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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