RFP No. NHLBI HC-98-08 Subclinical Cardiovascular Disease Study, Field Center This RFP consists of three Sections: I. Streamlined Technical RFP II. Specific RFP Instructions and Provisions III. Applicable RFP REFERENCES ****************************************************************** I. Streamlined Technical RFP A. Solicitation Form/Cover Letter Purchase Authority: 95-83, as amended RFP No. NHLBI HC-98-08 Title: Subclinical Cardiovascular Disease Study: Field Center Issued by: Cheryl A. Jennings Contracting Officer NIH/NHLBI Contracts Operations Branch Rockledge Building, MSC 7902 6701 Rockledge Drive Bethesda, MD 20892-7902 DATE ISSUED: November 4, 1997 DATE PROPOSAL DUE: January 28, 1998, 4:30 P.M. (EST) SMALL BUSINESS SET-ASIDE: X NO YES SIC Code: 8733 Ladies and Gentlemen: This Streamlined Technical RFP consists of this combined solicitation form and cover letter, and four additional components, as follows: B. Work Statement with Project Background; C. Reports/Deliverables; D. Special Requirements; and E. Evaluation Factors for Award, including Technical Evaluation Criteria. These components contain the technical information required for the submission of a proposal for this acquisition. In addition, there are two other sections to this specific RFP. The section entitled "Specific RFP Instructions and Provisions" contains, for example, the address for delivery of your proposal, as well as other provisions that provide specific information for this RFP. The section entitled "Applicable RFP REFERENCES" identifies those items resident on the Gopher directory that are applicable to this RFP. Although these documents contain sufficient information for you or your organization to submit a proposal, if you intend to submit a proposal in response to this RFP, IT IS ESSENTIAL THAT YOU IMMEDIATELY NOTIFY Cheryl A. Jennings OF THE NHLBI CONTRACTING OFFICE AT THE FOLLOWING INTERNET ADDRESS: cj19f@nih.gov IF YOU DO NOT NOTIFY THE CONTRACTING OFFICE OF YOUR INTENT, YOU WILL NOT RECEIVE NOTICE OF AMENDMENTS TO THE RFP. HOWEVER, ALL AMENDMENTS WILL BE POSTED ON THE NIH GOPHER. The original and thirty (30) copies of your technical proposal and the original and six (6) copies of your business proposal must be received by the Contracting Officer no later than January 28, 1998, at 4:30 p.m. local time (EST) at the address listed in the item entitled "Packaging and Delivery of Proposals" in the file entitled "Specific RFP Instructions and Provisions" found under the directory for this RFP. Also, refer to that file for the item entitled "Proposal Intent Response Sheet." Please complete this form and deliver it to the address indicated therein on or before December 5, 1997. This will allow us to expedite preparations for the peer review of proposals. You are reminded that the "Technical Proposal Cover Sheet" must be completed in full detail and used as the cover sheet for each copy of your technical proposal (a copy of this form is contained in this NIH Gopher under the FORMS, FORMATS, AND ATTACHMENTS subdirectory found in C. RFP REFERENCES.) This information will be used to ensure that there will be no conflict of interest when selecting review committee members. Also, your proposal must be organized and submitted in accordance with the "Technical Proposal Table of Contents" found in Section II, Paragraph I.of this RFP. NOTE; IF YOUR PROPOSAL IS NOT RECEIVED BY THE CONTRACTING OFFICER OR DESIGNEE AT THE PLACE AND TIME SPECIFIED, THEN IT WILL BE CONSIDERED LATE. THE PHSAR CLAUSE 352.215-10, "LATE PROPOSALS, MODIFICATIONS OF PROPOSALS, AND WITHDRAWALS OF PROPOSALS," is incorporated into this RFP. If you have any additional questions regarding this RFP, please contact Cheryl A. Jennings through the Internet using the electronic mail address listed above or telephone 301-435-0345 or facsimile 301-480-3430. COLLECT CALLS WILL NOT BE ACCEPTED. Sincerely, /s/ Cheryl A. Jennings Contracting Officer ****************************************************************** I. Streamlined Technical RFP ================================================================== WORK STATEMENT WITH PROJECT BACKGROUND PROJECT BACKGROUND 1. A general description of the required objectives and desired results The Field Studies and Clinical Epidemiology Scientific Research Group, Epidemiology and Biometry Program, Division of Epidemiology and Clinical Applications, NHLBI proposes to initiate a prospective observational study of the characteristics of subclinical cardiovascular disease (disease detected non-invasively before it has produced signs and symptoms) that predict progression to clinically overt cardiovascular disease in a diverse and representative population-based sample of men and women aged 35-84. The specific objectives of the study are: a. To determine characteristics related to progression of subclinical to clinical cardiovascular disease; b. To identify factors related to newer measures of subclinical disease and examine relationship of new to established measures; and c. To develop population-based methods, suitable for application in future screening and intervention studies, for identifying asymptomatic persons at highest risk of clinical events. 2. Background information helpful to a clear understanding of the requirements and how they evolved To further the study of the relationship between risk factors and atherosclerosis and to avoid the biases involved in relying solely on clinical disease outcomes, objective and unbiased measures of cardiovascular disease (CVD) have been introduced in NHLBI-initiated epidemiologic studies of CVD etiology. Two well-developed examples include echocardiography and carotid ultrasound. The observation that risk of subsequent cardiovascular events and mortality increased 1.5 to 2-fold per 50 gm/m of echocardiographically-defined left ventricular mass in Framingham led to inclusion of echocardiographic LV mass assessment in several population samples. Development and validation of duplex ultrasound imaging as a measure of atherosclerosis provided for the first time a method for visualizing the atherosclerotic process at the level of the vessel wall and suitable for application in population-based studies. Use of carotid ultrasound in the Atherosclerosis Risk in Communities (ARIC) Study has demonstrated strong relationships of carotid wall thicknesses to clinical CVD and to traditional CVD risk factors such as age, sex, lipids, hypertension, smoking, diabetes, obesity and dietary fat. Using the powerful nested case-control design, in which atherosclerosis cases and non-atherosclerotic controls are selected from the entire population distribution of wall thickness, ARIC has also demonstrated strong associations of carotid atherosclerosis with Lp(a) and Lp(a) phenotypes, antibodies to infectious agents, fibrinolytic factors and inflammatory factors, cellular adhesion molecules, homocysteine levels, and dietary magnesium and antioxidants. Carotid ultrasound and echocardiography were also included in the Cardiovascular Health Study (CHS) and were quickly demonstrated to bear strong relationships with overt CVD in this older population sample, to be associated with many conventional CVD risk factors, and to be strong predictors of subsequent overt cardiovascular events. More importantly, short-term risk of clinical events was shown to be low to non-existent in the absence of subclinical disease. Subclinical disease measures have thus enhanced studies of CVD risk by examining the early stages of CVD in an objective manner free of biases related to severity, diagnostic suspicion, or completeness of medical investigation. Because subclinical disease is asymptomatic and previously unknown to participants, it is unlikely to have any direct impact on health behavior, such as lifestyle modification or medication use, which may limit the detection of risk relationships with clinical disease. In addition, the continuous nature of most subclinical measures greatly increases power to detect risk associations compared to discrete measures, such as presence or absence of clinical events. Most importantly, subclinical measures now permit the epidemiologic investigation of CVD risk to focus on the biology of CVD rather than on vagaries in its diagnosis. Application of non-invasive measures in ongoing prospective, population-based studies has demonstrated a surprisingly high prevalence of subclinical disease. Atherosclerotic plaque is extremely common in the extracranial carotid arteries of U.S. men and women older than 45 years and can be detected in subjects at low risk as defined by traditional risk factors. Coronary calcium, a specific marker for coronary atherosclerosis, is present in 10% of women and 30% of men aged 30-39 and increases in prevalence with age. One-sixth of men and nearly one-fifth of women in Framingham have echocardiographically defined left ventricular hypertrophy, and over 30% of persons over age 65 in CHS have MRI-defined cerebral infarcts. Standardized measures of retinal arteriovenous nicking, which are strongly associated with hypertension and cerebral infarction, are present in 14% of middle-aged ARIC participants. Quantitative retinal arteriolar narrowing increases across the entire range of blood pressure, even in persons receiving effective antihypertensive therapy, and may provide an integrated measure of duration and severity of hypertension. Risk associated with subclinical disease measures has been shown to be graded and continuous (similar to risk associated with conventional CVD risk factors such as hypertension and cholesterol) rather than demonstrating a threshold level at which risk increases sharply. This suggests that interventions yielding even modest reductions in levels of subclinical disease should be explored for their potential impact on reducing CVD risk. To design such interventions, factors contributing to the development and progression of subclinical disease must be identified. The recognition that plaque rupture is a key event in coronary thrombosis and that plaques that rupture tend to be subcritical stenoses associated with lipid-laden lesions has shifted the focus of etiologic research to factors leading to formation and rupture of unstable plaque, such as inflammation and impaired endothelial function. Inflammatory and infectious factors have long been known to be associated with CVD in epidemiologic studies and recognition of the importance of plaque rupture provides a plausible mechanism for this relationship. Continued research on inflammation and CVD risk in populations thus provides a promising avenue for elucidating mechanisms of plaque rupture. It also exemplifies the cyclical and complementary nature of risk factor identification in population and experimental studies, progressing from clinical events at the population level to the tissue and cellular level experimentally, and back to the tissue and population level in studies of subclinical disease. Results of the proposed study will be applicable to clinical practice by identifying subclinical disease measures that best predict risk and by suggesting new interventions for preventing progression of subclinical to clinical disease. This information can be used to target subgroups who should undergo aggressive risk factor modification or other treatment. Some findings may be directly applicable to clinical practice, others may be used to design clinical trials or optimize interventions, and still others may lead to research resulting in new methods of intervention. Having demonstrated that subclinical disease measures are powerful discriminators of persons at high risk, three key research questions emerge with both etiologic and potential therapeutic implications: 1) How does subclinical disease progress to clinical disease? Although short-term risk of clinical events appears to be extremely low in the absence of subclinical disease, clinical events occur within 2.5 years in less than 10% of persons over age 65 with clear evidence of subclinical disease defined by a variety of techniques. Progression of subclinical disease to clinical events thus does not appear to be inevitable, and a critical unanswered question related to subclinical disease is the identification of factors promoting or retarding this progression. 2) What are the correlates of newer measures of subclinical disease, and how are newer measures related to existing measures in population-based samples? A variety of techniques for assessing subclinical disease have been introduced in the past several years and further refinements are under active development. Newer techniques permit imaging of the coronary bed and of lesion characteristics potentially indicative of high-risk plaque, allowing plaque biology to be studied in vivo on a population basis. Examination of correlates of these newer measures, such as inflammatory, hemostatic and genetic markers, is essential to understanding their etiology, their relationship to existing subclinical disease measures, and their progression to clinical events. 3) What is the most parsimonious combination of subclinical disease measures that reliably identifies high risk persons for targeted interventions? Current risk stratification algorithms identify persons with a high relative risk of disease, many of whom will never develop clinical events. Existing subclinical measures similarly identify many who do not develop events in the short term, and refinement of these measures is needed to provide effective targeting of interventions. Inclusion and comparison of multiple measures of subclinical disease will permit development of a hierarchy of measures allowing cost-effective screening and risk stratification of individuals. Recent developments in measurement of cardiovascular structure and function make the imaging of subclinical disease and measuring functional aspects of the vasculature in population-based studies feasible and accurate, providing specific, detailed information that relates more directly to pathology. Improved gray-scale ultrasound imaging of the carotid arteries and aorta, for example, can identify plaque characteristics related to rupture and thrombosis (such as echolucency and heterogeneity) associated with a 4-6-fold increased risk of acute myocardial infarction. Coronary calcium quantified by electron-beam computed tomography (EBCT) has correlations of >0.90 or greater with histological coronary plaque area, identifies persons with 5- to 20-fold increased risk for CHD events, and is thus the best available noninvasive technique for quantifying subclinical coronary atherosclerosis. Vascular stiffness and endothelial function are additional new noninvasive measures of early functional changes in the vasculature with strong relationships to existing disease, risk factor exposure, and effective treatment. This study will include a substantial proportion of previously understudied minority groups whose prevalence of risk factors and increased CHD risk related to specific risk factors has been shown or hypothesized to differ from that of the majority population. The prevalence of coronary heart disease differs among racial and ethnic groups in the United States of America. African Americans, composing approximately 12% of the U.S. population, tend to have higher CHD rates than whites, particularly among women. Prevalence of coronary calcification has been suggested to differ in blacks and whites, though population-based data are relatively sparse and clinical data are inconsistent. Hispanic populations, composing about 8% of the U.S. population, tend to have lower rates of clinical disease despite high risk factor levels, although data are not consistent in this regard. Pacific Islanders/Asians (particularly Chinese- and Japanese-Americans and immigrants from southeast Asia), composing about 3% of the U.S. population, have lower morbidity and mortality rates than whites. This group, particularly Pacific Asian women, has not been well-represented in population-based studies to date. Study of relatively low risk populations, especially those with comparable levels of subclinical disease, may provide clues to prevention of disease in other ethnic groups. In addition, levels of risk factors for cardiovascular disease differ among racial or ethnic groups. While it is clear that smoking, diabetes, hypertension, obesity, hyperlipidemia, low socioeconomic status and psychosocial stress are detrimental in all groups, the distributions of several risk factors and their associations with disease differ among groups. Notable examples of differences in distributions include higher blood pressure and rates of hypertension in blacks, higher levels of HDL-cholesterol in black men, higher levels of Lp(a) in blacks, and higher rates of obesity and diabetes in Hispanics and blacks compared to whites. Although data on subclinical disease in minorities are much more limited, initial ARIC and CHS data suggest greater carotid atherosclerosis in blacks than whites; limited data in Hispanics suggest slightly less carotid atherosclerosis than whites. Data in American Pacific Islanders/Asians are virtually nonexistent. The marked disparity in end-organ disease among black hypertensives, which remains unexplained by differing levels of blood pressure or treatment, suggests that subclinical disease indicators may be useful in distinguishing racial/ethnic variations related to vascular and end-organ biology from those due primarily to psychosocial and cultural differences. While some of these differences may be biological, evidence of true biological differences in disease pathogenesis among racial/ethnic groups has been relatively slim. Differences in environmental, behavioral and psychosocial conditions may be at least as important in disease development and progression, but have been inadequately examined in relationship to subclinical disease and its progression to clinical events. Substantial differences in use of invasive procedures, which have consistently been shown to be less frequently utilized in minority than majority populations, have not been explored in relationship to objective subclinical disease measures rather than subjectively measured symptoms or signs. For these reasons, adequate racial/ethnic diversity in studies of subclinical disease is essential. WORK STATEMENT: INTRODUCTION The Subclinical Cardiovascular Disease Study is a study of the characteristics of subclinical cardiovascular disease (disease detected non-invasively before it has produced clinical signs and symptoms) that predict progression to clinically overt - cardiovascular disease in a diverse and representative population-based sample of men and women aged 35-84. Eighteen thousand participants will be recruited from the Field Centers and screened for evidence of subclinical coronary atherosclerosis, using electron-beam computed tomography (EBCT) or another noninvasive measure of subclinical disease, and for coronary risk factors. To allow for the expected continued rapid evolution of subclinical disease measures in the next few years, the choice of the most appropriate screening measure will be made during final protocol development in collaboration with study investigators. A combination of measures, potentially involving multiple arterial beds, and biochemical tests may be utilized or a single method may be most appropriate. One such measure at present appears to be coronary calcium scores by EBCT, but an alternative method or combination of methods may be proposed. The proposed alternate method or combination of methods must be demonstrated to accurately predict coronary events or be correlated with angiographic or pathologic evidence of coronary artery disease, be reproducible, and be noninvasive and otherwise feasible for use in a multicenter population-based study. The final protocol will be reviewed and approved by an outside advisory panel of diverse expertise, including special expertise on imaging methodology and subclinical disease. A sample of those at highest risk for coronary heart disease events, within defined age-, sex- and ethnicity-strata and an age-, sex-, ethnicity-, center-matched sample of participants representing the normal spectrum of subclinical coronary disease will be reexamined in more depth approximately six months later for other evidence of subclinical disease and for characterization of possible precursors of disease events. Because the study will provide examination results to participants and their physicians, there is expected to be a significant amount of clinical intervention in individuals, depending on the severity of the disease, the acceptance of the test results by the medical community, and the aggressiveness of the individual treating physicians. The study will collect information on the nature and magnitude of such interventions to control for them in analyses. Approximately 15% of the highest risk participants will be selected for this comprehensive examination and follow-up. Assuming that a large proportion of these high risk participants will be referred for an intervention that substantially modifies their risk, the effective sample size after accounting for the intervention effect is assumed to be 10%, rather than 15%. All participants will be followed for identification and characterization of cardiovascular disease events, including acute myocardial infarction and other forms of coronary heart disease, stroke, and congestive heart failure; mortality; and for any cardiovascular disease interventions received. A timeline for the study is provided in Table 1 and Figure 1.. A list of exam components is in Table 2. The study will involve six to eight Field Centers, a Coordinating Center (which will subcontract for a Central Lipid Laboratory), a Special Laboratory Center; and separate Reading Centers for Ultrasonography, Magnetic Resonance Imaging, and Electron Beam Computed Tomography (EBCT). Principal Investigators from each of these 11-13 sites plus the NHLBI Project Officer form the study Steering Committee. Eighteen thousand men and women aged 35 to 84 will be recruited for an initial examination in this prospective study. The broad age range will permit analysis of important interactions between age and risk factor-subclinical disease relationships and between age and subclinical disease-event relationships. The large total number is necessary to ensure the accrual of a sufficient number of coronary heart disease events over a 5-6 year morbidity and mortality follow-up period. Initial recruitment will be population-based with the goal of enrolling approximately 50% minority participants, including roughly equal numbers of non-Hispanic blacks, Hispanics, and Pacific Islanders/Asians. There will be an initial 18-month protocol planning, OMB clearance, training, and pilot testing period. This will be followed by a two-year screening examination for all participants to identify the highest risk groups in age-race/ethnicity-gender-specific strata. A subsample of participants at the highest end of the subclinical disease distribution for their age, race/ethnicity and gender group and a random sample from the remainder of the distribution will undergo a comprehensive examination within 6 months of screening. The comprehensive examination will include more detailed measures of large and small vessel disease as described below. The numbers of participants in these subsamples will be determined during protocol development, based on the estimated power to conduct analyses of risk factors for subclinical disease progression and development of clinical events and for comparing the high risk subsample and random sample to identify relationships between risk factors and subclinical disease. For purposes of power and sample size estimation, each subgroup was assumed to be 10% of the total cohort, with oversampling of the high-risk group to compensate for medical and surgical intervention, as stated above. The remaining participants (those not in either subsample) will not be periodically re-examined as is typically done in traditional epidemiologic studies; rather, they will be contacted annually for ascertainment of morbidity and mortality only. For the high risk and random sample subgroups, follow-up examinations at periodic intervals (e.g., 6-12 months) will focus on biochemical and other factors more proximally associated with events. Smaller subsets of particular interest may be selected to undergo more frequent follow-up or specialized examinations particularly for subclinical disease. The timing and composition of repeat subclinical disease measures will depend on the temporal nature of the measurement in its relation to clinical outcomes, demonstrated reliability of the measurement techniques in this population, the relationships found among measures, and the specific measures found most likely to progress to clinically overt events. The subsamples will also be followed for morbidity and mortality for a 5-6 year period, to allow accrual of a sufficient number of fatal and nonfatal events for completion of study objectives 1 and 3 (related to risk of clinical events). The original cohort of 18,000 will also be followed for events, to allow relationships between screening variables and events to be analyzed. Completion of morbidity and mortality follow-up for the study will be followed by a period of final data analysis and study close-out, although initial data analysis is expected to begin using data from the baseline screening examination. The total contract period is 10 years. Table 1. Timeline for Subclinical Disease Study Activity Time period Protocol development September 1,1998--August 31,1999 (12 months) OMB clearance March 1,1999--August 31,1999 (6 months) Protocol review September 1,1999--February 29, 2000 (September 1999) Training (6 months) Pilot testing Baseline screening examination March 1,2000--February 28, 2002 (24 months) Comprehensive examination of September 1,2000--August 31,2002high risk subgroup and random (24 months) sample Follow-up of high risk subgroup March 1,2001--February 28, 2007 and random sample for changes (72 months) in subclinical disease and measurement of possible clinical disease precursors Follow-up of original cohort March 1,2000--February 28, 2007 and subgroups for morbidity (84 months) and mortality Close-out March 1,2007--August 31, 2008 (12 months) Note: Some activity periods overlap. Follow-up periods for morbidity and mortality and for repeat examinations for individual study participants are, on average, shorter than the total periods specified. For planning purposes, follow-up examinations are of three types: Approximately every 6 months, phlebotomy; approximately every 12 months, endothelial function and vascular stiffness; repeat EBCT (once, beginning in Year 5); repeat ultrasound (once, beginning in Year 6); repeat retinal photography (once, beginning in Year 6); and repeat MRI (once, beginning in Year 7). *Study Years are designated as follows: Year 1, September 1, 1998 - August 31, 1999 Year 2, September 1, 1999 - August 31, 2000 Year 3, September 1, 2000 - August 31, 2001 Year 4, September 1, 2001 - August 31, 2002 Year 5, September 1, 2002 - August 31, 2003 Year 6, September 1, 2003 - August 31, 2004 Year 7, September 1, 2004 - August 31, 2005 Year 8, September 1, 2005 - August 31, 2006 Year 9, September 1, 2006 - August 31, 2007 Year 10, September 1, 2007 - August 31, 2008 Figure 1. Timeline for the Subclinical Cardiovascular Disease Study Year | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | Month 9/ 3/ 9/ 3/ 9/ 3/ 9/ 3/ 9/ 3/ 9/ 3/ 9/ 3/ 9/ 3/ 9/ 3/ 9/ 3/ 9/ Year 98 99 99 00 00 01 01 02 02 03 03 04 04 05 05 06 06 07 07 08 08 | | | | | | | | | | | | | | | | | | | | | . . . . . . . . . . . Develop. . . . . . . . . . . proto- col |-----| . . . . . . . . . . . . . . . . . . . OMB clearance |--| . . . . . . . . . . . . . . . . . . . Revise protocol . . . . . . . . . . pilot/ training |--| . . . . . . . . . . . . . . . . . . . MRI protocol pilot/ training . |--| . . . . . . . . . . . . . . . . . . Screening examination . |-----------| . . . . . . . . . . . . . . . . Comprehensive examination . |-----------| . . . . . . . . . . . . . . . . Follow up phlebotomy . . |--|--|--|--|--|--|--|--|--|--|--|--| . . . . . . . . . . . . Follow up examination . . |-----|-----|-----|-----|-----|--| . . . . . . . . . . . . Follow up EBCT . . . . |-----| . . . . . . . . . . . . . . Follow up US . . . . . |-----| . . . . . . . . . . . . . Follow up MRI. . . . . . |-----| . . . . . . . . . . . . Morbidity/ mortality follow up . |-----------------------------------------------| . . . . . . . . . . Analysis/ publication . . . |--------------------------------------| . . . . . . . . . . Close-out . . . . . . . . |--------| Table 2. Examination Components Data to be collected is approximated by the following list of components, which may be modified during protocol development, for the approximate following number of participants: a. Baseline screening examination (N=approximately 18,000): I. Demographic information (age, sex, race, ethnicity, education) [Note: This information should also be obtained on people who decline participation (non-participants), as feasible.] ii. Anthropometry (height and weight), blood pressure, and smoking history iii. Medical history [Note: Selected medical history information should also be obtained on non-participants, as feasible.] iv. Electrocardiogram v. Fasting whole blood, serum, plasma, and special blood and tissue collection (e.g., DNA) vi. Electron beam computed tomography (EBCT) results, and/or results of screening for high risk, as specified in the protocol b. Comprehensive examination and periodic follow-up examinations (N=approximately 2,700 high risk and 1,800 random sample subgroups): I. Repetition of selected screening examination components ii. Enhanced grey-scale and Doppler ultrasound of artery iii. Measures of arterial compliance (stiffness) iv. Measurement of endothelial function v. MRI measures of cardiac and vascular morphology and function vi. Retinal photographs producing measures of vascular and other morphological characteristics of retinal anatomy vii. Resting and exercise-induced ankle-arm blood pressure index viii.Newly identified risk factors for cardiovascular disease including but not necessarily limited to measures of lipoprotein and fatty acid metabolism, homocysteine, thrombosis/hemostasis, antioxidation biochemical moieties, infectious agents, markers of immune and inflammatory response, and biochemical markers of endothelial function ix. Indicators of blood viscosity x. Genetic material [Note: For planning purposes, use the following schedule for follow-up examinations in both the high risk and random sample subgroups: (1) Approximately every 6 months (March 1, 2002 - February 28, 2007) phlebotomy to remeasure hemostatic and thrombotic factors, indicators of inflammation, and other factors that may enhance prediction of clinical events; (2) Approximately annually (March 1, 2002 - February 28, 2007) measurement of endothelial function and vascular stiffness; and (3) In order to measure progression of subclinical disease, one repeat examination of each of the following: in Year 5 (September 1, 2002 - August 31, 2003), EBCT of the heart; in Year 6 (September 1, 2003 - August 31, 2004), ultrasonography of the carotid arteries; and in Year 7 (September 1, 2004 - August 31, 2005), MRI of the heart and aorta.] c. Follow-up for morbidity (cardiovascular disease, including myocardial infarction, stroke, and congestive heart failure) and mortality: i. Dates of deaths and hospitalizations ii. Interview data from participants and relatives and other informants iii. Hospital discharge diagnosis and ICD9 codes iv. Classification of events as determined by the Morbidity and Mortality Committee v. Data collected from physician questionnaires vi. Data collected from hospital inpatient and outpatient records vii. Information on cardiovascular disease interventions as determined by the Morbidity and Mortality Committee ***************************************************************** 1. GENERAL REQUIREMENTS AND TASKS [Note: Throughout this statement of work, the terms "Contractor" and "Field Center" are used interchangeably.] Throughout the period of performance, the Contractor shall provide appropriate senior personnel with expertise in cardiovascular epidemiology, clinical cardiovascular disease, noninvasive imaging, laboratory measurements, statistics, and longitudinal studies management to: a. Take responsibility in particular scientific areas for protocol development, including leadership and participation in subcommittees; b. Recruit and examine a population-based sample of men and women aged 35-84 years; c. Participate in committees, such as the Steering Committee, Morbidity and Mortality Committee, Laboratory Committee, Imaging Committee, Quality Assurance Committee, Publications Committee, Operations Committee, and other subcommittees, as appropriate; [Note: For planning purposes, plan to include a representative on the Steering Committee and on three of the six other committees.] d. Be involved and closely familiar with data collection and quality assurance activities at own center; e. Work cooperatively with other study centers, including other Field Centers, Coordinating Center, Central Laboratories, Reading Centers, the Specimen Repository, and the NHLBI Project Office staff in all relevant aspects of study execution; and f. Participate actively in data analysis and publication. 2. SPECIFIC REQUIREMENTS AND TASKS a. During the period September 1, 1998 through February 29, 2000, the Contractor shall: [Note: See timeline (Article C1, Table 1 and Figure 1) for overview of periods and tasks.] i. Participate in study protocol development and pilot testing. [Note: The protocol for the baseline screening examination will be completed before completion of the protocol for the comprehensive examination, and priority will be given to obtaining clearance from the Office of Management and Budget (OMB) for the screening examination over the comprehensive examination. After draft protocols have been developed and approved by the Steering Committee, staff are to be centrally trained for each examination. Pilot testing for the screening examination and for the comprehensive examination will be conducted after training is complete and OMB clearance for each has been obtained, and will consist of performing the examination, according to the draft Manual of Operations, in approximately 10-20 volunteers per Field Center who are not study participants. The pilot tests also are to include shipping blood samples to the appropriate laboratories and transmission of images to the appropriate reading centers. Final modifications to the Manuals of Operations are to be made based on the pilot test results at the direction of the Operations Committee.] (1) Provide representation for Steering Committee meetings and for subcommittee meetings as appropriate; [Note: For planning purposes, assume the Contractor will be represented on the Steering Committee and three subcommittees and that Steering Committee meetings will take place in Bethesda, Maryland. Assume there will be 4 meetings during the first year, 3 during the second year, and 2 each year thereafter. Subcommittee meetings will generally take place in conjunction with Steering Committee meetings. The Morbidity and Mortality Committee may need to meet one or two additional times per year.] (2) Actively participate in development of study protocol, including the assumption of lead roles for development of particular aspects of the protocol; (3) Actively plan and conduct pilot testing for examination components as specified in the protocol; [Note: Plan pilot testing to include components of both the baseline screening examination and the comprehensive examination; pilot testing of some comprehensive examination procedures, particularly MRI, may be delayed up to 6 months if OMB clearance has not been obtained or if Reading Centers have not completed development of procedures. The pilot test should include EBCT and carotid ultrasound scanning and retinal photography in 20 volunteers. Plan to conduct pilot testing of MRI in 10 volunteers approximately 6 months later (i.e., beginning March 1, 2000). Repeat measurements should be planned for any examination component for which reproducibility is in question. Phlebotomy, using the protocol for the baseline screening examination, should be performed in 10 volunteers and, using the comprehensive examination protocol, should be performed in 10 volunteers.] (4) Redesign and implement changes in protocol, as recommended by the Steering Committee based on pilot testing results. b. During the period March 1, 2000 through February 28, 2002, 1. Recruit and examine a population-based sample of men and women aged 35-84 years. (1) Recruit, using methods approved by the Steering Committee, a population-based sample of 2,250-3,000 men and women aged 35-84, assuring representation from racial and minority ethnic groups and using methods to maximize participation. [Note: It is anticipated that a total of 18,000 participants will be recruited among six to eight Field Centers. It is further expected that approximately 50% of the cohort will be minority participants, including roughly equal numbers of non-Hispanic blacks, Hispanics, and Pacific Islanders/Asians. For purposes of the proposal, assume that 2,600 participants will be recruited by each Field Center. Each Field Center is expected to include at least 10% of two racial/ethnic groups.] (2) Obtain informed consent, using forms and procedures approved by the Steering Committee; (3) Perform clinic examinations which include the following (see Article C1, Table 2 for a complete list of examination components): (a) Electron-beam computed tomography of the heart, or equivalent baseline screening method or combination of measurements, to identify persons at very high risk for clinical cardiovascular disease events. The proposed baseline screening method must be demonstrated to accurately predict coronary events across a broad age range or be correlated with angiographic or pathologic evidence of coronary artery disease, be reproducible, and be noninvasive and otherwise feasible for use in a multicenter population-based study. [Note: Justification must be provided for the proposed screening strategy to identify the high risk group, documenting expected clinical cardiovascular disease event rates among those who screen positive, compared to those who screen negative.] (b) Information on sociodemographic characteristics, medical history, smoking, anthropometry, blood pressure, and electrocardiography. (c) Phlebotomy for lipid, blood chemistry, and long-term storage, and for processing and long-term storage of genetic material. [Note: Blood shall also be drawn for low temperature (-70øC) long-term storage at a central location. For planning purposes, plan that approximately 20 ml of blood will be drawn into three tubes and aliquotted into 16 microvials for shipping to laboratories and long-term storage.] c. During the period September 1, 2000 through August 31, 2002, within 6 months of each participant's baseline screening examination, (1) Based on the study protocol, identify participants at highest risk (based on an estimate of approximately the highest 15% in each stratum defined by race/ethnicity, sex, and 10-year age groups, using results of EBCT scanning or other proposed measurements of cardiovascular disease risk) for an in-depth, comprehensive examination of subclinical cardiovascular disease and other potential precursors of clinical cardiovascular events. (2) Identify a stratified random sample subgroup of participants from the baseline screening examination with a similar age, race/ethnicity, and sex composition as the high risk subgroup. [Note: Initially, identify participants in the highest (5% or 10% of risk) using published literature or other reference information to estimate the 90-95th percentile for the screening factor proposed (i.e., EBCT calcium score or other measurement). Include participants from the lower 80% in the random sample subgroup. After a sufficient number of participants has been accrued in the baseline screening examination (approximately 1,500 across the Field Centers), the Coordinating Center will identify and propose for the purpose of subsequent identification of high risk and random sample participants, the 85th percentile of risk, based on the observed distribution of risk in the cohort. For proposal purposes, assume that 375 high risk and 250 random sample participants will be followed at each Field Center.] (3) In both subgroups perform some or all of the following to characterize subclinical cardiovascular disease, particularly atherosclerosis: (a) Magnetic resonance imaging (MRI) of the heart and thoracic aorta under direction of the MRI Reading Center and a local radiologist or cardiologist. [Note: See Section 4 for list of MRI measurements to be included in the examination.] (b) Ultrasonography of the internal and common carotid arteries, using standard ultrasonography techniques, under direction of the Ultrasound Reading Center and a local physician-ultrasonographer. [Note: See Section 5 for description of ultrasound machine and a list of ultrasound measurements to be included in the examination.] (c) Measurement of ankle and brachial systolic blood pressure for estimation of ankle-arm index. (d) Measures of endothelial function, using ultrasound imaging or strain-gauge plethysmography of the forearm or other noninvasive technique. (e) Measurement of vascular stiffness using ultrasound of the brachial or carotid artery or pulse wave velocity measured in the forearm or other site. (f) Retinal photography using a nonmydriatic camera, in order to make standardized measurements of the arteriovenous ratio, arteriovenous nicking, and any other standardized measure appropriate to this technology as determined by the protocol, under the direction of the Retinal Artery Reading Center. (g) Other measurements of subclinical disease, as determined by the Steering Committee and Project Office. (4) In both subgroups perform phlebotomy using appropriate techniques 1) to measure hemostatic factors, factors related to lipoprotein metabolism, homocysteine, serology of infectious agents, immune or inflammatory markers, specific fatty acids, and circulating markers of endothelial function, and other measures as determined by the Laboratory Committee, 2) for long-term storage of serum, plasma and/or whole blood, as determined by the Laboratory Committee and the NHLBI Project Office, and 3) for extraction of DNA. (5) In comprehensive examinations, include approximately 5% duplicate measurements for quality control assessments of clinical chemistry laboratory and subclinical disease measurements, as specified in the protocol. (6) Provide for refrigerated centrifugation, temporary storage at low temperature, and shipping with dry ice for blood specimens. [Note: Blood shall also be drawn for low temperature (-70øC) long-term storage at a central location. For planning purposes, plan that approximately 30 ml of blood will be drawn into five tubes and aliquotted into 20 microvials for shipping to laboratories and long-term storage.] (7) Follow the remaining 13,500 screened participants for morbidity and mortality, as outlined below. d. During the period March 1, 2000 through February 28, 2007, i. Perform annual telephone or mail contacts as part of morbidity and mortality follow-up for the entire cohort of 18,000 screenees to ascertain: (1) Occurrence of cardiovascular events (including coronary heart disease, cerebrovascular disease, and congestive heart failure), other illnesses and hospitalizations, including information from participants, personal informants, hospitals and physicians, according to a standard protocol developed by the Morbidity and Mortality Committee and approved by the Steering Committee. Information to be collected on potential cardiovascular events includes: (a) Circumstances and life situations immediately prior to a cardiovascular event; (b) Use of medical services in conjunction with the event; (c) Diagnostic information, medical care and clinical characteristics from medical records; (d) Dates and recorded causes of all deaths using local vital statistics sources, obituaries, the National Death Index, and other sources; and (e) Circumstances surrounding death through interview of family members, physicians and review of coroners' and other records. [Note: Expect approximately 230 total deaths, 30 incident cases of nonfatal coronary heart disease, 85 incident cases of nonfatal stroke, and 60 incident cases of congestive heart failure per year from the cohort of 18,000. For each Field Center, expect approximately 35 total deaths, 4 incident nonfatal cases of coronary heart disease, 12 incident cases of nonfatal stroke, and 3 incident cases of congestive heart failure per year.] (2) Use of medical care, including diagnostic tests and therapeutic interventions, and medication type and dosages in relation to events. ii. Participate in classification of type and severity of cardiovascular events, using standard protocol developed and implemented by the Morbidity and Mortality Committee and approved by the Steering Committee. e. During the period March 1, 2001 through February 29, 2007, every 6 to 12 months, as specified in the protocol, re-examine each participant in the high risk and random sample subgroups, including the following measurements at the following approximate increments of time: (1) Approximately every 6 months, phlebotomy to remeasure hemostatic and thrombotic factors, indicators of inflammation, and other factors that may enhance prediction of clinical events; [Note: For planning purposes, expect to draw 20 ml of blood into three tubes, aliquot into 16 microvials, and ship to two laboratories.] (2) Approximately annually, measurement of endothelial function and vascular stiffness; (3) In order to measure progression of subclinical disease, repeat EBCT of the heart in Year 6 (September 1, 2003 - August 31, 2004, beginning 3.5 years after the start of the baseline screening examination), repeat carotid ultrasound in Year 7 (September 1, 2004 - August 31, 2005, beginning 4 years after start of the comprehensive examination), and repeat MRI of the heart and aorta in Year 8 (September 1, 2005 - August 31, 2006, beginning 5 years after start of the comprehensive examination); (4) Obtain measurements using new, yet to be identified, technologies based on emerging evidence or new hypotheses regarding their short-term predictive value or addition to the understanding of the pathophysiology of cardiovascular disease; and (5) Using passive surveillance and, at least every 6 months, obtain information on medical interventions for cardiovascular disease. Using standardized procedures developed by the Morbidity and Mortality Committee and approved by the Steering Committee, collect qualitative and quantitative information characterizing medical interventions undergone by participants, in order to estimate the probable impact on subsequent events. [Note: For the purpose of planning, the timing and composition of repeat subclinical disease measures described above will be used. The final protocol will depend on the proposed scientific rationale, the demonstrated reliability of the measurement techniques in this population, the relations found among measures, and the specific measures found most strongly related to progress to clinically overt events.] f. Throughout the contract period, analyze collected data and prepare abstracts, presentations, and manuscripts for publication of results. Submit at least one (1) manuscript for publication in each year beginning in Year 5, September 1, 2002 through August 31, 2007 (5 total). Submit abstracts and manuscripts proposed for presentation or publication to the Publications Committee and the NHLBI Project Office in advance for approval, as outlined in the section on Deliverables. [Note: Capability for data analyses will be established both centrally (at the Coordinating Center) and in each Field Center. Deliverables reflect the minimum number of manuscripts to be completed, however it is expected that a greater number will be completed. The proposal should include brief descriptions of at least five potential manuscript topics.] 3. SUBORDINATE TASKS Participate in other activities related to the successful completion of the project, as specified by the Steering Committee and/or NHLBI Project Office. This includes, but is not necessarily limited to the following: a. In collaboration with the Coordinating Center, provide results of each examination and an indication of any abnor- malities of clinical significance to the participant, and, with consent, to his/her physician. Provide recommendations for follow-up of abnormalities as appropriate. b. Participate in ancillary studies and substudies, as desired, feasible, and recommended by the Steering Committee. [Note: Investigators may propose ancillary studies and substudies to be conducted in one or more study Centers. A substudy is an investigation which, although not part of the core exam protocol, will yield additional information related to study objectives. An ancillary study is a study not funded by contract funds. Substudies and ancillary studies may include all or a subgroup of the cohort at a given center, and may involve additional interviews or examinations of study participants as well as analysis of blood or tissue samples, tapes, or images collected previously. Ancillary studies and substudies are subject to the same policies, reviews and approvals as the core protocol. Substudies involving additional participant burden will require OMB clearance. Investigators proposing substudies will also prepare a request for OMB clearance for the substudy; or, for case-control studies, a request for exemption from OMB review. Examples of such submissions will be provided on request. Ancillary study data, collected under a grant mechanism, are not required to become part of the public use data set; however, these data will be incorporated into the study data set after an appropriate period of time (generally 12 months after completion of data collection). Investigators conducting ancillary studies are to be viewed as collaborating investigators of the primary study, with appropriate access to the full data set and to analytic resources of the study. Ancillary studies and substudies will be evaluated by the Steering Committee. Highest priority will be given to studies which: 1) have the highest scientific merit, 2) do not interfere with the main study objectives, 3) produce the least burden on participants, 4) have objectives directly related to the study, and 5) require the unique characteristics of the cohort. For all substudies and ancillary studies, the contractor shall define the hypotheses to be investigated and the methodology to be used, and should estimate the cost and burden on participants. Study data collection must not interfere with the conduct of the core examination. All substudies in the proposal should be distinctly identified, with separate descriptions and estimates of costs. Ancillary studies and substudies may be proposed before and/or after contract award as scientific opportunities arise. All studies must be approved by the Steering Committee, the Monitoring Board, and the NHLBI Project Office before initiation.] c. Enter and edit the results from study interviews, examinations and quality assurance activities, including blind duplicates, into a computer, using software designed in cooperation with the Coordinating Center, and transmit the data to the Coordinating Center on a regular basis (at least monthly) as specified in the study protocol. Transmit quality control data to the Coordinating Center according to specifications of the study protocol. [Note: Quality assurance refers to a program to ensure conformance to established performance standards, including data collection and completeness, data coding and computer input, data storage and retrieval, data validation and analysis, and training and monitoring performance of technical staff. Quality control refers specifically to the procedures to assess and minimize measurement error. Quality control activities are to focus on measurement technology error sources, and methods appropriate to the technology are to be utilized.] d. Cooperate in providing up-to-date lists of publications and presentations coming from the Field Center for a data base to be managed by the Coordinating Center. 4. Summary of MRI Reading Center Specific Requirements and Tasks: a. The MRI examinations protocol will specify the equipment to measure cardiac and vessel characteristics as well as potential physiological characteristics in the heart and the in an examination not to exceed 30 minutes of a participant's time (examination time). Measurements will include cine visual images of the heart, and assessments of morphologic characteristics and physiologic functions. The examination will be sufficient to permit the following potential measurements to be made at the MRI Reading Center with the described equipment and procedure specifications: i. Quantitative Measurements: (1) Heart: (a) Left ventricular mass and end diastolic wall thickness (b) End diastolic, end systolic, and stroke volumes, including ejection fraction (c) Left atrial, right atrial, and right ventricular sizes (d) Left ventricular wall motion [Note: MRI tagging methods should be considered for assessment of regional wall motion. Use of these methods should not compromise the ability to capture the preceding measures of physiological function and morphological structure.] (2) Aorta (a) Stroke volume and cardiac output [Note: Proposal may advise about the value of secondary measures of stroke volume as a check of measures derived from heart imaging.] (b) Wall shear stress rate (see Technical Specifications below), potential for characterizing plaques. [Note: Proposal should advise about feasibility and accuracy of MRI technology in obtaining measures of plaque characterization.] (c) Compliance (pulse wave velocity) and vascular impedance (pattern of flow) ii. Technical Specifications (1) 1.5 Telsa system (2) Cardiac phased array coils for chest [Note: Proposal may include other coil arrangements, but should justify these based on proposed accuracy and precision of measures to be obtained.] (3) >60 T/m/s slew rate and >2.0 G/cm gradient amplitude (4) Pulse sequences: (a) Breathhold (with sampling throughout entire cardiac cycle on a breathhold), segmented k-space gradient recalled echo (GRE) (sequential, multiphase) with and without through-plane phase contrast velocity measures. [Note: Non-breathhold protocols may be proposed, but should be justified and the impact on measurement precision and accuracy described.] (b) Fast spin echo (FSE) sequence (5) Monitoring: non-invasive blood pressure, electrocardiogram. (6) Direct or indirect assessment of whole blood viscosity in the assessment of wall shear rate. iii. Suggested Imaging Protocols for the following views: (1) Sagittal Chest Localizer (2) Heart (long and short axes) (3) Aorta (axial at level of pulmonary artery bifurcation) (4) Suggest specifications appropriate to the above protocols for the follow procedures/parameters: (a) End expiratory breathhold (with sampling throughout entire cardiac cycle on a breathhold), segmented k-space, rf-spoiled, gradient recalled echo (b) Field of view (FOV), Matrix, Band width, K-space lines per segment, Gradient moment nulling (GMN) (Flow Compensation), Flip angle, Signal averages, Repetition time (TR) and echo time (TE), and Slice thickness [Note: Proposal should discuss advisability of zero gap versus overlapping gap for all slice thickness specifications.] 5. Summary of Ultrasound Reading Center Measurements Images will include two to three longitudinal views centered on the largest lesion or at bifurcation, if there is no lesion, in the right and left internal carotid arteries, and a single lateral view of the distal 10 mm of each common carotid artery. The examination will be sufficient to permit the following measurements to be made at the Ultrasound Reading Center: i. Quantitative measurements: (1) Vessel interfaces: Near and far wall adventitia-periadventitia, media-adventitia, lumen-intima of both common carotid arteries, carotid bulbs, and internal carotid arteries. (2) Wall thicknesses: Mean and maximum intimal-medial thickness of near and far walls of both common carotid arteries, carotid bulbs, and internal carotid arteries. (3) Minimum residual lumen of the common and internal carotid arteries. (4) Vessel width: Mean and maximum width of the common carotid arteries, carotid bulbs, and internal carotid arteries. (5) Doppler frequency shift or velocity at point of maximum disease in the assessment of stenosis. (6) Lesion characteristics such as homogeneity, density, and regularity of surface. ******************************************************************** C. REPORTS/DELIVERABLES 1. REPORTS a. Semi-annual progress reports (3 copies), indicating general progress in study activities and administrative issues; personnel with FTE level for the reporting period; changes in personnel; specific problems encountered or anticipated and attempts to resolve such problems; and progress in publications activities, including an updated list of ongoing and completed manuscripts (not to exceed 4 pages). b. Quarterly financial reports (3 copies). Use form NIH 2706. c. A final report, due on or before expiration of the contract on August 31, 2008 (10 copies), documenting and summarizing the results of the entire contract work, including recommendations and conclusions based on both the general experience and the special viewpoint of the center not to exceed ten (10) pages. d. With the final report, a summary (not to exceed 200 words) of salient results achieved during the performance of the contract (3 copies). 2. DELIVERABLES Delivery Item # Description Quantity Schedule Information 1. Data from 20 February 29, 2000 Coordinating pilot study Center 2. Data from MRI 10 August 31, 2000 Coordinating pilot study Center 3. Consent forms 1 August 31, 1999 Project Office 4. Examination 1 Weekly Coordinating data Center 5. Events data 1 Within 90 days of Coordinating notification of Center possible event 6. Clinical 2,600 Within 3 months Participant on findings screening and/or Examination health care provider 7. Progress 3 February 28-29 Project Office Reports August 31 (2 copies) Contracts Office (1 copy) 8. Abstracts 2 2 weeks prior to Publications submission Committee (1 copy per member) Project Office (2 copies) 9. Manuscripts 2 4 weeks prior to Publications (Applies to Submission Committee (1 all) copy per member) Project Office (2 copies) 10. Manuscript 1 per July 31, 2002-2007 Coordinating analysis year Center programs 11. Manuscripts* 1 per August 31,2002-2007 Project Office Year (as in 9. above) 12. Raw data 1 As requested Project Office 13. Financial 3 Quarterly Contracts Office Reports (Form NIH 2706) 14. Final report 10 August 31, 2008 Project Office and summary (2 copies) Contracts Office (8 copies) *Minimum number of distinct manuscripts from Field Center first authors submitted for publication each year. ***************************************************************** D. SPECIAL REQUIREMENTS (as applicable) Clearance of all forms used during participant recruitment, interim contact, and clinic examinations and scans that represent a burden of time to the participant must be cleared by the Office of Management and Budget (OMB) prior to use in the study. Human Subject Certification by the local institution's IRB must be obtained prior to participant contact. Additionally, a study certificate of confidentiality at each field center will be obtained to protect genetic information from disclosure. Access to a facility conducting electron-beam computed tomography (EBCT) of the heart is desirable. The facility must be able to accommodate the participants for this study during the required time frame and in a manner feasible for the conduct of the study. The facility should be accessible to the participants during convenient hours. Alternative methods for identifying high risk participants may be proposed or a request may be made for partial funding of a scanner. However, it is anticipated that only one such request may be fulfilled among the six to eight Field Centers. Computer hardware and software which may be needed for data transfer and communication between the Field Centers and the Coordinating Center selected in response to the RFP will be provided by the Coordinating Center; a need for comparability between the Coordinating Center and the Field Centers has been factored into the estimated costs. The Contractor shall supply all materials and facilities for the conduct of this study, except for the Toshiba SSH-160A ultrasonography machine, which will be furnished by the Government to each of the Field Centers. Availability of genetic material and data related to genetic assessments for further research and development shall be handled in accordance with the NHLBI policy in effect at the time of award. It is expected that this policy will be made available for discussion with offerors in the competitive range. Industry/Third Party contributions shall be processed in accordance with Federal regulations and NHLBI policy. **************************************************************** TECHNICAL EVALUATION CRITERIA/METHOD OF REVIEW The technical proposal will receive paramount consideration in the selection of the contractor for this procurement. The evaluation will be based on the demonstrated capabilities of the prospective contractors in relation to the needs of the project as set forth in the RFP. The merits of each proposal will be evaluated carefully, based on the thoroughness and feasibility of the technical approach taken. Although cost is not a specific evaluation criterion, it will be assessed. In the event that the technical evaluation reveals that two or more offerors are approximately equal in technical ability, then the estimated cost may become significant in determining award(s). In any event, the Government reserves the right to make an award to the best advantage of the Government, cost and other factors considered. This research project involves human subjects. Offerors must make every effort to seek out and include (a) study goal of 50% women within each racial/ethnic minority group aged 35-84, and (b)overall study goal of 50% U.S. racial/ethnic minority populations of roughly equal numbers of non-Hispanic blacks, Hispanics, and Pacific Islanders/Asians. A major goal of this solicitation is to have good representation of women and of minority populations. The numbers of women and minority participants may vary from center to center depending on local population composition and other characteristics that influence access to care. However, each Field Center is expected to include at lest 10% from each of two racial/ethnic groups. The NHLBI reserves the right to make awards under this RFP in a manner that accomplishes the overall recruitment goals for women and minorities. Thus, a higher ranked proposal may be passed over for a lower ranked proposal if the lower ranked proposal is needed to fulfill recruitment goals. Where inclusion of proper representation of women and/or minority populations is not feasible, the offeror must submit with the technical proposal a clear justification. The NHLBI will review this justification in light of the research design and desired women and minority representation in the proposal study. If the rationale is not considered acceptable by the Government and the offeror is included in the competitive range, the offeror will be afforded the opportunity to further discuss and/or clarify its position during discussions and in the best and final offer (BAFO). If the offeror's exclusion position is still considered unacceptable by the Government after discussions, the proposal may not be considered further for award. As an agency of the U.S. Public Health Service, the National Heart, Lung, and Blood Institute is responsible for sponsoring research programs and for disseminating information that will serve to improve the health of the population of the United States. Therefore the recruitment into this program of foreign populations that have significantly different social, cultural and economic conditions could substantially alter the study results. As a result, the award of contracts for performance as Field Centers under this program shall be made only to offerors who are located in the United States of America. Proposals received from offerors located outside of the United States of America will not be considered for contract award. Proposals submitted in response to this solicitation will be reviewed by a peer group of scientists under the auspices of the Review Branch, Division of Extramural Affairs, NHLBI, and subsequently by a review group within NHLBI. TECHNICAL EVALUATION CRITERIA SPECIFIC TO THE REQUIREMENT: 1. Adequacy of plans and demonstrated capacity to recruit a representative sample from the general population with a high level of participation. (25 points) 2. Adequacy of plans and demonstrated capacity for fulfilling the other Field Center functions outlined in the statement of work. These include plans for participating in development of the study protocol and all aspects of implementation of the protocol, including data collection, quality assurance activities, participation in subcommittees, and scientific productivity. (25 points) 3. Demonstrated knowledge and experience of key staff in cardiovascular epidemiology, longitudinal studies, and statistical analysis; specific expertise in clinical cardiovascular disease, noninvasive imaging and subclinical cardiovascular disease, and technical areas of quality assurance; commitment of time and direct involvement by senior staff in the study, and ability to assume leading roles in protocol development, study monitoring, scientific data analysis and publication of results; and commitment to and evidence of ability to follow a standard protocol and work collaboratively. (30 points) 4. Adequacy of the facilities and equipment, administrative structure, support staff, and institutional support and ability to modify procedures as necessary in response to demands. (20 points) ****************************************************************** THE REMAINDER OF THIS GOPHER RFP CONSISTS OF THE FOLLOWING SECTIONS: II. Specific RFP Instructions and Provisions, and III. Applicable RFP REFERENCES ******************************************************************* II. Specific RFP Instructions and Provisions ================================================================== NOTICE TO OFFERORS: This attachment contains proposal instructions and information which are specifically related to this acquisition. The information provided below is only a portion of the instructions and notices required for the submission of a proposal. References to additional, more general, information and forms regarding proposal preparation are contained under Applicable RFP REFERENCES. Listing of Contents: A. Proposal Intent Response Sheet (submit prior to proposal submission) B. Packaging and Delivery of Proposal C. Privacy Act System of Records D. SIC Code and Small Business Size Standard E. Number and Type of Award(s) F. Estimate of Effort G. Service of Protest H. Travel Requirements for Solicitation Purposes I. Technical Proposal Table of Contents J. Reference Materials K. Other Provisions 1. ROTC Access and Federal Military Recruiting on Campus 2. Continued Ban on Funding of Human Embryo Research ****************************************************************** A. PROPOSAL INTENT RESPONSE SHEET RFP No. NHLBI HC-98-08; TITLE OF RFP: Subclinical Cardiovascular Disease Study: Field Center PLEASE REVIEW THE ATTACHED REQUEST FOR PROPOSAL. FURNISH THE INFORMATION REQUESTED BELOW AND RETURN THIS PAGE BY December 5, 1997. YOUR EXPRESSION OF INTENT IS NOT BINDING BUT WILL GREATLY ASSIST US IN PLANNING FOR PROPOSAL EVALUATION. =================================================================== I INTEND TO SUBMIT A PROPOSAL =================================================================== COMPANY/INSTITUTION NAME: ADDRESS: PROJECT DIRECTOR'S NAME: TITLE: TELEPHONE NUMBER: NAMES OF COLLABORATING INSTITUTIONS AND INVESTIGATORS (include Subcontractors and Consultants): =============================================================== RETURN TO: Review Branch or FAX TO: Dr. James Scheirer NIH, NHLBI 301-480-3541 Attention: Dr. James Scheirer Rockledge Building, Room 7220 6701 ROCKLEDGE DR MSC 7924 BETHESDA MD 20892-7924 B. PACKAGING AND DELIVERY OF THE PROPOSAL Your proposal shall be organized as specified in Section C.1., "Standard RFP Instructions and Provisions." Shipment and marking shall be as indicated below. EXTERNAL PACKAGE MARKING In addition to the address cited below, mark each package as follows: "RFP NO. NHLBI HC-98-08 TO BE OPENED BY AUTHORIZED GOVERNMENT PERSONNEL ONLY" NUMBERS OF COPIES The number of copies required of each part of your proposal are as specified below. TECHNICAL PROPOSAL ONLY ORIGINAL* AND Thirty (30) COPIES BUSINESS PROPOSAL ORIGINAL* AND Six (6) COPIES COPIES TO: If hand-delivered or delivery service- Review Branch Division of Extramural Affairs National Heart, Lung, and Blood Institute Rockledge Building, Room 7091 6701 Rockledge Drive MSC 79924 Bethesda, MD 20817-7924 If using U.S. Postal Service- Review Branch Division of Extramural Affairs National Institutes of Health National Heart, Lung, and Blood Institute 6701 Rockledge Drive MSC 79924 Bethesda, MD 20892-7924 *THE ORIGINAL PROPOSAL MUST BE READILY ACCESSIBLE FOR DATE STAMPING. NOTE: The U.S. Postal Service's "Express Mail" is delivered a Rockville, Maryland address. Any package sent to this address via this service will be held at a local post office for pick-up. The Government is not responsible for picking up any mail at a local post office. If a proposal is not received at the place, date, and time specified herein, it will be considered a "late proposal." GOVERNMENT NOTICE FOR HANDLING PROPOSALS An Offeror shall place this notice on top of each copy of the technical proposal. "This proposal shall be used and disclosed for evaluation purposes only, and a copy of this Government notice shall be applied to any reproduction or abstract thereof. Any authorized restrictive notices which the submitter places on this proposal shall also be strictly complied with. Disclosure of this proposal outside the Government for evaluation purposes shall be made only to the extent authorized by, and in accordance with, the procedures in HHSAR paragraph 315.608-72." (For information regarding authorized restrictive notices, offerors should refer to the "Confidentiality of Proposals" section of the STANDARD RFP INSTRUCTIONS AND PROVISIONS subdirector of the RFP REFERENCES director of the Gopher RFP.) C. PRIVACY ACT SYSTEM OF RECORDS This procurement action requires the field centers to do one or more of the following: design, develop, or operative a system of records on individuals to accomplish an agency function in accordance with the Privacy Act of 1974. Public Law 93-579, December 31, 1974 (5 USC 552a) and applicable agency regulations. All data except personal identifiers will be transmitted to the NHLBI by coordinating center. All data collected will be used only for group analyses, and information on individually identifiable participants will not be sent to the NHLBI or disseminated or used in publications or presentations. The field centers will be required to keep the records confidential and protect the individual's privacy. The data may be used only by the contractor, the study chairman, and the NHLBI. The most recent Publication of Notices of Systems of Records upon award will be applicable. The current Privacy Act System of Records applicable to this project is identified as follows: NIH NHLBI 09-25-0126, Clinical Research: Epidemiology and Biometrics, HHS/NIH/NHLBI, as set forth in the Federal Register Vol. 60. No. 13, January 20, 1995. D. SIC CODE AND SMALL BUSINESS SIZE STANDARD NOTE: The following information is to be used by the offeror in preparing its Representations and Certifications (See Section C.4 of the Gopher RFP, specifically in completing the provisions entitled, SMALL BUSINESS PROGRAM REPRESENTATIONS (OCT 1995), FAR 52.2219-1: The standard industrial classification (SIC) code for this acquisition is 8733. The small business size standard is $5,000,000. THIS REQUIREMENT IS NOT SET-ASIDE FOR SMALL BUSINESS. However, the FAR requires in every solicitation (except for foreign acquisitions) the inclusion of the SIC and corresponding size standard which best describes the nature of the requirement in the solicitation. E. NUMBER AND TYPE OF AWARD(S) It is anticipated that six to eight awards will be made from this solicitation and that awards will be made on or about September 7, 1998. It is anticipated that the award from this solicitation will be a multiple-year cost reimbursement, completion type contract with a period of performance of ten (10) years, and that incremental funding will be used [see paragraph (6) of Business Proposal Instructions, in the "Standard RFP Instructions and Provisions" of the Gopher RFP.] F. ESTIMATE OF EFFORT It is estimated that percent effort to be provided per year is as indicated below. Yr.1 Yr.2 Yr.3 Yr.4 Yr.5 Yr.6 Yr.7 Yr.8 Yr.9 Yr.10 PI/Proj.Dir. 25 25 25 25 25 25 25 25 20 20 Other Investigators 75 80 100 100 100 100 100 100 80 60 Other 60 380 580 500 370 340 340 300 170 70 All staffing levels should be accompanied by specific justifications as to the type and hours of work expected to be performed by all personnel. [NOTE: Field Centers requesting more than the minimum investigator effort required for conduct of examinations and follow-up and for participation in study-wide committees are expected to use this additional effort to provide leadership in preparation and publication of study manuscripts,i.e, chairing manuscript writing groups.] Offerors will be required to propose levels of commitment whether compensated or donated effort, necessary to complete the work described in their proposals. It is expected that realistic levels of effort will be proposed such that an offeror's understanding of the work will be apparent. G. SERVICE OF PROTEST In accordance with FAR 52.233-2 SERVICE OF PROTEST (NOV 1988): (a) Protests, as defined in Section 33.101 of the Federal Acquisition Regulation, that are filed directly with an agency, and copies of any protests that are filed with the General accounting Office (GAO) or the General Services Administration Board of Contract Appeals (GSBCA), shall be served on the Contracting Officer (addressed as follows) by obtaining written and dated acknowledgment of receipt from: Mr. Robert R. Carlsen Hand-Carried Address: National Institutes of Health National Heart, Lung, and Blood Institute Contracts Operations Branch II Rockledge Center, Room 6122 6701 Rockledge Drive, MSC 7902 Bethesda, MD 20817 U.S. Postal Service: National Institutes of Health National Heart, Lung, and Blood Institute Contracts Operations Branch II Rockledge Center, Room 6122 6701 Rockledge Drive, MSC 7902 Bethesda, MD 20892-7902 The copy of any protest shall be received in the office designated above on the same day a protest is filed with GSBCA or within one day of filing a protest with GAO. H. TRAVEL REQUIREMENTS FOR SOLICITATION PURPOSES Investigators should plan to travel to Bethesda, Maryland for all Steering Committee and Monitoring Board meetings. Travel to Field Centers for site visits and two scientific meetings should be planned within the continental United States; however, for planning purposes, assume that these meetings will also be in Bethesda. Assume that each trip will be two (2) days long. Annual trips for the Field Center--plan for eight (8) trips in the first year and six (6) in each year thereafter. I. TECHNICAL PROPOSAL TABLE OF CONTENTS IMPORTANT: Technical proposals submitted in response to this RFP MUST NOT EXCEED 25 PAGES, however, this limitation does not include the cover sheet, table of contents, abstract or copies of biosketch or appendices. Please number each page of text. Type density and size must be 10-12 points. If constant spacing is used, there should be no more than 15 cpi, whereas proportional spacing should provide an average of no more than 15 cpi. There must be no more than six lines of text within a vertical inch. The technical proposal should be organized as follows: 1. TECHNICAL PROPOSAL COVER SHEET (Format in the NIH Gopher RFP under "FORMS, FORMATS, ATTACHMENTS").................Page 1 2. TECHNICAL PROPOSAL TABLE OF CONTENTS.................Page 2 3. ABSTRACT.............................................Page 3 State the proposal's broad, long-term objectives and specific aims. Briefly and concisely describe the research design and methods for achieving these goals. DO NOT EXCEED one page in providing the abstract. Identify the RFP Number, Institution and Principal Investigator on the abstract. 4. TECHNICAL PLAN (LIMIT 25 PAGES) Refer to Technical Proposal Instructions, Standard RFP Instructions and Provisions, Gopher RFP for more detail. a. WORK STATEMENT 1. Objectives...................................Page # 2. Approach.....................................Page # 3. Methods......................................Page # 4. Schedule.....................................Page # b. Personnel 1. List of all Personnel in the project including Subcontractors, Consultants/Collaborators, by name, title, department and organization..............Page # PROVIDE NARRATIVE FOR: 2. Principal Investigator/Project Director......Page # 3. Other Investigators..........................Page # 4. Additional Personnel.........................Page # [NOTE: For personnel, include a two-page biosketch under APPENDICES below.] c. FACILITIES, EQUIPMENT AN OTHER RESOURCES........Page # List/describe all facilities, equipment and other resources available for this project. D. OTHER CONSIDERATIONS.............................Page # (Use specifically titled subparagraphs, as applicable.) 5. OTHER SUPPORT........................................Page # Include form "summary of Current and Proposed Activities." All key personnel must be listed on this form. It is located in the NIH Gopher RFP under "FORMS, FORMATS, & ATTACHMENTS." 6. HUMAN SUBJECTS AND MINORITY AND GENDER ISSUES NOT OTHERWISE ADDRESSED............................................Page # 7. TECHNICAL PROPOSAL COST INFORMATION..................Page # (Form located in the NIH Gopher RFP under "FORMS, FORMATS, & ATTACHMENTS.") 8. LITERATURE CITED....................................Page # 9. APPENDICES...........................................Page # List each Appendix and identify the number of pages for each one. Appendices must be clear and legible, and easily located. ,End form - Technical Proposal Table of Contents ********************************************************** J. REFERENCE MATERIALS Protocols and Manuals of Operation from the Cardiovascular Health Study, the Atherosclerosis Risk in Communities Study, and the Coronary Artery Risk Development in Young Adults Study will be made available in a reading room upon request of the Contracting Officer. K. OTHER PROVISIONS 1. ROTC ACCESS AND FEDERAL MILITARY RECRUITING ON CAMPUS Section 514 of the FY 1997 Appropriations Act prohibits NIH from providing contract funds to educational institutions that the Secretary of Defense determines have a policy or practice (regardless of when implemented) that either prohibits, or in effect prevents (1) the maintaining, establishing, or operation of a unit of the Senior Research Officer Training Corps at the covered educations entity; or (2) a student at the covered educational entity from enrolling in a unit of the Senior Research Officer Training Corps at another institution of higher education. Further, contract funds may not be provided to educational institutions that have a policy or practice that prohibits or prevents (1) entry to campuses, or access to students (who are 17 years of age or older on campuses, for purposes of Federal military recruiting; or (2) access by military recruiters for purposes of Federal military recruiting to information pertaining to students (who are 17 years of age or older) enrolled at the covered educational entity. 2. CONTINUED BAN ON FUNDING OF HUMAN EMBRYO RESEARCH Section 512 of the Fiscal Year 1997 Appropriations Act contains language identical to that contained in the Fiscal Year 1996 Balanced Budget Down payments Act (P.L. 104-99) that prohibits NIH from using appropriated funds to support human embryo research. Contract funds may not be used for (1) the creation of a human embryo or embryos for research purposes; or (2) research in which a human embryo or embryos are destroyed, discarded, or knowingly subjected to risk or injury or death greater than that allowed for research on fetuses in utero under 45 CFR 46.208(a)(2) and Section 498(b) of the Public Health Service Act (42 U.S.C.289g(b)). The term "human embryo or embryos" include any organism, not protected as a human subject under 45 CFR 46 as of the date of the Act, that is derived by fertilization, parthenogenesis, cloning or any other means from one or more human gametes. ****************************************************************** III. Applicable RFP REFERENCES ================================================================== This section identifies the items located in the Gopher direct at URL gopher://gopher.nih.gov:70/11/res/rd-rfp/rfppref.c "RFP REFERENCES" that are applicable to this RFP. 1. The entire file entitled "STANDARD RFP INSTRUCTIONS AND PROVISIONS" is applicable to this RFP, except as otherwise may be modified by the inclusion of an item from the "OPTIONAL RFP INSTRUCTIONS AND PROVISIONS" below. 2. The following items are applicable from the file entitled "OPTIONAL RFP INSTRUCTIONS AND PROVISIONS": (1)LATE PROPOSALS, MODIFICATIONS OF PROPOSAL, AND WITHDRAWALS OF PROPOSALS, PHS 352.215-10 (2) HUMAN SUBJECTS (3) SMALL, SMALL DISADVANTAGED AND WOMEN-OWNED SMALL BUSINESS SUBCONTRACTING PLAN, FAR 52.219-9 [NOTE: A Subcontracting Plan is not due with the initial proposal. The Contracting Officer will notify offerors if a plan becomes due.] (4) INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS. 3. The following items are applicable from the subdirector entitled "FORMS, FORMATS, AND ATTACHMENTS": APPLICABLE TO TECHNICAL PROPOSAL: (1) Technical Proposal Cover Sheet (2) Technical Proposal Cost Information, Dec 1988 (3) Summary of Current and Proposed Activities, July 1995 APPLICABLE TO BUSINESS PROPOSAL: (4) Contract Pricing Proposal, SF-1411, (Rev. 10/9995) (5) Proposal Summary an Data record, NIH-2043 (Rev. 6/82) (6) Business Proposal Cost Information (7) Disclosure of Lobbying Activities, OMB SF-LLL4. (8) Representations and Certifications are applicable. A completed copy must be submitted with offeror's business proposal. This form can be found in the Gopher System [URL gopher;//gopher.nih.gov:70/00/res/rd-rfp/rfpref.c/reps_cer.gph]. TO BECOME CONTRACT ATTACHMENTS: (9) Invoice/Financing Requests Instructions for NIH Cost-Reimbursement Type Contracts, NIH(RC)-1, (Rev. 5/97) (10) Instructions for Completing Form NIH 2706 (Financial Report) (11) Procurement of Certain Equipment, NIH(RC)-7 (12) NIH Women and Minority Policy (13) Protection of Human Subjects - Assurance Identification/Certification/Declaration, OF 310 OTHER - TO BE SUBMITTED: (14) Certificate of Current Cost or Pricing Data, NIH-1397, to be submitted with the Best and Final Offer, as directed by the Contracting Officer. (15) Subcontracting Plan to be submitted as directed by the Contracting Officer, after the competitive range is determined. 4. The "sample Contract Format-General" is applicable. ************************************************************* End of document