Path: utzoo!utgpu!watserv1!watmath!uunet!bionet!GENBANK.BIO.NET!kristoff From: kristoff@GENBANK.BIO.NET (Dave Kristofferson) Newsgroups: bionet.sci-resources Subject: NIH Guide, vol. 19, no. 40, pt. 3, 9 November 1990 Message-ID: Date: 9 Nov 90 18:56:13 GMT Sender: kristoff@genbank.bio.net Lines: 1311 REQUEST FOR RESEARCH COOPERATIVE AGREEMENT APPLICATIONS: RFA: HL-91-03-P INSULIN, INSULIN RESISTANCE, HYPERGLYCEMIA AND CARDIOVASCULAR DISEASE: Field Centers, Coordinating Center and Central Laboratories P.T. 34; K.W. 0715075, 0715040, 0755018 NATIONAL HEART, LUNG, AND BLOOD INSTITUTE Letter of Intent Receipt Date: February 1, 1991 Application Receipt Date: April 5, 1991 PURPOSE The Division of Epidemiology and Clinical Applications (DECA) invites cooperative agreement applications for investigators to participate, with the assistance of the National Heart, Lung, and Blood Institute (NHLBI), in a multicenter study of the relationship of insulin and insulin resistance to cardiovascular disease (CVD) and its risk factors over a range of glucose tolerance from normal to overt diabetes. This study will be performed among persons with clinical diabetes, with asymptomatic abnormalities of glucose metabolism, and control subjects with normal glucose metabolism. The assistance mechanism used to support the study is the cooperative agreement, which is similar to the traditional NIH research grant. It differs from a research grant in the extent and nature of NHLBI staff involvement. Applications received in response to this request will participate in a single competition. A center selected as an field center also may serve as the Coordinating Center, and/or a Central Laboratory for the overall study. DISCIPLINES AND EXPERTISE The expertise appropriate for this research program includes a knowledge of both epidemiologic and clinical aspects of cardiovascular disease and diabetes, as well as administrative skills and experience in the design and conduct of collaborative epidemiologic studies. Skills in data base management and statistical analysis are appropriate for the Coordinating Center. Experience in laboratory methodology for measuring lipids, lipoproteins, insulin, and hemostatic factors is appropriate for applicants for the Central Laboratory. BACKGROUND General Patients with diabetes mellitus have an increased incidence of CVD compared to individuals with normal glucose tolerance. The risk of CVD also appears to be increased among subjects with milder degrees of glucose intolerance. A recent review of available information by the National Diabetes Advisory Board recommended increased research to understand the development of CVD in diabetics. Research to clarify the associations between insulin and insulin resistance with CVD was recommended by an NHLBI Workshop on Insulin, Sex Hormones and Atherosclerosis (May 1987). A workshop sponsored by the American Diabetes Association also recommended further studies on the association of diabetes and cardiovascular diseases (1). This initiative is in response to these recommendations. The initiative was approved by the National Heart, Lung and Blood Advisory Council at its September 1990 meeting. Scientific Background An association between overt diabetes and cardiovascular disease has been observed in many studies (2-5). This excess of CVD in diabetics includes increases in both incidence and case fatality rates from acute myocardial infarction (3,5), in mortality in the months following discharge after an acute myocardial infarction (6), in unexplained chronic congestive heart failure (7), in cerebrovascular disease (8), and in peripheral vascular disease (9). Among persons with Type II (noninsulin dependent) diabetes mellitus in the U.S., 60 percent of deaths are attributed to ischemic heart disease and 20 percent to other heart and vascular disease (10). The association between milder degrees of glucose intolerance (impaired glucose tolerance and mild diabetes with normal or near normal fasting glucose concentrations (11) and CVD is less established. Several studies suggest a relatively continuous gradient of increasing risk as glucose tolerance deteriorates (5,12). In contrast, a review of several other studies found a small and inconsistent effect of mild hyperglycemia upon CVD risk, especially after adjustment for other known CVD risk factors (14). Subjects with mild abnormalities of glucose tolerance are important since they comprise more than half of those with abnormal glucose tolerance in the U.S. population. In these subjects, excess CVD may be the major adverse effect of hyperglycemia. Recent studies have suggested that hyperglycemia may be part of a syndrome involving abnormalities in adipose tissue deposition, blood pressure, and lipid levels linked to elevations of insulin or insulin resistance (15-18). It has been suggested that the increased risk of CVD associated with diabetes may develop in the prediabetic period when glucose levels are normal or minimally elevated (19). These observations suggest that elevations in insulin or insulin resistance may contribute to an increased risk of CVD in the general, normoglycemic population. This syndrome may affect a substantially greater proportion of the U.S. population than the estimated 22 to 30 million with detectable abnormalities in glucose tolerance. Previous studies of hyperglycemia as a risk factor for CVD and of its associations with other CVD risk factors often utilized techniques of risk factor and disease measurement that are crude by current standards. In most studies focused on diabetes, measures of vascular disease and CVD risk factors were limited. In most studies focused on CVD and its risk factors, definitions of diabetes were imprecise or inadequate numbers of diabetics were identified for detailed study. The presence of diabetes may increase the risk of CVD more in women than in men (3). The reasons for this difference are unknown. In many studies, sample sizes have been too small to investigate the apparent differences and the contribution of other risk factors. Recent advances in understanding the evolution of Type II diabetes and in the measurement of CVD risk factors provide opportunities to reevaluate the relationship of glucose tolerance to cardiovascular disease and to other known CVD risk factors. Hyperglycemia is associated with alterations in lipoprotein distribution and metabolism. Hyperglycemia may promote atherogenesis by increasing glycosylation of lipoproteins and other circulating, enzymatic, and structural proteins. Correlations have been described between insulin and insulin resistance and both hypertension and dyslipidemias. Abnormalities in platelet function, in characteristics of erythrocytes and in activity of the coagulation system correlate with hyperglycemia. Many of these risk factors have been measured in small groups of subjects and the changes to be found over a range of glucose tolerance are largely unknown. Advances have also occurred in techniques to assess cardiovascular disease by non-invasive measures which can be utilized in epidemiologic studies (20,21). Episodes of ischemia can be assessed by exercise testing and ambulatory monitoring. Cardiac structure and function can be assessed by echocardiography. Atherosclerosis can be assessed by ultrasonography. The application of these and/or other measurement techniques will allow investigation of the relationships of hyperglycemia and related metabolic factors to evidence of disease. Many reasons exist to investigate the role of insulin in the development of atherosclerosis. Insulin is the major hormone controlling the assimilation and utilization of nutrients. It has multiple effects, not only upon carbohydrate metabolism, but also upon fat and amino acid metabolism, body salt and water balance, and cell growth. Insulin promotes development of atherosclerotic lesions in animals (22). Population studies indicate that hyperinsulinemia, either fasting or following a challenge, is an independent risk factor for CVD (13,23,24). These associations of insulin with vascular disease could be mediated indirectly, through changes in risk factors, particulary lipids and blood pressure, or directly, through stimulation of cell growth in arterial walls (22). Insulin concentrations may be correlated with CVD risk factors in the general population as well as in those with hyperglycemia. Levels of insulin or insulin resistance may contribute to alterations among the previously recognized CVD risk factors of obesity, hypertension, hyperglycemia and hyperlipidemia (15-19). In view of the large percentage of the adult population with at least one of these disorders, more detailed assessments of the role of insulin in altering CVD risk factors over a range of deteriorating glucose tolerance are needed. Despite this evidence, it is difficult to explain the excess of CVD in diabetics solely as a consequence of elevations in insulin levels. Insulin secretion is usually greatest in those with impaired glucose tolerance or mild diabetes, groups at lower risk of CVD than diabetics with fasting hyperglycemia (5,25). Recent, more limited, studies suggest that part of the risk previously associated with hyperinsulinemia may be correlated more strongly with high levels of insulin resistance. Since insulin response to a challenge is diminished while insulin resistance remains high or continues to increase as glucose levels increase within the diabetic range, these observations may help to explain the higher risk of CVD in overt diabetics (26). More detailed assessments of the role of insulin resistance relative to insulin levels in altering CVD risk factors are needed. Despite several studies that indicate an increased risk of CVD associated with hyperglycemia, it remains unclear how much of this risk is independently associated with hyperglycemia, how much can be explained by adverse effects on conventional CVD risk factors, and how much may be related to risk factors that were not measured in previous population studies. In diabetics with fasting hyperglycemia, the increased risk of CVD appears to be mediated both by increases in other CVD risk factors and by hyperglycemia or related unmeasured metabolic abnormalities (5,12). At high concentrations, glucose may have a direct toxic effect upon endothelial cells (27). In subjects with impaired glucose tolerance or mild diabetes, most of the excess risk of CVD may be attributed to risk factors other than hyperglycemia. Assessments of hyperglycemia as an independent risk factor for CVD after adjustment for other known risk factors may underestimate the risk related to abnormal carbohydrate metabolism since conventional risk factors, especially blood pressure and lipids, are altered adversely as glucose tolerance deteriorates (28-29). The increased risk of CVD that accompanies hyperglycemia may be mediated, at least in part, by both direct and indirect effects of glucose and insulin concentrations and levels of insulin resistance. Some CVD risk factors might be altered adversely by high or low insulin concentrations while others might be more affected by changes in insulin resistance. It appears best to investigate the relationships among CVD risk factors over a spectrum of glucose tolerance from normal to diabetes with fasting hyperglycemia. No distinct shift in the risk of CVD or in CVD risk-factor levels is found between recognized diagnostic categories of glucose tolerance. The National Diabetes Data Group and WHO criteria for the definition of diabetes and impaired glucose tolerance are based in part upon the risk of developing microvascular complications of diabetes and are related only indirectly to the risk of developing CVD (11,30). Moreover, the major changes thought responsible for the development of impaired glucose tolerance and Type II diabetes, increasing insulin resistance and an initial increase and subsequent decrease of endogenous insulin secretion, occur at glucose levels which correspond imperfectly to the established diagnostic categories. Other observations support the concept of studying risk-factor relationships across the spectrum of glucose tolerance. Marked differences in levels of a risk factor may exist within the range of glycemia encompassed by a diagnostic category. Serum insulin response to a glucose challenge, for example, is usually above normal in subjects with mild diabetes but is almost uniformly below normal in diabetic subjects with fasting hyperglycemia (25). In addition, the change in individual risk factors with increasing glucose concentrations is variable and shows little relationship to the diagnostic categories. Abnormalities in lipids and in the glycosylation of proteins provide examples. With mild glucose intolerance, lipid concentrations are increased due to increased lipid synthesis. With severe hyperglycemia, lipid levels are increased further due to impaired lipid clearance (31). With mild glucose intolerance, protein glycosylation is essentially normal but when fasting hyperglycemia is present, glycosylation increases substantially. In previous studies, the numbers of subjects studied usually were too small to characterize risk factor differences within diagnostic categories. Studies are needed with adequate sample sizes and distributions to investigate these relationships. Such information will help to define goals for future interventions attempting to reduce the risk of CVD associated with hyperglycemia. Several abnormalities in CVD risk factors that have been associated with hyperglycemia are outlined below. Only limited information is available about their alterations in relation to levels of glucose tolerance, insulin, or insulin resistance. Obesity is both a risk factor for the development of Type II diabetes and usually persists after the disease is manifest (32). In addition, obesity is associated with adverse changes in many CVD risk factors (33). The central distribution of body fat, as measured by the waist-to-hip ratio, is positively associated with diabetes prevalence (34). This distribution of fat has been associated with elevated levels of insulin and insulin resistance (35). Obesity consistently shows one of the strongest associations with increased levels of insulin and insulin resistance. The majority of the macrovascular complications of diabetes occur in subjects with concomitant hypertension (36). Compared to subjects with normal glucose tolerance, blood pressure is increased in both subjects with impaired glucose tolerance and with diabetes (28). The earliest changes leading to hypertension in hyperglycemic subjects are not known. Subclinical involvement of the kidneys by diabetic microvascular disease has been postulated as a cause of hypertension but probably cannot account for the excess hypertension associated with mild glucose intolerance. Hypertension has been linked with hyperinsulinemia in both nondiabetic and diabetic subjects (15). A recent small study has found an association between increased insulin resistance and hypertension in normal weight, normoglycemic subjects (37). Mechanisms underlying this association may include alterations in renal sodium clearance and activation of the sympathetic nervous system (38). Lipid abnormalities become more pronounced as glucose concentrations increase and suggest several ways in which hyperglycemia can contribute to accelerated atherosclerosis. Hypertriglyceridemia has been recognized for decades as the most characteristic lipid abnormality of diabetes mellitus (39). In most diabetics, only modest elevations are found in total cholesterol levels. Elevations are found in very low density lipoproteins (VLDL) and in low density lipoproteins (LDL). In Type II diabetic subjects, high density lipoproteins (HDL) are decreased and this abnormality is partially corrected by treatment (29). In one study, the improvement achieved by therapy appeared related to insulin administration and not to the degree of improvement in metabolic control, suggesting an independent role for insulin in the control of lipoprotein metabolism (40). The reduced HDL concentrations found in Type II diabetics are inversely correlated with insulin resistance (41). Lipid abnormalities in diabetics also include alterations in the metabolism and composition of lipoprotein particles (42). VLDL degradation leads to an increased formation of highly atherogenic particles which usually circulate for only brief periods. Even in diabetics with apparently normal total lipids the concentration of remnant particles may be increased (43). Specific apoprotein E phenotypes and allele frequencies may be associated with hyperlipidemia in diabetics (44). Alteration of lipoprotein molecules may increase their atherogenicity (45). Apoproteins can undergo glycosylation in a hyperglycemic environment. In addition to glycosylation of apoproteins, hyperglycemia leads to slow, irreversible nonenzymatic glycosylation of multiple other proteins in vivo. A recent review indicates how these abnormalities could contribute to accelerated atherosclerosis (46). Abnormalities in platelet function, clotting factors and blood viscosity also may contribute to the increased occurrence of CVD in diabetics (47,48). In some instances, these abnormalities may be the result of damage from existing vascular disease. Abnormalities of platelet function have been described in diabetics but their relationship to clinical cardiovascular disease is uncertain. Changes in platelet function also may occur in nondiabetic subjects with hypertension (49). Abnormalities in clotting factors have been described in association with diabetes or atherosclerosis (50,51). The effects of differing degrees of hyperglycemia on these alterations are not known. Abnormalities in DNA segments may identify diabetics at increased risk of atherosclerosis (52). Further definition of genetic factors that alter susceptibility to atherosclerosis could help to identify individuals with glucose intolerance at particularly high risk of developing macrovascular complications. Studies to date on the relationship of insulin and insulin-resistance levels to abnormalities in CVD risk factors have mainly been conducted in Caucasian subjects. Recent studies have suggested that CVD risk-factor levels may have different associations with documented risk of CVD in Hispanic vs. non-Hispanic whites (53). The well established relationship of insulin levels with blood pressure levels may be reduced or absent in some American Indian tribes and possibly in Blacks (54-56). Studies comparing levels of glucose, insulin, and insulin resistance, and their associations with other CVD risk factors and prevalence of cardiovascular disease among racial and ethnic groups within the U.S. population may help to clarify the role of hyperglycemia and hyperinsulinemia in altering CVD risk. In addition to the relatively acute effects of hyperglycemia, more chronic complications of diabetes may contribute to CVD mortality. Diabetics, especially those receiving insulin therapy for many years, have numerous abnormalities of autonomic nervous system function (57). When severe, these abnormalities are associated with sudden death. Other potential risk factors, such as an excess of silent ischemia, have been reported in diabetics (58). In summary, deficits in information from earlier epidemiologic studies and recent advances in understanding of risk factors for CVD and methods to measure CVD in population studies make it promising to investigate the associations between levels of glucose, insulin and insulin resistance, and other known CVD risk factors and their relationship to prevalent cardiovascular disease. It is essential that future studies examine risk-factor levels over a wide spectrum of glucose tolerance from normal through impaired glucose tolerance to diabetes with fasting hyperglycemia. Differing patterns of risk- factor abnormalities may be found at different points on this spectrum. Such patterns may help to explain the different rates of CVD and the apparent discrepancies in the independent contribution of glucose concentration to CVD risk over the spectrum. An improved understanding of the relation of insulin concentrations and insulin resistance to CVD risk factors also will help to explain a component of CVD risk in the general, normoglycemic, population as well as in that portion of the population that has hyperglycemia. GOAL OF THE ACTIVITY The primary purpose of this Request for Applications (RFA) is to stimulate a collaborative, multidisciplinary investigation of the relationships between blood glucose and insulin concentrations, insulin resistance, and other CVD risk factors and cardiovascular disease in subjects with diabetes and in subjects with asymptomatic glucose intolerance as compared to subjects with normal glucose tolerance. OVERVIEW The objective of this RFA is to assess the relationships of increasing concentrations of glucose and changing levels of insulin and insulin resistance to other recognized CVD risk factors, and to the presence of atherosclerotic vascular disease using standard methodology and a large enough population so there are adequate numbers for comparisons of changes across the range of glucose tolerance. This study will provide insight into the reasons for the changing risk of CVD at increasing glucose levels and may help to explain the reported differences in the contribution of hyperglycemia to the risk of CVD in men and women and in minority populations. Several features of this study are specified so that applicants have common understanding of factors necessary for the collaborative effort, e.g. its magnitude, phases, and the handling of certain central functions. Many characteristics of the subjects to be studied are specified. However, the nature of the studies to be carried out in the collaborative investigation of the relationships between levels of glucose and insulin, insulin resistance, other CVD risk factors and cardiovascular disease are in the hands of the investigators. A number of possible components are listed purely for illustrative purposes. The collaborative protocol will be developed by the Project Steering Committee, composed of the awardees and the NHLBI Project Scientist. The protocol will be subject to peer review by an uninvolved expert group. The study will move into its second (or operational) phase only with the concurrence of both the awardees and the Institute. SCOPE OF ACTIVITY The studies are envisioned as taking place in two to four field centers and as involving between 1600 and 1800 subjects. Applicants should plan the study in four phases: (I) collaborative protocol development, (II) sample selection, (III) sample examination, and (IV) data analysis and reporting. This is further described under the section "Study Phases". Central functions of the collaborative activity, a Coordinating Center and a Central Laboratory, will probably be performed by or under the direction of one or more of the field centers. This will require separate applications and is described in detail under the section "Central Functions". The characteristics desired of the study sample are outlined below. To avoid bias, the subjects should be recruited from a defined population. A critical component of this study is to achieve a stratified sample with subjects distributed in approximately equal numbers across a range of glucose concentrations from normal through impaired glucose tolerance to overt diabetes. In addition, efforts should be made to recruit approximately equal numbers of men and women over the age range 40 to 69 years. Each group should have a comparable range of obesity and include subjects treated and untreated for hypertension. The study will not include funding to support general population screening for glucose tolerance. Considerable reduction in screening costs can be achieved by use of existing data even as simple as a recent fasting glucose determination. Potential subjects with varying degrees of glucose tolerance must be available, but their prior characterization by standardized glucose tolerance testing is not mandatory. Information should be provided concerning the type and time of prior testing and the availability of test results. Investigators should be aware that NIH requires applicants to give added attention, where feasible and appropriate, to the inclusion of minorities and women in study populations. Gender and minority population differences must be noted and analyzed whenever possible. If minorities and/or women are not included in a given study, a clear reason for their exclusion must be provided. Merely including an arbitrary number of minority group and women participants in a given study is insufficient to guarantee generalization of results. In view of recent evidence that the risk of CVD associated with abnormalities in glucose and insulin homeostasis may vary among non- Hispanic white and minority populations, investigators are strongly encouraged to include minorities in the populations they propose for study. This should be done in a way that provides the strongest scientific design to investigate the origin of the potential differences. Based upon what is known, what is needed, and what is deemed feasible, NHLBI intends that the collaborative study will include sufficient subjects of at least one or two minority populations to test for possible differences. The Institute would prefer to have such diversity of populations at each awardee institution. However, the characteristics of this study may militate against this. The Institute may have to achieve its minority population goal by the selection of awardees in part on the basis of the populations and mix of populations that they will bring into the collaborative study. Each applicant should propose the study design he or she believes most appropriate for this project. Each application should include a description of the characteristics of the reference population and of the sample to be selected. Applicants should discuss any factors that they believe should exclude a participant from the study. Evidence might be presented indicating the availability of health care records of prospective subjects for review during the screening phase. Since duration of hyperglycemia may be important in the pathogenesis of vascular disease, data on duration of documented diabetes or hyperglycemia, if available, may be particularly valuable. Applicants should discuss the advantages and disadvantages of their proposed approaches to the study and describe their plan for obtaining collaboration for the examination. Whatever strategy is proposed for subject selection, applicants should provide a detailed justification for the projected selection plan, an estimate of the number of subjects in the source population and in the final examination sample, as well as an estimate of the necessary time and effort to identify the Phase III study subjects. Applicants unable to recruit at least 400 subjects for the Phase III examination are unlikely to receive awards. All centers must be willing to implement the selection and examination strategies developed collaboratively by the Steering Committee during protocol development and to supply their data and necessary specimens to the Coordinating Center and other central facilities for combination and analysis. Applicants should indicate what data they propose for collection in the collaborative endeavor and provide justification for each component of their proposed examination. For illustrative purposes, tests that might be included in the study are outlined below. This is not intended to constrain applicants who are encouraged and expected to propose the study design they believe best to achieve the goals of the project. The collaborative protocol will be developed during Phase I. Core examinations might include interview data including a limited dietary assessment and a limited physical examination concentrating on evidence of cardiovascular disease and CVD risk factors. Blood pressure and heart rate might be measured both supine and erect. Adiposity and its distribution might be assessed. Laboratory tests might include assessment of evidence of CVD and CVD risk factor levels. Laboratory tests might include some or all of the following and any additional tests that the applicant believes worthwhile. It is expected that most of the proposed measurements will be conducted at each institution under the core protocol. For some measurements requiring complex techniques, however, investigators may propose to perform tests in a defined subgroup of the study population. Measures of cardiovascular disease: Electrocardiogram Additional measures of cardiac disease such as echocardiography Additional measures of atherosclerotic vascular disease such as carotid ultrasonography Laboratory measurements of: Glucose, both fasting and after a standard load Insulin, both fasting and after a standard load Insulin resistance Glycosylated hemoglobin Insulin secretion over 24 hours Cholesterol, Triglycerides Lipoproteins (LDL, HDL, VLDL and possibly IDL) Glycosylated LDL or other lipoproteins Apoproteins, including A1, B and E Post prandial lipids Urinary protein excretion Coagulation measurements Platelet function Clotting factors, including fibrinogen, Factors VII and VIII Blood viscosity alterations Applicants should discuss the relative merits of assessing each of the risk factors they propose to measure in terms of current knowledge, new information to be obtained, potential importance as a cause of CVD, and the precision of available measurement techniques. A similar discussion should be provided for each proposed measure of existing cardiovascular disease. They also should discuss how, when, where, and by whom the data are to be collected as well as the procedures essential for assuring proper collection, completeness and accuracy of the data, and prompt transmission to the Coordinating Center. Applicants must be able to interact effectively with the Coordinating Center for data transmission and editing. STUDY COMPONENTS A. Field Centers The Field Centers will recruit subjects, review necessary records and perform examinations for the study. Central functions will be performed by or under the direction of one or more of the Field Centers. B. Central Functions Each Field Center applicant is encouraged to apply to serve as one or more of the central support units for the study. A separate application should be submitted for each support unit. It is unlikely that an award will be made for a support unit independent of a field center award. Applicants should discuss the special functions of any proposed support activity, including methodology and quality control assessment, provide a budget and an estimate of time for the work to be completed. The specific areas to be addressed in applications for support units are outlined in the Review Criteria section. 1. Coordinating Center The Coordinating Center will serve as the central data management facility for the study. This center will participate in protocol development, produce the Manual of Operations, the data collection forms, and oversee training for the study. Data collected in the Field Centers and generated in the central laboratory will be transmitted to the Coordinating Center for storage and analysis. This center will oversee performance of any special measurements at other laboratories. The Coordinating Center will play a lead role in monitoring subject recruitment and the quality control of the study. It will prepare reports for the Steering Committee and Data Monitoring Board and will provide data analysis for final study publications. 2. Central Laboratory The Central laboratory will perform or, in special cases, arrange for, the laboratory determinations specified in the study protocol. The laboratory will be responsible for developing a procedure manual for sample acquisition and processing in the Field Centers, sample shipment to the appropriate laboratory and analyze measurement methodology. Together with the Coordinating Center, it will be responsible for monitoring quality control of all samples. It will be responsible for prompt performance of assays and timely transmission of data to the Coordinating Center. STUDY PHASES The study may be divided into four main phases, a planning phase (Phase I), a record review and subject selection phase (Phase II), an examination phase (Phase III), and a data analysis and report preparation phase (Phase IV). Phase I The goal of Phase I will be to design the study. This phase should take approximately 12 months. Meetings of the Steering Committee composed of the Principal Investigators and the NHLBI Project Scientist will be held approximately 4 to 6 times during this period in Bethesda, MD. The primary issues to be resolved by the Steering Committee during this phase include design of the study and determination of eligibility criteria for participation in the sample selection and examination Phases (II and III). Other key staff involved in the study may be invited to participate in planning. This phase will have the following objectives: 1. To develop a common protocol using standardized methods for selection of subjects and review of existing records to classify them with respect to glucose tolerance and the presence or absence of existing CVD. 2. To develop a common protocol for testing subjects to assess current level of glucose tolerance. 3. To develop a common protocol for a limited examination for objective evidence of CVD and the measurement of selected CVD risk- factor levels among members of the final (Phase III) stratified sample. Additional objectives for this phase will be to develop data collection forms and a Manual of Operations for the study; to recruit and train key staff in procedures for medical record review and for the examination of subjects. Near the conclusion of this phase, a two to three day training session will be held. Staff representing each functional category requiring training should be available for a training meeting to be held at a central location (Bethesda should be used for cost estimation) prior to the start of examinations. At the end of Phase I, a pilot study will be conducted to insure that standardization of core protocol procedures is achieved among all centers. Phases II and III The goal of Phase II is the selection of the stratified sample for the Phase III examination. This phase should take approximately eight months. All participating centers must implement the common protocol developed by the Steering Committee during Phase I. The Steering Committee will meet approximately twice during this phase. The goal of Phase III is to conduct the examination of the stratified sample. This phase will take approximately sixteen months. During this period, the Steering Committee will meet approximately every four months to review progress. Additional communication will be by telephone conference calls, approximately monthly. Note: Investigators proposing to use populations with previously defined glucose tolerance may find it more efficient and economical to combine Phases II and III. Phase IV Phase IV will be a period for "close-out" activities, data analyses, and manuscript preparation. This phase should take approximately twelve months. Reduced support will be continued for a limited period for field centers to complete final data entry and respond to edit queries from the Coordinating Center. The Coordinating Center will support the preparation of study reports and manuscripts with data analyses, statistical consultation, editorial and clerical tasks, and coordination of meetings. It is anticipated that at least one meeting of the Steering Committee, as well as periodic conference calls, will be necessary during this period. STUDY RESPONSIBILITIES, GOVERNANCE and FUNDING The primary governing body of the study will be the Steering Committee, composed of the principal investigators of the study centers and the NHLBI Program Scientist. Subcommittees will be formed on such topics as study design and execution, quality control, and publications, and will also have NHLBI representation. Unless otherwise explicitly provided, the non-NHLBI investigators will have the lead role in the Steering Committee and its subcommittees. The first meeting of the Steering Committee will be convened by the NHLBI Program Scientist. All major scientific decisions will be determined by vote of the Steering Committee. The Committee will have primary responsibility for the development of the study protocol, facilitating the conduct of the study, and reporting of the study results. It is expected that data will be submitted centrally and that the protocol will define rules regarding access to data and publications. A Data and Safety Monitoring Board, to be appointed by the Institute, will review progress at least annually and report to the Institute. TERMS AND CONDITIONS OF AWARD It is anticipated that two to four awards will be made under this RFA for a total of approximately $7.0 million (including direct and indirect costs for field centers and all central functions) over a four-year period. Funding is expected to begin on or about September 30, 1991. Applications from foreign institutions will be considered only if the applicant provides detailed evidence of unique opportunities not available in a U.S. population. The administrative and funding mechanism to be used to undertake this program will be cooperative agreements, an assistance mechanism. Under the cooperative agreement, the NIH assists, supports and/or stimulates and is involved substantially with recipients in conducting a study by facilitating performance of the effort in a "partner" role. Consistent with this concept, the tasks and activities in carrying out the studies will be shared among the awardees and the Institute project scientist. The tasks or activities in which awardees will have substantial responsibilities include protocol development, patient recruitment and follow-up, data collection, quality control, interim data and safety monitoring, final data analysis and interpretation, preparation of publications, collaboration with other awardees, and collaboration with the NHLBI project scientist. The NHLBI project scientist will have substantial responsibilities in protocol development, quality control, interim data and safety monitoring, final data analysis and interpretation, preparation of publications, collaboration with awardees, coordination and performance monitoring. It is anticipated that awardees will have lead responsibilities in protocol development, final data analysis and interpretation, and in the preparation of most publications. The NHLBI project scientist will have lead role responsibilities in quality control and interim data and safety monitoring and in the preparation of some publications. The NHLBI project scientist will have membership on the Steering Committee and its subcommittees and on the Data and Safety Monitoring Board. The Institute reserves the right to terminate or curtail the study (or an individual award) in the event of a substantial shortfall in (a) patient recruitment, follow-up, data reporting, quality control, or other major breech of the protocol; or (b) substantive changes in the agreed-upon protocol to which the Institute does not agree; or (c) reaching a major study endpoint substantially before schedule with persuasive statistical significance; or (d) human subject ethical issues that may dictate a premature termination. Any disagreement that may arise in scientific matters between award recipients and NHLBI may be brought to arbitration. An arbitration panel will be composed of three members - one selected by the Steering Committee (with NHLBI member not voting) or by the individual awardee in the event of an individual disagreement, a second member selected by NHLBI and the third member selected by the two prior members. This special arbitration procedure in no way affects the awardees right to appeal an adverse action that is otherwise appealable in accordance with the PHS regulations at 42 CFR part 50, subpart D and HHS regulation at 45 CFR part 16. These special Terms of award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS Grant Administration Regulations at 45 CFR part 74, and other HHS, PHS, and NIH grant administration policy statements. REVIEW PROCEDURES AND CRITERIA General Considerations All applicants will be judged on the basis of the scientific merit of their proposed study and their documented ability to conduct the essential study components as outlined in the Activities Sought and Overview sections of this RFA. Review Method Upon receipt, applications will be reviewed for their responsiveness to the objectives of this RFA. If an application is judged unresponsive at this stage, it will be returned to the applicant. All applications responsive to this RFA will be reviewed initially for scientific and technical merit by a special review group, convened by the Division of Extramural Affairs, NHLBI, to review these applications. Subsequently, they will be reviewed by the National Heart, Lung and Blood Advisory Council, most likely at its September 1991 meeting. Following primary scientific merit review, some applicants may receive further inquiry from Institute program staff. This may focus upon scientific or technical questions arising from the peer review or upon primarily operational and administrative questions. The inquiry may involve no more than a telephone call or letters, or it may take the form of a site visit or a reverse site visit. If the application submitted in response to this RFA is substantially similar to a research grant application already submitted to the NIH for review, but that has not yet been reviewed, the applicant will be asked to withdraw either the pending application or the new one. Simultaneous submission of identical applications will not be allowed, nor will essentially identical applications be reviewed by different review committees. Therefore, an application cannot be submitted in response to this RFA which is essentially identical to one that has already been reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an Introduction addressing the previous critique. Review Criteria Applicants are encouraged to submit and describe their own ideas on how best to meet the goals of the study. Applications will be judged primarily on the scientific quality of the application, the availability of a study sample with adequate numbers of subjects across a range of glucose tolerance from normal to overt diabetes, the ability to select and measure CVD risk factors and to identify prevalent cardiovascular disease, the discussion of considerations relevant to this RFA, expertise of the investigators, their capability to perform the work proposed, and a demonstrated willingness to work together with other Centers, the Coordinating Center, and NHLBI project scientist. Criteria for review of the applications will include, but not necessarily be limited to, the following: For Field Centers: 1. Scientific merit of the proposed study design including: o methods to assess glucose tolerance, insulin response, and insulin resistance o CVD risk factors to be assessed and proposed methodology o measures of prevalent CVD and proposed methodology o discussion of the relative merits of measuring each of the CVD risk factors that the applicant proposes for inclusion in the study in terms of current knowledge, new information to be obtained, its potential importance as a cause of CVD, and the precision of available measurement techniques o discussion of the relative merits of each of the measures of prevalent CVD that the applicant proposes for inclusion in the study in terms of current knowledge, new information to be obtained, and the precision of the proposed measurement techniques. 2. Availability of a population with the appropriate distribution of glucose tolerance and an adequate distribution by age, sex, and obesity. Availability of medical records to review and the ability to recruit participants for the examination phase including: o the availability of results and distribution of glucose levels from previous studies in the source population for study subjects o the stratified sample proposed for examination o the criteria proposed for exclusion of subjects o evidence to indicate the likelihood of acceptable exam participation rates o the ability to complete the work proposed in a timely manner Note: Based upon what is known, what is needed, and what is deemed feasible, NHLBI intends that the collaborative study will include sufficient subjects of at least one or two minority populations to test for possible differences. The Institute would prefer to have such diversity of populations at each awardee institution. However, the characteristics of this study may mitigate against this. The Institute may have to achieve its minority population goal by the selection of awardees in part on the basis of the populations and mix of populations that they will bring into the collaborative study. 3. Qualifications, experience, and commitment of key personnel including: o expertise of the investigators and other key personnel in the conduct of epidemiologic studies of cardiovascular disease and/or diabetes; expertise of investigators in cardiology and endocrinology o expertise of relevant investigators in performance of proposed special laboratory or clinical tests o ability of key personnel to devote adequate time for the effective conduct of the study o administrative capabilities of the Principal Investigator and other key team members o willingness to work in cooperation with other Centers, the Coordinating Center, and the NHLBI in the manner summarized in the RFA, including implementation of the common protocol selected Note: It is the belief of NHLBI that cooperation between experts in cardiovascular disease and diabetes and between epidemiologists and experts in clinical research is essential for efficient exploration of the relationships among insulin, insulin resistance, and CVD. Inadequate strength of proposed collaborative efforts was apparent in many responses to the RFA on Hyperglycemia and Cardiovascular Disease (NIH-88-HL-11-P) issued by NHLBI in July 1988 and was a factor in the decision not to fund this earlier program. Multidisciplinary approaches to this problem are strongly encouraged. 4. Ability to implement the data collection and reporting procedures. 5. Appropriateness of the budget for the work proposed. 6. A description of facilities and resources available and/or needed For the Coordinating Center: Criteria 3 through 6 under Field Centers plus: o ability to develop protocols including forms development and related instructional materials and the study Manual of Operations o ability to process the volume of data expected and manage the study data base o plans to assure quality control of data o ability to monitor study recruitment o ability to provide analytical support o ability to provide interim reports to the Steering Committee o ability to complete work on schedule For the Central Laboratory: Criteria 3 through 6 under Field Centers plus: o ability to develop and monitor procedures for sample collection, processing, and transportation to the required laboratory(ies) o ability to process the volume of specimens and data expected o ability to assure quality control of data generated o laboratory methodology proposed for each test o ability to complete work on schedule o ability to transmit data promptly to the Coordinating Center o plans for subcontracting any component(s) of the laboratory determinations (if applicable) Each applicant must submit an adequately justified budget for each 12- month period for a total of four years of support. Estimates of staffing needs, including the Principal Investigator and other professional and support staff, must be included. To assist with program planning, each applicant is also asked to submit a budget for each phase of the study as an appendix to the application. METHOD OF APPLYING Letter of Intent Prospective applicants are asked to submit a letter of intent. This should be brief but indicate whether the applicant intends to apply for only a field center site or whether separate applications will also be submitted for one or more central support functions. It should indicate the Principal and Co-Investigators, and identify cooperating institutions. The Institute requests such letters only for the purpose of providing an indication of the number and scope of applications to be received and usually does not acknowledge their receipt. A letter of intent is not binding, and it will not enter into the review of any application subsequently submitted, nor is it a necessary requirement for applications. This letter of intent, which should be received no later than February 1, 1991, should be sent to: James C. Scheirer, Ph.D. Review Branch, DEA, NHLBI Westwood Building, Rm 648 5333 Westbard Avenue Bethesda, MD 20892 Format for Applications Submit applications on form PHS 398 (revised 10/88), the application form for the traditional research project grant. This form is available in an applicant institution's office of sponsored research or business office, or from the Division of Research Grants, Office of Grants Inquiries, Westwood Bldg., Rm 449, 5333 Westbard Avenue, Bethesda, MD 20892. Use the conventional format for research project grant applications and ensure that the points identified in the section on "Review Procedures and Criteria" are fulfilled. The format and instructions for budget estimates provided should be followed. Indirect costs will be awarded in the same manner as for research grants. All costs for travel to meetings should be estimated on the basis of a round trip to Bethesda, MD. Budgets will be reviewed on the basis of appropriateness for the work proposed. Allowable costs and policies governing the research grant programs of the NIH will prevail. Overlapping support or duplication of funding will not be allowed, and a summary of all actual and pending sources of support for each key investigator participating in the study should be included. These summaries of other funding should identify by name the Principal Investigator of each award and should include the source of the funds with identifying grant or other award number, percent effort committed, the amount of the award for the current year, the total amount of the award, the project period for which the award was made. This RFA is a one-time request for applications. To identify the application as a response to this RFA, check "yes" on Item 2 of page 1 of the application and enter the title, Insulin, Insulin Resistance, and Cardiovascular Disease: RFA HL-91-03-P. For each application, in the upper left hand corner of the face page enter the words Field Center, Coordinating Center, or Central Laboratory, as appropriate. Application Procedure THE RFA LABEL FOUND IN THE FORM PHS FORM 398 APPLICATION KIT MUST BE AFFIXED TO THE BOTTOM OF THE FACE PAGE OF THE ORIGINAL COMPLETED APPLICATION FORM PHS 398. FAILURE TO USE THIS LABEL MAY RESULT IN DELAYED PROCESSING OF YOUR APPLICATION SUCH THAT IT MAY NOT REACH THE REVIEW COMMITTEE IN TIME FOR REVIEW. Send or deliver the original, signed application and four (4) complete photocopies of it to: Division of Research Grants Westwood Building, Room 240 National Institutes of Health Bethesda, MD 20892** Send two (2) additional copies of the application to: James C. Scheirer, Ph.D. Review Branch, DEA, NHLBI Westwood Building, Rm 648 5333 Westbard Avenue Bethesda, MD 20892 Telephone: (301) 496-7363 IT IS IMPORTANT TO SEND THESE TWO COPIES AT THE SAME TIME AS THE ORIGINAL AND FOUR COPIES ARE SENT TO THE DIVISION OF RESEARCH GRANTS. OTHERWISE, THE NHLBI CANNOT GUARANTEE THAT THE APPLICATION WILL BE REVIEWED IN COMPETITION FOR THIS RFA. Application must be received by April 5, 1991. An application not received by this date will be considered ineligible. Time table Letter of Intent February 1, 1991 Application Receipt Date April 5, 1991 Review by National Heart, Lung and Blood Advisory Council September 12-13, 1991 Anticipated Award Date September 30, 1991 Inquiries Inquiries regarding this announcement may be directed to the Project Scientist: Peter J. Savage, M.D. Clinical and Genetic Epidemiology Branch, DECA, NHLBI Federal Building, Rm 300 7750 Wisconsin Avenue Bethesda, MD 20892 Telephone 301-496-4333 REFERENCES 1. American Diabetes Association. 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Metabolism 34:Suppl 1, 37-44, 1985. 47. Ostermann H, Van de Loo J. Factors of the hemostatic system in diabetic patients. A survey of controlled studies. Haemostasis 16:386-416, 1986. 48. McMillan DE. Effects of insulin on physical factors: Atherosclerosis in diabetes mellitus. Metabolism 34:Suppl 1, 70-77, 1985. 49. Kjeldsen SE, Lande K, Gjesdal K, Westheim A, Foss OP, Leren P, Eide IK. Increased platelet release reaction in 50-year old men with esential hypertension: Correlation with atherogenic cholesterol fractions. Am Heart J 113:151-155, 1987. 50. Kannel WB, Wolf PA, Castelli WP, D'Agostino RB. Fibrinogen and the risk of cardiovascular disease: the Framingham Study. J Am Med Assoc 258:1183-1186, 1987. 51. Breddin HK, Krzywanek HJ, Althoff P, Schoffing K Oberia K. PARD: Platelet aggregation as a risk factor in diabetics: Results of a prospective study. Horm Metab Res 15:[Suppl] 63-8, 1985. 52. Mandrup-Poulsen T, Owerbach D, Nerup J, Johansen K, Ingerslev J, Hansen AT. Insulin gene flanking sequences, diabetes mellitus and atherosclerosis: a review. Diabetologia 28:556-564, 1985. 53. Mitchell BD, Stern MP, Haffner SM, Hazuda HP, Patterson JK. Risk factors for cardiovascular mortality in Mexican Americans and non- Hispanic whites. San Antonio Heart Study. Am J Epidemiol 131:423-33, 1990. 54. Saad MF, Knowler WC, Pettitt DJ, Nelson RG, Mott DM, Bennett PH. Insulin and hypertension: Relationships to obesity and glucose intolerance in Pima Indians. Diabetes, in press. 55. Saad MF, Lillioja S, Nyomba B, Raz I, Zurlo F, Castillo C, Ferraro R, Knowler WC, Bennett PH, Howard BV, Bogardus C. Ethnic differences in the relationship between blood pressure and insulin resistance. Am J Hypertension 3:25A, 1990. 56. Manolio TA, Savage PJ, Burke GL, Liu K, Wagenknecht LE, Sidney S, Jacobs DR Jr., Roseman JM, Donahue RP, Oberman A. Association of fasting insulin with blood pressure and lipids in young adults: the CARDIA study. Arteriosclerosis 10:430-36, 1990. 57. Boulton AJM, Knight G, Drury J, Ward JD. The prevalence of symptomatic diabetic neuropathy in an insulin treated population. Diab Care 8:125-128, 1985. 58. Nesto RW, Phillips RT. Asymptomatic myocardial ischemia in diabetic patients. Am J Med 80:(4C)40-7, 1986. The programs of the Division of Epidemiology and Clinical Applications, National Heart, Lung and Blood Institute, are identified in the Catalog of Federal Domestic Assistance, Numbers 93.837-93.839. Awards will be made under the authority of the Public Health Service Act, Section 301 (42 U.S. 241) and administered under PHS grant policies and Federal regulations, most specifically 42 CFR Part 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372, or to Health Systems Agency review. Brought to you by Super Global Mega Corp .com