Full Text MH-94-010

GENETIC ANALYSIS OF BIPOLAR DISORDER AND SCHIZOPHRENIA

NIH GUIDE, Volume 23, Number 28, July 29, 1994

RFA:  MH-94-010

P.T. 34

Keywords: 
  Schizophrenia 
  Genetics 
  Molecular Genetics 
  Epidemiology 


National Institute of Mental Health

Application Receipt Date:  October 19, 1994

PURPOSE

The National Institute of Mental Health (NIMH) is soliciting
applications to use the resources and experience of funded
investigators of the NIMH's "Diagnostic Centers for Psychiatric Linkage
Studies" to complete the objectives outlined in the original request
for applications (RFA) for this program (RFA: MH-89-05), and to move to
the second phase of study of the genetics of bipolar disorder and
schizophrenia: genotyping and genetic analysis of material from
subjects ascertained during the data collection phase of this study.
Combining expertise in the areas of diagnosis, genetic epidemiology,
biostatistics, and molecular genetics should make it possible to
identify those genetic factors that have a significant impact on the
expression of these disorders.  The NIMH is especially interested in
applications that can demonstrate the ability to work with other
participating centers and NIMH staff in developing a plan for DNA
preparation, obtaining probes, genotyping, and analyzing genetic data;
determine methods for sharing data among centers with special expertise
in molecular biology and/or genetic epidemiologic methodologies;
develop plans for replication of results; and address issues of
generalizability and heterogeneity.  The applicants are expected to use
data from the families ascertained and assessed by the Diagnostic
Centers.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000,"
a PHS-led national activity for setting priority areas.  This RFA,
Genetic Analysis of Bipolar Disorder and Schizophrenia, is related to
the priority area of mental disorders in adults.  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).

ELIGIBILITY REQUIREMENTS

Only currently funded bipolar disorder or schizophrenia Diagnostic
Centers for Psychiatric Linkage Studies are eligible to apply for up to
three years of support.  The six currently active Diagnostic Centers
for Psychiatric Linkage Studies are considered uniquely structured to
undertake this study for several reasons:  their use of a common
protocol for data collection that has included uniform assessments and
extension rules permitting pooling of data across sites; their ability
to follow subjects longitudinally and track changes in diagnoses or
compare diagnoses; and their existing infrastructure, scope and aims,
and multidisciplinary staffing.

MECHANISM OF SUPPORT

Awards will be made as cooperative agreements (U01).  In cooperative
agreements, unlike traditional research grants, substantial NIMH
programmatic involvement with the recipient is anticipated during the
performance of the planned activity.  It is expected that up to
$250,000 in direct costs for each cooperative agreement study site will
be available in fiscal year 1995.

FUNDS AVAILABLE

The NIMH expects to support six cooperative agreements funded during
fiscal year 1995.  Applicants may request funds for salary, research
costs, consultants, consortium/contractual costs, travel (including
travel to Steering Committee meetings), alterations and renovations,
patient costs, equipment, supplies, other allowable expenses, and
appropriate indirect costs.

Cooperative agreements are awarded directly to the applicant
institution.  Funds may be used only for those expenses clearly related
to and necessary to carry out the project and must be expended in
conformance with the PHS Grants Policy Statement (rev. 4/1/94).

RESEARCH OBJECTIVES

Background

The role of genetic factors in the observed familial aggregation of
schizophrenia and bipolar disorder is well supported by family, twin,
and adoption studies.  However, attempts to fit genetic models to
family data have yielded contradictory results.  In 1987, NIMH began to
develop a program to study the genetic basis of vulnerability to these
disorders.

The primary goals of the 1987 program were to:  (1) develop a set of
common protocols to assess subjects; (2) develop a comprehensive set of
reliable and valid assessment instruments and to adopt a common
protocol and criteria for diagnosing subjects across centers; (3)
design and implement an ascertainment plan for collection of a large
number of families with each of the disorders in order to have
sufficient power to perform genetic analyses under conditions of
heterogeneity; and (4) provide the scientific community with a national
resource of DNA contained in immortalized cell lines as well as
diagnostic information on probands and their families.

The NIMH initiated its "Diagnostic Centers for Psychiatric Linkage
Studies" in fiscal year 1989.  After rigorous peer review, three
centers were selected to plan and coordinate the assessment and
collection of data from affected sibling pairs and family members with
schizophrenia, three centers for bipolar disorder, and a fourth center
for bipolar disorder at the NIMH Intramural Research Program.

Concomitantly, NIMH established a National Cell Repository (Coriell
Institute for Medical Research) to store DNA and cell lines
immortalized from subjects' blood in addition to a repository of
clinical information, the Data Management Center (SRA, Inc).  In accord
with the assistance aspects of a cooperative agreement, the Principal
Investigators retain primary custody of all collected data, which
include subject identifiers, while anonymous information about family
structure, age, sex, and diagnosis is sent to the Data Management
Center to form a national resource.

Since their primary function is the acquisition and storage of cells
and data to be used as a national resource, these repositories were
funded through separate contract mechanisms.

Because the public health implications of identifying genes for
schizophrenia and bipolar disorder are substantial, the genotyping data
gained from this study will become part of the national resource
already being established by the NIMH Genetics Initiative.  As part of
this resource, the genotyping data will be made available to other
researchers at a suitable time to minimize redundancy in research and
promote early identification of the genes involved in these disorders
in the most efficient and cost-effective manner.

Objectives and Scope

This cooperative agreement for genetic analysis of data collected by
the Diagnostic Centers for Psychiatric Linkage Studies project is
intended to allow participants to:  (1) screen DNA from bipolar and
schizophrenia families (collected as described above) for potentially
relevant mutations; (2) perform the necessary computer simulations
using existing family structures and various genetic models to
determine optimum analytic strategies as new data become available; (3)
search for genes associated with bipolar disorder or schizophrenia,
using the best available genetic analytic techniques; and (4) use
existing and new highly polymorphic markers to better define the
regions where linkages are found.  It is anticipated that once
genotyping begins these data will be transferred to the data management
center on a regular basis.

SPECIAL REQUIREMENTS

Terms and Conditions of Award

Assistance via cooperative agreements differs from the traditional
research grant in that NIMH anticipates substantial technical
involvement during the performance of the project.  It is the right and
responsibility of the awardees to control and direct the development,
conduct, and publication of their studies with the assistance of NIMH.
Although awards will be based on the quality of the individual
applications received, awardees must demonstrate willingness to
cooperate with each other with NIMH assistance.  The intent of NIMH is
to assist the awardees in the development and implementation of common
procedures and evaluation tools in order to maximize the capacity of
individual awardees to contribute to a combined analysis across all
disorder-based sites.  Applicants must include in the application a
plan for fulfilling the terms of cooperation with other awardees with
NIMH assistance.

Special Requirements:  Terms and Conditions of Award are in addition
to, and not in lieu of, otherwise applicable OMB administrative
guidelines, HHS grants administration regulations at 45 CFR Part 74,
and other HHS, PHS, and NIH grants administration policies.

The nature of staff involvement is described below. Applicants will be
responsible for the planning, direction, and execution of the proposed
project.

Responsibilities of Awardees

1.  Shortly after the awards are made, the Principal Investigators and
their key personnel will be required to cooperate with each other, with
NIMH assistance, to develop procedures that will ensure quality control
of data management, laboratory studies, and analytic procedures.

2.  It will be the responsibility of each Principal Investigator to
attend Steering Committee meetings.  Principal Investigators should
include in their budgets three two-day trips per year to NIMH for
themselves and personnel they deem necessary.

3.  Each awardee will be responsible for transferring genotyping data
and analytical results to the Data Management Center on a timely basis.

4.  Publications will be a high priority.  Publication of data findings
and procedures by each awardee is encouraged.  It is the responsibility
of the investigators to provide copies of publications and major
presentations to the NIMH Project Coordinator.  Collaborative
publications among awardees and NIMH are anticipated, with inclusion of
NIMH staff as co-authors if NIMH participation in the analysis warrants
it.  Publication policies developed by the Steering Committee will be
followed, and the quality of publications will be the responsibility of
the authors. No NIMH clearances will be required except for NIMH staff
who may serve as coauthors.

Responsibilities of NIMH Staff

The NIMH staff role in this cooperative agreement will extend beyond
the level normally required for stewardship of a grant because of the
need for coordination of study protocols among centers, technical
assistance in the analysis of data, and monitoring and possible
reassessment of project objectives as the study proceeds.

1.  The Program Official has overall responsibility for monitoring the
conduct, progress, and fiscal management of the program.  Progress of
the program will be reviewed by the Program Official annually at the
time of each continuation application to assure that satisfactory
progress is being made in achieving the objectives of the program and
that each performance site is following the program goals and
procedures recommended for use by all participants in the cooperative
program and approved by the Steering Committee.   The Program Official
performs the usual stewardship functions.

2.  The Project Coordinator, who will be appointed by the NIMH
Director, will coordinate the work of the disorder-based groups with
each other, with the Data Management Center, and with the National Cell
Repository and will be a voting member of the Steering Committee.

NIMH Intramural Participation

The Neurogenetics Branch of the NIMH Intramural Research Program will
also continue to participate as a site for bipolar disorder (not funded
under this award) in addition to the six extramural sites.  As such,
the Neurogenetics Branch functions in a manner analogous to the
awardees, rather than to NIMH staff, and is subject to the same
requirements as outlined above.

Collaborative Responsibilities

The Steering Committee will be the primary decision-making body of this
collaborative multi-site study.  The NIMH Project Coordinator will be
a member of the Steering Committee but cannot hold the position of
chair.  Membership will be composed of the Principal Investigator from
each site including the NIMH Intramural site (one vote per site), and
the NIMH Project Coordinator (one vote).  All decisions will be made by
majority vote, with an attempt for consensus when possible.  Failure to
comply with the decisions of the panel will be considered a material
failure to comply with the terms and conditions of the grant award and
may result in termination of support for the awardee by NIMH.  The
Steering Committee will meet at least three times per year, generally
in the Washington, DC Metropolitan Area.  Each disorder- based group
will form a disorder-based subcommittee which cannot be chaired by NIMH
staff.  Additional subcommittees will continue or be formed on an
as-needed basis.  The NIMH will centralize the management of coded data
without subject identifiers.

Data Rights

Awardees will retain custody of and primary rights to the data
developed under these awards, subject to Institute rights of access and
consistent with current HHS, PHS, and NIH policies.

Availability of Unique Resources to the Broader Research Community:
The data produced by this program constitute a valuable resource.
Because of the expense and expertise needed to produce them, these
resources cannot readily be replicated by other investigators.
Therefore, consistent with PHS policy relating to the distribution of
unique research resources produced with PHS funding (NIH Guide, Vol.
23, No. 26, July 15, 1994), the data should not only serve the needs of
this study but should also be a resource to the larger scientific
research community.

Thus, applicants must formulate a statement of their data and resource-
sharing policy based on the above-cited PHS policy.  Investigators must
include within their application a description of their plans to ensure
compliance with this policy.  This description should include, at a
minimum, procedures to assure timely access to qualified investigators.

Arbitration

Any disagreement that may arise in scientific or technical matters, not
resolved by the normal deliberations of the Steering Committee, or a
disagreement regarding scientific collaboration between award
recipients and the NIMH staff coordinator may be brought to mediation.
A mediation panel will be composed of three members, one selected by
the individual awardee in the event of an individual disagreement, a
second member selected by NIMH, and the third member selected by the
two prior members.  Decisions of this panel will be by majority vote.
Failure to comply with decisions of the panel will be considered a
material failure to comply with the terms and conditions of the grant
award and may result in NIMH termination of support for the awardee.
This special mediation procedure in no way affects either the
Government's right to bring an adverse action or the awardee's right to
appeal an adverse action in accordance with PHS regulations at 42 CFR
Part 50, subpart D and HHS, Grant Administration Regulations at 45 CFR
Part 74, and HHS regulations at 45 CFR Parts 16.  Applicants must
describe plans to accommodate these requirements, including involvement
of Institute staff.

STUDY POPULATIONS

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 subpopulations 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 new policy results from
the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43)
and supersedes and strengthens the previous policies (Concerning the
Inclusion of Women in Study Populations, and Concerning the Inclusion
of Minorities in Study Populations), which have been in effect since
1990. The new policy contains some provisions that are substantially
different from the 1990 policies.

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 reprinted in
the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18,
1994.

Investigators also may obtain copies of the policy from the program
staff listed under INQUIRIES.  Program staff may also provide
additional relevant information concerning the policy.

APPLICATION PROCEDURES

Applications are to be prepared on the grant application form PHS 398
(rev. 9/91).  The application form is available at most institutional
offices of sponsored research and from the Office of Grants
Information, Division of Research Grants, National Institutes of
Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone
(301) 710-0267.  The RFA label available in the PHS 398 (rev. 9/91)
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
(Genetic Analysis of Bipolar Disorder and Schizophrenia, MH-94-010)
must be typed on line 2a of the face page of the application form and
the YES box must be marked.

A completed original application and five copies must be sent to:

Division of Research Grants
National Institutes of Health
Westbard Building, Room 240
Bethesda, MD  20892**

This is a one-time only application with a receipt date of October 19,
1994.  Applications received after that date will be returned to the
applicant's institutional organization without review.  Scientific/
technical merit review will take place in November 1994; National
Advisory Mental Health Council review will be in early 1995, with a
possible start date in March 1995.

REVIEW CONSIDERATIONS

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 NIMH in accordance with the review
criteria stated below.  As part of the initial merit review, a process
(triage) may be used by the initial review group in which applications
will be determined to be competitive or non-competitive based on their
scientific merit relative to other applications received in response to
the RFA.  Applications judged to be competitive will be discussed and
be assigned a priority score.  Applications determined to be non-
competitive will be withdrawn from further consideration and the
Principal Investigator and the official signing for the applicant
organization will be notified.  A second level of review will be
conducted by the National Advisory Mental Health Council.

Review Criteria

Applications will be judged on:

o  Evidence of familiarity with and understanding of relevant research
literature

o  Quality of the project design and methodology

o  Demonstrated scientific and technical capability, experience, and
level of commitment of the Principal Investigator and proposed research
staff

o  Availability of research expertise in the areas of assessment,
molecular biology, and genetic epidemiology

o  Adequacy of facilities, general environment, core resources, and
collaborative relationships for the development and implementation of
the proposed research

o  Evidence of the institution's research and administrative support
commitment

o  Adequacy of the plan to protect research participants

o  Adequacy of plans to implement the Special Requirements: Terms and
Conditions of Award section including provisions for the involvement of
NIMH Staff

o  Adequacy of the plans for the inclusion of women and minorities

o  Appropriateness of budget requested

AWARD CRITERIA

In making awards, the following criteria will be used for applications
that have been recommended for approval, provided the applicant has
complied with all legislative, regulatory, and policy requirements of
the Public Health Service:

o  Quality of application as documented by IRG and Council reviews
o  Availability of NIMH funding

INQUIRIES

Written and telephone 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:

David Shore, M.D.
Division of Clinical and Treatment Research
National Institute of Mental Health
5600 Fishers Lane, Room 18C-26
Rockville, MD  20857
Telephone:  (301) 443-3683

Inquiries pertaining to grants management may be directed to:

Bruce L. Ringler, Chief
Grants Management Branch
National Institute of Mental Health
5600 Fishers Lane, Room 7C-08
Rockville, MD  20857
Telephone:  (301) 443-3065

AUTHORITY AND REGULATION

This program is described in the Catalog of Federal Domestic Assistance
93.242, Mental Health Research Grants.  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 as
implemented through DHHS Regulations at 45 CFR Part 100.

The Public Health Service strongly encourages all grant recipients to
provide a smoke-free workplace and promote the non-use of all tobacco
products.  This is consistent with the PHS mission to protect and
advance the physical and mental health of the American people.

.

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