EXPLORATORY PROJECTS FOR LONGITUDINAL GENETIC EPIDEMIOLOGIC STUDIES ON AGING Release Date: May 7, 1999 RFA: AG-99-007 P.T. National Institute on Aging National Institute of Environmental Health Sciences Letter of Intent Receipt Date: September 30, 1999 Application Receipt Date: January 12, 2000 PURPOSE The National Institute on Aging (NIA) and the National Institute of Environmental Health Sciences (NIEHS) is soliciting proposals for exploratory research projects to identify appropriate populations, phenotypes, designs and methods for longitudinal genetic epidemiologic studies to identify effects of genetic factors on rates of age-related physiologic and pathologic changes, and/or survival outcomes such as age of onset of disease or disability. The NIA will use information derived from these projects in decisions regarding possible establishment of full-scale genetic epidemiologic studies on these topics. NIEHS is interested in how genetic factors interact with exposures to environmental agents that may contribute to age-related physiologic and pathologic changes in human populations. NIEHS is also interested in how genetic factors interact with the body burden of environmental chemicals and other exposures that change as populations age. 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 Request for Applications (RFA), Exploratory Projects for Longitudinal Genetic Epidemiologic Studies on Aging, is related to several priority areas applicable to aging. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0) or "Healthy People 2000" (Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402- 9325 (telephone 202-783-3238). These documents are also available on the World Wide Web at http://www.crisny.org/health/us/health7.html. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, 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. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) research project grant (R01). The total project period for an application submitted in response to this RFA may not exceed three years. The anticipated award date is July 2000. This RFA is a one-time solicitation. FUNDS AVAILABLE $2.6 million for total (direct plus indirect) costs is available for the first year of support for awards. Total funding for the second and third years of awards will be at approximately the same level. NIA anticipates issuing four to six awards for responses to this RFA. NIEHS anticipates contributing up to $100,000 per year to each project where environmentally relevant exposures are measured. The total contribution that NIEHS plans to make is $500,000. Funding is contingent on availability of funds and receipt of proposals of high scientific merit. The size of awards may vary given the potential variation in the nature and scope of the research projects proposed in response to this RFA. RESEARCH OBJECTIVES Background The use of longitudinal data in genetic epidemiologic studies has great potential to reveal genetic factors that affect physiologic and pathologic rates of change with age (rate-of-change phenotypes), and the duration of survival without one or more specific diseases or disabilities (survival phenotypes). The identification of genetic factors and their interactions with environmental factors contributing to desirable outcomes of these types, such as minimal rates of decline (or lack of decline) with age in a particular physiologic property, and/or prolonged survival without onset of morbidity, is of particular interest because of its value in identifying protective factors against disease and disability. Existing longitudinal studies, particularly those with familial data or for which familial data could be obtained, are especially valuable for this purpose, as are family studies, twin registries, and genealogic registries with opportunities to collect longitudinal data. Though evidence exists for significant genetic influences on rate-of-change and survival phenotypes, the development of studies to identify the effects of genetic factors on these phenotypes would benefit from additional data relating to the feasibility, optimal design, choice of phenotypes, and sample size requirements for specific research projects. The acquisition of such data could benefit from collaboration among researchers from fields such as epidemiology, genetics, gerontology, geriatrics, demography, environmental health, and statistics. Research Goals and Scope This RFA solicits proposals for exploratory studies that will determine the feasibility, optimal study design, and sample size requirements for projects to identify effects of genetic and gene-environmental interactions on human rate-of- change and/or survival phenotypes. Phenotypes The selection of specific rate-of-change and/or survival phenotypes is at applicants' discretion. These phenotypes may be studied in both middle-aged and older individuals, as appropriate to the phenotype of interest. Applicants are particularly encouraged to consider extreme phenotypes (e.g., very slow rates of change with age, or survival to advanced age without morbidity) even though individuals with such phenotypes may be rare, since they may lead to the identification of polymorphisms with strong protective effects. Populations The populations from which data are to be collected in these exploratory studies may be (but are not required to be) the same as the populations under consideration for full-scale studies. However, if they are not the same, applicants must demonstrate the applicability of the exploratory study data to the populations for which they analyze the feasibility, design, and sample size requirements of full-scale studies. Populations from which exploratory data may be collected and/or analyzed, and populations for which calculations relating to feasibility, design, and sample size of full-scale studies are made include, but are not limited to, participants in existing longitudinal studies, family studies, twin registries, population registries, genealogic registries (including those containing historical data), and registries of persons of advanced age. Applicants are encouraged to consider recruiting additional subjects (e.g., family members) beyond those presently enrolled in such studies or registries. Data Collection and Analyses The selection of specific data to be collected and analyzed as a basis for design choices, and for estimates of feasibility and sample size for full-scale studies, is at applicants' discretion. Examples of data collection and analyses that could be conducted include, but are not limited to: o Determination of the degree of familial aggregation, pattern of segregation within families, and other information indicating the strength and nature of possible genetic effects, for specific rate-of-change or survival phenotypes. Analyses of phenotypic and family data to identify very specifically defined subphenotypes that may have strong familial clustering are also appropriate. o Data collection and analyses to determine statistical power and population requirements (including family structures) of designs for full-scale studies to identify effects of genetic factors on rate-of-change and/or survival phenotypes in the populations of interest. Applicants are encouraged to consider a wide range of possible linkage and/or association study designs in attempting to identify those with the best combination of statistical power and low risk of artifactual results in the populations under consideration for full-scale studies. o Exploratory studies to test possible sampling frames, recruitment strategies and approaches to obtaining informed consent, for estimates of potential yield of appropriate subjects for full-scale studies. o Preliminary testing of relationships between specific polymorphisms and phenotypes of interest, as an approach to identifying promising polymorphisms and/or phenotypes for more intensive consideration in full-scale studies. o Development and refinement of analytic tools for use in the exploratory and the full-scale longitudinal genetic epidemiologic study designs and populations being considered, such as (but not limited to), repeated-measures and survival analyses, approaches to obtaining needed haplotype information in the absence of parental DNA, and analysis of effects of environmental changes over time on gene- environment interactions. o For studies proposing to examine genetic interactions with environmental exposures, collection of baseline data on exposure to environmentally relevant chemicals and other environmental exposures should be included. Exposure data can include environmental measures and body burden. Study of the feasibility and timing of serial collections of such exposure data and their correlations over time is encouraged. Use of biomarkers of exposure, such as, PAH-DNA- adducts and k -XRF levels of lead exposure, may also be useful. In the development of these studies, interdisciplinary research teams of epidemiologists, geneticists, gerontologists, geriatricians, demographers, statisticians, and researchers in environmental health sciences and other pertinent specialties are strongly encouraged where appropriate. Attention to specific ethical issues that may arise in the consideration of study options for genetic epidemiologic studies is also encouraged. SPECIAL REQUIREMENTS Awardees will meet as a group once a year in Bethesda, Maryland with NIH program staff to exchange information on progress of the studies. Applicants should request sufficient funds in their proposed budgets to support travel and lodging expenses for three individuals to attend these meetings. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS 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 biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided 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 research involving human subjects should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994. Investigators may also obtain copies of the policy from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. NIH POLICY AND GUIDELINES ON THE INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS. It is the policy of the NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications for receipt dates after October 1, 1998. However, the scientific goals of this RFA are focused on aging issues that occur in adults and older persons. In describing the plan to recruit human subjects investigators may cite a focus on aging or on aging-related aspects of disease as the justification for why children will be excluded. In this regard applicants may use Justification 1, the research topic to be studied is irrelevant to children, from the policy announcement. LETTER OF INTENT Prospective applicants are asked to submit, by September 30, 1999, a letter of intent that includes a descriptive title of the proposed research; the name, address, and telephone number of the Principal Investigator; the identities of other key personnel and participating institutions; and the number and title of the RFA in response to which the application may be submitted. 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 staff to estimate the potential review workload and avoid conflict of interest in the review. The letter of intent is to be sent to Evan Hadley, M.D. Associate Director (Geriatrics) National Institute on Aging Gateway Building, Suite 3E327 7201 Wisconsin Avenue, MSC 9205 Bethesda, MD 20892-9205 Telephone: (301) 435-3044 FAX: (301) 402-1784 Email: hadleye@exmur.nia.nih.gov APPLICATION PROCEDURES The research grant application form PHS 398 (rev.4/98) is to be used in applying for these grants. Applications kits are available at most institutional offices of sponsored research, or may be obtained from the Division of Extramural Research Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone, 301-435-0714; e- mail: grantsinfo@nih.gov. Applications are also available on the World Wide Web at http://grants.nih.gov/grants/funding/phs398/phs398.html. The RFA label available in the PHS 398 (rev.4/98) 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 on line 2 of the face page of the application form and the YES box must be marked. 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 It is important to send these copies at the same time as the original and three copies are sent to the Center for Scientific Review. Applications must be received by January 12, 2000. If an application is received after that date, it will be returned to the applicant without review. 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. The CSR 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 already reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by CSR and responsiveness by the NIA. Incomplete applications will be returned to the applicant without further consideration. If the application is not responsive to the RFA, CSR staff may contact the applicant to determine whether to return the application to the applicant or submit it for review in competition with unsolicited applications at the next review cycle. 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 will receive a written critique and may undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed, assigned a priority score, and receive a second level review by the appropriate national advisory council or board. Review Criteria The overall criterion for review of responses to this RFA is the ability of the proposed exploratory study to identify feasible and appropriate phenotypes, designs and populations for full-scale genetic epidemiologic longitudinal studies to identify effects of genetic factors on human rate-of-change and/or survival phenotypes. General scientific criteria which apply to the consideration of responses to the RFA include: o Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? o Approach: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? o Innovation: Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? o Investigator: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? o Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? The initial review group will also examine: the appropriateness of proposed project budget and duration; the adequacy of plans to include both genders and minorities and their subgroups as appropriate for the scientific goals of the research, and plans for the recruitment and retention of subjects; the provisions for the protection of human and animal subjects; and the safety of the research environment. AWARD CRITERIA Applications will compete for available funds with all other approved applications. The following will be considered in making funding decisions: o Quality of the proposed project as determined by peer review o Availability of funds o Program priorities INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Evan Hadley, M.D. Associate Director (Geriatrics) National Institute on Aging Gateway Building, Suite 3E327 7201 Wisconsin Avenue, MSC 9205 Bethesda, MD 20892-9205 Telephone: (301) 435-3044 FAX: (301) 402-1784 Email: hadleye@exmur.nia.nih.gov Gwen W. Collman, Ph.D. Program Administrator National Institute of Environmental Health Sciences Division of Extramural Research and Training P.O. Box 12233 Research Triangle Park, NC 27709 Telephone (919) 541-4980 FAX: (919) 541-4937 Email: collman@niehs.nih.gov Direct inquiries regarding fiscal matters to: Ms. Cynthia Riddick Grants and Contracts Management Office National Institute on Aging Gateway Building, Suite 2N212 7201 Wisconsin Avenue, MSC 9205 Bethesda, MD 20892-9205 Telephone: (301) 496-1472 FAX: (301) 402-3672 Email: riddickc@exmur.nia.nih.gov Mr. David Mineo Grants Management Officer National Institute of Environmental Health Sciences Division of Extramural Research and Training P.O. Box 12233 Research Triangle Park, NC 27709 Telephone: (919) 541-1373 FAX: (919) 541-2860 Email: mineo@niehs.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.866. 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 Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant and contract recipients to provide a smoke- free workplace and promote the non-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.
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