first review that you would talk about.  And for some reason, the timing just didn't work out, because their meetings ended up being in August for about half the chapters, and then October for the draft final report.  There really should have been three meetings.
		DR. STOTO:  We really had the first and the third of the meetings I spoke about, and the first one late.
		DR. GRUBBS:  Yes. 
		DR. MICHALEK:  I think the problem has been, when you decide up front we're going to have a meeting in September, you always have problems trying to get this committee to meet in a particular month, because everybody's busy.  And so you try and then you fail, and then so the meeting slips a month or two, and that's --
		DR. HARRISON:  I agree; I think, though, one of the advantages that we have this time, and I don't think we've done this like this before is that we're talking about three years--
		DR. MICHALEK:  Down the road.
		DR. HARRISON:  So we can really start to plan meetings ‑‑ hopefully I won't be here, but we can start planning meetings now for when ‑‑.
		One other thought crossed my mind, and that is, am I not remembering that there is essentially software now that's used to do collaborative writing?  You know, you all are doing Microsoft Word, but as I recall, I remember reading packages where you're the author so the author's copy is locked, but the collaborator's copies are open to change and somehow the software reconciles those changes?
		MS. YEAGER:  You can do that in Word as well.
		DR. HARRISON:  I guess I might have to get Word.  I'm an anything-but-Microsoft person.
		But that might be something else to consider; and that is, instead of pulsing the chapters, that we'll work out the assignments and the chapters will roll; when you deliver draft two, you'll deliver draft 2 to the Air Force and to the Committee reviewers.
		DR. STOTO:  Is that in addition to the meetings?
		DR. HARRISON:  Yes.  In addition to meetings. I'm not suggesting ‑‑ in fact, I'm saying that we're starting to plan well enough that we should be able to have the meetings and have them in the right time frames with lead time.
		That's very helpful, thank you. 
		Any other comments on scheduling this kind of analysis?
		No.  Surely we can get a few consultants back during that time.
		All right.  What else?  Can we quit for today?
		DR. STOTO:  When would be the next meeting.
		DR. HARRISON:  Here's what I was going to suggest.
		DR. MICHALEK:  When and where?
		DR. HARRISON:  First of all, let me make this suggestion:  Why don't we discuss that in the morning?
		DR. MICHALEK:  Great.
		DR. HARRISON:  The only person who for sure isn't supposed to be here is Dr. Favata, who is not coming to the next meeting.   Look at the smile on her face.
		VOICE:  Mary's not going to be here, either.
		MS. JEWELL:  It's been a delight.
		LTC FOX:  And I won't be able to attend; I've got a research conference that begins tomorrow morning.
		DR. HARRISON:  What kind of research conference?
		LTC FOX:  Gulf War Veterans Illness Research Conference.
		DR. GOUGH:  This has to be relaxing compared to that.
		DR. HARRISON:  That sounds --
		DR. STOTO:  What do we have on the agenda for tomorrow?
		DR. HARRISON:  Well, first of all we have to ‑‑ and so I don't see any reason for us to beat ourselves over the head on when our next meeting date's going to be when we are going to be here tomorrow, and have something to discuss. 
		DR. STOTO:  That's fine.
		DR. HARRISON:  I'm not opposed to doing it now, if you all want to.  It's just, to walk in here to sit around for a few minutes to see if Ms. McCarthy, is it, shows up.  You know ‑‑ it'll save something for us to do.
		There is that and there's something else that you mentioned.
		MS. JEWELL:  Writing the letters.
		DR. HARRISON:  Yes, I'll give a try at ‑‑ or Len can give a try at putting a draft letter together.  He took all the notes; and then tomorrow morning we can sit here and shove that around a little bit.
		DR. STOTO:  Okay.
		DR. GOUGH:  The other thing is, is the Air Force clear about the recommendations we made?
		DR. MICHALEK:  I'm clear.  
		DR. GOUGH:  All right.
		DR. MICHALEK:  I don't think I'm confused.
		DR. HARRISON:  Also the Statement of Work is going to be in your hands in two weeks.   And if it turns out the Joel has misunderstood something, I'm sure that ‑‑.
		Is that satisfactory to everyone, that we will meet here tomorrow morning?  What time.
		DR. STOTO:  Say 11. 
		(Laughter) 
		DR. MICHALEK:  Same time?
		DR. HARRISON:  8:30.  Meet here at 8:30.  Okay.
		Oh, just before the tape gets turned off, we should have one last expression of appreciation to Dr. Favata, the only polymath on the Advisory Committee.
		Thank you.
		DR. FAVATA:  Thank you all.  
		[Applause.]
		MR. COENE:  And for the record we have -- along with other problems with the Secretary's office ‑‑ a certificate of appreciation.  Unfortunately, it didn't get --
		MS. JEWELL:  It's coming, but it's because of the transition, and you don't expire until the 31st, so she's not the Secretary then, so --
		MR. COENE:  Mr. Thompson will sign it.
		MS. JEWELL:  You kind of got caught in the middle there, so it is coming.  
		DR. FAVATA:  Not a problem.
		MS. JEWELL:  I will Fedex it.
		DR. STOTO:  It's your term that expires, not you. 
		(Laughter) 
		[Whereupon, at 4:01 p.m., the meeting concluded for the day, to resume at 8:30 a.m. the following day, January 24, 2001.]
	- - -

	RANCH HAND ADVISORY COMMITTEE

	Department of Health and Human Services

	Wednesday, January 24, 2001

	Day III

	Meeting

	 Parklawn Conference Center
	Conference Room K
	Parklawn Building
	5600 Fishers Lane
	Rockville, Maryland

	ATTENDANCE
Committee:
Robert W. Harrison, M.D., Univ of Rochester, Chairman
Michael A. Stoto, Ph.D., George Washington University
Michael Gough, M.D., Consultant
Paul R. Camacho, Ph.D., Univ of Massachusetts-Boston
Ronald F. Coene, P.E., Consultant [former staff]
Leonard M. Schechtman, NCTR, staff
Barbara Jewell, NCTR, staff
Attendees:
LTC Karen A. Fox, M.D., Brooks Air Force Base 
LTC Bruce Burnham, Chief of Population Research
Dr. Joel Michalek, Principal Investigator
Dr. Judson Miner, Program Management Support
Manuel A. Blanca, Program Management Support
Robert Newman, House Sub on Nat'l Security and VA
Mary Ellen McCarthy, House Veterans Affairs
Dr. Gary Kayajanian

	C O N T E N T S	

Review and Discussion of the SOW for the 6th Cycle of the AF Health Study  (Continued)

Drafting Letter 	539

Agenda	566

Future Meeting Dates	576

	P R O C E E D I N G S
	[8:53 a.m.]
		DR. HARRISON:  (Reading draft letter.)
		(Discussing the wording of the letter.)
 		DR. HARRISON:  I just put another sentence in here.  I just want to read it.  You know, what will happen is that when I send this around, if I put in something that you haven't heard before, it'll be kind of out of context, and you won't really quite know why it was there.
		But I just put in there as a last sentence: "Please also realize that inertia is such that this is an urgent problem that needs immediate action" -- underline immediate -- "to avoid loss."
		That kind of addresses what Len was saying, and that is to point out that if planning is left until 2006, that that guarantees loss of sample, that something needs to be in place now.  
		DR. CAMACHO:  You know what I would like to do also, I would like us to either informally or formally as a Committee outline the difficulties that we talked about yesterday; the ethical difficulty, the possible need while we're on that issue. 
		DR. HARRISON:  All I put down here was we would like --
		DR. CAMACHO:  Not in that letter.
		DR. HARRISON:  -- we would like this meeting -- 
		DR. CAMACHO:  Not in the letter.  
		DR. HARRISON:  -- "we would like the VA to determine the ethical and scientific issues at stake."  I included that as part of the letter, because -- 
		DR. CAMACHO:  In general.  
		DR. HARRISON:  Yes.  
		DR. CAMACHO:  Okay.  
		DR. STOTO:  Maybe we could add that, you know, we'd be happy to work with whoever takes a responsibility for doing this, considering these issues.
		DR. CAMACHO:  Yes.  I wasn't referring to the letter, Michael, I was referring to 
the --
		DR. STOTO:  That may be self-evident.
		DR. CAMACHO:  -- to the points that we talked about yesterday.
		DR. HARRISON:  Well, let's see.  "We feel strongly..." (reading).  
		DR. STOTO:  I think it's self-evident.
 		DR. CAMACHO:  I'm not referring to the letter. 
		DR. HARRISON:  All right.  So this is a first cut.  This is not a commitment by anything, and I would certainly -- you know, I won't do anything until we're all satisfied that it's appropriate.
		I've got down that this goes to the Secretary.  It gets cc'd to the VA Secretary.  It's going to have as attachments right now the previous letter as well as a copy of the Public Law.
		DR. CAMACHO:  Would you throw in the sheet of his Powerpoint?  That won't make sense, though.
		DR. HARRISON:  No. No.  
		Should this also go to the Air Force Surgeon General?  That's a committee question.
		DR. GOUGH:  I think so.  Because it's the Air Force study.
		DR. HARRISON:  We wouldn't want the Surgeon General to be blindsided by a letter that they're not aware of.
		Going once?  Going twice?
		LTC BURNHAM:  So you'd be happy if there's a repository for the samples and records?  Is that what you're -- 
		DR. CAMACHO:  That's a minimum.
		DR. HARRISON:  Well, I'm not saying what I'd be happy with because I'm not sure I have the expertise to say that.  I think what I would be happy with would be to have people that I would respect; epidemiologists like Mike, and ethicists.  I would be happy to know that they met and seriously considered this, that they invited you all, that they made sure that they were well aware of what had gone before, and then decided, you know, "This stuff is worthless.  Can it."
		I mean, as long as it's given serious consideration, I don't think you can -- you then have to go with whatever the decisions are.
		DR. GOUGH:  The letter says, it's a storage while you make up your mind about what to do with it.  
		DR. HARRISON:  Right.  
		DR. GOUGH:  There's two parts.
		DR. HARRISON:  But if you think about it, you can't store something unless you're going to figure out, try to figure out, at last make a commitment to try to figure out what to do with it.  
		DR. GOUGH:  I think you underestimate the government.  
		LTC BURNHAM:  No, that's true.  CDC has thousands of serum samples just in freezers in case someone wants to use them in the future.
		MR. COENE:  You've given a solution, Bob.  I would suggest, as you put it down, look at Section 7 and Section 8 of the law, and that contains tissue archive system and scientific research and feasibility studies program, that we want the Secretary to know that this needs to be implemented.  
		DR. HARRISON:  Okay.  I'll tell you what.  What would be the best way to do this?
		Can you all produce a word processor version of this text with appropriate sections underlined, so that what I'll include in the letter is, I'll say "see this attachment, especially underlined portions." 
		That way, again, it won't be a part of the letter.  It won't detract from the punch of the letter.  
		MR. COENE:  That is on the web.  You can download it from the web.  
		DR. HARRISON:  It's in Joel's database.
		DR. MICHALEK:  I'll email it to you.
		LTC BURNHAM:  Does it have the site on the top?
		DR. MICHALEK:  The web site?  No.  What happened was I downloaded it from the web, put it into a Word document and printed it, so I will e-mail it to you when I get back. 
		DR. HARRISON:  But you see what I'm saying?  Instead of having it in the letter, some way -- 
		MR. COENE:  By the way, I told you wrong.  Our web site's not public yet, or at least NCTR isn't public, and therefore you can't get it.  Otherwise, it would have a date of this meeting and the Minutes of the last -- not this last meeting, but -- 
		Dr. MICHALEK:  That's another point.  I'd really like to have a copy of the Minutes of this meeting for my folder, for my record.
		MR. COENE:  Okay.  That's something we need to do anyhow because that's one of the action items.  Okay.  
		DR. STOTO:  When I get your draft, I'll see whether I might be able to correct a sentence or two that says a little bit more about what the law says that might fit in there.
		DR. HARRISON:  Okay.  All right.
		Gary, good to see you again.
		DR. KAYAJANIAN:  Thank you.
		DR. HARRISON:  We just finished discussing our concern for disposition of the Air Force samples at the scheduled end of the study and our desire that the appropriate agencies begin making plans of how to maintain and preserve these samples for future scientific use.  
		The last item of business -- Jay says that there are a couple of left over things.  What do we have left over?  
		DR. MINER:  We didn't ever finish the serum dioxin testing for everybody versus not.
		DR. MICHALEK:  We'd like your opinion.
		DR. MINER:  If we can open that up again.
		DR. MICHALEK:  In the hypothetical case that we did have the funding, does the Committee think we should do the TEQ or the dioxin again on every subject?
		DR. HARRISON:  Okay.  Mike's comment was that TEQ was not -- he felt it wasn't useful, as I recall, because dioxin was the contaminant de jur in Agent Orange.  
		DR. STOTO:  The dioxin measure in this study is a measure of exposure to the herbicides.  That's presumably better than --
		DR. MICHALEK:  Do you think that we should do a dioxin measurement again on this subject?
		DR. HARRISON:  And then Mike thought, the other Mike thought that everybody should have two points.
		DR. GOUGH:  I was initially opposed to that; but he's right.  If you're trying to do individual elimination rates, you need those‑‑.
		DR. HARRISON:  So I think, that was actually my understanding of the committee's position.  Was that dioxin should be measured, not TEQ, and that those individuals who only had one measurement, attempts should be made to have two measurements made, whether they were Ranch Handers or comparisons.
		DR. STOTO:  That would allow people to do some more sophisticated statistical modeling to get at some of these things.
		DR. MICHALEK:  Then my opinion would be that you should do a dioxin measure on everyone.  Because if you were to do only those that only had one point, you would be not taking advantage of the very last time you're going to see these individuals.  And there would be a benefit to measuring every single subject.
		You're talking about skipping about 400 people if you don't.  This is your last time.
		DR. STOTO:  I think having the point separated in time is --
		DR. HARRISON:  That's fine.  That's fine.  Well, is it this below-quorum committee's consensus that --
		DR. STOTO:  I think that if it turns out they can get some of the resources but not all, then we need to consider what ‑‑ but I think that it would --
		DR. HARRISON:  So our first priority would be to have two points, the next priority would be to have everybody, and the very wasteful priority would be to do TEQs on everybody.
		DR. STOTO:  Something like that.  But I think that we can consider the priorities on every stage if we need to.
		DR. MICHALEK:  So the first priority is two points on every subject.
		DR. CAMACHO:  Second one is every subject.
		DR. MICHALEK:  Second one is do everyone, whether they have multiple points or not, and the last priority is to do a TEQ.
		DR. HARRISON:  Don't even put that in.  Because Mike's argument was that that was wasteful anyway.  
		DR. MINER:  We have asked you to do fiscally unrestrained recommendations.  Now we'll have to go back and look.  
		DR. HARRISON:  The science says there's no way to use the TEQ.
		DR. GOUGH:  The only place it would be of interest is if we had a lot of guys in the comparison group or a lot of guys in the Ranch Hand group who had unexpectedly high concentrations.  And I would expect them to have really different profiles, because they have 2 3 7 8 and then they have all those pintas and octas.  But I think that's a minor gain because we don't have very many people like that.
		DR. MICHALEK:  Well, we don't know.
		DR. GOUGH:  Well, we do know.  The highest comparison --
		DR. MICHALEK:  We've never measured the other congeners.
		DR. GOUGH:  What's the highest comparison guy?
		DR. MICHALEK:  50 parts per trillion.
		DR. HARRISON:  But you know that ‑‑ okay, you're making a point, though.  You're saying that it could also be looked at, if you had the funds; it would be looked at as surveying that group with the possibility that there's some oddity that's producing elevations of other forms of dioxins.
		DR. STOTO:  That makes it a different study.
		DR. HARRISON:  Yes, but it would be a way of ‑‑ if you did that and there weren't other congeners, it would give you, your statistical analysis a little more ‑‑ it would give you a little more confidence because you would have ruled out a possible unexamined confounder.
		DR. MICHALEK:  That's right.
		DR. GOUGH:  How much more does it cost?
		DR. MICHALEK:  Not much.  In fact, I talked to CDC and they'll produce the entire panel of 36 congeners for the same price as they'll produce the TCDD.
		DR. HARRISON:  Oh, gees.
		DR. STOTO:  Then do it. 
		(Laughter) 
		DR. MICHALEK:  So there's no issue on cost.
		DR. HARRISON:  But the other thing is, we now have identified a possible use for the measurement, so ‑‑.
		DR. MICHALEK:  What you've done is extended the use of the data to humanity after we all leave and the Agent Orange issue is closed.  You'll be able to use the data for other purposes.
		DR. STOTO:  Can I give another thing in this hierarchy of possibilities?  The best thing would be to get everybody.  The next thing would be to get a measure on the people who only have one, so far.  The next thing I would say is get the people ‑‑ if you can't afford that, get the people who have elevated measures.
		DR. MICHALEK:  Okay, those Ranch Handers in the pharmacokinetic study.  Those are the ones above 10.
		DR. HARRISON:  Okay, to get another point that is very likely on the first order --
		DR. STOTO:  If their first measure was below ten, getting another measure is not going to be all that valuable.
		DR. MICHALEK:  Do above ten only.  That's going to be about 600 people.
		DR. STOTO:  It's best to get everybody, and it's next best to get --
		DR. HARRISON:  The problem with those low numbers is, how are you going to analyze it?  Either numbers above ten will follow first order kinetics; the ones below ten are following some life cycle of the sun and --
		DR. STOTO:  That's why I suggested this intermediate position.
		DR. MICHALEK:  We believe the ones below ten are in steady state, although we don't have any data to show that.  But this would give us the data to show it.
		DR. HARRISON:  But you said they weren't in steady state, because the level keeps dropping.
		LTC BURNHAM:  Dropping.
		DR. MICHALEK:  That's true; and if it hadn't been for environmental cleanup and the whole population coming down, they would be in steady state.  But this is your chance to know and to eliminate an assumption.
		DR. HARRISON:  I'm not opposed to it; I was just --
		DR. STOTO:  But it's clearly more valuable to have the second measures on people who had a higher level to begin with.
		DR. MICHALEK:  Right.
		DR. KAYAJANIAN:  If you want to look, you want to look, for example, in the below 10, you look at 8 to 10 or 6 to 10, because they have a chance of coming down.  I sort of sense a somewhat different --
		DR. STOTO:  I don't want to make distinctions in there. 
		DR. KAYAJANIAN:  No, no.  I'm simply saying if you have to.
		DR. HARRISON:  I don't think that's going to be necessary.  Joel will write a check for this himself if he has to.
		DR. MICHALEK:  Don't worry.
		DR. GOUGH:  This is beyond the scope of work I think right now, but we have archived serum samples, right?
		DR. MICHALEK:  Yes.
		DR. GOUGH:  Well, if we're going to do TEQs on everybody here, it would be probably of some use to do TEQs on the high guys.
		DR. MICHALEK:  Closer to Vietnam.
		DR. GOUGH:  Then if I think what is true is true, then there really is going to be a spike for 2 3 7 8.  And that would be a useful bit of information.  And also tell us something about what I expect is a decrease in 2 3 7 8 and an increase in these other things over time.
		DR. HARRISON:  Actually, what I would do is, I would use that as the argument for why these samples should be maintained and preserved.  Because that's a very useful item that's not a part of this study.
		DR. STOTO:  It's not part of Cycle 6.
		DR. GOUGH:  No, and it has nothing ‑‑ 
		DR. HARRISON:  You should write a grant.
		DR. GOUGH:  I can always get Ben & Jerry's to underwrite it. 
		(Laughter) 
		DR. HARRISON:  We don't want to put the dioxin content of Ben & Jerry's ice cream on record.
		DR. KAYAJANIAN:  It's already on record. 
		DR. MICHALEK:  Thank you.  That was very helpful.
		DR. HARRISON:  Len was saying it would be good to know as soon as possible if you thought you were going to be able to do this.  But I'm thinking two weeks is when you've got to respond anyway.  That's your turnaround time for the revised statement of work.
		DR. MINER:  So we're going to go back and have a very long and interesting meeting on funding on what we can afford, yes.
		DR. HARRISON:  Okay, but the point is that that Statement of Work that's coming back in two weeks will say whether or not you're going to try and do this.
		DR. MICHALEK:  I'd just like to make a point to anyone who has any influence over funding.  The Air Force would simply request that the money, if any money would be added to the study, be given directly to CDC, so that the assays ‑‑ we don't need to handle the money.  What you need to do is fund CDC.  They're the recipient; that's where the lab is.
		And if money were to be made available, it need not be made available all at once; it can be made available in installments to CDC.  
		DR. HARRISON:  In fact, let me ask you this.  Let me point out something that you can do.  And that is, you can do the dioxin draw on everybody.
		DR. MICHALEK:  Yes, and save those serum, and wait.
		DR. HARRISON:  So I think we could pretty much agree right here today that the Statement of Work will include a dioxin draw and storage.
		Now the real question is, will it also include analysis?  And if so, which samples will be analyzed?
		LTC BURNHAM:  53,000 samples.
		DR. GOUGH:  Well, yes, incremental.
		DR. HARRISON:  In endocrinology we have "didja-tubes"; you know, when someone says, well, did you measure this?  You go back and grab the tube.
		DR. MICHALEK:  Shows there's a lot of degrees of freedom here.
		DR. MINER:  The other issue; you had asked me, we had talked about ‑‑ Epstein-Barr transformations.
		DR. HARRISON:  You're right; I did ask.  Just to provide some context here, I saw you visited the University of Utah some years ago, and Utah of course has one of the finest genetic programs, as a state, that you ever want to see.  Of course with all the genealogical records, it makes it easy to do conventional genetics.  But essentially everyone who enters the clinical research center at the University of Utah contributes a sample of blood, the nucleated blood cells of which are then transformed, using Epstein-Barr virus, which then produces cells that divide and grow.  Those cells are then grown, frozen and stored for future genetic studies.
		The point is that you not only have a DNA sample, but you actually have a living DNA sample if you do the Epstein-Barr transformation.
		DR. MICHALEK:  So we could end up cloning this whole group a hundred years from now.
		DR. HARRISON:  We could end up with gazillions of Ranch Handers.
		DR. MINER:  Don't call it that.
		DR. MICHALEK:  Make a new Ranch Hand cohort.
		DR. HARRISON:  So that was the context that I was asking about Epstein-Barr transformations.
		DR. MINER:  Okay.  So I called Dr. Jeffrey ‑‑ 
		[Simultaneous discussion] 
‑‑ and after several weeks of telephone tag, we got ‑‑ he said, "Well, I'm not quite the one you should be talking to, it ought to be Dr. Francesca Grieder at NCRR," and I finally got ahold of her, and she says "Well, I'm not quite the one you should be talking to," and I got ahold of Dr. Phi Kraus, and he said "Well, yeah, that's a great idea.  It's wonderful," but he's not the one I should be talking to.  So I have Jeff Cohen and a couple of ours.
		But you also asked about costs, and I found on the Internet a place where you can order Epstein-Barr virus transformations, 155 Eurodollars.   But they say growth and preparation of a cell bank to inquire.  I haven't followed up on that yet.
		I also found on the Web a request for a Statement of Work, actually, on the Crohn's-Colitis Foundation, requesting applications for a DNA cell line repository to receive and process peripheral blood cells or to establish cell lines; and if I would change the verbiage in this to Ranch Hands instead of Crohn's, that's what we want done.  So I'm going to try and contact these folks over the next couple of weeks and see what kind of bids they got in to do that.
		DR. HARRISON:  But you never talked directly to the University of Utah people?
		DR. MINER:  No, I didn't get led down that path.
		DR. HARRISON:  Well, that might be worth ‑‑ if that's something that you all are, you think is even feasible to consider --
		DR. MINER:  Well, we collect the white blood cells anyway.  We just throw them away now.
		DR. HARRISON:  Yes, but this is a whole different level of consent.
		DR. MINER:  Yes, that's correct.
		DR. STOTO:  Is there even time to do this now?  The Statement of Work.
		DR. MINER:  Yes.
		DR. GOUGH:  What's the justification for this?
		DR. HARRISON:  It's the ultimate didya-tube.  Really.  For instance, yesterday we were talking about ‑‑ we were talking; I was talking --
		DR. GOUGH:  That's why I don't remember it.
		DR. HARRISON:  ‑‑ about the differences in the repeat elements and exons and how that has been discovered to relate to prostate disease; or put another way, to any androgen-sensitive activity.  So it's an 'if' kind of thing.  I don't know that there's a specific study.
		LTC BURNHAM:  Well, the best thing, you mentioned about cirrhosis.  Some people are going to get it where others aren't.  We may find a gene that someone is sensitive or resistant to --
		DR. HARRISON:  It wouldn't surprise me if someone were interested in looking at polymorphisms of the AH receptor. 
		DR. MICHALEK:  That was one of our ‑‑ it's in the addendum.  That's Longnecker's proposal that we've included in the Statement of Work.  We're going to save red blood cells.  Well, save cellular material; we're going to save cells.  
		DR. HARRISON:  Red blood cells don't have nuclei.
		DR. GOUGH:  I'm in favor of that.
		DR. HARRISON:  So the idea here is, if  you save white blood cells, you're saving a finite resource.
		DR. GOUGH:  Yes.
		DR. HARRISON:  If you Epstein-Barr transform white blood cells and freeze them away, you have an infinite resource.
		DR. GOUGH:  I'm for you.
		DR. HARRISON:  So it's the sense of the committee that this is at least an acceptable addition to the biological sample?  On the one hand, think of it, this is really silly.  On the one hand, think of it, this is really silly.  On the one hand we're worried that this stuff is going to be destroyed in another few years; on the other hand we're thinking about how to immortalize a sample.
		DR. GOUGH:  But it increases the intrinsic value of the rest of the samples to do this, because if people do want to come back and look at polymorphisms, they'd like to have all this other stuff.
		DR. HARRISON:  Good point.
		DR. GOUGH:  Whoever is taking minutes, notice I used the word "intrinsic."
		DR. HARRISON:  Anything else, Jay?
		DR. MINER:  No, that's enough.
		DR. HARRISON:  If you want to give me a call and have me call the people out at the University of Utah and see if they have a protocol.  I don't actually know them.  I can tell you, though, one part that's interesting, and that is that that group is almost entirely Howard Hughes Medical Institute investigators, and if there's any group that could crank up a quick half a million dollars to do something fun like this, it would be them.  I mean, I used to be a Howard Hughes investigator, and around November they'd call up wanting to know what I wanted. I've never had a granting agency do that. 
		(Laughter) 
		Anything else from leftover stuff.  Let's see, we've done that, we've done the letter.  So all we have to do now is agree on the ‑‑ when we need to meet next, and I have one suggestion to make for this.
-		That is, I think SAIC should include the Advisory Committee meeting as part of its program project planing.  It would make contextual sense.  You all know, they know when you need advisory committee responses, and you have the stuff planned out for the next five years.
		DR. OGERSHOK:  We also do our own overall project plan.  Actually, they're integrated into our plan.
		DR. HARRISON:  Well, in fact, when I said SAIC, I take that the back.  I'm just suggesting, though, that the advisory committee meeting schedule be thought of as a part of the project.  I don't think anyone on the Advisory Committee has a vested interest in whether we meet in June or August; the real thing that we have a vested interest in is that we meet in a timely fashion.
		DR. STOTO:  Right. And that we know far enough in advance when it's going to be so we can keep the dates.
		DR. OGERSHOK:  One time we did that; but when things started to fall apart, then we stopped doing it.
		DR. HARRISON:  Well, I think -- 
		DR. STOTO:  That's why you need it in the plan, so that --
		DR. HARRISON:  I would urge you to keep it in the plan, because what falls apart, as we've said before, is support for this committee.  And I think that if I were you, I would keep it in the plan and make the failure to meet the responsibility of some other agency other than our lack of planning.
		DR. OGERSHOK:  Okay.  It makes sense.
		DR. HARRISON:  So when are we going to meet next?
		MR. COENE:  What's on the agenda?  What needs to be ‑‑ and I know one subject, and that's ‑‑ well, one is a response to Mike's request and the second is the research proposals.  The review of the research proposals.
		DR. MICHALEK:  What was Mike's request again? 
		MR. COENE:  The outstanding --
		LTC BURNHAM:  The carotid artery stuff.
		DR. MICHALEK:  That's what I meant, sure.  And I would call that the science presentations.  I would say that we'd be ready to give you an in-depth science presentation within six months.  So I was hoping to have a meeting around September, October of this year.
		DR. HARRISON:  The science that you're discussing is a part of the Cycle 6 ‑‑?
		DR. MICHALEK:  No; it's just an update on diabetes and carotid artery and anything else we're doing.  Because we will not have collected Cycle 6 data yet.  Cycle 6 data won't start to come in until March or April of 2002.
		DR. HARRISON:  Let's back up for a minute.  There are science projects that are associated with the upcoming Cycle 6 ‑‑ that have not been reviewed, that have not been assessed for scientific credulity.
		DR. STOTO:  We looked at them in very brief form last time.
		DR. MICHALEK:  Oh, I'm sorry, I misunderstood.
		MR. COENE:  We were going to put reviewers on them.
		DR. MICHALEK:  I thought you did that already.  You haven't done that yet.
		MR. COENE:  No.
		DR. GOUGH:  Well, we haven't even seen them all, I don't think.
		MR. COENE:  You actually went back, you remember they were buried?  Some of them were buried?
		DR. MICHALEK:  Yes, and I reduced it to four.  I sent you four proposals.
		MR. COENE:  Right, but we weren't going to take those up today.
		DR. HARRISON:  So we have proposals, you're saying?
		DR. MICHALEK:  Yes.  There were four proposals I sent to the committee.
		DR. STOTO:  Are they proposals or are they paragraphs?
		DR. MICHALEK:  No, no, these are proposals; these are full blown writeups.
		DR. HARRISON:  So we need to select some reviewers.  If there's not appropriate reviewers on the Advisory Committee --
		DR. MICHALEK:  That has to be done soon.
		DR. HARRISON:  -- and that was my concern, is now we're all ‑‑ because the Statement of Work gets driven into granite when?
		DR. MICHALEK:  What's the deadline?
		DR. MINER:  The proposal is supposed to go out the 2nd of March.  Now, it can take some minor tweaking.
		DR. HARRISON:  We can't possibly --
		DR. GOUGH:  Review proposals.
		DR. HARRISON:  I mean, this is --
		DR. MINER:  Up until about the middle of March.
		MR. COENE:  How will these research proposals impact on the scope of work?
		DR. MICHALEK:  Well, there were four of them.  One was the IMT, the intima media thickness measurement, and that's an onsite procedure; it will be done right at Scripps by Dr. Dwyer.  And so that's written into the Statement of Work already, it was an addendum.
		DR. HARRISON:  That's the carotid artery --
		DR. MICHALEK:  Carotid artery thickness.  Then there's the blood pressures, peripheral blood pressures, and that's in the Statement of Work currently, and that's another one you were to review; and then there was Matt Longnecker's proposal to look at AH receptor polymorphisms by simply saving white blood cells, to be done some time in the future; that's in there.
		Then the last one was the electrophysiological measurement; the neurological function, namely the nerve conduction velocities, and that's in there.
		DR. GOUGH:  So if it's in there, what are we ‑‑?
		DR. MICHALEK:  Well, I assume --
		DR. HARRISON:  Well, the problem, though, see, is that when you look at this ‑‑ for instance you look at this carotid artery thickness study, and I know that carotid artery thickness studies are being done, that that's an endpoint that seems to be used by people; but as I expressed yesterday when we were going over it, I wasn't real happy with the explicit description of how it was going to be done.
		DR. HARRISON:  Okay.  Then if you tell us more about what you need, he'll rewrite the proposal.
		DR. HARRISON:  We have no neurologists at all; you know, I ‑‑ I have no idea.  I can look at the neurological section and I can say ‑‑ 
		DR. MICHALEK:  It's in the addendum.
		DR. HARRISON:  ‑‑ that it's consistent; you know, I know nerve conduction studies, what neurologists do.  But I feel certain that any neurologist is going to say "Well, you know, are you going to do it the XXX way, or the YYY way, or the ZZZ way?"  And if the question is nerve conduction problems secondary to diabetes, you look at one form, and --
		DR. MICHALEK:  It's in the addendum, in the Statement of Work.  Unless I gave it to  you separately, as a separate document.
		DR. HARRISON:  But we don't have a reviewer. 
		DR. GOUGH:  And we got the addendum the day before yesterday.
		DR. HARRISON:  I don't care when ‑‑ we don't have --
		DR. MICHALEK:  But I gave those proposals to Ron several months ago.
		DR. HARRISON:  ‑‑ so --
		MR. COENE:  But the record ‑‑ okay.
		DR. HARRISON:  Can we at this point ‑‑ at this point what should we do?  Shall we take the nerve conduction study addendum ‑‑.
		DR. STOTO:  It's not like reviewing a proposal at this point.  It's reviewing a protocol to see whether or not it is clear enough and appropriate, so on.
		DR. HARRISON:  Well, I'm not real pleased with this.
		DR. STOTO:  Well, I understand.
		DR. HARRISON:  I just have to say that I think this is a good way of avoiding scientific review.  And I think it's ‑‑ I can't think of anything that I feel so dissatisfied about.
		MR. COENE:  Let's back up.  There was a point when we thought we were going to have another meeting in March, and it was my understanding that it would be at the March meeting then that we were going ‑‑ that's why I questioned you yesterday.
		DR. MICHALEK:  Sorry, I forgot that.
		MR. COENE:  Yes, that we were going to meet in March, and that the meeting in March was to conduct this review, and that I didn't bother Bob about identifying reviewers, because  you talked about reviewers.  I do have them, but they weren't to be done at this meeting.
		This meeting was to address the scope of work.
		DR. HARRISON:  But, see, the thing about it is that they really ‑‑ they've essentially been integrated into the Statement of Work ‑‑.
		DR. MICHALEK:  Well, we were waiting for you to tell us your impression.
		DR. GOUGH:  Can we pull them out if we don't like them?
		MR. COENE:  Yes.  Well, I mean --
		DR. GOUGH:  No, no, no.  I mean it's in the Statement of Work as it is now.  If we meet in March and decide there's no scientific justification for them, can't they just be pulled out of the Statement of Work?
		DR. MINER:  Yes.
		DR. GOUGH:  That won't create a great deal of trouble, will it?
		MR. COENE:  Well, now --
		DR. MICHALEK:  They can be taken out later.
		DR. HARRISON:  I'm just thinking.
		DR. GOUGH:  That would be a suitable solution to me, but I do think we need outside reviewers.  Because Landrigan, if he ever comes to a meeting, and you are the only clinicians, right?
		DR. HARRISON:  Well, now that Elissa's gone.
		MR. COENE:  And Osei.
		DR. HARRISON:  Oh, yes, Kwame Osei.
		DR. GOUGH:  So he would be a good one.
		DR. HARRISON:  Actually, even Sills is a pathologist.
		MR. COENE:  Yes.
		DR. HARRISON:  I mean, he's an animal pathologist, but at least he, you know, knows that red blood cells don't have DNA in them.
		DR. GOUGH:  Large animals, or?
		DR. HARRISON:  So we have four proposals.  We need at least ‑‑ of those four proposals, we need to inquire as to which committee members feel they have sufficient expertise to judge those proposals.
		Where there are less than two reviewers available from the committee, not necessarily who will be able to attend the meeting but who will be able to review the proposal, then we need to find an outside reviewer who can receive some honorarium for performing the review, and we need to meet in March and as early in March as possible.
		DR. GOUGH:  I'm with you.
		DR. HARRISON:  Does that ‑‑?
		DR. OGERSHOK:  That sounds better.
		DR. HARRISON:  Okay.  So ‑‑.
		MR. COENE:  We have to go to the Federal Register next week.
		DR. OGERSHOK:  Yes, but that's only four weeks.
		MR. COENE:  We, you, somebody has to go to the Federal Register next week, the first of February.
		DR. HARRISON:  Actually, do you know what I have down here that's interesting?  I have March 18th, "hold for Agent Orange."
		MS. JEWELL:  That's because when we put a calendar out there, several people were available.
		MR. COENE:  You told us to do that; we did that.
		DR. STOTO:  That whole week I have as a possibility.
		DR. HARRISON:  All right.  Well.  I'm just ‑‑ you know. 
		[Simultaneous discussion] 
		DR. HARRISON:  Okay, let's travel on the 11th and meet on the 12th.  
		MS. JEWELL:  You have to check with your Exec Sec.
		DR. HARRISON:  Yes, he said the first part of March.  
		MS. JEWELL:  First week, he said.
		MR. SCHECHTMAN:  First week in March is my only open week in March.  
		DR. HARRISON:  That's too soon.  
		MR. SCHECHTMAN:  The week of the 5th.
		DR. STOTO:  I'm tied up on Thursday and Friday.
		DR. CAMACHO:  So you're talking about one day?
		DR. HARRISON:  Yes, we could do this in one day.  But you've got a travel day. and you've got ‑‑.
		MR. SCHECHTMAN:  You could do it two half days.  A travel day and a --
		DR. HARRISON:  Well, Len, when do you open back up again?
		MR. SCHECHTMAN:  After March, do you mean?
		DR. HARRISON:  Yes.  
		DR. GOUGH:  Do you have any days in the latter half of March?
		MR. SCHECHTMAN:  No, it's gone.
		April --
		DR. HARRISON:  April Fool's Day?
		MR. SCHECHTMAN:  First week in April.  About the 3rd or 4th of April it opens up again.
		LTC BURNHAM:  Is it not possible to have it the week of the 5th of March, if it's a one day deal?
		DR. GOUGH:  We have to find reviewers and get them to review it.  Who knows, that's a short period of time.
		DR. HARRISON:  Let's consider two possibilities.  There's the 8th April ‑‑ sorry, the meeting date would be the 9th of April.
		DR. GOUGH:  That's no good; I'm gone that week.  
		DR. STOTO:  Okay for me, it's a good week for me.
		DR. GOUGH:  I can't review any of these things; I'm not a clinician.  It doesn't make any difference.
		LTC BURNHAM:  Got to have a quorum, though.
		DR. HARRISON:  Yes, but --
		DR. GOUGH:  I'll send somebody in my place.
		DR. HARRISON:  We also have to have an Executive Secretary.  
		So let's consider traveling on the 8th and meeting on the 9th.  Let's also consider now going back in March; let's consider traveling on the 4th and meeting on the 5th.
		That actually becomes a little difficult for me because Mondays are one of my clinic days, and I'm already scheduled through April.  So this means that I'm going to tell my  secretary to cancel that clinic and reschedule those patients.
		DR. CAMACHO:  A Friday-Saturday is easier for me, if you need the quorum person.
		DR. HARRISON:  Friday-Saturday is easier for you?
		DR. CAMACHO:  If you need a quorum person, yes.  And I'm the least qualified to look at it.
		DR. HARRISON:  I mean if we travel on a Thursday and meet on a Friday?
		DR. STOTO:  Those two days, Thursday and Friday are out for me.  But again, I'm not the most important person for the subject matter, either.
		DR. CAMACHO:  You travel on Friday afternoon.
		DR. HARRISON:  Always gets down to statistics.
		DR. CAMACHO:  Then you meet on Saturday.
		DR. STOTO:  I don't want to do that.
		DR. CAMACHO:  You don't want to do that.
		MR. SCHECHTMAN:  Can you keep your clinic day on the 5th and travel the following day?
		DR. CAMACHO:  I've already missed a couple of teaching classes.
		DR. HARRISON:  Well, actually, I have an even worse clinic on the 6th.  Let's see if ‑‑ let's try for one ‑‑ if we met on April 9th and if there was something that was really a problem at that point, that would still be ‑‑ it would still be possible to pull that.
		What we're doing is playing spoiler here, right?  If everything's okay, then the meeting is okay; if there's something that's a real problem, that either has to be corrected or pulled, that can still be done the first week of April.
		DR. OGERSHOK:  What we would do, we were just discussing it, what we would do is put out, make them price everything and then just tell them certain things could be dropped out, which is fairly easy to do.
		DR. HARRISON:  Okay.  So instead of really killing ourselves, why don't we try for April 8th, travel on the 8th and meet on the 9th, is it?
		MR. COENE:  I would like to say the mechanics of running a review of that makes more sense.  I mean, we've got contracts in place.
		DR. HARRISON:  Travel on the 8th, meet on the 9th.  
		Now what we're going to do is we're going to agree at this meeting ‑‑ this is what I'm suggesting ‑‑ we're going to agree at this meeting that that is our next meeting date.
		DR. GOUGH:  Yes.  I just won't be here.
		DR. HARRISON:  I understand.
		DR. CAMACHO:  It will be very hard for me.
		DR. HARRISON:  Well, that's going to be our meeting date.  If we have to get Kwame Osei on the telephone to make the quorum work, we're going to meet on that day.
		DR. CAMACHO:  I could do a telephone -- I've got to be back on the 9th at 6:30.
		MS. JEWELL:  I have no problems with that where we have to have a quorum, and you have to understand that whether it be by phone or whatever, that's the requirement.
		DR. HARRISON:  I understand, but one way or another, we're going to have a quorum.  We're meeting only to review these four protocols.  So we can probably get that done in one morning.
		MR. COENE:  May I ask the format that you would propose?  Everything else being equal, how would you like, who would you like to have?
		DR. HARRISON:  Everything else being equal, I would ask that reviews be done pretty much in an NIH-type style, that there be a written resume with a critique of the proposal and a recommendation from the reviewer as to whether it should be performed or not.
		MS. JEWELL:  Back to the reviewers.  If we don't have two with the expertise on the Board, we're going for outside reviewers?
		DR. HARRISON:  Right, and it will be our responsibility, mine and yours and Len's to find the appropriate reviewers.  I don't think that will be real hard.  These are not such advanced science projects that only one or two people in the world can understand them.  So I don't think finding someone ‑‑ you know, finding a neurologist who understands what's being proposed and can, and has worked with diabetic neuropathy and has some feel for that is, is going to be acceptable, I think.
		DR. STOTO:  Are these proposals to collect data during Cycle 6, they're at least that, do they also include money for the people who work in their lab?
		DR. MICHALEK:  No.  
		DR. STOTO:  Or for their time, or?
		DR. MICHALEK:  No.
		DR. STOTO:  So it's only for data to be collected.
		DR. MICHALEK:  To be collected at Scripps Clinic.  These men are not going to benefit in any way from this.
		DR. GOUGH:  How can you review that?  How can that possibly be reviewed?		
		MR. COENE:  The IRB, where's the IRB?
		DR. GOUGH:  No, no.  If we don't know what, the analysis of the samples is going to be, how can you review the proposal?
		DR. MICHALEK:  You have already seen the ‑‑ nerve conduction velocities will be used in the assessment of peripheral neuropathy, and you saw that in the Neural section of the Statement of Work.
		DR. GOUGH:  So what are we looking at?
		DR. MICHALEK:  You're looking at the actual clinical procedure to assess nerve conduction velocities.  This is a routine procedure, according to Jim Albers, University of Michigan.
		DR. STOTO:  But we need to have a justification for what new you will learn by doing this, how the data will be analyzed --
		DR. MICHALEK:  I presented that in a justification that I gave to Ron Coene.  I wrote a paper explaining why this method is important for the study.
		MR. COENE:  You asked for that and he has provided that.
		DR. STOTO:  Did he see it?
		MR. COENE:  Yes.  I mean, I have not shared any of it with anybody since it was not on the agenda for today.
		DR. MICHALEK:  I also wrote material justifying the IMT, the intimedial thickness.  The reason there is we're seeing a trend of increased thickness with increased dioxin.  And that presentation I couldn't make today because I wasn't ready.  But we're also seeing an effect on peripheral neuropathy with dioxin that seems unrelated to diabetes, whether we include diabetics or not in the analysis; and that's also part of the justification.
		DR. STOTO:  I think that what we need, and maybe it exists to some degree already in this document, is a proposal for why it would make sense to study a certain thing. 
		DR. MICHALEK:  That's exactly what I wrote.
		MR. COENE:  He's done that.
		DR. STOTO:  Good.  Let me say more.  I think what we need is a proposal that says basically, why does it make sense to study this thing.  And that includes a background on what this thing is and what we know about its relationship to dioxin or the different outcomes we're interested in and so on.  The second thing is a protocol that says exactly what would be done in terms of gathering the data and how the data would be analyzed.
		DR. MICHALEK:  Everything you have described.
		DR. STOTO:  Good.  That's what we need.  And if it's there already, that's fine.
		DR. MICHALEK:  It's done.
		DR. HARRISON:  What I'm trying to do, or at least what I'm interested in, and it's pretty late in the whole study for this, but you've got what's-his-name off in California doing adipose tissue samples; you've got some guy down in Arkansas doing glucose clamp studies; and they're all a part of this ‑‑ it's a way of adding science projects to this study that seems ad hoc to me; and I've been trying to figure out how we can bring some more reasonable review into that process.  
		Rather than just what's being said, you know, "Nokamura out at such-and-such has got five adipose samples."  The fact that those adipose samples have already been obtained is not sufficient justification to just allow somebody to use them.  There needs to be someone who looks at ‑‑ who knows what they're looking at, who looks at the protocol and says "I think this is worth doing."
		It would be even better ‑‑ this is one of the reasons for the letter last year, it would be even better if there were 50 or 100 competing applications and you could say "Well, this is the best one."  And that's not what we have right now.
		What we have are one or two people who happen to know that there's an Air Force health study and that there's a little treasure trove over here, and get together and say "We want to do, we want to study these hangnails."
		DR. MICHALEK:  That's not how it happened.
		DR. HARRISON:  Yes, it is.
		DR. MICHALEK:  No, it isn't.
		DR. HARRISON:  It's not happening with an RFP, it's not happening with a review of scientific peers --
		DR. MICHALEK:  That's true.
		DR. HARRISON:  ‑‑ and the Advisory Committee is not acting like an NIH advisory committee which sets direction and determines what the priorities should be in terms of what should be looked at next.  It's none of those things.
		DR. MICHALEK:  That's true.
		DR. HARRISON:  So at the very least I think that we should just make sure that the new things that are added ‑‑ I consider carotid artery thickness to be a new thing, really.  Is ‑‑ I'd like to see that, that at least someone can say "Yes, this is the right way to do it."
		DR. GOUGH:  Or, "this has really shown to be of value."
		DR. HARRISON:  Yes, as opposed to someone saying, "Jesus, we stopped measuring that ten years ago."
		DR. MICHALEK:  Since you brought up Dr. Matsamura, for the record I would just like to say that Matsamura didn't know about the study; we approached Matsamura, not the other way around.
		The idea was presented to peer review, to Linda Birnbaum at EPA, Mike DeVito, and other scientists that I know in Washington connected with EPA and NIEHS.
		DR. HARRISON:  That's not peer review.
		DR. MICHALEK:  I know that.
		DR. HARRISON:  That's you writing --
		DR. MICHALEK:  It's not what you described, either. What happened was --
		DR. HARRISON:  Either way, it's just as bad.
		DR. STOTO:  Actually, it's even worse that you went and found him.  That's one less--
		DR. MICHALEK:  No, I didn't seek him out; I said who would be the best person to do this job?
		DR. HARRISON:  It's the same thing.
		DR. GOUGH:  I think what you're talking about is different.  Joel thinks in terms of contracts, you're thinking in terms of grants.
		DR. STOTO:  Right.
		DR. HARRISON:  Also what I'm thinking about is in terms of, you know, I'm talking about peer review.
		DR. GOUGH:  Oh, I completely agree.
		DR. HARRISON:  And even in the contracts process, it's not sufficient for the contractor ‑‑ I know you'll consider this overstated ‑‑ but it is not acceptable for the contractor to call up his buddy and ask his buddy if his buddy thinks that it's okay for them to do it this way.
		DR. STOTO:  It's even more than peer review; the system we have is that it's investigator-initiated projects that has worked so well, and the way it works is that you allow investigators to come up with ideas based on their understanding of the science.
		DR. HARRISON:  That surprise you.
		DR. STOTO:  Yes.  And if more people knew about this opportunity, you'd get a lot better --
		DR. HARRISON:  Now let me say, Joel, that I'm really pleased with what you've done.  And the part that I think is really outstanding that you've done is the you've brought the Air Force Health Study into the peer reviewed literature in a consistent way, and I can't help but feel that that's raised the visibility of the project in the scientific world and added to its credibility in a way that you could not have done any other way.
		So I want you to understand, I'm real ‑‑ just because I'm a little unhappy with one side doesn't mean that I'm unhappy with the whole shooting match.  I really think that that part of it, I mean, you know, you're a wild man.
		DR. MINER:  How true, how true. 
		(Laughter) 
		DR. MICHALEK:  All right.
		DR. HARRISON:  All right, so we're going to meet in April.  Really, I didn't want to end on saying that something was not -- 
		DR. MICHALEK:  I agree.  Yes, there was no peer review of the kind that you and I would like to have on the adipose tissue, and that's true.
		DR. HARRISON:  And I understand it's the circumstances.  I'm just trying to add a little something or suggest that we add a little something.
		DR. MICHALEK:  I agree with you.
		DR. HARRISON:  So we're going to meet in March.  Do we need to schedule another meeting now? 
		VOICES:  April.
		DR. HARRISON:  I mean, April.
		DR. CAMACHO:  By phone or bodies?
		DR. HARRISON:  Whoever we need by phone we'll do by phone.  Whoever can actually come and sit and --
		DR. GOUGH:  Pontificate is the word you're looking for?
		DR. HARRISON:  Yes.  
		Do we need another meeting date?  Is there anything else known about the project schedule now that says that another review would be useful?
		DR. OGERSHOK:  The only other one I can ‑‑ and that's sometime in the future ‑‑ I know we've got to do one, we should do one once we get ready to go into our exams, prior to the exams.
		DR. HARRISON:  So you're talking about the spring of 2002.
		DR. OGERSHOK:  Yes.  That's quite a bit in the future.  Spring of 2002, right.
		DR. MICHALEK:  Do you want one before we start the exams, or after, or what?
		DR. OGERSHOK:  Usually we do --
		DR. MINER:  Usually we like to have them out soon after exams are started so they can actually see the process, and get a good feel for how data are collected and handled.
		DR. MICHALEK:  So we want the committee to come to Scripps Clinic after the exams start to observe the process.
		DR. STOTO:  If they've resolved their power problems in California?
		MS. JEWELL:  Joel, you said something about having a meeting, or somebody did, in six months, though; September or October.  Are we not going to do that now?
		DR. MICHALEK:  Yes.  That's my own scientific thing, where I'd like to be able to stand up and show you some new science.
		DR. HARRISON:  I think we should have a fall meeting.
		DR. MICHALEK:  When do you want to see that?
		DR. HARRISON:  I think to wait for one whole year is --
		DR. OGERSHOK:  That's a good idea; plus we'd already be on contract, and we can give you an update of everything that's going on.
		MR. COENE:  We also have the VA.
		DR. STOTO:  Yes, I was going to ask about that.
		MR. COENE:  Han Kang just doesn't --
		DR. HARRISON:  They don't want to meet with us.
		DR. MICHALEK:  We need to coordinate with the Army Chemical Corps study.
		MR. COENE:  We'll probably bring Han Kang in in March, to get a report.
		DR. HARRISON:  So let's do this.  Len, can we put out an e-mail calendar with "cannot meet" "can meet" dates in September - October?
		MR. SCHECHTMAN:  It will be September for me; October is gone.  I'm sorry.
		DR. MICHALEK:  September is fine with us.  
		[Simultaneous discussion] 
		DR. HARRISON:  Let's do September.
		DR. MICHALEK:  The end of September is out.
		DR. STOTO:  Right now September looks good for me.
		MS. JEWELL:  First two weeks, we're talking, then, Joel?
		DR. MICHALEK:  The week of the 10th I'll be at the Dioxin Conference the whole week.  So can't do that.
		MS. JEWELL:  Is that the only week?
		DR. MICHALEK:  That's the only week I know of.
		MS. JEWELL:  Can we get back to this April meeting?  What about the VA?  Am I to invite the VA?
		DR. HARRISON:  If the VA has something to present, then that changes the whole schedule.  Not only that, but it also changes -- see, if we're just going to meet to review four projects, we could do that with one or even two people on speakerphone.  But if we're going to have the VA present slides and try to review their project, then we are actually going to need to have a quorum present.
		I don't think we can do it remotely.
		MR. COENE:  Maybe just limit it to an update, and then get him scheduled into September.
		DR. HARRISON:  Okay, I'm amenable to whatever you all think is fair.
		MR. COENE:  Well, it's up to you.  Do you want to know what's going on?  You can ask him to come front and center.
		DR. HARRISON:  So we'll invite the VA to update us in April, and we'll expect a full two day meeting in September that will include a detailed presentation by the VA.
		DR. STOTO:  You can also, if they need to have a Powerpoint presentation for their update, they can e‑mail that to the people who are going to be on the phone.
		DR. HARRISON:  That's true.  The other thing, though, is what we're seeing right now is that the September meeting, that the Air Force presentation will essentially be science.  Joel's going to present what new things they've written and published, and so that's kind of consistent that the VA then will be presenting their nuts and bolts of the Chemical Corps study.
		MS. JEWELL:  Okay.
		DR. MICHALEK:  Did we settle on a day in September yet? 
		VOICE:  No.
		DR. HARRISON:  I don't know ‑‑ we can settle on a day that we can't.  I mean, you've said that we can't do the week of the 10th.  But I think that so many members of the committee are not here, that we should at least make an attempt to contact them and see when they can --
		MS. JEWELL:  I'll do it tomorrow, this afternoon or tomorrow, I'll try to opinion the date down.
		DR. HARRISON:  Sounds good.  Sounds good to me.  That will work for me.
		What else do we need?
		DR. GOUGH:  Is there any possibility of replacing Dr. Favata?
		DR. HARRISON:  I don't think we could ever replace Dr. Favata.
		DR. GOUGH:  No, I know that; but as I said ten years ago, this committee needs more clinicians.  
		MS. JEWELL:  The proposal right now is to try to reinstate Dr. Terwyn for four years.
		DR. HARRISON:  Oh, from Kansas?
		MS. JEWELL:  He's been off a year, and the veterans organization hadn't suggested that we try to bring him back for four years.  And I talked yesterday to ‑‑ what was her name, the new person ‑‑ Captain Caldwell, and she thought that would be a good idea.
		So that's kind of where we are.
		DR. HARRISON:  What's Ron's expertise?  Wasn't he an epidemiologist as well?
		MR. COENE:  Toxicologist.  You ought to know, we're not obligated to do that.
		MS. JEWELL:  No, and she'll take --
		MR. COENE:  Because we've got three members from the veterans organizations on the committee now.
		LTC BURNHAM:  You mean Lambert?
		DR. HARRISON:  Terwyn.
		LTC BURNHAM:  Who did you talk to?  You mean Mary lambert?
		MS. JEWELL:  Lambert.  She just replaced Peter Mazella.  And she said that would be fine with her; she had no problem.  But I'm sure if you had someone else in mind, we could send both down and they can select.
		DR. GOUGH:  I don't have anybody in mind.  But it's just a deficit.
		DR. STOTO:  I think the clinical is important. 
		DR. GOUGH:  Yes.
		MS. JEWELL:  And we do have three veteran reps on; this would have been a fourth.  So it's not going to be a problem if you want--
		DR. STOTO:  And Trewyn really is not a clinical person.
		LTC BURNHAM:  No, he's not a physician.
		DR. HARRISON:  I didn't think he was.
		LTC BURNHAM:  He's not.
		DR. HARRISON:  It's not so much whether you're a physician as much as whether--
		DR. GOUGH:  Yes. 
		(Laughter) 
		DR. GOUGH:  I really think so, Bob.
		DR. HARRISON:  Okay.  I mean, I don't know anyone personally that I would ‑‑.
		One of the universities in Texas was interested at one point in archiving the, in being the repository for --
		VOICES:  Texas Tech. 
		DR. MICHALEK:  Wait a minute, there's a guy at UT health science center, Michael Weiss, who's really good, and he's a physician.  He's also on the IOM or was on the IOM, and reviewed our diabetes material.  I think he's off the IOM now, so he's a really good clinician, I think.
		DR. HARRISON:  I was thinking that surely, wherever there was an institutional interest in this, there might well be a physician with an interest as well.  So that might be someone to at least ‑‑ Joel, do you know him?
		DR. MICHALEK:  Yes.
		DR. HARRISON:  Do you know him well enough to ask him if he would send his c.v.?
		DR. MICHALEK:  Yes, I do.  I can send him an e‑mail and ask him to communicate.
		DR. HARRISON:  You know, if he wouldn't feel insulted by being asked to submit a ‑‑ not submit a c.v., but just so that we've got some idea --
		MR. COENE:  Put his name in nomination for appointment to this committee.
		DR. HARRISON:  I was thinking you could send it to you.
		LTC BURNHAM:  Mike, do you know of other people --
		DR. STOTO:  I ‑‑  
		[Simultaneous discussion] 
		DR. HARRISON:  I would just like to at least get an idea of who we're talking about.
		MR. COENE:  By the first of February they need to be moving ahead.
		DR. HARRISON:  The other thing you might ask him in that e‑mail message is, that if he knew of any other physicians who would have an interest in various organo-whatever those things are called.
		DR. MICHALEK:  I think a good place to go would be the SAB, for example, for the EPA, is filled with clinicians and pathologists who are interested in dioxin, and they already know the issue.  And they're up to speed.
		DR. HARRISON:  You know something?  Now that I think about it again, I'm not sure that's a good idea.
		DR. MICHALEK:  You don't think so?  And the IOM.
		DR. HARRISON:  Because everybody there has got an attitude. 
		(Laughter) 
		DR. MICHALEK:  You want somebody fresh.
		DR. HARRISON:  Well, seriously.
		DR. MICHALEK:  I agree with you.
		LTC BURNHAM:  I think the group that Mike was on at the IOM back when is perfect.  Because those people were picked because they didn't have an attitude.
		DR. MINER:  They quickly develop one.
		DR. MICHALEK:  Is that true?
		DR. STOTO:  Yes.  It's hard to find people like that.
		(Laughter) 
		DR. HARRISON:  You know, to some extent I'm not really worried, because the way committees operate, you tend to knock off the corners on people; you know, a person with an attitude doesn't really last very long, doesn't really keep their attitude very long once they're on a committee that ‑‑ you know, unless the committee --
		DR. STOTO:  It helps to get fresh people, I think, on these committees.
		DR. HARRISON:  Yes.
		LTC BURNHAM:  They were picked because they were leading experts, no conflicts of interest, and have taken no public position concerning the potential health effects of herbicides in Vietnam veterans.
		DR. MICHALEK:  Very good.  So who is the IOM point of contact?
		DR. STOTO:  David Butler.
		DR. MICHALEK:  David Butler may know some people.
		DR. HARRISON:  Mike, you could look into that, couldn't you?
		DR. STOTO:  I could look at the list, too. I mean, he came up with me, I think last time somebody asked him.
		MS. JEWELL:  I was just going to say, that's how we got you.
		DR. HARRISON:  You could also just ‑‑ I mean, you know people over there; you could call and say --
		DR. STOTO:  I'm going to touch bases with them to see about this thing we're writing the Secretary about, too.  
		So if I could ask at that time.
		DR. HARRISON:  Try to do it sooner.
		DR. STOTO:  Okay.
		DR. HARRISON:  What else?  
		Oh, I'm sorry.  Ma'am, I'm afraid I don't recognize you. 
		MS. McCARTHY:  Mary Ellen McCarthy, House Veterans Committee.
		DR. HARRISON:  Glad to meet you.  This is obviously not a real, formal thing here.  You're the lady that Rick Weidman mentioned yesterday was planning to dome today.
		We're ahead of time and really done.  Is there any question that you have? 
		MS. McCARTHY:  One question I had is did the issue of the dioxin measurement on the cycle get resolved, and do you need to try and get funding from the Department in order to do that?
		DR. HARRISON:  Yes, and yes.
		MS. McCARTHY:  And the amount is about $2 million?
		DR. MICHALEK:  $2 million would cover it, I believe.
		DR. MINER:  But don't say from Department of Defense.
		LTC BURNHAM:  The point that you missed out was that we would rather the funds go to CDC.   Because what traditionally happens is, they tell the Air Force to do it, without any funding, and then it gets shifted from bombs to research, makes everybody mad at us.
		MS. McCARTHY:  That's all right; they can be mad at us, that's fine.  But you need about $2 million --
		DR. MICHALEK:  About $2 million.
		MS. McCARTHY:  ‑‑ to go to CDC, because drawing the blood is really not going to cost you much more.
		DR. HARRISON:  Let me run through ‑‑ because we did it in levels.  We said, number one, that everyone should have a dioxin draw, whether there were funds to do the assay or not, because ‑‑ and you missed this, this was earlier, we are concerned about future archiving of these, and maintenance of these samples; and a letter is being prepared for the Secretary of Health and Human Services asking that a process be put in place to resolve that issue.
		So we want the samples drawn.  The committee recommends that as the first cut.
		MS. McCARTHY:  Okay.
		DR. HARRISON:  There are two possible assays to do; dioxin and total dioxins, TEQs; and it turns out that the CDC will do the total thing for the same price as the dioxins, as dioxin itself.
		So we would like all of the, the entire cohort to have an additional assay performed.  If for some reason there is insufficient funds for that, there is a cohort whose dioxin levels were still high, that we would say that would be ‑‑ if we had to select a group, the subgroup of the cohort, it would be those with high dioxin levels.  
		So we've made recommendations.  And the justification --
		DR. GOUGH:  No, I thought we were going to do the people with only one point first.
		DR. HARRISON:  Well, I'm glad I reviewed this, because I thought it was pretty clear that it was felt that adding additional point to the high values that still had first order kinetics would come first.
		DR. GOUGH:  I thought other way around, actually.
		DR. CAMACHO:  What was the last thing we --
		DR. MICHALEK:  All right.  First priority was to do everyone; if we couldn't afford that, then we would get at least two points on everyone. 
		DR. HARRISON:  Okay.  
		DR. MICHALEK:  And finally, we do above ten only.
		DR. HARRISON:  Okay.  I'm glad I --
		MS. McCARTHY:  So the third one is everybody who was above ‑‑ 
		DR. CAMACHO:  Above ten.
		DR. MICHALEK:  And that's about 500 people.
		Getting a second point on those that already have one, will be about 1500 people, and doing everyone would be about 2300 people.  And we think the current price at CDC is about $800, in round numbers.  So $800 times 2300 will be the maximum cost, which would be about $2 million.
		DR. HARRISON:  And the reason for doing the TEQs rather than just dioxins is the possibility that there may be ‑‑ the unlikely possibility but still finite possibility that there would be a confounding other dioxin that might actually had a health effect.  And this would be one last chance to rule that out as a possibility. 
		[Simultaneous discussion] 
		And if you all could get another ten thousand or so just sent directly to me ‑‑ 
		(Laughter) 
		MS. McCARTHY:  Sorry, we don't take requests.  
		[Simultaneous discussion] 
		DR. HARRISON:  My real complaint is that I didn't get to fleece.
		DR. CAMACHO:  There's also a disposition of ‑‑ I thought we talked about ‑‑ having some kind of a forum about just bringing the -- 
		DR. MICHALEK:  There are two conversations in the room and it's hard to concentrate.
		DR. GOUGH:  Mike?
		DR. CAMACHO:  I thought there was also a concern of getting some kind of a panel together among ourselves with the Veterans Affairs committee and others that are interested, to just brainbust and discuss the closing of the study.  And I think that's important from my point of view, that all the committee members get it in their head what's going to happen here.  So we're not just yanking a plug out of the wall in 2006.
		There's a lot of ideas, legal issues and ethical issues.
		DR. HARRISON:  Paul, what we agreed was that I would send a letter to the Secretary of Health and Human Services, Secretary of the VA and Secretary of the Air Force, expressing the concern of the committee that plans be made for disposition ‑‑ well, for maintenance and preservation of what really is an irreplaceable treasure trove of scientific material.
		And we discovered that there's a basis for the VA being responsible for organizing the discussion of this; because there's a Public Law 104, Section 8 says that the VA should be doing this.  
		VOICE:  1024, Section 8.
		DR. HARRISON:  And if you'd like to have a copy of that letter when it's prepared, I'd be happy to forward it to you.  Because we've agreed that the public itself, and our previous letter to the previous Secretary of Health and Human Services would be included in this new letter.
		And we'd be happy to bring you up to speed on that as well.
		DR. STOTO:  It turns out that what Bruce and I were talking about was the same issue.  And I think the point that we've got to be clear is, because of the budgeting cycle in the Defense Department, decisions need to be made soon about what might happen in '07.  And I hope that we get that in the letter.
		DR. HARRISON:  Well, I didn't spell it out that way; I said that this is an urgent problem that needs immediate, and I was going to underline "immediate action" to --
		DR. STOTO:  Maybe you should say because of the DoD's budgeting cycle or something like that.
		DR. HARRISON:  Okay. 
		[Simultaneous discussion] 
		DR. STOTO:  I don't think we need to say the specifics of it, but just to say that--
		DR. HARRISON:  To meet the budgeting cycle and avoid loss.
		MS. McCARTHY:  You need this money allocated for FY 2002?
		DR. MICHALEK:  For the assays?
		DR. MINER:  We start them in '03 and probably will finish them up either that year or for '04.
		DR. MICHALEK:  FY.
		DR. MINER:  FY.
		MS. McCARTHY:  FY'03?
		DR. MICHALEK:  FY'03 and 4. 
		MS. McCARTHY:  But you basically need some kind of commitment now because you're getting ready to do your --
		DR. MICHALEK:  To start.
		For the record, I'd just like you to know that what we just heard just now was the content of a hone call I made to Mr. Darryl Dero and to you last week; and it was the reason why we wanted to meet with you, and we still do, to show you in detail, to flush out some more detail.
		MS. McCARTHY:  Actually Joel, Dero and I aren't actually the right people.  We're the benefits subcommittee; we really don't ‑‑ I cover these because of my boss's long standing interest in Agent Orange and its side effects, and the importance it had on the com side.
		It's really probably ‑‑ it's probably more appropriate in the Armed Services arena, because ‑‑ I would probably sit in on a meeting that took place.  It does make sense to have a meeting at some point, possibly; but I need to talk to you about who the right people are.
		DR. MICHALEK:  Good.  And of course I called you and Darryl because you're the only two I know personally.  
		DR. HARRISON:  But you don't write the purchase order?
		MS. McCARTHY:  I don't write the purchase order; I just pass on the information to ‑‑ 
		DR. HARRISON:  Understood.
		MS. McCARTHY:  My boss ‑‑ ranked member of the Committee on Veterans Affairs, is both on Armed Services and the ranking member on the Veterans Affairs Committee.  And he has a liaison in his office that's actually half time staff to the committee and half time with DoD.  So we have overlapping functions.  Usually Tom O'Donnel in Lane's office takes the lead on that, and I did inform him of our conversations.
		But I know that has to get cleared through all the DoD bureaucracy and that kind of stuff, but if something needs to happen, we'll just make sure we got the proper information.
		DR. HARRISON:  Okay.  Anything else?
		So the agenda for April are the review of the four scientific studies ‑‑ and a VA update, and the agenda for September will be hopefully a fuller VA review of the Chemical Corps study and an update on the Air Force's scientific publication process.
		Anything else?
		DR. GOUGH:  I just want to put on the record, after the criticisms we heard about the committee support yesterday or the day before--
		DR. HARRISON:  Yesterday.
		DR. GOUGH:  And the man who had the criticisms also said it wasn't directed at the FDA staff.  And I want to underline that while I was chairman of this committee, and so far as I know while Bob's been the chairman of this committee, Barbara and Ron have been always a pleasure to work with and responsible, and it's not their fault, any shortcomings.  I think it's far higher up in the Department than you guys.
		DR. HARRISON:  I agree.  The only thing that I've ever noticed is that Barbara and Ron bust their butts to get everything done, and it's ‑‑ you can imagine, they're like that person in the circus with the rings on both feet and both arms ‑‑ it's a shame to hear so much frustration from the representatives of the veterans organizations and from us, and to know that it's not, we're not getting the kind of support that this project deserves, I think.
		DR. GOUGH:  I'm finally finished.
		DR. HARRISON:  Okay.  Going once, going twice -- sold.
		[Whereupon, at 10:23 a.m., the meeting adjourned.]
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