Full Text HL-94-011 GENETIC DETERMINANTS OF HIGH BLOOD PRESSURE NIH GUIDE, Volume 23, Number 10, March 11, 1994 RFA: HL-94-011 P.T. 34 Keywords: Genetics Hypertension National Heart, Lung, and Blood Institute Letter of Intent Receipt Date: June 17, 1994 Application Receipt Date: September 16, 1994 PURPOSE The Division of Heart and Vascular Diseases and the Division of Epidemiology and Clinical Applications invite cooperative agreement applications to establish networks that, with the assistance of the National Heart, Lung, and Blood Institute (NHLBI), will participate in a coordinated effort to elucidate the major genetic factors involved in the etiology and pathogenesis of hypertension. The objective of this request for applications (RFA) is to establish: (1) Genetic Networks of collaborating investigators to exploit modern molecular genetic tools to map and identify the major genetic determinants of high blood pressure, and (2) Genetic Epidemiology Networks that, in addition to gene mapping and identification described above, will also study interactions between genetic and non-genetic determinants of hypertension in defined populations. Support for Genetic Epidemiology Networks will not be provided for de novo recruitment of probands who have not previously been examined and had their blood pressures measured and family histories of high blood pressure ascertained. An essential feature of these collaborative research efforts, both within and among networks, is the sharing of technology, data, skills, biological materials, as well as population resources. The studies may employ a variety of genetic strategies using family configurations, including linkage analysis of affected sib-pairs and extended families. Case-controlled allelic association studies are considered responsive to this RFA only when the investigator expresses a clear intent to confirm any positive findings with evidence from other sorts of studies (e.g., linkage analysis). Approaches may incorporate candidate genes and/or anonymous genetic markers. As the intent of this RFA program is to map and identify genetic factors in humans, mapping studies using animal models will only be considered responsive if they meet the criteria outlined later in this document under the section titled "Role of an Animal Mapping Center." Although each network will be fully capable of pursuing all necessary facets to map and identify genetic factors responsible for high blood pressure, each network may differ in terms of strategy, design, and methodology. Hence, in order to achieve the goals of this RFA in the most effective manner possible, there will be a Program Steering Committee to ensure collaborative efforts among networks, assure comparability of results within and across networks, promote and coordinate collaboration among networks, develop uniform protocols and standard methods, facilitate sharing of resources, and plan and evaluate changes in research design as developments warrant. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This RFA, Genetic Determinants of High Blood Pressure, is related to the priority area of heart disease and stroke. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic, for-profit, and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of state and local governments, and eligible agencies of the Federal government. Foreign organizations are not eligible to apply. However, under exceptional circumstances, a foreign component, which is critical to the success of the network and minor in its magnitude, may be included as part of a domestic application. Applications from minority individuals and women are encouraged. MECHANISM OF SUPPORT The administrative and funding instrument to be used for this program will be a cooperative clinical research agreement (U10), an "assistance" mechanism, in which substantial National Institutes of Health (NIH) scientific and/or programmatic involvement with the awardee is anticipated during performance of the activity. Under the cooperative agreement, the NIH purpose is to support and/or stimulate the recipient's activity by involvement in and otherwise working jointly with the award recipient in a partner role, but it is not to assume direction, prime responsibility or a dominant role in the activity. Details of the responsibilities, relationships, and governance of the study to be funded under cooperative agreement(s) are discussed later in this document under the sections titled "Special Requirements" and "Terms and Conditions of Award." The total project period for applications submitted in response to the present RFA may not exceed five years. The anticipated award date is April 1, 1995. The number of awards and level of support depend on receipt of a sufficient number of applications of high scientific merit. Although this program is provided for in the financial plans of the NHLBI, awards pursuant to this RFA are contingent upon the availability of funds for this purpose. Because the nature and scope of the research proposed in response to this RFA may vary, it is anticipated that the amount of funds to establish each network will also vary. This RFA is a one-time solicitation. Future unsolicited competing continuation applications may compete with all investigator-initiated applications and be reviewed according to the customary peer review procedures. FUNDS AVAILABLE Up to four networks may be funded under this RFA, depending upon availability of funds for this purpose. A network will be comprised of components. Each component will be directed by a Principal Investigator and will receive a separate award. As network tasks can be organized according to a number of different organizational strategies, each network could be comprised of four to seven components (awards). Hence, if four networks are funded, the total number of awards might vary from 12 to 28. A maximum of about $30 million (including direct and indirect costs) over a five-year period will be awarded. Approximately $4.50 million may be available for the first year, $6.00 million for the second year, $6.24 million for the third year, $6.50 million the fourth year and $6.76 million for the last year. RESEARCH OBJECTIVES Background Hypertension, a complex disease that involves the interplay of genetic and environmental factors, affects an estimated 50 million Americans and is a major predisposing factor for myocardial infarction, vascular disease, stroke, and renal failure. It has been estimated from segregation analysis and twin studies that approximately 45 percent of the interindividual differences in blood pressure are accounted for by genetic differences. The identification of the genes whose variants contribute to high blood pressure will have far-reaching effects on our understanding of the pathophysiology of the circulation and may suggest new preventive measures and rational therapeutic approaches. One of the principal advantages of the genetic approach is that it identifies primary molecular defects. The division of the general hypertensive population into subgroups, defined by genotypes, may allow the evaluation of therapies in more homogeneous groups. On the one hand, knowledge of these defects may provide new targets for specifically-designed therapies. On the other hand, it may prove possible to use existing approaches in a more directed way to treat individuals with specific genotypes. Similar considerations apply to the evaluation of preventive measures. In a complex and heterogeneous disease, the use of a preventive measure that produces no obvious benefit when applied to the whole patient group may be effective in a subgroup with a particular etiology. Subdivision of hypertension according to the genotypes of major contributing genes is likely to provide one of the most powerful means of defining etiologically homogeneous groups. It may not be necessary to negate the effects of all the genes contributing to hypertension to treat the disease in an individual case. It is likely that many genetic effects are additive and that neutralizing one or two of the genetic determinants operating in an individual may be sufficient to reduce blood pressure to a level that has no associated risk. The identification of hypertension genes provides the basis for an understanding of the interactions between genes and environmental factors. It is very likely that particular environmental variables exert effects only in the presence of certain genotypes. Moreover, the effects of certain environmental factors may be "lost" in a genetically heterogeneous group. Some of these factors have large effects in some genetically-defined populations. Until recently, the techniques for dissecting the genetic determinants of high blood pressure were not available or were not developed to an extent that would make the proposed project feasible. Several recent advances in technology and analytical methods, together with the rapid construction of genetic maps, have substantially improved the chances of detecting these genetic factors. These techniques have already been applied with considerable success to single-gene disorders, such as Duchenne muscular dystrophy, retinoblastoma, cystic fibrosis, neurofibromatosis, and many others. Examples of developments that make the use of genetic strategies in the study of hypertension timely include: The Human Genome Project has developed (and continues to develop) physical and high-resolution genetic maps; genes encoding proteins important in controlling blood pressure are being isolated at an unprecedented pace, providing a set of "candidate genes"; genomic localization of newly cloned genes is now routine, so that the locations of many physiologically important genes are becoming known; the construction of comparative human/mouse maps allows information gained from studies of the mouse to be applied rapidly to humans; automated methods of studying genetic polymorphism and mutation are being developed at an accelerated pace, and; there are several new techniques for the identification of single-base changes, such as single-stranded conformational polymorphism, denaturing gradient gel electrophoresis, chemical cleavage, and direct sequencing by machine, that allow candidate genes to be screened rapidly. The confluence of these methodological, analytical, and technological developments makes it an opportune time for a comprehensive and coordinated program that will systematically map and identify the genetic factors involved in complex polygenic disorders, such as hypertension. Objectives and Scope The goal is to identify the genes involved in hypertension by using an alliance of talented investigators skilled in the appropriate scientific disciplines who will use the most sophisticated and modern molecular genetic approaches. In addition to gene mapping and identification, investigators may also apply to study interactions between genetic and non-genetic determinants of hypertension in defined populations. Consequently, support will be provided to collect and characterize appropriate family configurations, to phenotypically and genotypically characterize members of these configurations, and to perform genetic and statistical analyses to localize and identify genetic factors responsible for high blood pressure. Studies utilizing genetic inbred animal models (especially rats) may also be included under special circumstances, as presented below ("Role of the Animal Mapping Center"). Study Design, Methodology, and Analysis There are a number of feasible study designs that could achieve the objectives of this program, depending upon the varying degrees of certainty regarding the true modes of inheritance, the understanding of underlying physiology of disease processes, and the availability of appropriate intermediate phenotypes. Therefore, the exact study design(s), methodology, and analytical tools employed may differ among networks. Regardless of the particular strategy chosen, it is absolutely critical for the applicants to carefully justify the methodology, strengths, and limitations of the study design, analytical strategies, statistical tools, and the selection of the population. For example, the research plan should specify the numbers and relationships of individuals and families to be studied and specify their age, sex, and race composition, as well as their hypertensive status. Sample size estimates and power calculations should be provided. Clinic procedures and laboratory assays and methods should be described. In addition, the research plan must include a scheme to address the ethical, legal, and social aspects of conducting genetic research. Examples include informed consent, confidentiality, access to information, and privacy. As an example of a substantive issue that needs to be addressed, genetic heterogeneity may substantially increase the difficulty of identifying genes involved in high blood pressure. The extent of genetic heterogeneity cannot be accurately determined and is likely to become apparent only when the molecular determinants of the trait have been elucidated. There are, however, ways to reduce the impact of heterogeneity. One way is to subdivide the population by defining intermediate phenotypes. Another way is to study populations which have probably originated from a restricted founder population or have been isolated in some other manner so that the number of genetic variants present in the population is limited. A different approach is to sample many small families and perform linkage mapping using a "simultaneous search strategy". Another strategy is to utilize high resolution genetic maps and high quality genetic markers that allow genetic analysis of smaller and therefore more homogeneous populations. A number of different genetic methodologies may be used that employ family configurations, such as the sib-pair method and other combinations of affected related individuals, genetic linkage analysis of pedigrees, and nonparametric analyses and refinements. The development and application of new methods to extract mapping information in the presence of genetic heterogeneity is highly desirable. Case-controlled allelic association studies are considered responsive to this RFA only when the investigator expresses a clear intent to confirm any positive findings with evidence from other sorts of studies (e.g., linkage analysis). Examples of responsive strategies include generalized linkage entailing a whole genome search using anonymous highly-informative genetic markers spread throughout the genome or within "candidate" genes. Regardless of strategy, there are a number of different methods for characterizing DNA polymorphisms that are suitable. It is anticipated that polymerase chain reaction (PCR) typing of microsatellite repeats will be a major approach, which may be supplemented by more effective methods as they become available. Genotyping may use currently existing and/or generate new highly polymorphic markers as needed to better define the chromosomal region of a genetic marker by refined genetic and physical mapping to determine the disease locus. In addition, a Genetic Epidemiology Network would be capable of performing analyses that will address: distributions of blood pressure and related characteristics in individuals and families; correlations and clustering of determinants of blood pressure and of clinical attributes associated with hypertension, genetic and environmental contributions to phenotypic variance, measures of association of determinants of blood pressure with blood pressure levels and clinical manifestations of hypertension in related and unrelated individuals, as well as other genetic analyses. Purpose and Characteristics of a Network The most effective way to achieve the objectives of this RFA program is to establish highly interactive networks that will pursue the requisite tasks and provide the essential tools and infrastructure. A network will link the best people and resources in several locations and provide essential cohesion and coordination. Effective genetic research requires the help of collaborators from many disciplines, such as genetics, epidemiology, biostatistics, clinical and laboratory science, and expertise in the molecular techniques of gene mapping, characterization and cloning. Additional skills include genotyping, data management, and informatics. In order to effectively perform research, a network will also need to establish and share the requisite resources, including technology, data, biological materials, and population resources. The collection of adequate numbers of well characterized subjects is central to the success of the genetic approach. However, it is inevitable that the subjects will be geographically dispersed and that more than one location will be required to establish, in a timely fashion, a sample of sufficient size to provide statistical power appropriate for the study design. It is anticipated that, although some existing research centers may have access to all necessary resources, many of the investigators critical to the success of the project will be located in institutions that lack important elements. Hence, a network will allow a group of investigators at distinct geographical locations to interact and share resources. Each application to establish a network must be submitted by a group of investigators who are capable of forming a dynamic, highly interactive, cohesive, coordinated network that is fully capable of independently pursuing all necessary facets required to map and identify genetic factors responsible for high blood pressure, including recruitment, phenotyping, genotyping, and data management and analysis. These tasks can be organized according to a variety of schemes and rationales to form a network, as long as all requisite activities essential to achieving the objectives of this RFA are included. In addition, a network must have the appropriate areas of expertise and infrastructure, include mechanisms to achieve coordination and communication within a network, and be willing to participate in multi-network activities. Key members who desire to establish a network and who are expert in the necessary tasks must be involved in the preparation of the research plan, study design, and all other crucial aspects of the application that is submitted to the NHLBI. For purposes of illustration only, these network tasks and activities could be organized into the following components: Field Centers, Laboratory Center, Genotyping Center, Data Coordinating Center (DCC), and Animal Mapping Center. This model is not meant to limit other organizational strategies. It is used solely to help articulate specific functions necessary to build a successful network and to simplify the description of the terms, conditions, governance, and other requirements of this RFA program. Role of Field Centers: Network Field Centers could be used to implement its plan for subject selection and recruitment, ascertainment, characterization, and classification of hypertension and related characteristics. Identification and characterization of participants might be accomplished through questionnaires, extensive interviewing (e.g., about risk factors and medical history), clinical examinations and procedures, and laboratory studies, including biological measures of phenotypic characteristics relevant to genetic studies of hypertension. These Centers should be able to maintain contact with study participants, follow subjects longitudinally, propose and implement criteria and procedures for referring participants for further investigation and medical care, if needed, and track changes in critical parameters. All Field Centers would employ a common, comprehensive set of standardized, reliable, and valid assessment protocols and instruments. In addition, Field Centers will need a plan to enter collected data and transmit it to the DCC. Field Centers might also be used to collect, prepare, and ship samples for measurement, quality control, and storage (e.g., blood samples for laboratory analysis, DNA extraction, and isolation and transformation of lymphocytes into permanent cell lines). Central training of Field Center staff within each network (and possibly across all networks), plus certification of staff and monitoring of performance at each site, is an approach that would ensure uniformity, reproducibility, and comparability of data and results. If the use of ECGs, echocardiography, Holter monitors, and other similar devices is proposed, then their measurement, reading, and interpretation could also be the responsibility of the Field Centers, either directly or by subcontract. Expertise in diagnosis and characterization of hypertensives should also be available at the Field Center. Role of a Laboratory Center A Laboratory Center could be used to perform blood, urine, and other essential biological and biochemical measures, and ensure quality control. Measurements that may serve as intermediate phenotypes could be performed here as well. Sample assays might include plasma renin activity, cortisol and aldosterone, angiotensin II, sodium and potassium, erythrocyte Na/Li countertransport, kallikrein, and creatinine. A Laboratory Center would assure standardization of measurements through the use of an operating quality control program to assess and control within-run and between-run variability, accuracy and long-term drift for all measurements. In addition, the Laboratory Center could coordinate efforts with the Field Centers such that there is uniform collection, preparation, storage, and shipping of samples. In addition, the Laboratory Center can collaborate with the DCC to develop and utilize mechanisms to transmit data generated by this study to the DCC. Also in conjunction with the DCC, the Laboratory Center would develop a record keeping and catalogue system for stored materials, which could be then maintained and updated at the DCC. Role of a Genotyping Center: A Genotyping Center could be used to slow freeze lymphocytes for storage, transform lymphocytes and store them as permanent cell lines, extract and store DNA, and analyze DNA for variations in structure. The latter information can be used to test for linkage or association with phenotypic markers, depending upon the study design. In addition, the Genotyping Center would work with the DCC to develop and utilize mechanisms to transmit genotypic data generated by this study to the DCC. Also in conjunction with the DCC, the Genotyping Center may develop a record keeping and catalogue system for stored materials (DNA, cell lines), which could then be maintained and updated at the DCC. Role of an Animal Mapping Center (optional) Gene mapping efforts in humans can be greatly facilitated by judicious use of inbred animal models. Advantages include short generation times, availability for thorough measurement of quantitative risk factors under controlled conditions, and the ability to control and alter environmental factors. Therefore, for the purposes of this RFA, animals (especially rats) can be used for direct mapping of genes responsible for hypertension (e.g., searching for quantitative trait loci, either by a total genomic search or candidate gene strategy, followed by synteny conservation mapping) as long as they are an integrated part of a network in which the results are expeditiously exploited for comparative gene mapping efforts directed toward the identification of the corresponding genes in humans. If animal mapping studies are included, a plan to this effect must be presented by the applicant. Role of a Data Coordinating Center The DCC would supply critical, specialized data management and statistical and analytical expertise and participate fully with the other key network components to conceive and develop the research plan and study design that form the basis of an application submitted to the NHLBI to establish a Genetic or Genetic Epidemiology Network. Hence, close interaction of the DCC and other members of the network team is strongly encouraged in order to submit an application in response to this RFA. The strongest network applications would involve key members who are independently recognized scientists with a track record of publications in relevant areas, such as the analysis of genetic data and population genetics. A DCC could receive, edit, and store all relevant research data collected in a network, including data pertinent to ascertainment and assessment, genetic and phenotypic information, family structures, blood and urine samples stored and analyzed at the Laboratory Center, cell lines and DNA stored at the Genotyping Center, and other data required for the analyses to be undertaken by the network. In addition, the DCC would possess the capabilities for implementing remote site data entry and for interacting with all other performance sites [eg., Field Centers, Laboratory Center, Genotyping Center, Animal Mapping Center (if included)] of the network. The DCC could also be responsible for providing appropriate access by participant investigators and for distribution of information to investigators both internal and external to the network, as appropriate. The DCC could recommend and, after approval by the Internal Network Coordinating Committee, purchase hardware and software for use at each Field and Laboratory Center. Other relevant responsibilities could include setting up data entry and transmission at each site, training and monitoring performance of personnel at each site, preparing forms and data entry screens, and integrating and producing multi-network protocols and manuals of procedures. Multi-network Activities Although the networks funded by this program may differ in strategies and design, there will be numerous beneficial and exciting opportunities for collaboration among the different networks that will expedite and enhance the specific aims of each network and the overall objectives of this RFA. Consequently, a Program Steering Committee will be used to facilitate the establishment and conduct of multi-network activities, such as develop and initiate collaborative studies, develop uniform protocols, standardize methods, share data and resources, generate new ideas and strategies that result from new research findings, and ensure a minimum of research and budgetary duplication. Because genetic studies of complex, quantitative traits like hypertension require great care with respect to the methods used to characterize subjects, a Program Steering Committee will also serve as a mechanism to help ensure comparability of results within and across networks. Timetable In order to assist applicants in preparing a budget, broad guidelines of the total scope and objectives for this RFA are presented in the approximate timetable presented below. There may be some overlap of functions within each of the three stages, and the time estimates are only approximate. Because different networks may be at different stages upon initiation of this program, due to differences in such elements as study design or prior recruitment and characterization of study participants, budgets proposed by different networks will vary. However, all networks must anticipate the time required in the first year to develop multi-network standard procedures and collaborative protocols. Year 1: Develop multi-network study protocols specifying objectives, organizational structure, and study designs; prepare manuals of operation detailing standardized methods and procedures including questionnaires, examination and laboratory procedures, diagnostic criteria, quality control, data management and analysis; recruit and train personnel; select study individuals and families; animal genetic mapping studies (if proposed); select Program Steering Committee chairperson; organize subcommittees of the Program Steering Committee. Years 2 - 3: Pilot test examination and laboratory procedures; recruit, examine and follow-up study participants; perform laboratory assays and genotyping; store specimens; perform data analysis; continue animal genetic mapping studies (if proposed). Years 4 - 5: Continue laboratory assays and genotyping; follow-up study participants; examine selected pedigrees, if indicated; data analysis; report results; continue animal genetic mapping studies (if proposed). SPECIAL REQUIREMENTS Internal Network Coordinating Committees: Each network will use an Internal Network Coordinating Committee to govern its own activities. An Internal Network Coordinating Committee will be used to achieve suitable coordination within a network, and should be comprised of the Network Director, the PIs of its various components (eg., Field Centers, Laboratory Center, DCC, Genotyping Center, and Animal Mapping Center), and one NHLBI representative. An application must also indicate who would be responsible for assisting the Network Director with the day-to-day administrative details, program coordination, and with the planning and evaluation of the program. The Network Director must exercise great diligence in preserving the interactions of the participants and the integration of its components in order to maintain cohesiveness and synergism. Inter-network Governance by the Program Steering Committee A Program Steering Committee will be the main governing body of multi-network studies and activities. Membership will consist of two representatives from each network, one of whom must be the Network Director, and the two NHLBI Project Scientists. The Chairperson, who will be someone other than an NHLBI staff member, will be selected by the Program Steering Committee. Recommendations regarding all scientific issues will be decided by majority vote. As it is responsible for the overall guidance of multi-network coordination, the Program Steering Committee will: establish and encourage well focused collaborations among the different networks; develop uniform protocols, standard methods, and the manner and extent of data sharing; facilitate the sharing of resources, and; plan and evaluate changes in research design and strategies as developments warrant. The extent of standardization, uniformity of protocols, and sharing of data, reagents, and specimens will be determined on the basis of feasibility and greatest promise from the approved research scope of the networks awarded. THOSE ASPECTS OF A NETWORK THAT DO NOT INVOLVE SHARING AND COLLABORATION BETWEEN NETWORKS MAY BE PURSUED INDEPENDENTLY. Because of the magnitude and complexity of this program, it is anticipated that the Program Steering Committee will convene subcommittees to cover specific cross-cutting areas, such as diagnosis and subject ascertainment, human subjects protection, family design and recruitment, quality control, genetic analysis and mapping strategies, phenotypic measurements, genotyping, longitudinal follow-up, data collection, data analysis, sharing of study data and materials, ethics, legal and social issues, intellectual property rights, publication policies and procedures, and the rights to authorship. Although the Program Steering Committee will develop procedures and assign responsibilities for preparation of publications resulting from collaboration among networks, this does not abrogate each network's ability to publish its own findings. Publication and ancillary study policies should be included in the protocol and agreed to by all awardees. Membership of subcommittees will be determined by the Program Steering Committee and consist of scientists engaged in the network and others as needed to ensure appropriate coverage of subject matter and balance. An NHLBI scientist (or where necessary, scientists) will serve on subcommittees as deemed appropriate by the NHLBI Project Scientists. Program Steering Committee meetings, which will be held in Bethesda, MD, will take place at approximately one month intervals during the first six months, at three month intervals during the second six months, and at intervals of six months throughout the remainder of the study. Additional communication will be made by telephone conference calls, approximately monthly, as needed. Willingness to Collaborate As described above, representatives of network components and the NHLBI Project Scientists will collaborate to develop common protocols, standard procedures, and centralized training for multi-network efforts. Hence, prospective network representatives, such as the PIs of the Field Centers, Genotyping Center, Laboratory Center, DCC, and the Animal Mapping Center, must agree to serve on the Internal Network Coordinating Committee, express willingness to collaborate in multi-network studies, and be willing to serve on the Program Steering Committee. Budget and Related Issues Applications should present five budget periods of 12 months each. Applicants should provide adequate budget justification and all applicable direct and indirect costs should be included. Estimates of staffing needs, including the PIs, other professional and support staff must be included. The suggested minimum level of effort for Network Directors, PIs (and Co- Investigators, if applicable) is 20 percent each. Other personnel such as clinic coordinator, technicians, research assistants and secretary should be carefully outlined and justified in the application. Travel costs for Program Steering Committee meetings, as detailed under the section titled "Inter-network Governance by the Program Steering Committee," must be budgeted, along with statements indicating willingness to participate in these meetings. These awards will be subject to administrative review annually. Future year awards may be redistributed based on the final protocols and standardized procedures, actual recruitment, and overall performance. Requests for expensive special equipment may be permitted on a case-by-case basis following staff consultation. Such equipment requires in-depth justification. Final decisions will depend on the nature of the justification and the Institute's fiscal situation. Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. If so, a letter of agreement from either the GCRC Program Director or PI should be included with the application. Terms and Conditions of Award 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 Grants Administration policy statements. [Part 92 applies when state and local governments are eligible to apply as a "domestic organization."] The administrative and funding instrument used for this program is the cooperative clinical research agreement (U10), an "assistance" mechanism (rather than an "acquisition" mechanism) in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during performance of the activity. Under the cooperative agreement, the NIH purpose is to support and/or stimulate the recipient's activity by involvement in and otherwise working jointly with the award recipient in a partner role, but it is not to assume direction, prime responsibility or a dominant role in the activity. Consistent with this concept, the dominant role and prime responsibility for the activity resides with the awardee(s) for the project as a whole, although specific tasks and activities in carrying out the studies will be shared among the awardees and the NHLBI Project Scientists. Awardees will have the usual responsibilities of award recipients, including protocol development, participant recruitment and follow-up, data collection, quality control, interim data monitoring, final data analysis and interpretation, and preparation of publications, as well as responsibilities for collaboration with other awardees, and collaboration with the NHLBI Project Scientists. The NHLBI Project Scientists (the Associate Director, Arteriosclerosis, Hypertension, and Lipid Metabolism Program, Division of Heart and Vascular Diseases; and the Associate Director, Epidemiology and Biometry Program, Division of Epidemiology and Clinical Applications), in addition to the usual stewardship responsibilities, will have responsibilities in protocol development, quality control, interim data monitoring, final data analysis and interpretation, preparation of publications, collaboration with awardees, and project coordination. Awardees will have lead responsibilities for the project as a whole and it is anticipated that the awardees will have lead responsibilities in all joint tasks and activities, except it is anticipated that the NHLBI Project Scientists will have lead responsibilities in quality control and catalyzing interim monitoring of data and may, consistent with publication policy to be adopted by the Program Steering Committee, have lead responsibilities in the preparation of some publications. A Program Steering Committee will be the main governing body of multi-network studies and activities, and will have primary responsibility for developing common protocols, facilitating the conduct and monitoring of studies, and reporting study results. Membership will consist of two representatives from each network, one of whom must be the Network Director, and the two NHLBI Project Scientists. The Chairperson, who will be someone other than an NHLBI staff member, will be selected by the Program Steering Committee. Subcommittees will be established by the Steering Committee, as it deems appropriate. An NHLBI scientist (or where necessary, scientists) will serve on subcommittees as deemed appropriate by the NHLBI Project Scientists. Collaborative protocols will be developed by the Program Steering Committee. These protocols may be reviewed by an external committee convened by NHLBI. These protocols will be implemented only with the concurrence of the awardees and NHLBI. The protocols will define rules regarding access to data and publications. Awardees will retain custody of and have primary rights to their data developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies. The NHLBI reserves the right to terminate or curtail the study (or an individual award) in the event of (a) failure to develop or implement a mutually agreeable collaborative protocol, (b) substantial shortfall in participant recruitment, follow-up, data reporting, quality control, or other major breech of the protocol, (c) substantive changes in the agreed-upon protocol with which NHLBI cannot concur, (d) reaching a major study endpoint substantially before schedule with persuasive statistical significance, or (e) human subject ethical issues that may dictate a premature termination. Any disagreement that may arise in scientific/programmatic matters (within the scope of the award), between award recipients and the NHLBI may be brought to arbitration. An arbitration panel will be composed of three members--one selected by the Program Steering Committee (with the 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 awardee's 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. STUDY POPULATIONS SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH STUDY POPULATIONS NIH policy is that applicants for NIH clinical research grants and cooperative agreements are required to include minorities and women in study populations so that research findings can be of benefit to all persons at risk of disease, disorder, or condition under study; special emphasis must be placed on the need for inclusion of minorities and women in studies of diseases, disorders, and conditions which disproportionately affect them. This policy is intended to apply to males and females of all ages. If women or minorities are excluded or inadequately represented in clinical research, particularly in proposed population-based studies, a clear compelling rationale must be provided. The composition of the proposed study population must be described in terms of gender and racial/ethnic group. In addition, gender and racial/ethnic issues must be addressed in developing a research design and sample size appropriate for the scientific objectives of the study. This information must be included in the form PHS 398 (rev. 9/91) in Sections 1-4 of the Research Plan, and summarized in Section 5, Human Subjects. Applicants are urged to assess carefully the feasibility of including the broadest possible representation of minority groups. However, NIH recognizes that it may not be feasible or appropriate in all research projects to include representation of the full array of United States racial/ethnic minority populations (i.e., Native Americans [including American Indians or Alaskan Natives], Asian/Pacific Islanders, Blacks, Hispanics). The rationale for studies on single minority population groups should be provided. For the purpose of this policy, clinical research includes human biomedical and behavioral studies of etiology, epidemiology, prevention (and preventive strategies), diagnosis, or treatment of diseases, disorders or conditions, including but not limited to clinical trials. The usual NIH policies concerning research on human subjects also apply. Basic research or clinical studies in which human tissues cannot be identified or linked to individuals are not subject to these policies. However, every effort should be made to include human tissues from women and racial/ethnic minorities when it is important to apply the results of the study broadly, and this should be addressed by applicants. If the required information is not contained within the application, the application will be returned. Peer reviewers will address specifically whether the research plan in the application conforms to these policies. If the representation of women in a study design is inadequate to answer the scientific question(s) addressed AND the justification for the selected study population is inadequate, it will be considered a scientific weakness or deficiency in the study design and will be reflected in assigning the priority score to the application. All applications for clinical research submitted to NIH are required to address these policies. NIH funding components will not award grants or cooperative agreements that do not comply with these policies. LETTER OF INTENT Prospective applicants are asked to submit, by June 17, 1994 a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Network Director, the identities of other key personnel and participating institutions, and the number and title of this RFA. A letter of intent is not required, is not binding, and does not enter into the review of subsequent applications. The information that it contains is helpful in planning for the review of applications. It allows NHLBI staff to estimate the potential review workload and to avoid conflict of interest in the selection of reviewers. The letter of intent is to be sent to: C. James Scheirer, Ph.D. Division of Extramural Affairs National Heart, Lung, and Blood Institute Westwood Building, Room 648 Bethesda, MD 20892 Telephone: (301) 594-7452 FAX: (301) 402-1660 The Network Application Investigators who wish to establish a collaborative network will submit concurrent, cross-referenced individual research grant applications together as a package. Each network component (e.g., Field Center, Laboratory Center, Genotyping Center, Data Coordinating Center, Animal Mapping Center) will be directed by a Principal Investigator (PI). In addition, the application submitted by the Network Director, who will be responsible for organizing and maintaining effective integration and interaction, must also include a clear description of the relationship among the various network components; describe plans for collaboration, interaction, communication, and sharing among investigators in the network; and indicate the mechanisms for handling day-to-day administrative details, program coordination, planning and evaluation. A separate award will be issued to each successful applicant in a network. APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 9/91) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research and from the Office of Grants Information, Division of Research Grants, National Institutes of Health, 5333 Westbard Avenue, Room 449, Bethesda, MD 20892, telephone (301) 710-0267; and from the NIH Project Scientists listed under INQUIRIES. The RFA label available in the PHS 398 application form must be affixed to the bottom of the face page of the application. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed in line 2a of the face page of the application form and the YES box must be marked. Send or deliver the original, signed application and three legible complete photocopies to: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** Send two additional copies of the application to: C. James Scheirer, Ph.D. Division of Extramural Affairs National Heart, Lung, and Blood Institute Westwood Building, Room 648 Bethesda, MD 20892 Telephone: (301) 594-7452 It is important to send these two copies at the same time as the original and that three 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. Applications must be received by September 16, 1994. If an application is received after this date it will be returned to the applicant without review. The Division of Research Grants (DRG) will not accept any application in response to this announcement that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The DRG will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS General Considerations All applicants will be judged on the basis of the scientific merit of their proposed research project and their documented ability to conduct the essential study activities as broadly outlined in this RFA. Review Method Upon receipt, applications will be reviewed by the DRG for completeness and by NHLBI staff for responsiveness to this RFA. Incomplete applications will be returned to the applicant without further consideration. Those applications that are complete and responsive will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NHLBI. The initial review will include a preliminary evaluation to determine scientific merit relative to the other applications received in response to this RFA (triage); the NIH will remove from further consideration applications judged to be noncompetitive and promptly notify the Principal Investigator and the official signing for the applicant organization. Those applications judged to be competitive will be further evaluated for scientific/technical merit by the usual peer review procedures, including, if deemed appropriate, an applicant interview in or near Bethesda at the applicant's expense. Subsequently, applications recommended for further consideration will receive a second level of review by the National Heart, Lung, and Blood Advisory Council. A network application must include all requisite functions organized into appropriate components. Each network component will receive a priority score. In addition, each network will receive an overall priority score. Inclusion of weaker components will compromise the enthusiasm for the overall network and may seriously jeopardize its establishment. Under certain, highly special cases, weaker components that are not critical to the success of a network may be removed (eg., a poorly integrated Animal Mapping Center or a Field Center not required for appropriate statistical power). Review Criteria Applicants are encouraged to submit and describe their own ideas on how best to meet the goals of the RFA and their specific protocols, but they are expected to address all issues identified in this Request for Applications. Major factors to be considered in the evaluation of applications include: o Scientific merit of the hypotheses, methodology, study design, analytical strategies, statistical tools, and the selection of the study population. o Adequacy of the environment for performance of the proposed research including access to study participants; laboratory facilities; instrumentation; data management systems; and institutional research and administrative support and commitment. o Leadership, scientific stature, research experience, and level of commitment of the Network Program Director and PIs of network components; competence of the investigators to accomplish the proposed research goals and their time commitment to the program; and availability of all areas of expertise necessary to accomplish all facets of the proposed network. o The plans for coordination, cooperation, and sharing of biological and informational resources, both within a network and across networks. o Adequacy of plans to implement the "Special Requirements" and "Terms and Conditions of Award" sections, including provisions for involvement of Institute staff and willingness to participate in multi-network efforts, as well as any other conditions and specifications stipulated elsewhere in the RFA. o Appropriateness of the budget for the proposed network. o Adequacy of the provisions for the protection of human subjects and the welfare of animal subjects, as applicable. o Evidence of inclusion of appropriate numbers of women and minorities. AWARD CRITERIA Applications recommended by the National Heart, Lung, and Blood Advisory Council will be considered for award based upon (a) scientific and technical merit (b) program balance, including in this instance, sufficient compatibility of features to make a successful, multi-network collaborative program a reasonable likelihood, and (c) availability of funds. Letter of Intent Receipt Date: June 17, 1994 Application Receipt Date: September 16, 1994 Review by NHLBI Advisory Council: February 9-10, 1995 Anticipated Award Date: April 1, 1995 INQUIRIES Written and telephone inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Stephen C. Mockrin, Ph.D. Division of Heart and Vascular Diseases National Heart, Lung, and Blood Institute Federal Building, Room 4C10 Bethesda, MD 20892 Telephone: (301) 496-1613 FAX: (301) 402-2044 EMAIL: SM60D@NIH.GOV Millicent Higgins, M.D. Division of Epidemiology and Clinical Applications National Heart, Lung, and Blood Institute Federal Building, Room Bethesda, MD 20892 Telephone: (301) 496-2327 FAX: (301) 402-1624 Direct inquiries regarding review and application procedures to: C. James Scheirer, Ph.D. Division of Extramural Affairs National Heart, Lung, and Blood Institute Westwood Building, Room 648 Bethesda, MD 20892 Telephone: (301) 594-7363 FAX: (301) 402-1660 Direct inquiries regarding fiscal and administrative matters to: Ms. Jane Davis Division of Extramural Affairs National Heart, Lung and Blood Institute Westwood Building, Room 4A15C Bethesda, MD 20892 Telephone: (301) 594-7436 FAX: (301) 594-7492 AUTHORITY AND REGULATIONS This project is described in the Catalog of Federal Domestic Assistance No. 93.837. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR 74. This project is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. .
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Department of Health and Human Services (HHS) |
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