Full Text MH-93-006

DIAGNOSTIC CENTERS FOR PSYCHIATRIC LINKAGE STUDIES

NIH GUIDE, Volume 22, Number 27, July 30, 1993

RFA:  MH-93-006

P.T. 34

Keywords: 
  Psychiatry 
  Diagnosis, Medical 
  Gene Products 
  Schizophrenia 
  Senile Dementia 


National Institute of Mental Health

Application Receipt Date:  December 3, 1993

PURPOSE

The National Institute of Mental Health (NIMH) wishes to solicit
applications to use the resources and experience of investigators of
the NIMH-funded "Diagnostic Centers for Psychiatric Linkage Studies" to
complete the objectives set forth in the original request for
applications (RFA) for this program (RFA: MH-89-05) and to support the
research necessary to identify genes that influence susceptibility to
Alzheimer's disease, bipolar disorder, and schizophrenia.  The NIMH
anticipates funding three centers for Alzheimer's disease, three
centers for schizophrenia, and three centers for bipolar disorder in
September 1994.

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

MECHANISM OF SUPPORT

Awards will be made as cooperative agreements (U01).  In cooperative
agreements, unlike individual research project grants, substantial NIMH
programmatic involvement with the recipient is anticipated during the
performance of the planned activity.

Prior to termination of this Cooperative Agreement, NIMH will evaluate
long-term plans for resource sharing to be submitted by the Principal
Investigators.  A determination of the mechanism for continued support
of the resource contracts will be made no later than year 08.

FUNDS AVAILABLE

The NIMH expects to support nine cooperative agreements funded during
fiscal year 1994.  It is expected that up to $175,000 in direct costs
will be available for each cooperative agreement in fiscal year 1994.

RESEARCH OBJECTIVES

Background

The role of genetic factors in the observed familial aggregation is
well supported by twin and adoption studies in schizophrenia and
bipolar disorder and in twin studies of Alzheimer's disease.  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 three 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 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 three disorders in order to have sufficient
power to perform genetic analyses such as linkage studies 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 coordinate the assessment and collection of
data from affected sibling pairs and family members with Alzheimer's
disease, three centers for probands and family members with
schizophrenia, and three centers for bipolar disorder, in addition to
a fourth center for bipolar disorder at the NIMH Intramural Research
Program.

Concomitantly, NIMH established resource contracts for a National Cell
Repository (Coriell Institute for Medical Research) 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
IDENTIFIABLE data collected, while anonymous information about family
structure, age, sex, and diagnosis is sent to the Data Management
Center to form part of a national resource. Since their primary
function is the acquisition and storage of cells and data to be used as
a national resource, the repositories were funded through separate
contract mechanisms.

Research Goals and Scopes

This extension of the Diagnostic Centers for Psychiatric Linkage
Studies project is intended to allow completion of the collection of
pedigree data and blood for future genetic studies and for longitudinal
follow-up of subjects enrolled in the study.  The collaboration of
experts from a wide range of scientific disciplines is necessary for
this undertaking.

SPECIAL REQUIREMENTS

Terms and Conditions of Award

Assistance via cooperative agreements differs from the individual
research project grant in that substantial technical involvement by
NIMH staff is anticipated 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 the
willingness to cooperate with each other, with NIMH assistance.  The
intent of the NIMH is to assist the awardees in the development of
common data elements, procedures, and evaluation tools to maximize the
capacity of individual awardees to contribute to a combined analysis
across all awards.  Applicants must include in the application a plan
for fulfilling the terms of cooperation with other awardees with NIMH
assistance.

The nature of staff involvement is described below.  Awardees will be
responsible for the planning, direction, and execution of the proposed
project.  Specifically, each applicant will be responsive to the
requirements and conditions set forth in this Letter of Solicitation.

A.  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 continue developing common data elements,
evaluation instruments, and procedures which will ensure quality
control.  It will be the responsibility of each Principal Investigator
to attend Steering Committee meetings.  Principal Investigators should
include in their budgets three 2-day trips per year to NIMH for
themselves and personnel they deem necessary.

2.  Each awardee will continue to be responsible for maintaining a data
management system that meets high standards of quality control.  Each
Principal Investigator will be responsible for supplying computerized
data, in the previously agreed upon format, to the Data Management
Center to enable analyses across projects.  The comparative analyses
will be joint efforts of the awardees and NIMH.

3.  Each awardee will continue to be responsible for drawing and
sending blood to the Cell Repository for DNA extraction and cell
transformation to enable analyses across projects.

4.  Publications will be a high priority.  Publication of data findings
and procedures by each awardee are 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.  NIMH staff will
be included as coauthors if NIMH participation in the analysis warrants
it.  Publications policies developed by the Steering Committee will be
followed.  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.

B.  Responsibilities of NIMH Staff

NIMH Staff Role:  The NIMH staff role in this cooperative agreement
will extend beyond the level usually 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 will coordinate the work of the three
disorder-based groups with each other and with the Data Management
Center and the National Cell Repository and will be a voting member of
the Steering Committee.  The Scientific Coordinator will contribute
assistance especially with regard to psychiatric research issues and
will be a voting member of the Steering Committee from NIMH Staff.

3.  One Staff Coordinator for each disorder-based group will continue
to have input in their area of expertise as needed, in collaboration
with award recipients, in both the planning and conduct of the study,
but will not be a member of the Steering Committee.

C.  NIMH Intramural Participation

The Neurogenetics Branch of the NIMH Intramural Research Program will
also continue to participate as a co-equal site for bipolar disorder
(not funded under this award) in addition to the nine 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 (A1 through A4) as outlined above.

D.  Collaborative Responsibilities

The Steering Committee will be the primary decision-making body of this
collaborative multi-site study.  Several NIMH staff will be members 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), the NIMH
Scientific Coordinator (one vote), and the NIMH Project Coordinator
(one vote).  All decisions will be made by majority vote with an
attempt for consensus when possible.  The Steering Committee will meet
at least three times per year in the Washington, DC Metropolitan Area.
Each disorder-based group will form a disorder-based subcommittee.  No
subcommittees will be chaired by NIMH staff.  Additional subcommittees
will continue (publications, administration, ethics) or be formed on an
as-needed basis.  NIMH will centralize management of non-identifiable
data and storage of transformed cell lines and DNA using the contract
mechanism described above.

E.  Data Rights

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

Availability of Unique Resources to the Broader Research Community:
The data, cell lines, and DNA produced by this program constitute
valuable resources.  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:  Volume 21, Number 33, September 11, 1992, pages 4-5), the
data and DNA repositories should not only serve the needs of this
study, but they should be a resource to the larger scientific research
community as well.

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

F. 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 coordinators 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 termination of support for the awardee by NIMH.
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 Part 16.

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

Applicants must describe plans to accommodate these requirements,
including involvement of Institute staff.

STUDY POPULATIONS

SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS

NIH policy is that applicants for NIH clinical research grants and
cooperative agreements will be required to include minorities and women
in study populations so that research findings can be of benefit to all
persons at risk of the disease, disorder or condition under study;
special emphasis should be placed on the need for inclusion of
minorities and women in studies of diseases, disorders and conditions
which disproportionately affect them.  This policy is intended to apply
to males and females of all ages.  If women or minorities are excluded
or inadequately represented in clinical research, particularly in
proposed population-based studies, a clear compelling rationale should
be provided.

The composition of the proposed study population must be described in
terms of gender and racial/ethnic group.  In addition, gender and
racial/ethnic issues should be addressed in developing a research
design and sample size appropriate for the scientific objectives of the
study.  This information should be included in the form PHS 398 in
Sections 1-4 of the Research Plan AND summarized in Section 5, Human
Subjects.

Applicants are urged to assess carefully the feasibility of including
the broadest possible representation of minority groups.  However, NIH
recognizes that it may not be feasible or appropriate in all research
projects to include representation of the full array of United States
racial/ethnic minority populations (i.e., Native Americans (including
American Indians or Alaskan Natives), Asian/Pacific Islanders, Blacks,
Hispanics).

The rationale for studies on single minority population groups should
be provided.

For the purpose of this policy, clinical research includes human
biomedical and behavioral studies of etiology, epidemiology, prevention
(and preventive strategies), diagnosis, or treatment of diseases,
disorders or conditions, including but not limited to clinical trials.

The usual NIH policies concerning research on human subjects also
apply.  Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are excluded.  However,
every effort should be made to include human tissues from women and
racial/ethnic minorities when it is important to apply the results of
the study broadly, and this should be addressed by applicants.

For foreign awards, the policy on inclusion of women applies fully;
since the definition of minority differs in other countries, the
applicant must discuss the relevance of research involving foreign
population groups to the United States' populations, including
minorities.

If the required information is not contained within the application,
the application will be returned.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
women or minorities in a study design is inadequate to answer the
scientific question(s) addressed AND the justification for the selected
study population is inadequate, it will be considered a scientific
weakness or deficiency in the study design and will be reflected in
assigning the priority score to the application.

All applications for clinical research submitted to NIH are required to
address these policies.  NIH funding components will not award grants
or cooperative agreements that do not comply with these policies.

Protection of Human Subjects

The Department of Health and Human Services has regulations for the
protection of human subjects and has developed additional regulations
(45 CFR 46, Protection of Human Subjects) and those pertaining
specifically to children are available from the Office of Protection
from Research Risks, National Institute of Health, Bethesda, MD 20892,
telephone 301/496-7041.  Specific questions concerning protection of
human subjects in research may be directed to NIMH staff members listed
under INQUIRIES.

Allowable Costs

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 Public Health Service Grants Policy Statement
(rev. 10/90).

APPLICATION PROCEDURES

Applications are to be prepared on the form PHS 398 (rev. 9/91).  The
PHS 398 application form is available at most institutional offices of
sponsored research; from the Grants Management Branch, National
Institute of Mental Health, 5600 Fishers Lane, Room 7C-05, Rockville,
MD 20857, telephone 301/443-4414; and from the Office of Grants
Information, Division of Research Grants, National Institutes of
Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone 301
435-0714.  On line 2a of the application face page, applicants must
enter the number of the Letter of Solicitation as MH-93-006; for 2b,
the title, "Diagnostic Centers for Psychiatric Linkage Studies."  The
RFA label (found in the 10/88 revision of application form PHS 398)
must be affixed to the bottom of the face page of the original copy of
the application.  Failure to use this label could result in delayed
processing of your application such that it will not reach the review
committee in time for review.

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**

REVIEW CONSIDERATIONS

This is a one-time-only application process with a receipt date of
December 3, 1993.  Applications received after that date will be
returned to the applicant's institutional organization without review.
Scientific/technical merit review will take place in February or March
1994; National Advisory Mental Health Council review will be in May
1994, with a start date in September 1994.

Applications submitted in response to this RFA will be reviewed in
accordance with the usual NIH peer review procedures for research grant
applications.  Review for scientific and technical merit will be by an
initial review group (IRG) convened by NIMH and composed primarily of
non-Federal scientific experts, and 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  Evidence of significant progress in the first five years of data
collection

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 area 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
Institute Staff

o  Adequacy of the plans for the inclusion of females 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.

Potential applicants may seek additional information and consultation
from the NIMH by contacting:

Kate Berg, Ph.D., Chief
Division of Clinical and Treatment Research
National Institute of Mental Health
5600 Fishers Lane, Room 18C-14
Rockville, MD  20857
Telephone:  (301) 443-3524

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-15
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.

.

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