THE NATIONAL INSTITUTE ON AGING MULTICENTER STUDY ON EXCEPTIONAL SURVIVAL IN FAMILIES (U01) RELEASE DATE: February 25, 2003 RFA: AG-03-004 Update: The following update relating to this announcement has been issued: July 29, 2009 - This RFA has been reissued as (RFA-AG-10-005). National Institute on Aging (NIA) (http://www.nih.gov/nia/) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER: 93.866 LETTER OF INTENT RECEIPT DATE: May 19, 2003 APPLICATION RECEIPT DATE: June 24, 2003 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirements o Where to Send Inquiries o Letter of Intent o Submitting an Application o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations o References PURPOSE OF THIS RFA The National Institute on Aging (NIA) invites applications for cooperative agreements (UO1s) to participate in the design and implementation of a Multicenter Study on Exceptional Survival in Families (ESF). This study will determine the degree and patterns of familial transmission and aggregation of exceptional longevity and healthy survival to advanced age as characterized by a variety of phenotypic measures. This Request for Applications (RFA) solicits proposals for: (1) Study Centers to design and implement the ESF study, and (2) a Data Management and Coordinating Center (DMCC) that will interact with the Study Centers, a Steering Committee, a Monitoring Board, and NIA staff by providing administrative, logistical, and data management support for the ESF Study. Exceptional longevity (i.e., survival to extreme old age) is one of a set of favorable exceptional survival outcomes, including unusually long survival before the occurrence of significant morbidity ("health span") or disability (active life expectancy). This set of outcomes is referred to in this document as "exceptional survival" (ES). Understanding the factors that contribute to ES could lead to better understanding of contributors to long and healthy life in humans in general, not just the very old. In view of evidence that exceptional longevity is associated with other ES outcomes and shows a pattern of familial aggregation, information from exceptionally long- lived families provides a starting point for identifying patterns of and appropriate measures for exceptional survival. Results of the ESF study will provide a better understanding of the degree and patterns of familial aggregation of ES outcomes. In addition, the data from the ESF study will provide a strong information-base on the characteristics of exceptionally long-lived families that will aid in identifying research strategies that are likely to be successful for future studies on factors contributing to exceptional survival. This is a one-time solicitation to support the Study Centers and the DMCC for 5 years. The DMCC and a participating Study Center may be located at the same Institution, however each must be administratively and fiscally distinct from the other. RESEARCH OBJECTIVES Background and Rationale A primary public health objective of aging research is to identify ways to help people be as healthy as possible, as long as possible. Elucidating the multiple potential genetic and environmental factors and their various interactions that contribute to long and healthy survival in the general population is a complex and daunting task. One approach to achieving this objective is to characterize groups of individuals with exceptionally favorable survival outcomes and to identify contributory factors that lead to them. One such outcome is exceptional longevity (EL) (i.e., survival to extreme old age). EL is among a group of positive survival outcomes worthy of study. Other exceptional survival outcomes include survival time in the absence of certain diseases ("health span") and disabilities (active life expectancy). Research has shown that individuals who live to extremely old ages tend to have maintained good health throughout most of their lives, suggesting that exceptionally long life is associated with exceptionally long healthy life (1). Thus collecting information on EL is a first step in identifying the kinds of information necessary to identify factors that may contribute to exceptional survival. There is increasing evidence that EL and other ES traits are clustered in families. Siblings of exceptionally old people have been found to have an increased chance of surviving to extremely old age than the average population, and the chance of surviving to exceptionally old age is especially high if the siblings come from families with many exceptionally long-lived members (2-3). Offspring of centenarians have been found to have lipid profiles associated with lower risk for cardiovascular disease (4). There is also evidence of a genetic basis for at least some of the familial clustering of EL. Comparisons of the degree of association of exceptionally long life between sibling-pairs vs. less closely-related pairs have found that the pattern is consistent with effects of a small number of genes contributing to EL (5). Additionally, a genome-wide scan in exceptionally old sibling pairs indicated that a region on chromosome 4 is likely to contain at least one gene with significant effects on the likelihood of reaching exceptional old age (6). Given that familial factors contribute to longevity and other ES traits, information from families with exceptionally long-lived individuals could lead to the identification of factors that contribute to unusually long and healthy life. In addition to information on long-lived probands and relatives in their generation, information on subsequent generations would be useful in identifying phenotypes expressed earlier in life that may contribute to exceptional survival, and factors contributing to these phenotypes. The design of studies to identify such factors in families would be aided by better knowledge of the patterns of transmission of EL and other exceptional survival traits within families, using tools such as segregation analysis and other approaches. Collecting and characterizing accurate pedigree information, detailed phenotypic information, and information on shared and non-shared environmental factors, is needed for such analyses. Based on this, subsequent studies to identify specific genetic, physiologic, and environmental contributors to EL and other exceptional survival traits can be done. Thus, studies on multiple generations in families with exceptionally long- lived members comprise an appropriate target population for studying favorable survival outcomes. To account for the numerous environmental and other variations among these families, large numbers of them will likely be needed to identify the full range of contributory factors. However, though some families with significantly high proportions of family members living to extreme old ages have been identified, the number of such families that might be identified using different criteria for exceptional longevity (e.g., different ages, or different degrees of familial aggregation) is unknown, as is the yield rate of efforts to recruit members of such families for research. Thus information on the prevalence and yield rate of families with clustering of EL using different definitions is crucial for decisions about feasible study designs and subsequent recruitment efforts for such studies. Further background on this topic is contained in recommendations from an NIA Advisory Panel on Exceptional Longevity (APEL). (The report of the APEL can be found at (http://www.nia.nih.gov/research/meetings/apelreport.pdf.) Goals and Scope The primary goal of this RFA is to establish a study to determine the degree and patterns of familial aggregation and transmission of ES traits, specifically to: o Determine patterns of occurrence of exceptional longevity within families, using segregation analyses and other approaches to identify modes of transmission (e.g., Mendelian, polygenic, environmental) of EL among family members; o Test for familial aggregation of specific exceptional survival phenotypes in addition to longevity (e.g., exceptionally long survival without certain diseases or impairments), and possible differences among families in patterns of extended survival (e.g., lower mortality risks at all ages vs. slower exponential rate of rise in mortality risk with age); Applications for Study Centers should include detailed plans, specifically to: o Select a sampling frame based on geographic location (e.g., national or regional) or on descent (e.g., common ancestry) from which a representative sample of multigenerational families with exceptionally long-lived members can be drawn; o Determine demographic characteristics of the sampling frame from which families are enrolled, in order to establish relative (percentile) degree of survivorship within the sampling frame; The use of population-based sampling frames is encouraged. o Develop an appropriate recruitment strategy, including methods of identifying, contacting and obtaining information from study subjects; o Determine the yield rates of families with patterns of exceptional survival, using different definitions of exceptional survival (e.g., different age criteria, different family risk scores or other measures of familial aggregation of exceptional survival, or different survival curve parameters), from the selected sampling frame and the selected recruitment strategy; o Collect complete and verified pedigree information for exceptionally long- lived probands, their parents, their siblings, and members of at least one subsequent generation; Methods for validation of ages and familial relationships must be included. o Collect phenotypic information from family members; All plans must include the minimum set of phenotypic measures established by the NIA Panel on the Characterization of Participants in Studies of Exceptional Survival in Humans (explained below), in addition to other appropriate measures selected by the applicants. o Collect information on environmental exposures, including shared and non- shared exposures, (e.g. diet, lifestyle, etc.) from family members; o Develop and apply appropriate strategies to analyze the data collected to characterize familial aggregation and transmission of ES traits. o Obtain appropriate informed consent from family members for possible subsequent DNA and/or cell collection (including potential future contact with family members for studies of exceptional survival patterns in younger generations as they transition to older age groups, to validate measures identified in the exceptionally long-lived probands); o Collect cells/DNA appropriate for establishment of lymphoblastoid cell lines, from exceptionally long-lived probands who may not be alive at a later date when genotype analyses will be designed and when DNA would be collected from other family members; o Develop a data sharing plan according to the specifications listed below under "Data sharing"; o Test and evaluate the successfulness of strategies for the identification and recruitment of families with exceptionally long-lived members, as well as methods for collection of phenotypic, genotypic and other data from such families. o Demonstrate willingness to enter into a collaborative relationship with other investigators, who together will develop and use common protocols and analyze common data, based on the data collection and analyses plans submitted by successful applicants. Participation in the ESF Study will be a complex and time-consuming undertaking. Applicants for Study Centers must have the necessary experience and expertise to conduct studies involving elderly and/or other hard-to-reach populations. Evidence of such experience must be provided in the application. Prospective Study Centers must have and document in the application, experience and expertise in the conduct of large population-based and/or family studies, and demonstrated access to a sufficient number of study subjects to accomplish their part of the ESF Study protocol. An appropriate time commitment is expected from the leadership (i.e., Principal Investigator and any Co-investigators) at each Study Center. A detailed description of the appropriate time commitment and how it will be maintained throughout the full project period, as well as evidence of time commitments from prior studies, must be provided in the application. Each applicant should propose the study design that s/he believes best addresses the objectives of the ESF Study and is most appropriate for their target population. Applicants should provide a detailed justification for the proposed study subject selection strategy including the rationale and criteria for selection, an estimate of the number of families in the target population, statistical power calculations showing the appropriate number of families needed for significant results, documentation of the ability to recruit sufficient numbers of families, and an estimate of the necessary time and effort needed for recruitment. It is not the intent of this RFA to solicit elaborately detailed research plans for the implementation of the ESF Study. Applicants should provide sufficient details to determine the merits and feasibility of the proposed study design with the understanding that the final protocol will be developed collaboratively by the investigators and the NIA during the planning phase (Phase I) of the study described below under "Study Structure." The ESF DMCC will be responsible for organizational, informational, and data management and analyses functions for the ESF Study. Specifically it will work in collaboration with the ESF Study Centers and NIA program staff to: o Coordinate, with the Steering Committee, the development of standardized data and biological sample collection, recruitment procedures, methods to validate familial relationships and ages all family members, and all standardized forms to be used for the operation of the study; A data entry system should be established along with a plan for data verification and maintenance. Prepare disseminate, and update an ESF Study Manual of Procedures (MOP), data collection forms, databases, and results reporting summaries of the ESF Study. o Provide or arrange for training of all ESF Study personnel, as needed, on data and biological sample collection, management and analysis, quality control, and quality assurance; o Collaborate with ESF Study Centers (conditional on approval by the Steering Committee and NIA Project Official ) in data analysis both for internal use by the Study Centers and for publications; o Provide the NIA Project Official, the Monitoring Board, and the Steering Committee with reports based on biostatistical and other analyses of issues relating to the data, or other needs that arise during the course of the study; o Take initiative, with the Study Centers, in the development of data quality control procedures and information databases regarding the data and biological samples and analyses over the course of the ESF Study; o Coordinate and administer the establishment, operation, and quality control of a database and a repository for biological samples, and the establishment of lymphoblast cell lines from collected biological materials; This includes the development of procedures for assuring data quality control, procedures for transfer of data and biological samples to the database and the repository. The establishment of cell lines and a repository for biological samples may require the use of a contractor. In such a situation, all NIH policies and procedures governing cooperative agreements must be adhered to. o Maintain informed consent records and contact information of family members for potential follow-up contact and data collection; o Prepare detailed reports in standardized formats on progress of subject recruitment and data collection for use by the Steering Committee, the Monitoring Board, and NIA Project Official; o Support the activities of the ESF Study Centers, the Steering Committee, and the Monitoring Board through provision of materials, documentation support, meeting planning and logistics, and conference call coordination; This includes attendance at Steering Committee, and Monitoring Board meetings to perform the functions listed above. o Participate in all Steering Committee and Monitoring Board meetings and conference calls as needed; o Prepare and distribute minutes and action items from the Steering Committee and Monitoring Board meetings and conference calls, ESF site visits, and provide timelines for the completion of action items and updates on the status of action items as required; o Assist the NIA Project Official in written, telephone, and electronic communications with the study sites and with various committees as requested; o Establish databases that catalogue and disseminate information about all ESF Study publications; o Develop and maintain a public and private (secured, password-protected) ESF Study Web Page. Applicants for the DMCC should address the potential requirements of the ESF Study by providing a description of projected tasks likely to be performed by the DMCC consistent with resources projected to be available for the ESF Study. Plans for collection, handling, and analysis of data and biological samples consistent with the projected needs of the Study Centers should be addressed. Plans for ensuring data integrity and quality control should be addressed. The application for the DMCC must describe the expertise of key scientific, technical and administrative personnel and include a mechanism for replacing key professional or technical personnel should the need arise. Any staffing changes must be approved by NIA. The Principal Investigator of the DMCC should have strong biostatistical expertise and experience in directing a coordinating center for large-scale collaborative multicenter studies or other large-scale epidemiological research project focusing on elderly populations and/or other hard-to-reach populations, involving multiple institutions. Such experience must be clearly documented in the application. Staff needs may be modified as the ESF Study progresses; however, adequate support staff should be designated to manage routine tasks as follows: o The Principal Investigator of the DMCC will serve as the DMCC Director and should provide overall scientific and biostatistical guidance. o A Deputy Director, qualified to fulfill the duties of the Director of the DMCC must be designated. o A Project Manager will attend to day-to-day details and communicate necessary information to Study Centers and/or to the other ESF Study organizational components, and to plan and coordinate project staff training; o Biostatisticians and demographers will assist with data analysis; o System analysts will help with developing and managing the database programs; o Computer programmers will develop computer databases; o Clerks and administrative assistants will help in administrative work and data entry. Study Structure The NIA ESF Study will be organized into several components including 2-4 Study Centers, a Steering Committee, (the main decision-making body for the study), a Monitoring Board (a group of independent experts that will review research progress), a Data Management and Coordinating Center (responsible for organizational, informational, and data management and analyses functions for the study) and an NIA Project Official. The NIA ESF Study will be conducted in three phases as follows: Phase I: Protocol refinement (up to one year) o Awarded Study Center investigators will meet in Bethesda, MD to develop a common protocol and organize recruitment strategies (e.g., geographical coverage, sampling techniques), and methods to validate familial relationships and ages of all family members, based on the plans submitted in the successful NIA ESF applications. All Study Centers will use the standardized protocol. Study Centers may be required to restructure their originally submitted budgets and scientific approaches, including recruiting from different sampling frames than initially proposed in the applications, to achieve broad geographical coverage and other specifications, based on study planning at the Post-Award meeting. o The Steering Committee will develop standardized protocols for data collection and analytical approaches that will then be reviewed by the monitoring board before implementation. Phase II: Implementation: Data Collection (up to three years) o Collection of complete verified familial information, appropriate informed consent, phenotypic and genotypic data, and other information from family members as described in the "Goals and Scope" section above. o The Steering Committee will review the data collected and determine appropriate analytical approaches that will then be reviewed by the monitoring board before implementation. Phase III: Implementation: Data Analysis and Reporting (up to one year) o Analysis and reporting of data as described in the "Goals and Scope" section above. Organizational Components 1. Study Centers A Study Center is the Institution that receives an Award for conducting the investigations under this RFA. There must be evidence of strong Institutional support for the Study Center and a stated willingness to participate in common aspects of study design, employ statistical and biological measures, and perform analyses as approved by the Steering Committee. 2. Steering Committee A Steering Committee will serve as the main decision-making body for the study. The Steering Committee will have the overall responsibility for the development and finalization of standard definitions and protocols common to all Study Centers. The Principal Investigators of the Study Centers, the Principal Investigator of the DMCC, and the designated NIA Project Official will comprise the voting members of the Steering Committee. The study will proceed into the next phase only after approval by the Steering Committee of the common protocols, review and approval by the Monitoring Board, and acceptance by the NIA. The Steering Committee will meet every three to six months or as needed. 3. Monitoring Board A Monitoring Board will be formed to advise the Study Centers by periodically reviewing their research progress and the safety of the study subjects, as well as resolve any serious conflicts over how the overall study should proceed. The Monitoring Board will be comprised of independent experts in relevant clinical, statistical, and bioethical fields. The Monitoring Board's approval will be required for the Study to transition from Phase I to Phase II and again from Phase II to Phase III. The Chairperson of the Steering Committee and the NIA Project Official will participate as non-voting members of this Monitoring Board. 4. Data Management and Coordinating Center A Data Management and Coordinating Center will coordinate the decision making processes and administration of study-wide activities, and participate in development of common operating procedures and common protocols, organize and administer data collection and storage, and provide biostatistical support. MECHANISM OF SUPPORT This RFA will use the NIH UO1 award mechanism. As an applicant you will be solely responsible for planning, directing, and executing the proposed project. The NIH UO1 is a cooperative agreement award mechanism in which the Principal Investigator retains the primary responsibility and dominant role for planning, directing, and executing the proposed project, with NIH staff being substantially involved as a partner with the Principal Investigator, as described under the section "Cooperative Agreement Terms and Conditions of Award". This RFA is a one-time solicitation. The total project period for an application submitted in response to this RFA may not exceed five years. The anticipated award date is February 2004. Future unsolicited, competing- continuation applications based on this project will compete with all investigator-initiated applications and will be reviewed according to the customary peer review procedures. FUNDS AVAILABLE The NIA intends to commit, in total first-year costs, $3,750,000 in FY2003 to fund 2-4 Study Centers (at a cost of $3,000,000) and one Data Management and Coordinating Center (DMCC) (at a cost of $750,000) in response to this RFA. An applicant for a Study Center or the DMCC may request a project period of up to five years. For the Study Centers total costs may not exceed $750,000 per year. For the DMCC it is permissible to request funding for increments above $750,000 per year, not to exceed 4% per year for future years. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Applications requesting total cost budgets above these amounts in the first year will be deemed non-responsive to this RFA and returned to the applicant institution. Although the financial plans of NIA provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. At this time, it is not known if this RFA will be reissued. ELIGIBLE INSTITUTIONS You may submit (an) application(s) if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Domestic or Foreign Institutions INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs. Disciplines and expertise appropriate for the ESF Study include, but are not limited to, geneticists, epidemiologists, gerontologists, demographers, and statisticians. SPECIAL REQUIREMENTS Under the terms of the cooperative agreement, the awardee defines the details of the project within the guidelines of the RFA, retains primary responsibility for the performance of the activity and for the analyses and publication of the results. The awardee agrees to accept assistance, close coordination and participation of the designated NIA Project Official in all aspects of the scientific and technical management of the project in accordance with the terms of this RFA. The NIH will have the option of halting the study, the individual Study Centers, or the DMCC if the program objectives are not being met, or have been met prior to the full 5-year period. The maximum duration of the proposed projects may not exceed five years. Variations in project length will be due to differences in time needed for subject recruitment and data collection. All Study Centers must include the minimum set of phenotypic measures established by the NIA Panel on the Characterization of Participants in Studies of Exceptional Survival in Humans, and listed below, in addition to other appropriate measures selected by the Steering Committee. A report of this panel is available at http://www.nia.nih.gov/research/meetings/espreport.htm. Minimal requirements for applicants for the ESF Study DMCC are: o The applicant must have demonstrated prior experience as a coordinating center in multicenter studies. Evidence of previous experience in population- or family-based research focusing on, and data collection from, elderly and/or other hard-to-reach populations is required. o The Principal Investigator and other staff, must have appropriate statistical data, (including biological samples) management, and coordination expertise. o The applicant must have the willingness and ability to assist in designing protocols and the data collection system, including transmission via the Internet. o The applicant must demonstrate the willingness and ability to cooperate with the ESF Study Centers and NIA staff in all design, data collection and analysis functions. The applicant should provide a plan for developing a cooperative relationship among the ESF Study Centers and among the various ESF organizational components. o The applicant must have an established data system for collection and statistical analysis of common data. Data Sharing Restricted availability of unique research resources, upon which further studies are dependent, can impede the advancement of research. The NIH is interested in ensuring that the research resources developed through this grant become readily available to the broader research community in a timely manner for further research, development, and application, in the expectation that this will lead to products and knowledge of benefit to the public health. It is expected that resources to be shared will include all data and biological samples collected and all analyses techniques. To address this interest in assuring research resources are accessible, NIH requires applicants who respond to this RFA to submit plans for: (1) sharing the research resources generated through the grant; and (2) addressing how they will exercise intellectual property rights, should any be generated through this grant, while making such research resources available to the broader scientific community. The sharing of research resources plan and intellectual property plan must make unique research resources readily available for research purposes to qualified individuals within the scientific community in accordance with the NIH Grants Policy Statement (http://grants.nih.gov/grants/policy/nihgps/) and the Principles and Guidelines for Recipients of NIH Research Grants and Contracts on Obtaining and Disseminating Biomedical Research Resources: Final Notice, December 1999 (http://www.ott.nih.gov/policy/rt_guide_final.html) and (http://ott.od.nih.gov/NewPages/64FR72090.pdf)). These documents also define terms, parties, responsibilities, prescribe the order of disposition of rights, prescribe a chronology of reporting requirements, and delineate the basis for and extent of government actions to retain rights. Patent rights clauses may be found at 37 CFR Part 401.14 and are accessible from the Interagency Edison web page, http://www.iedison.gov. In the peer review of applications submitted in response to this RFA, reviewers will comment, as appropriate, on the adequacy and feasibility of the sharing of research resources plan and the intellectual property plan. Comments on the plans and any concerns will be presented in an administrative note in the Summary Statement. These comments will not affect the priority score of the proposal. NIH program staff will consider the adequacy of the plans in determining whether to recommend an application for award. The approved plans will become a condition of the grant award and Progress Reports must contain information on activities for the sharing of research resources and intellectual property. Budget Preparation by Study Phase Study Centers Each applicant for a Study Center should submit adequately justified budgets for the entire anticipated project period. The budget for each phase of the ESF Study should be clearly delineated. Detailed budgets will vary according to policies of the applicant institution and specific needs identified in response to this RFA. Applicants should prepare individual budgets for each of the three planned study phases. Phase I activities will require phasing-in staff at least six months prior to initiating study subject recruitment. Budgets should allow for three persons, including the Principal Investigator, to participate in at least three Steering Committee meetings during this phase. Detailed budget estimates for Phase II and Phase III should be based on the applicant's proposed plan. Budgets for Phases II and III will be modified based on the final protocol developed collaboratively during Phase I. However, applicants should budget for at least three persons, including the Principal Investigator, to participate in three Steering Committee Meetings during each year of Phases II and III. The initial Steering Committee Meeting will take place in Bethesda, MD. However, the location of the subsequent Steering Committee Meetings may change over the course of the full project period. Specific locations will be determined by the Steering Committee. All Steering Committee meetings should be assumed to last two days at a cost of $1200 per person. Data Management and Coordinating Center (DMCC) The Phase I budget should include costs of establishing the DMCC staff, as required to carry out DMCC functions (including costs of training personnel of ESF Study Centers for management and analyses, and quality control and quality assurance of common data). Phase I also will involve development of the protocols and manuals of operations by the study sites, in conjunction with the Steering Committee for the ESF Study and creation of a database. Budgets should include costs of organizing at least three "in person" Steering Committee meetings and for attendance of necessary DMCC staff to these meetings. The Phase II budget should include projected data handling costs, reporting functions, meetings and other communications costs, and the projected expense of performing any interim analyses that may be requested by the Monitoring Board. The DMCC applicant also should address the potential requirements of the ESF study by budgeting for tasks to be performed for the development of a repository to store patient samples. Applicants must include the costs of cell line establishment. The specific facilities and budgets to be supported through subcontracts will depend on the final protocol developed cooperatively by the Steering Committee. It should, however, be understood that the specific centralized facilities required and their final budgets will be determined following the design of the final study protocols and the writing of the manual of operations by the study sites and the Steering Committee. Budgets should also include costs of organizing three Steering Committee meetings per year and providing for attendance of necessary DMCC staff. The Phase III budget should be concerned with study close-out, data analyses, and reporting of results in collaboration with the Study Centers. Budgets should include the costs of organizing three meetings of the Steering Committee and providing for attendance of necessary DMCC staff. The initial Steering Committee Meeting will take place in Bethesda, MD. However, the location of the subsequent Steering Committee Meetings may change over the course of the full project period. Specific locations will be determined by the Steering Committee. All Steering Committee meetings should be assumed to last two days at a cost of $1200 per person. Cooperative Agreement Terms and Conditions of Award The following 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 Parts 74 and 92 and other HHS, PHS, and NIH Grant Administration policy statements. The administrative and funding mechanism used for this program is a cooperative agreement (UO1), and assistance mechanism (rather than an acquisition mechanism) in which substantial NIH scientific and/or programmatic involvement with the awardees 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 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 awardees for the project as a whole, although specific tasks and activities in carrying out the collaborative aspects will be shared among the awardees and the designated NIA Project Official. 1. Awardee Responsibilities Awardees will have primary authorities and responsibilities to define objectives and approaches, and for participant recruitment and follow-up, quality control, data analyses and interpretation, and for preparation of publications for their projects. Awardees at the Study Centers shall retain custody of, and primary rights to, the site-specific data developed under their award, subject to Government rights of access, consistent with current HHS, PHS, and NIH policies. In addition, awardees will engage in collaborative activities through participation in Steering Committee meetings and potential conference calls in the development and implementation of common measures across Study Centers. The Steering Committee will define the rules regarding access to, and publication of, findings from analyses of common data. The Study Centers will work collaboratively to develop the study design, collect appropriate data and biological samples, and perform analyses for the ESF Study as approved by the Steering Committee. Study Center Principal Investigators will be expected to maintain close communications with the NIA Project Official and the DMCC. The DMCC will be involved in collaborations with the NIA and the ESF Study Centers during all phases of the studies. The DMCC is responsible for working cooperatively with Study Centers and sponsoring organizations in a multicenter study and in overseeing the implementation of, and adherence to, a common protocol, as well as assuring quality control of the data collected. In addition to organizing and attending regular meetings, the DMCC will be expected to maintain close communications with the NIA Project Official and the Principal Investigators of the ESF Study Centers. 2. NIA Staff Responsibilities The designated NIA Project Official will have substantial scientific/programmatic involvement during conduct of this activity, through technical assistance, advice and coordination above and beyond normal program stewardship of cooperative agreement awards, assisting in those aspects of the ESF Study described below. Awardees agree to accept assistance from the designated NIA Project Official, as follows: o Participate in the monitoring of issues relating to recruitment, data collection, quality control, and analyses. o Assist in the development and/or adjustment of study protocols. o In conjunction with the Steering Committee, approves the transition of Study Centers from Phase I to Phase II and Phase II to Phase III. Prior to Phase II, after approval from the Monitoring Board, the NIA must accept (approval by the Director, NIA) the protocol before it can be implemented. The NIA reserves the right to terminate or curtail the study (or an individual award) in the event of substantial shortfall in participant recruitment, follow-up, data reporting, quality control, or other major breach of the protocol; if human subject safety or ethical issues dictate a premature termination; or if there is failure to develop or implement mutually agreeable protocols. o The Project Official will be a voting member of the Steering Committee. o Assistance in data analyses o An NIA Program Director will be responsible for normal program stewardship. The Program Director may also serve as the Project Official. 3. Collaborative Responsibilities A Steering Committee will serve as the main decision-making body for the shared aspects of the study. The Steering Committee will have the overall responsibility for developing and finalizing standard definitions and protocols common to all of the Study Centers. The Principal Investigators of the Study Centers, the Principal Investigators of the DMCC, and the designated NIA Project Official will comprise the voting members of the Steering Committee. Appropriate DMCC staff should also attend the Steering Committee Meetings. The study will proceed into the next phase only after approval of the Steering Committee of the common protocols, review and approval by the Monitoring Board, and acceptance by the NIA. The Steering Committee will meet every three to six months, or as needed. A Monitoring Board will be formed to advise the Study Centers by periodically reviewing their research progress and the safety of the study subjects on a regular basis, and will resolve any serious conflicts over how the overall study should proceed. The Monitoring Board will be established by NIA staff and approved by the Director, NIA, and will be comprised of experts in relevant clinical, statistical, and bioethical fields. The Monitoring Board's approval will be required for study site transition from Phase I to Phase II and again from Phase II to Phase III. The Chairperson of the Steering Committee and the NIA Project Official will participate as non-voting members of this Monitoring Board. 4. Arbitration Any disagreement that may arise on scientific/programmatic matters (within the scope of the UO1 award), between UO1 awardees and the NIA may be brought to arbitration. An arbitration panel will composed of three members: one selected by the Steering Committee (without NIH representatives voting) or by the individual UO1 awardee in the event of an individual disagreement; a second member selected by the NIA; and, a third member selected by the two prior selected members. For UO1 awardees, this special arbitration procedure will in no way affect the awardee's right to appeal an adverse action in accordance with PHS regulation at 42 CFR Part 50, Subpart D, and HHS regulations at 45 CFR Part 16. WHERE TO SEND INQUIRIES We encourage inquiries concerning this RFA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues: o Direct your questions about scientific/research issues to: Winifred K. Rossi, M.A. Special Assistant for Planning Geriatrics and Clinical Gerontology Program National Institute on Aging 7201 Wisconsin Avenue, Suite 3C3O7 MSC 9205 Bethesda, MD 20892-9205 Telephone: (301) 496-3836 Email: email@example.com o Direct your questions about peer review issues to: Mary Nekola, Ph.D. Chief, Scientific Review Scientific Review Office National Institute on Aging 7201 Wisconsin Avenue, Room 2C212 Bethesda, MD 20892-9205 Telephone: (301) 496-9666 Email: firstname.lastname@example.org o Direct your questions about financial or grants management matters to: Ms. Linda Whipp Grants and Contracts Management Office National Institute on Aging 7201 Wisconsin Avenue, Suite 2N212, MSC 9205 Bethesda, MD 20892-9205 Telephone: (301) 496-1472 FAX: (301) 402-3672 Email: email@example.com LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed project o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o Number and title of this RFA Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review. The letter of intent is to be sent by the date listed at the beginning of this document. The letter of intent should be sent to: Mary Nekola, Ph.D. Chief, Scientific Review Scientific Review Office National Institute on Aging 7201 Wisconsin Avenue, Room 2C212 Bethesda, MD 20892-9205 Telephone: (301) 496-9666 Email: firstname.lastname@example.org SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). The PHS 398 is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 435-0714, Email: GrantsInfo@nih.gov. SUPPLEMENTAL INSTRUCTIONS: See additional instructions in the GOALS AND SCOPE and SPECIAL REQUIREMENTS sections of this RFA. USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. 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 on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the application, including the Checklist, and three signed, photocopies, in one package to: Center for Scientific Review National Institutes of Health 6701 Rockledge Drive, Room 1040, MSC 7710 Bethesda, MD 20892-7710 Bethesda, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application must be sent to: Mary Nekola, Ph.D. Chief, Scientific Review Scientific Review Office National Institute on Aging 7201 Wisconsin Avenue, Room 2C212 Bethesda, MD 20892-9205 Telephone: (301) 496-9666 Email: email@example.com APPLICATION PROCESSING: Applications must be received on or before the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within 8 weeks. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to an RFA, it is to be prepared as a NEW application. That is the application for the RFA must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes. While the investigator may still benefit from the previous review, the RFA application is not to state explicitly how. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NIA. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NIA in accordance with the review criteria stated below. As part of the initial merit review, all applications: o Will receive a written critique o May undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed and assigned a priority score o May receive a second level review by the National Advisory Council on Aging REVIEW CRITERIA The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to discuss the following aspects of your application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals: o Significance o Approach o Innovation o Investigator o Environment The scientific review group will address and consider each of these criteria in assigning an application's overall score, weighting them as appropriate for each application. An application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an applicant may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. Review Criteria for the Study Centers (1) SIGNIFICANCE: Does the proposed project address an important problem? If the aims of the application are achieved, how do they advance scientific knowledge? What will be the effect of these studies on the concepts or methods that drive this field? (2) APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Is the potential sampling frame available to the investigator clearly outlined? Does the investigator provide realistic estimates of the number of study participants meeting the inclusion criteria for the study? Have sample size and power calculations been adequately addressed? What plans are presented to ensure high rates of participation and follow-up? What steps are planned for data quality control? How will missing follow-up data be handled? Are plans presented to ensure the complete, reliable, and timely transmission of study data to the DMCC? Does the investigator show knowledge of possible problems associated with the conduct of a multicenter population- based study and of other potential issues relevant to the ESF Study? Are alternative tactics considered? (3) INNOVATION: Does the proposed project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? (4) INVESTIGATORS: Is the Principal Investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the applicant's experience level as the principal investigator and to that of other researchers (if any)? Is appropriate expertise in genetics, epidemiology, gerontology, demography, and statistics and/or similar fields represented within and documented for the study team? Are the Principal Investigator and other study team members experienced in working with elderly populations? Are the Principal Investigator and his/her co-investigators experienced in collaborating with other investigators in a multicenter study? Do the Principal Investigator and other members of the proposed study team possess experience in recruiting participants to long-term follow-up studies? (5) ENVIRONMENT: Does the scientific environment in which the work will be done contribute to the probability of success? Does the proposed research plan take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of Institutional support? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, applications for the Study Centers will also be reviewed with respect to the following: o COLLABORATION: Demonstration of willingness to enter into, and collaborate within, a network of investigators that will develop and use common protocols and analyze common data. o SCIENTIFIC PLAN: The appropriateness and soundness of sampling and data collection strategies, familial structures sought, informed consent plans, validation methods, and management, and analyses. Are the sampling and data collection strategies appropriate? Are familial structures sought appropriate? Are the familial validation approaches appropriate? o DATA SHARING: Reviewers will comment, as appropriate, on the adequacy and feasibility of sharing the research resources plan and the intellectual property plan. Comments on the plans and any concerns will be presented in an administrative note in the Summary Statement. These comments will not affect the priority score of the proposal. NIH program staff will consider the adequacy of the plans in determining whether to recommend an application for award. The approved plans will become a condition of the grant award and Progress Reports must contain information on activities for the sharing of research resources and intellectual property. o PROTECTIONS: The adequacy of the proposed protection for humans, animals, or the environment, to the extent they may be adversely affected by the project proposed in the application. o INCLUSION: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria included in the section on Federal Citations, below) o BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. Review Criteria for the DMCC The final design of the ESF Study protocol will be developed collaboratively by the Steering Committee, based on individual protocols proposed by awarded Study Centers. In assessing applications for the DMCC, the scientific review group will focus on whether the applicant recognizes the significance of the issues involved and has the knowledge necessary to contribute meaningfully to the final study design, including understanding the scientific, ethical, and practical issues underlying the ESF Study. (1) SIGNIFICANCE: Does the proposed approach for managing logistical and data coordination have scientific and technical merit? Are the proposed plans and experience related to data collection, management, editing, processing, analysis, and reporting adequate? Are the plans for coordination with the Study Center investigators adequate? Is the approach to developing a cooperative relationship among the Study Centers and among the various ESF organizational components adequate? Are the plans for exercising appropriate leadership in matters of study design, data acquisition, data management and data analysis demonstrated? (2) APPROACH: Does the proposed plan demonstrate the ability to identify and enlist the cooperation of central facilities to carry out centralized support functions for the Study Centers? Is the plan to develop and maintain a public and private (secured, password-protected) ESF Study Web Page adequate? (3) INNOVATION: Does the DMCC applicant offer innovative ideas on how to achieve the goals of the ESF Study with regard to its design and administration? Does the proposal address problems that may arise during the study and provide innovative solutions to such problems? (4) INVESTIGATORS: Is the Principal Investigator appropriately trained in biostatistics? Does the Principal Investigator possess experience in directing a Coordinating Center for large-scale collaborative multicenter studies or other large-scale epidemiological research project focusing on elderly populations and involving multiple Study Centers? Does the application provide evidence of specific competence and relevant experience of professional, technical, and administrative staff pertinent to the operation of a Coordinating Center for multicenter studies? Do the Principal Investigator and his/her co-investigators have prior experience collecting data and biological samples from multiple Study Centers, database development, data management, monitoring the data quality, and developing and utilizing statistical methods for analysis of data? Is there evidence of experience in, and willingness to, participate appropriately in a collaborative study as described in this RFA among within the study team? Are there adequate assurances that the DMCC personnel have experience in utilizing procedures that ensure the safety and confidentiality of study subject identity and data? (5) ENVIRONMENT: Has the application documented the adequacy of the proposed facility, technical hardware, and space for the DMCC? Is there an appropriate organizational and administrative structure to the proposed DMCC? Is there evidence of institutional support and commitment, including adequate space, for the proposed program? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, applications for the DMCC will also be reviewed with respect to the following: o COLLABORATION: Is there demonstration of willingness to enter into and collaborate within a network of investigators that will develop and use common protocols and analyze common data? o SCIENTIFIC PLAN: Is there demonstration of understanding of the scientific, statistical, logistical and technical issues underlying multicenter studies, including issues related to collecting, handling, storage, and analysis of biological samples from elderly populations. Is there demonstration of leadership in statistics, data acquisition and management, data quality control, data analysis and multicenter coordination? o DATA SHARING: Reviewers will comment, as appropriate, on the adequacy and feasibility of sharing the research resources plan and the intellectual property plan. Comments on the plans and any concerns will be presented in an administrative note in the Summary Statement. These comments will not affect the priority score of the proposal. NIH program staff will consider the adequacy of the plans in determining whether to recommend an application for award. The approved plans will become a condition of the grant award and Progress Reports must contain information on activities for the sharing of research resources and intellectual property. o PROTECTIONS: The adequacy of the proposed protection for humans, animals, or the environment, to the extent they may be adversely affected by the project proposed in the application. o INCLUSION: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria included in the section on Federal Citations, below) o BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: May 19, 2003 Application Receipt Date: June 24, 2003 Peer Review Date: November 2003 Council Review: January 2004 Earliest Anticipated Start Date: February 2004 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit (as determined by peer review) o Availability of funds o Programmatic priorities. REQUIRED FEDERAL CITATIONS MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components involving Phase I and II clinical trials must include provisions for assessment of patient eligibility and status, rigorous data management, quality assurance, and auditing procedures. In addition, it is NIH policy that all clinical trials require data and safety monitoring, with the method and degree of monitoring being commensurate with the risks (NIH Policy for Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: http://grants.nih.gov/grants/guide/notice-files/not98-084.html). INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the AMENDMENT "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are available at http:// grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this RFA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This RFA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople/. AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance No. 93.866, and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies described at http://grants.nih.gov/grants/policy/policy.htm and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. The PHS strongly encourages all grant recipients to provide a smoke-free workplace and to discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people. REFERENCES (1) Hitt R, Young-Xu Y, Silver M, Perls T. Centenarians: the older you get, the healthier you have been [letter]. Lancet 1999; 354(9179):652. (2) Perls TT, Bubrick E, Wager CG, Vijg J, Kruglyak L. Siblings of centenarians live longer. Lancet 1998 May 23;351(9115):1560 (3) Perls T, Shea-Drinkwater BA, Bowen-Flynn J, Ridge SB, Kang S, Joyce et al. Exceptional familial clustering for extreme longevity in humans. JAGS 2000; 48: 1483-5. (4) Barzilai N, Gabriely J, Gabriely M, Ienkowitz N, Sorkin JD. Offspring of centenarians have a favorable lipid profile. Journal of the American Geriatrics Society 2001; 49(1):1-4. (5) Kerber R, O'Brien E, Smith K, Cawthon R. Familial excess longevity in Utah genealogies. J. Gerontol Biol Sci 2001; 56a: B1-B10. (6) Puca AA, Daly MJ, Brewster, Matise TC, Barrett J, Shea-Drinkwater M, et al. A genome-wide scan for linkage to human exceptional longevity identifies a locus on chromosome 4. PNAS 2001; 98(18) 10505-8.
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