RFP No. NHLBI HC-98-07 Subclinical Cardiovascular Disease Study, Coordinating 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-98-07 Title: Subclinical Cardiovascular Disease Study: Coordinating 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 Throughout the period of performance, the Contractor shall provide appropriate senior personnel with expertise in cardiovascular epidemiology, clinical cardiovascular disease, statistics, noninvasive imaging, laboratory measurements, and longitudinal studies management to, a. Facilitate and coordinate development of the study protocol by the Steering Committee and implementation of the study protocol by the Field, Reading, and Laboratory Centers, in accordance with the study timelines (Table 1 and Figure 1 above), b. After award of contract and in collaboration with NHLBI Project Office, identify, provide, and manage subcontracts for a Central Lipid Laboratory, a Specimen Repository, an Electrocardiogram Reading Center, and a Retinal Artery Reading Center, c. Maintain data bases, d. Direct quality assurance programs, e. Conduct statistical analyses for quality assurance, and scientific publications and presentations, and f. Perform administrative duties to support productive collaboration among the study centers and the NHLBI Project Office. [Note: In the proposal, evidence of timeliness in protocol development, data analysis and data tape preparation; flexibility; helpfulness; and ability to collaborate with other Centers in all relevant aspects of Coordinating Center functions must be provided.] 2. SPECIFIC REQUIREMENTS AND TASKS a. Protocol Development and Implementation i. Support the functions of the Steering Committee in all aspects of protocol development and implementation. The Steering Committee will be comprised of one representative from the Coordinating Center, the Field Centers, Reading Centers, and Laboratory Centers, and the NHLBI Project Office. ii. In conjunction with the Field Centers, develop and, to the extent possible, standardize methods of participant recruitment and retention across Field Centers, including the development of a computerized tracking system for use by the Field Centers to monitor number of contacts, demographic features of persons contacted, outcome of contacts, and limited data collection from non-participants.(See Table 2, Examination Components). [Note: Assume that 18,000 participants recruited from seven (7) Field Centers will participate in a screening examination. From this group, 2,700 high risk and a random sample of 1,800 are expected to participate in a subsequent comprehensive examination, with periodic follow-up for re-examination. All screened participants will be followed for morbidity and mortality.] iii. Coordinate the identification and development of examination, interview, and measurement procedures among Field, Reading, and Laboratory Centers during the protocol development/pilot testing phase, including quality assurance activities. [Note: The protocol for the baseline screening examination will be completed before completion of the protocol for the comprehensive examination, and priority for obtaining clearance from the Office of Management and Budget (OMB) should be given to the screening 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. Pilot testing will consist of performing the examination, according to the draft Manual of Operations, in 10-20 volunteers per Field Center, who are not study participants. The pilot tests 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.] iv. Develop, maintain, and revise Manuals of Operations describing in detail study protocols, quality assurance activities, Steering Committee policies, functions and responsibilities of each subcommittee, procedures for the Morbidity and Mortality Committee, data analysis, describing data base features (structure, access, and management) and analysis definitions. Periodically update manuals as needed. Provide hard copies of manuals to each Center and the NHLBI Project Office. Produce Web-ready versions of manuals and distribute to interested parties via the World-Wide Web. v. Facilitate meetings and communications among all Centers, subcontractors, and the NHLBI Project Office as necessary to facilitate progress in protocol development. [Note: For planning purposes, 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.] vi. Support, review, and monitor the activities and outcomes of the Publications and Presentations Committee, Morbidity and Mortality Committee, Quality Assurance Committee, Laboratory Committee, Imaging Committee, Operations Committee, and other subcommittees, and facilitate communications among these committees and the Steering Committee. Incorporate subcommittee recommendations approved by the Steering Committee into the Manuals of Operations for which the Coordinating Center is responsible.. (1) Coordinate the activities of the Morbidity and Mortality Committee, which will be comprised of representatives knowledgeable about nosology and clinical assessment of cardiovascular diseases from the Coordinating Center and Field Centers. The committee will meet every 3 to 6 months. Support the development and continuing application of standardized procedures to identify and classify morbid cardiovascular events (including myocardial infarction and other forms of coronary heart disease, stroke, and congestive heart failure) and all mortal events. The Committee will also develop methods for collecting qualitative and quantitative information to characterize medical interventions undergone by participants. Assure standardization of methodology and consistency of procedures over time with appropriate quality assurance activities. [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) Coordinate activities of the Quality Assurance Committee. (See below for information about the Quality Assurance Committee.) (3) Coordinate activities of all remaining subcommittees. The Steering Committee will advise NHLBI on the mandate and members composing all remaining subcommittees. [Note: The Laboratory and Imaging Committees will consist of content experts in the respective areas and advise the Steering Committee on the scientific merits and feasibility of new laboratory and imaging measures. The Publications Committee will set, disseminate, and enforce policies for use of data in abstracts, presentations, and publications and develop and help to maintain the publications data base of the Coordinating Center. The Operations Committee will consist primarily of clinic coordinators and recruitment personnel and will develop and standardize, to the extent possible, techniques for recruitment and retention and clinic operations, and advise the Steering Committee on facilitating clinic operations and optimizing participant comfort, interest, and satisfaction.] vii. Perform biennial National Death Index searches on participants lost to follow-up. g. Selection and Management of Subcontracts for a Central Lipid Laboratory, a Specimen Repository, an Electrocardiogram Reading Center, and a Retinal Artery Reading Center After award of the contract, the Coordinating Center will collaborate and cooperate with the NHLBI Project Office in establishing these subcontracts. The selection will be via a competitive process, and the Coordinating Center will establish the subcontract and monitor performance for the following activities and functions: [Note: The proposal should include a set of selection criteria and list of potential offerors for each subcontract.] i. A Central Lipid Laboratory, for the measurement of total cholesterol, HDL-cholesterol, triglycerides, glucose, creatinine, and any other analyses commonly determined by clinical biochemistry laboratories, as specified by the Steering Committee. ii. A Specimen Repository, for long-term storage of specimens. The proposal should describe the following features: (1) System for cataloguing information about specimens, including type, amount, previous thawing and specific location in repository, (2) Alarm systems, including persons responsible for responding to alarm, and managing freezers In the event of freezer malfunction or power failure, (3) Power systems, (4) Responsibilities of personnel for routine periodic checks of freezers, (5) Certification protocol for personnel responsible for managing freezers, and (6) Safeguards against loss of multiple aliquots from individual participants in the case of freezer failure. iii. An Electrocardiogram Reading Center, for the planning and coordination of digitally acquired electrocardiograms to make standardized measurements of cardiac wave forms and rhythm, diagnoses of myocardial infarction and arrhythmias, and measurement of left ventricular mass and any other measurements appropriate to this technology and pertinent to cardiovascular disease risk. iv. A Retinal Artery Reading Center, for the planning and coordination of retinal photography using a nonmydriatic camera to make standardized measurements of the arteriovenous ratio, arteriovenous nicking, and any other standardized measurement appropriate to this technology and pertinent to cardiovascular disease risk. h. Data Management i. Establish and maintain central data base management systems and data base. ii. Design procedures for transfer of raw data between each of the Field, Reading, and Laboratory Centers and the Coordinating Center. iii. Coordinate collection, transmittal, and integration into the main data base of all laboratory, examination, interview, and follow-up data, imaging measurements and results, and quality control measurements, at the protocol development/pilot testing phase, at the screening examination, at the comprehensive examination and periodic re-examinations, from the follow-up for ascertainment of morbidity and mortality, and from substudies and ancillary studies. iv. Prepare quality assurance reports (including summaries of quality control results), summaries of study data, and clinical results on measurement findings for the Field, Reading, and Laboratory Centers, the Steering Committee, the Monitoring Board, and the NHLBI Project Office. Coordinate Field Center preparation of reports on clinical information for participants and their physicians. v. Purchase, distribute, and coordinate utilization of appropriate common mechanical and electronic equipment among all centers, including but not limited to computer hardware and software, and electrocardiogram machines. vi. Finalize forms and distribute forms and/or software to the Field Centers to reproduce such forms. vii. Develop and coordinate management of a system to archive records and specimens, including the generation of periodic reports for the Steering Committee, the Monitoring Board, and the NHLBI Project Office that delineate the number and type of specimens, location, condition (such as previous thawing and refreezing) and any other pertinent information. viii. Approximately 4 months before the end of the baseline screening examination and the comprehensive examination, produce draft Data Analysis Manuals with descriptions and names of all variables. ix. As determined by the Steering Committee, prepare data sets of examination results, medical interventions, but generally within 4 months at the end of each examination cycle, and Morbidity and Mortality events with documentation (Data Analysis Manual) for distribution to and use by investigators at each of the collaborating Centers and the NHLBI Project Office. Provide updates with corrections to or clarifications of the data base as necessary and update the Data Analysis Manual annually or as necessary. x. Develop and maintain a publications and presentations data base. Elements are to include but not necessarily be limited to title, author, manuscript proposal date, date for completion, submission date to study review committee(s), submission date to journal, status of manuscript with the journal, publication date, date of presentation, and title of meeting. Ensure ability to provide individual status reports to authors, to generate progress reports for the Publications and Presentations Committee, the Steering Committee, the Monitoring Board and the NHLBI Project Office, and to use information to identify obstacles to productivity. xi. Create data base that uses standardized query language allowing user-initiated specific online data requests via the Internet by each of the collaborating Centers and by the NHLBI Project Office. xii. Five years after the completion of 1) the screening examination, 2) the baseline comprehensive examination, 3) each follow-up examination, and 4) close-out of the study, create respective public use data sets with documentation. These should exclude individual identifiers and ancillary study data, but include detailed documentation appropriate for independent use by an investigator external to the study and unfamiliar with details of the data. Reproduce copies and distribute the data sets and the documentation upon request, preferably by CD ROM. [Note: These data sets will contain all the data deriving from an examination cycle or data collection activity, but may exclude raw data that is used solely for the purpose of creating summary or derived variables. Data will not be released if believed to be unreliable or invalid by the Steering Committee or the NHLBI Project Office. Data may be delayed for release if they are actively being used by study investigators with documented timelines for completion of analyses and publication of results, and upon review of justification by the NHLBI Project Office. Ancillary study data, collected under a grant mechanism, are not required to become part of the public use data set. Reimbursement for costs of the public use data set and documentation from public requests is recommended to be limited to $50 per tape, diskette, or CD ROM, and $0.10 per page of photocopying. The Coordinating Center and designated investigators of the study are expected to respond to questions about data set characteristics, format, and content, during and after completion of the study, and it is expected that such questions will be minimized by high quality of documentation.] i. Quality Assurance [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.] i. In collaboration with Reading, Laboratory, and Field Centers, develop and maintain, in conjunction with the Quality Assurance Committee, a quality assurance program for all questionnaire, interview, morbidity and mortality follow up, laboratory, and instrument based measurements. As part of an integrated quality assurance program, establish quality control methodologies and standards. Where warranted, provide for approximately 5% blind duplicate measurements within an examination cycle (e.g., certain biochemical laboratory based and imaging measures). Develop and modify as necessary similar standards for Reading Center measures and Field Center measures. Include assessment and control of measurement temporal drift within and between examination cycles for each laboratory and reading center measurement. Include assessment of stability of stored laboratory specimens. ii. Provide professional expertise and oversight of quality assurance activities in all measurement areas of performance as input to the Quality Assurance Committee. This includes but is not necessarily limited to: (1) Oversight of assessments of clinical cardiovascular disease (CVD, including myocardial infarction and other forms of coronary heart disease, congestive heart failure, and stroke) and CVD risk factors measured by committee review of morbidity and mortality data, interviews and physical examinations of field technicians, and standard clinical laboratory measures, (2) Clinical chemistry assessment of all laboratory-based biochemical and physical measurements, and (3) Clinical and engineering/physical sciences quality assurance assessment of all imaging measurements. iii. Develop and modify as necessary the Manual of Operations to include written standard operating procedures for the implementation of all aspects of the study protocol. This includes Field Center Operations, Morbidity and Mortality, and Data Analysis. The Field Center Manual may refer to Field and Reading Centers to be developed by the EBCT Reading Center, the Ultrasound Reading Center, and the MRI Reading Center. Sections on collection of laboratory specimens, will be provided by the Special Laboratory Center and the Central Lipid Laboratory. iv. Provide reports to the Steering Committee and to the Monitoring Board to include a review of collected data every three months for six months, then every six months, for each examination cycle (baseline screening examination, comprehensive examination, and each follow-up examination). Verify completeness, timeliness, reliability, and accuracy of collection and coding. Include in the review comparisons of measures of distribution of values between the Field Centers and/or technicians/instruments as appropriate to the measurement method. Include development and modification of standards to identify outlying values, and initiate and coordinate separate review of these observations for accuracy with the appropriate Field, Reading, and Laboratory Center. v. Maintain logs of data received, edit checks conducted, and identified errors; pursue missing data and correctable errors by communication with Field, Reading, and Laboratory Centers within two weeks of receipt and review of data; and develop, maintain, and modify an audit trail for all data entry and data correction activities, including electronically transferred data. vi. Review adherence to schedules for periodic re-examinations and all other data collection (e.g., surveillance for morbidity and mortality) quarterly. vii. Monitor scheduled maintenance of equipment at Field Centers in collaboration with appropriate Reading Centers and Laboratory Center. viii. Establish quality assurance activities for keypunching and data transmittal. ix. Coordinate initial certification and maintain ongoing retraining and recertification of performance capabilities of Field Center staff and Reading Centers staff through centralized and localized training appropriate to the Center. x. Coordinate laboratory measurement techniques and quality assurance among Field Centers of blood and tissue specimen tests conducted at the Field Center (as opposed to a central laboratory) for which timely decentralized measurement is necessary, as appropriate. xi. Participate in periodic site visits to the collaborating centers as needed. Site visits to each Field Center will be conducted during the first four months of the screening and first comprehensive examinations and periodically (approximately biennially) thereafter. xii. In collaboration with Field Centers, laboratories and Reading Centers, recommend further investigations into and modifications in procedures to improve reproducibility and reduce drift. j. Statistical analysis i. Analyze data in a timely fashion for the presentation and publication of study results for analyses originating with Coordinating Center investigators and other centralized analyses as determined by the Steering Committee or NHLBI Project Office. Submit for publication at least one (1) manuscript per year in Years 2-4 (ending August 31, 2000-2002) and at least two (2) manuscripts per year in Years 5-9 (ending August 31, 2003-7) from first authors at the Coordinating Center. [Note: Capability for data analyses will be established both centrally (at the Coordinating Center) and in each Field Center. Deliverables above reflect the minimum number of manuscripts to be completed. In addition, the Coordinating Center will conduct verifications of all final manuscript analyses and complete analyses for manuscripts originating from the Reading Centers Laboratories and NHLBI Project Office. The goal for manuscript completion from proposal to submission for publication for analyses completed by the Coordinating Center should be 12 months. The proposal should include brief descriptions of at least five potential manuscript topics.] ii. Provide statistical support for development and analysis of all quality assurance activities. iii. Conduct statistical analyses for all Coordinating Center presentations to the Steering Committee and Monitoring Board and provide timely responses to specific requests from the Steering Committee and Monitoring Board. iv. Provide statistical support to analysts and investigators at Field, Reading, and Laboratory Centers and the NHLBI Project Office for analysis of data. [Note: For purposes of the proposal, plan for one (1) analysis in Year 2, two (2) analyses in Years 3 and 4, and five (5) analyses for manuscripts in Years 5-9. See timeline for dates corresponding with Years.] v. Develop guidelines for analysts and investigators at Field, Reading, and Laboratory Centers and the NHLBI Project Office for providing data analysis programs to the Coordinating Center for verification prior to submitting manuscripts for publication. vi. Prior to manuscript submission, verify final data analyses performed at Field, Reading, and Laboratory Centers and the NHLBI Project Office and provide feedback within two weeks. k. Administrative Support i. Convene periodic Steering Committee and subcommittee face-to-face meetings and conference calls. For face-to-face meetings, distribute meeting materials and the agenda two weeks prior to meetings, and record and distribute minutes within 10 working days. For conference calls, distribute meeting materials and the agenda at least three working days prior to meetings, and record and distribute minutes within 5 working days. [Note: The Steering Committee will generally have meetings in Bethesda, Maryland, approximately every three months during protocol development/pilot testing phase and every 4 to 6 months thereafter, and have conference calls at least monthly.] ii. Arrange for and manage periodic meetings of the NHLBI Monitoring Board as directed by the NHLBI Project Office; distribute meeting materials two weeks prior to meetings; distribute meeting minutes as provided by the NHLBI Project Office within one week of receipt; provide expense reimbursement to Monitoring Board members. [Note: The Monitoring Board will meet approximately every eight months and will consist of 7-8 members.] iii. 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.] iv. Develop, maintain, and modify as needed an electronic mail network and a World Wide Web home page site connecting all Field, Reading, and Laboratory Centers and the NHLBI Project Office, providing lists of examination components, investigator addresses, and publications and allowing for selected and limited access to the main data base and any other data base of mutual benefit as determined jointly by the Steering Committee and/or the NHLBI Project Office. v. Develop, maintain, and modify as needed a World Wide Web home page site for the public, providing study descriptions, lists of examination components, investigator addresses, and publications and any other information, as determined by the Steering Committee and/or the NHLBI Project Office. vi. Develop, in conjunction with the collaborating Centers; maintain; modify; and provide to all collaborating Centers and to the NHLBI Project Office the Manual of Operations (for Field Center operations, Morbidity and Mortality, and Data Analysis), and provide in Web-ready format for all outside interested parties. vii. With Steering Committee input and final approval, write and distribute a periodic (semi-annual) newsletter to study participants and community organizations with the purpose of fostering enthusiasm and continued participation in the study. viii. By August 31, 1999, prepare OMB clearance packages in collaboration with the NHLBI Project Office. ix. Coordinate development of a core informed consent document among Field Centers to address but not necessarily be limited to specimen collection and disposition, the public release of study data without identifiers, and the Certificate of Confidentiality for DHHS Funded Studies.. x. Monitor the transport of specimens from Field Centers to the Central Lipid Laboratory, the Special Laboratory Center, and the Specimen Repository. The Central Lipid Laboratory will assist the Coordinating Center to develop, coordinate, and maintain methodologies for the collection, processing, cataloguing, and shipping from the Field Centers to the Central Lipid Laboratory, the Special Laboratory, and the Specimen Repository. The Coordinating Center will coordinate specimen cataloguing and data base linkage with the Specimen Repository. xi. At the termination of the contract, oversee the transport of all remaining repository specimens from the Specimen Repository and all other laboratories to a repository identified by the NHLBI Project Office. ******************************************************************** 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. Web site for 1 December 1, Notify Project investigators 1998 Office of operationalization 2. Web site for 1 September 1, Notify Project public 1999 Office of operationalization 3. Package for OMB 1 August 31, Project Office for screening 1999 examination 4. Package for OMB 1 February 29, Project Office for comprehensive 2000 examination 5. Steering 1 per 2 weeks All Centers Committee attendee before Project Office Reports meeting Contracts Office 6. Steering 1 per 10 days after All Centers Committee attendee meeting Project Office meeting minutes Contracts Office 7. Draft Field 7-9 August 1, 1999 Field Centers Center Manual Project Office of Operations 8. Field Center 7-9 September 1, Field Centers Manual of 1999 Project Office Operations (hard copy and Web-ready) 9. Draft Morbidity 7-9 August 1, 2000 Field Centers and Mortality Project Office Manual of Operations 10. Morbidity and 7-9 September 1, Field Centers Morality Manual 2000 Project Office of Operations (hard copy and Web-ready) 11. Data Analysis 12-14 February 28 All Centers Manual (hard 2002 Project Office copy and Web- (2 copies) ready) 12. Data Analysis 12-14 Annually, after All Centers Manual updates December 31, Project Office (Hard copy and 2002 (2 copies) Web-ready) 13. Semi-annual 3 February 28-29 Project Office progress reports August 31 (2 copies) Contracts Office (1 copy) 14. Quality Control 1 per Quarterly Project Office reports of Quality (2 copies) Assurance All Centers Committee 15. Monitoring Board 1 per 2 weeks before All Centers reports attendee meeting Project Office 1 per Contracts Office Center 16. Monitoring Board 1 per 1 week after All Centers meeting minutes attendee receipt from Project Office 17. Reprints of 5 2 weeks after Project Office published publication All Centers articles 18. Participant 4,500 Every 6 months All Centers Newsletter or as Project Office determined by Steering Committee 19. Raw data 1 as requested Project Office 20. Abstracts 2 2 weeks before Publications submission Committee Project Office 21. Manuscripts 2 copies 4 weeks before Publications submission Committee Project Office 22. Manuscripts* 1 per August 31, Project Office year 2000-2 2 per August 31, year 2003-7 13 total 23. Manuscript 1 August 31, Reading Centers, analyses 2000 Project Office, upon request 2 per August 31, year 2001-2 5 per August 31, year 2003-7 30 total 24. Manuscripts 7 per August 31, Field Centers verifications year 2002-7 Project Office 42 total 25. Financial Reports 3 Quarterly Contracts Office (Form NIH 2706) 26. Lab Specimens --- end of contract Specimen repository to be specified by Project Office 27. Data Base 1 4 months after Project Office completion of Field Centers data collection or as requested 28. Public-use 6 See below Project Office data sets with documentation (see below) Other requestors Screening exam 1 February 28, 2007 Comprehensive 1 August 31, exam 2007 Follow-up exams 3 August 31, 2009-2011 All exams 1 February 28, 2012 29. Final Report 10 Aug 31, 2008 Project Office (2 copies) and Summary Contracts Office (8 copies) *Minimum number of distinct manuscripts from Coordinating Center first authors submitted for publication. ***************************************************************** 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 a not 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 for fulfilling the Coordinating Center functions outlined in the statement of work and evidence of flexibility, timeliness, helpfulness and ability to cooperate in these functions. These include timely protocol development, scientific and operational study coordination, data and specimen management, design and implementation of quality assurance programs, performance of administrative functions, timely data analysis and publication of results, and selection and administration of subcontracts. (40 points) 2. Expertise, experience, and demonstrated scientific productivity of the professional staff pertinent to study objectives. Key staff must be knowledgeable about cardiovascular epidemiology, having experience in multicenter chronic disease studies and longitudinal study design, data collection, and statistical analysis; have specific expertise in clinical cardiovascular disease; and be knowledgeable in the technical areas of quality assurance responsibilities for laboratory, ultrasound, electron beam computed tomography, magnetic resonance imaging, and epidemiological measurements, particularly in methods for assessing and controlling measurement error. Senior staff must demonstrate an appropriate commitment of time and of direct involvement in the study be able to assume leading roles in protocol development, coordination, monitoring (quality assurance), and scientific data analysis and publication of results. (40 points) 3. The adequacy of administrative structure, support staff, and institutional support. The availability of adequate facilities and equipment, including information access facilities (e.g., libraries, computer based information search systems, etc.) and technical hardware, and the ability to develop, maintain, and modify technical software and hardware and operations, as necessary. (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-98-07; TITLE OF RFP: Subclinical Cardiovascular Disease Study: Coordinating 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-98-07 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 a single award will be made from this solicitation and that award 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. 30 30 30 30 30 30 30 30 30 30 Other Investigators 190 220 250 250 250 250 250 250 220 150 Other 200 250 360 350 340 340 340 340 280 210 All staffing levels should be accompanied by specific justifications as to the type and hours of work expected to be performed by all personnel. 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 Coordinating Center--plan for eight (8) trips per year. 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