Comments on "White Paper #2: Applying Genomics to Clinical Problems - Therapeutics"

Much of the "disease predisposition, initiation, and/or progression" discussed in this white paper would need to be studied in pediatric populations.

Most chronic disease problems associated with genetic predisposition, such as type 2 diabetes, begin in childhood, as do most single gene disorders.

The issues discussed in this white paper could be argued to be highly relevant to children, yet the concerns are different than with adults. This should be acknowledged in this white paper.

(65) Monday, December 22, 2008 11:15 AM

Incorporating genomics of the clinical trials represents a major research challenge. One important problem is that exposures and outcomes are not defined in a standard way across different clinical trials. Genomics research, by its very nature, requires huge sample sizes. It would be a shame if after spending tens to hundreds of millions of dollars on large scale clinical trials, data cannot be combined because compatibility was not considered ahead of time.

(67) Monday, December 22, 2008 11:48 PM

I really like the way this section is written. However, I wonder why it is targeted to therapeutics. With a little minor tweaking it could be made to include prevention and therapy. It would be a far better document in my opinion if written to include both aspects. If one prevents then one does not need to treat!! Both are medical intervention strategies and both approaches would be best identified in this section. I know White Paper 1 name implies a prevention approach but it really does not in my opinion!

(72) Sunday, December 28, 2008 3:41 PM

How does a system biology approach assist in understanding redundaces in humans. In other words, what molecular mechanisms counterbalance genetic alterations? How does this effect disease onset and natural history?

(76) Tuesday, December 30, 2008 2:36 PM

The questions raised in this White Paper are exactly on target. The Division of Gastroenterology, Hepatology and Nutrition at the University of Pittsburgh is structured to address these questions by approaching complex chronic inflammatory diseases of the liver, pancreas and intestine (IBD) using reverse engineering and mathematical modeling approaches. Perhaps illustrating the answers to many of these questions using chronic inflammatory GI diseases as models will provide a spring-board into revolutionary new disciplines....

(82) Thursday, January 1, 2009 7:04 AM

Advances in validating hypotheses with regard to mechanisms of disease or response to therapy are often made by testing lab-based questions in well-managed biological specimen repositories. For example, the MACS study for HIV or COG for childhood malignancy. The ability to generate and orchestrate meaningful data repositories must be facillitated if genetics-based approaches are going to be used in therapeutic evaluation. How can the NIH be a reource for this need, as opposed to supporting single investigators? Could blood samples, gene expression profiles, or immortalized lymphocytes be maintained in such a way that new questions could be asked by independnet investigators? This is an infrastructire gap, an obstacle to getting full value from clinical research, and an opportunity to include providers of healthcare in the research process. How many valuable patient samples have been wasted because there was no central way to bank genetic samples/data and to correlate this data with responses and outcomes? Why not have a national outcomes research center? or simply a national expression profiling center that can provide data to investigators, and the community at large? The data would be better standardized, and the results accessable. I am sure that a large user-friendly reource center would be utilized by investigatros and serve as a transformative force in how therapeutic outcomes are correlated to primary genetic data over the course of treatment. Only the NIH could fill this need.

(83) Friday, January 2, 2009 3:43 PM

I was struck by the dicotomy of professional inclusion between number 4 and 6. Whereas 4 seeks to find ways to collaborate, to partner, and to bring diverse disciplines together - which I completely agree with and support - number 6 speaks only to "physicians". This is likely an oversite and "unconscious", however, it speaks volumes. Even use of the word "clinicians" would be more inclusive but "clinicians" often does not include the important work of genetic counselors, behavioral scientists, social workers, psychologists, educators, etc who have a significant role to play in "translating" genetic/genomics research into practice and for the public. There is vast and important work to be done in all the areas touched on in this document - we need not only "all hands on deck" but also the diversity of philosophies and scientific thinking of the many.

(86) Saturday, January 3, 2009 2:10 PM

These questions seem very much pure research oriented. Until the sixth group of questions the concept of how to translate this to the patients and especially the clinicians is not addressed. Even in that section, nowhere are on-line resources or resources built into EHRs even mentioned. No matter how much pure research is done and how beautiful it is, if we cannot get the information to the clinicians and the patients in useful form it is worthless from a health care perspective. We need to start doing the research in how this will work in clinical practice as soon as possible, even if we have to create simulations to do so.

(91) Tuesday, January 6, 2009 9:37 AM

I think that we are at critical intersection of genomics and clinical medicine and many of the points outlined in this white paper are right on target in planning for the future and optimizing the successes that have been garnered to date. While complex traits are slowly being mapped and will eventually have an important impact on the populations health, the field that is most exciting at the intersection of these two fields right now is human Mendelian developmental disorders. The mapping of disease genes and understanding of the basic molecular and cellular mechanisms involved in their pathogenesis has led to startling breakthroughs and the realization that we can now begin to think of biochemical therapeutics for such disorders as Marfan syndrome, Tuberous Sclerosis, Fragile X syndrome and others.
Developing initiatives that would encourage pooling of patient cohorts to power studies identifying modifiers for these Mendelian traits through National and International collaborations and common clinical and sample databanks would help propel this research to a new level and identify both important counseling markers and therapeutic targets. Mechanisms that encourage the interaction of academic clinicians with basic scientists working in areas related to specific diagnoses should be the standard for PPGs and other large funding mechanisms.
We are on the cusp of developing active therapeutics for behavioral and cognitive deficiencies that would never have been dreamed of 10 years ago. Developing the infrastructure to help support this ground breaking research and to catalyze the rate at which these breakthroughs are achieved should be a priority for the future.

(94) Wednesday, January 7, 2009 4:13 PM

2. Developing clinically usable gene-pathway-drug resources should be a very, very high priority. Clinical geneticists are increasingly availed of new errors in gene dosage in unique or rare disease patients who will never be the subject of clinical trials. We can potentially provide them (and their insurers) value beyond the identification of the genetic defect, i.e., treatment options informed by biological knowledge of the pathways affected by their particular genotype that, coupled with compatible clinical features that fall within the scope of drug indications, could provide a basis for informed drug selection and application. This should target FDA-approved drugs in the beginning, then orphan drugs. Environmental toxin exposure avoidance can be added to this. This approach will turn out to be applicable to less rare diseases as well.
At this time, I believe the relative impact of nutritional modifications in this context will be too small to be relevant.

(100) Wednesday, January 7, 2009 7:58 PM

Q1 First bullet. Alternatively, given evidence that gene pathways are significantly more complex than previously appreciated, will a major gene approach impair identification of potential treatments for both Mendelian disorders and complex disease that might be found using other approaches?
Q4 First bullet. What is meant by an "unconventional" academic discipline? Also, the players are defined as academics and industry. Without engagement of a broader range of health care providers (e.g. VA, private not-for-profit systems capable of participating in research such as Kaiser, Mayo, Intermountain) many opportunities will be unrealized. Involvement of systems such as these will be particularly critical in addressing the issues raised in Q6 as academia has been singualarly unsuccessful in addressing educational shortcomings in practicing physicians.
Q5 Arguably the most successful model testing therapeutic interventions is the Children's Oncology Group. Also, there is an emerging model funded through the National Coordinating Center (HRSA) to develop a network for studying outcomes and treatment of inborn errors of metabolism. This suggests the potential for NHGRI to partner with other governmental groups outside of NIH to promote this type of cooperative approach.
One of the other issues not mentioned is the inherent difficulty of translating clinical trial results into practice--specifically the recognition that real world implementation frequently doesn't show the benefit seen in a tightly controlled trial, for a multitude of reasons. I think Q5 needs to include questions about the role of so-called real world clinical trials including how these should be designed and funded, when real world trials are appropriate, how are outcomes data collected and shared, who coordinates analysis and follow-up.
Q6 overlaps a number of issues raised in the 'Applying Genomics-Diagnostics, Preventive Medicine' white paper. I've commented on that previously and will not repeat here, other than to say some resources need to be devoted to new ways to educate at the point of care (so-called just-in-time education).

(105) Thursday, January 8, 2009 10:25 AM

This discussion misses several points - most cases of disease are not the consequence of simple mendelian inheritance; age of onset for most cases of disease can be modified by reductions in exposure (obesity, smoking, etc) and most treatments involve responding to somatic rather than germinal events.

(111) Monday, January 12, 2009 10:55 AM

These are well posed questions. There is still a sense of a dichotomy between rare, high penetrance genetic variation and common low penetrance variation. It's not clear whether this is real in human populations, or just a simplification. In terms of defining genetic disease risk, this needs to be addressed. It may be less relevant for identification of new therapeutic targets.

Are genetic/genomic research programs too basic, insufficiently associated with translational research to follow? For example, is it necessary to identify all genetic factors of disease when only about 10% of the protein-coding repertoire is accessible to classical small molecular chemistry?

(112) Monday, January 12, 2009 3:34 PM

Gene profiling has had its best use in breast cancer. The results are decidedly mixed. There are now multiple gene signatures being marketed and patients are paying out of pocket for them. In my opinion they add little, over and above the free Adjuvant! online tool. A huge clinical trial is being conducted by ECOG to test one of these prospectively. Are we going to launch a trial for each genetic event that shows a decent correlation to survival?
In my opinion the only genetic tools of worth will tell patients that they do not need therapy, or that they will benefit from one therapy more than others.

(113) Monday, January 12, 2009 4:10 PM

This set of questions is more objectively worded and structured in a way that is easier to follow - suggest similar structure for the first paper.

In terms of content, comprehensive and interesting questions are raised.

Agree that prevention needs more emphasis here.

(129) Wednesday, January 28, 2009 11:20 AM

We suggest that question 6 on education initiatives necessary for maximizing progress be further expanded to address the need to develop resources such as a catalog of signatures for different disease processes. Standards are also needed across these trials so that the data can be pooled across trials for more robust analysis.

In addition the expansion of question 6, these additional questions should be asked:

What further clinical/epidemiology resources and strategies are needed for the discovery and validation of gene variants (including gene-gene and gene-environment interactions) as determinants of human disease?

What biologic mechanisms contribute to the racial and ethnic disparities in disease incidence and mortality?

(134) Thursday, January 29, 2009 9:05 AM

Overall: This process of open comment shows NHGRIýs commitment to community engagement. We suggest that NHGRI make the conversation accessible to more people by using plainer language where possible (e.g., where technical language is not required).

Overall: What are the benefits of targeted therapeutics relative to costs?

Question 2 and 4 : What is the role of the private sector in comparison to or in partnership with NIH? What is the role of NIH in terms of coordinating efforts and creating incentives for collaboration (national and international)? Recognizing the overlap between the three papers, weýd advocate for a more integrated approach. In doing so, the idea of ýbuilding a bigger sandbox with incentives for all to play in fairly,ý could be addressed as opposed to alone in the third paper.

Question 5: Involving public health professionals or utilizing the approaches and lessons learned in this field will assist in efforts to educate patients and physicians.

Question 6: What is the impact of variations in therapeutic response that correlate with existing socially defined groups? How can negative impacts, such as stigma, be avoided?

Question 6: The questions as they are currently written do not portray neutrality. Rather than asking about social and behavioral practices or biases that limit acceptance, we recommend asking how research can be conducted, therapeutics marketed, therapies prescribed by providers so as to reduce the limited acceptance and utilization by patients. Rather than asking about how to ýshapeý expectation questions could ask, 'What are the expectations?' or ýWhat created these expectations?ý

(138) Thursday, January 29, 2009 7:16 PM