MOLECULAR GENETICS OF SCHIZOPHRENIA AND DEPRESSION

Release Date:  November 18, 1998

RFA:  MH-99-005

P.T.

National Institute of Mental Health

Letter of Intent Receipt Date:  January 22, 1999
Application Receipt Date:  February 23, 1999

PURPOSE

The purpose of this Request for Applications (RFA) is to solicit applications for
multidisciplinary, collaborative research projects that employ state-of-the-art
diagnostic procedures and analytic methods to (1) collect and clinically
characterize a large pedigree sample of adequate statistical power for
identifying genomic regions which may harbor loci conferring susceptibility to
schizophrenia or early-onset recurrent unipolar depression, and (2) conduct a
whole-genome scan to establish the chromosomal localization of such loci.  This
is a follow-up to RFA MH-98-010, Molecular Genetics of Mental Disorders, which
in Fiscal Year 1998 solicited applications for molecular genetic studies of
bipolar disorder, depression, and schizophrenia.  Data and biological materials
collected and produced in projects funded under this RFA will augment existing
resources distributed by the National Institute of Mental Health (NIMH) for
genetic analyses by the wider scientific community.

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, Molecular Genetics of
Schizophrenia and Depression, is related to the priority area of Mental Health
and Mental Disorders.  Potential applicants may obtain a copy of "Healthy People
2000" at http://www.crisny.org/health/us/health7.html

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign for-profit and nonprofit
organizations, public and private organizations 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.

The large-scale collection of clinically well-characterized samples of sufficient
size for linkage analyses and for linkage disequilibrium mapping studies in
genetically isolated populations may be facilitated by the establishment of
international consortia.  Full collaborations between American scientists and
scientists at international institutions are encouraged, when scientifically
appropriate. In these cases, awards may be made to international institutions or
to domestic applications that include international components.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) individual research
project grant (R01) or the collaborative research project grant (R01) for
clinical studies of mental disorders.  The multi-institutional cooperative
research project grant (R10) mechanism will no longer be accepted by NIMH, as
indicated in a notice in the December 19, 1997 issue of the NIH Guide for Grants
and Contracts on the World Wide Web at 
http://grants.nih.gov/grants/guide/notice-files/not97-248.html.  Further
information on the collaborative R01 research project grant may be found in a
program announcement entitled, "Collaborative R01s for Clinical Studies of
Mental Disorders" in the December 19, 1997 issue of the NIH Guide on the Web
at http://grants.nih.gov/grants/guide/pa-files/PAR-98-017.html.

Responsibility for the planning, direction, and execution of the proposed project
will be solely that of the applicant.  This RFA is a one-time solicitation. 
Future unsolicited competing continuation applications will compete with all
other unsolicited applications, and will be reviewed according to customary peer
review procedures.  All awards will be issued and managed by NIMH.

The earliest anticipated award date is September 30, 1999.

FUNDS AVAILABLE

This RFA is a one-time solicitation.  It is anticipated that $3 million
(including direct and indirect costs) will be available for this initiative in
Fiscal Year 1999, during which it is anticipated that 8-10 awards will be made. 
Awards pursuant to this RFA are contingent upon the availability of funds for
this purpose.  The amount of funding for this initiative may be increased if a
large number of highly meritorious applications are received and if funds are
available.  Only applications that are found to be of the highest scientific
merit will be considered for funding, and not all of the funding will be spent
if there are not enough highly meritorious applications.  Funding in future years
will be subject to the availability of funds.

The total project period for an appliction submitted in response to this RFA may
not exceed 4 years.  Because the nature and socpe of the research proposed in 
response to this RFA may vary, it is anticipated that the size of an a ward will 
also vary.

RESEARCH OBJECTIVES

Background

It is expected that greater understanding of the genetic bases of common diseases
will revolutionize diagnosis, treatment, and prevention.  This will ultimately
facilitate characterization of the non-genetic, environmental contributions to
illness.  While breathtaking advances have occurred in mapping and cloning genes
for rare diseases like cystic fibrosis that follow predictable Mendelian patterns
in families, the discovery of genes that influence susceptibility to more common
human conditions like mental disorders has proceeded much more slowly.  A major
reason has likely been the inherent difficulty in detecting modest gene effects
in small data sets.

While considerable research has been conducted to investigate the familial bases
of schizophrenia - with data from family, twin and adoption studies spanning six
decades consistently supporting the involvement of genetic factors in familial
transmission - conclusive identification and replication of a chromosomal region
that harbors a susceptibility locus has not been forthcoming.

Depression is a very heterogeneous disorder, of which genetic factors are likely
to contribute to the familial aggregation of only some variants.  In several
family studies probands were subdivided according to age-of-onset and/or history
of recurrent depression; greatest risk was to relatives of early-onset, recurrent
depressive probands.  Consequently, depression appears more familial when
probands are chosen on the basis of an early-onset recurrent illness.  A recent
segregation analysis of early-onset recurrent depression yielded some evidence
of a major gene effect.  Reported associations between unipolar depression and
two candidate genes have not been replicated in other samples.  No molecular
genetic studies have focused exclusively on the early-onset recurrent variant.

In summary, the mode of inheritance of schizophrenia is complex and likely
involve environmental factors and multiple genes in interaction.  It is clear
that single major genes do not account for their familial aggregation in most
pedigrees.  The number of susceptibility loci involved and the recurrence risk
ratios conferred by each, the extent of locus heterogeneity, the role of gene-
environment interaction, and the degree of epistatic interaction all remain
unknown.  A similar lack of knowledge exists regarding the mode of inheritance
of early onset recurrent depression, which is likely to be the most heritable
variant of depressive illness.  Molecular genetic studies of schizophrenia have
implicated several chromosomal regions that may harbor susceptibility loci, but
the magnitude of the statistical evidence and/or the failure to convincingly
replicate demonstrate that these are clearly not confirmed findings. 
Inconsistent results may reflect the influence of small relative gene effects,
locus heterogeneity, false-positive results, or a lack of power in small samples.
Insufficient data exist to strongly implicate a genomic region as containing a
susceptibility locus for early onset recurrent depression.

New technologies have been developed for rapid high-throughput genotyping, and
dense maps of polymorphisms are widely available.  Automated methods for the
discovery and scoring of simple, bi-allelic polymorphisms (termed single
nucleotide polymorphisms, or SNPs) currently being developed will lead to the
generation of a dense map of thousands of new markers across the genome and will
permit the rapid and efficient cataloging of human DNA sequence variation.  These
developments will complement the three major analytic methods that have proved
successful for the discovery of Mendelian disease genes: localization to a
chromosomal region of several Megabases (Mb) by linkage analysis of family data,
followed by fine genetic mapping; analysis of haplotypes for linkage
disequilibrium mapping; and direct detection of an increased prevalence of a
functional variant in affected individuals, through association analysis.

Dramatic progress in genetic analytic methods and technologies will clearly
facilitate the discovery of genes influencing susceptibility to mental disorders
and other complex diseases.  However, it seems clear that ultimate success will
require new large-scale data collection efforts to obtain samples of sufficient
size that have high power for the detection of susceptibility loci of small
relative effect.  Such large-scale data collection efforts by a single principal
investigator, or by self-selected teams of principal investigators working in
collaboration, will permit the application of uniform methods for data
acquisition, diagnosis, and comprehensive, state-of-the-art clinical
characterization on a scale unprecedented in the molecular genetic studies of
these disorders.  Whole-genome analyses conducted in such data sets will have
tremendous potential for identifying chromosomal regions that harbor
susceptibility loci.  Such achievements will set the stage for a new era in the
genetic analysis of mental disorders, in which research efforts will dramatically
shift from initial localization to gene identification.

Scope of Work

The molecular and statistical tools that will greatly facilitate gene discovery
for complex human diseases like mental disorders are just beginning to emerge. 
Such tools undoubtedly will require clinically well-characterized samples of
adequate statistical power for the detection of genes that exert a small relative
effect.  Therefore, NIMH seeks the new collection of large samples, in which
probands and their relatives are clinically characterized through the application
of state-of-the-art diagnostic methods and comprehensive assessments of
psychopathology.  Data collection may occur within the context of a linkage study
in an outbred population, or a linkage disequilibrium mapping study in a
genetically isolated population.  Application of rapid and highly cost-effective
genotyping will permit initial scans to identify chromosomal regions that harbor
disease susceptibility genes.  It is expected that data and biological materials
collected and produced in projects funded under this RFA will augment those to
be collected in projects funded under RFA MH-98-010, and also existing resources
distributed by NIMH for genetic analyses by the wider scientific community. 
Positional cloning, in which a gene is identified and cloned by virtue of its
subchromosomal location in the genome rather than by using knowledge of its
biochemistry, has become increasingly straightforward but remains a formidable,
multi-step task.  Genetic mapping of affected families with polymorphic markers
spanning the genome permits localization of the putative disease genes to a
candidate region, often in the range of 2 to 5 Mb.  Such intervals are physically
mapped with overlapping DNA clones, which usually serve as substrates to identify
genes (transcripts). Subsequently, the genes are examined for large-scale
sequence mutations in affected individuals. 

Cloning susceptibility genes for common, complex diseases like mental disorders,
in which there is not a perfect correspondence between phenotype and genotype,
presents additional difficulties not encountered when mapping simple Mendelian
traits.  Given such complexities, the focus of molecular and statistical analyses
supported under this RFA will be limited to the goal of initial chromosomal
localization.  This in itself will represent a significant achievement, and set
the stage for future positional cloning efforts.
 
Principal investigators, or self-selected teams of principal investigators, are
expected to focus their application on schizophrenia or early-onset recurrent
unipolar depression.  Recruitment efforts may be consolidated, and a commensurate
time and cost savings expected, if a principal investigator proposes to collect
and analyze data for more than one disorder.  In such cases, review and award
criteria will consider the feasibility of large-scale data collection and
analysis of each disorder. Regardless of the scope of the project, it is expected
that applications will include a multidisciplinary team comprised of clinicians,
diagnosticians, molecular geneticists, and statistical geneticists. It is
expected that the first three years of the project will be focused predominantly
on pedigree ascertainment and phenotypic assessment, with genetic analyses being
conducted in the final year.  Each of the following areas is expected to be
comprehensively addressed in the application.

1) Pedigree Structure

Applications are solicited for the collection of family data that can be analyzed
using the methods that have proved successful for the mapping of Mendelian
disease genes.  These methods require ascertainment of: (1) extended pedigrees
in genetically isolated populations, for linkage disequilibrium mapping studies;
or (2) small nuclear or extended pedigrees consisting of affected sibling pairs
(ASPs) or of multiple affected individuals, for linkage analyses.  Data
collection from affected individuals and two parents for family-based association
analyses is strongly encouraged, but only when such a configuration occurs within
a pedigree containing an ASP or multiple affected individuals.  Collection of
pedigrees for family-based association analyses in which diagnostic data and
biological materials can be collected only from an affected individual and his
two parents will not be supported by this RFA.  Applicants must adequately
justify the proposed sample size targets for a three-year data collection period
as being both feasible and sufficient for the chromosomal localization of
susceptibility genes for the disorder under investigation, given the proposed
analytic method. 

2) Structured Diagnostic Criteria

The application of standardized and structured diagnostic criteria is essential
to the accurate phenotyping of subjects for genetic analyses of mental disorders. 
While the use of operational diagnostic criteria has undeniably improved the
reliability of psychiatric diagnoses, the validity of any such category is
indeterminate.  Most importantly, it is still unclear which, if any, diagnostic
system offers the phenotypic definitions that correlate most highly with
underlying genotypes. In this sense, there is no clear indication as to which
diagnostic system (e.g., the revised third (DSM-III-R) or fourth (DSM-IV)
editions of the American Psychiatric Association's Diagnostic and Statistical
Manual for Mental Disorders, Research Diagnostic Criteria (RDC), International
Classification of Diseases (ICD)) should be employed.  On the other hand, efforts
to replicate results and combine data across different samples may be hampered
if diagnostic criteria for pedigree recruitment are widely variable. 

Consequently, the definition of affected status when defining ASPs or when
specifying a minimum number of affected individuals in projects supported under
this RFA, for the purpose of pedigree ascertainment, is expected to follow DSM-IV
criteria.  This will permit pooling of these data with existing NIMH resources
and will provide some uniformity, but does not in any way preclude the use of
other diagnostic systems and criteria in establishing diagnoses in probands and
relatives.  In fact, where scientifically appropriate, investigators are
encouraged to use the full range of diagnostic definitions under multiple systems
when making phenotypic assessments. 

Given that it is unclear which diagnostic system offers the phenotypic
definitions that correlate most highly with underlying genotypes, it is essential
that it be possible to establish diagnoses in multiple diagnostic systems.  Such
a polydiagnostic approach requires recording clinical information accurately and
in sufficient detail to allow different definitions of an illness to be applied. 
The comprehensive phenotypic information collected in projects funded under this
RFA (see below) is expected to permit the establishment of diagnoses within a
multitude of systems, according to different criteria sets.  In addition, such
information may form the basis for future approaches to phenotyping after
susceptibility genes are discovered.

Most importantly, the definition of affected for the purpose of ascertainment
should be limited exclusively to core phenotypes (schizophrenia or early-onset
recurrent unipolar depression), that are diagnosed with greater reliability than
broadened illness definitions (so-called spectrum phenotypes).  Such a focus is
expected to decrease misclassification and diagnostic error while maximizing
genetic homogeneity.  For example, an applicant proposing to collect 500 ASPs to
identify genes that confer susceptibility to schizophrenia will assure that both
siblings in each ASP are diagnosed with DSM-IV schizophrenia.

Other diagnostic systems, criteria sets, and phenotypes may be used to classify
subjects as affected in the analyses conducted; however, each ascertained
pedigree will have either multiple affected individuals and/or an ASP in which
affected status reflects a DSM-IV diagnosis of a core phenotype.  While there is
no DSM-IV criterion for early onset recurrent depression, the applicant is
expected to clearly specify the age-cutoff for onset that was uniformly applied.

3) Comprehensive Phenotypic Assessment

Minimization of phenotypic error and imprecision, especially that which
contributes to false-positive diagnoses of affected status, requires the careful
application of state-of-the-art diagnostic techniques.  This is expected to
include the comprehensive synthesis of information systematically collected from
structured or semi-structured diagnostic interviews of high reliability, medical
records, and multiple family informants.  Applicants should fully document their
procedures for establishing such a final best estimate lifetime psychiatric
diagnosis.  Establishment of a highly reliable psychiatric diagnosis is
facilitated by the use of a structured or semi-structured diagnostic interview.
Applicants shall use one of the self-report interviews currently available and
ready for use at the time the project is to begin.  Such an interview is expected
to have an associated data entry system by which information may be rapidly and
efficiently entered into a computer database (see below).  It is expected that
the project does not include any percentage effort or any costs for the
development or modification of existing instruments.  One such set of instruments
is the Diagnostic Interview for Genetic Studies (DIGS) and the Family Interview
for Genetic Studies (FIGS) that were developed for the NIMH Human Genetics
Initiative.  Blank forms and training and code manuals are available via the Web
at http://zork.wustl.edu/nimh/digs/newpage11.htm.  While their use
is not required, applicants who choose not to use them must clearly document
the reliability and adequacy of their instruments for assessing a
comprehensive range of clinical psychopathology.

The structured interview utilized by the investigator must be sufficiently broad
to incorporate the criterion sets for diagnosing major mental disorders in
multiple systems.  This is important to permit creation of the broadest possible
dataset for genetic research on mental disorders, ensure maximum comparability
with other data sets, and to permit comparisons to older studies using different
criterion sets.  While it is not required that investigators establish diagnoses
in systems (e.g., ICD, RDC, DSM-III-R) other than DSM-IV, sufficient clinical
data must be collected to allow diagnostic determinations in multiple systems.

Currently, there is an imperfect correlation between a phenotype established
according to any psychiatric diagnostic criteria set and an underlying genotype. 
The future discovery of susceptibility genes for mental disorders may
significantly change current diagnostic criteria.  Consequently, phenotypic
assessments are expected to include not only a psychiatric diagnosis but also
determination of a comprehensive range of clinical psychopathology.  The
diagnostic interview utilized by the applicant is expected to a broad range of
psychopathology that may form the basis for future studies that correlate
phenotypic characteristics, and not exclusively existing diagnostic categories,
to underlying genotypes.

It is expected that the principal investigator will demonstrate high diagnostic
reliability among raters and/or collaborating sites when employing the diagnostic
interview of choice.  It is strongly encouraged that this be demonstrated prior
to award.  If this is not feasible, training exercises and limited reliability
studies are expected to occur and be completed during the project's first month
or two.  Most importantly, such efforts must not impede or delay the commencement
of large-scale data recruitment efforts.

4) Computerized Database

The creation and maintenance of a computerized database that includes a
comprehensive array of clinical, family structure, diagnostic, and genotypic
information is essential for rapid and efficient genetic analyses.  Creation of
such an electronic database is quite time-consuming and labor-intensive.  Thus,
it is expected that the applicant will have already developed, or have access to,
such resources prior to the initiation of this project.  Inclusion of a
comprehensive range of information about psychopathology may be facilitated
through the use of software that permits incorporation in an electronic database
of all the information collected from a comprehensive structured interview.  All
of the data collected from the DIGS interview (but not the FIGS) may be input
into such a database via a Windows 95 operating system graphical user interface. 
Software is available via the Web at http://zork.wustl.edu/nimh/digs/
newpage11.htm. While the use of DIGS software is not required, applicants
who choose not to use it must clearly document the existence and utility of a
transparent graphical user interface through which data on a comprehensive
array of clinical psychopathology data gathered through use of the diagnostic
instrument they propose to use may be directly entered into an electronic
database.  The applicant must maintain a high-quality electronic database for
data entry and analyses throughout the period of the funded project.

It is expected that investigators shall establish electronic databases of all
clinical, final best estimate diagnostic, and family structure information for
wide dissemination to qualified investigators in the scientific community for use
in genetic analyses, in accordance with a data sharing plan developed by the
investigator (see below, section 7).  The creation and validation of such
datafiles are expected to occur at frequent and regular intervals prior to the
genetic analyses conducted in the last year of the award.  It is expected that
the minimum data provided for each subject will include a unique subject and
family identification number (ID), parental IDs, sex status, death status,
ethnicity, age, twin status, final best estimate DSM-IV diagnosis, best estimate
of the age at onset, and the comprehensive range of clinical information obtained
from a structured interview.  Data will be maintained without personal
identifiers and thus are unlinked to their sources; such materials are anonymous
samples.  Creation and initial validation of such databases will signify that
genetic analyses are to begin.  Only at that time is it expected that DNA samples
as extracted from cell lines (see below, section 5) will be required by
investigators.

It is also expected that genotyping data produced in projects funded under this
RFA - including DNA marker names, allele sizes in base pairs and corresponding
frequencies, and relative map distances - will be widely distributed to qualified
investigators in the scientific community, according to the investigator's data
sharing plan (see below, section 7).

If requested by the investigator, NIMH will provide no-cost access to a data
management facility; extensively documented electronic files ready for immediate
genetic analysis will be created for use by the wider scientific community. 
Rapid and efficient creation of such files is expected to occur upon receipt of
data at frequent and regular intervals.  Applicants may request funds to defray
the costs of establishing databases with extensive documentation for wide
distribution to the scientific community, with adequate justification.  If
another resource is utilized, it is expected that the adequacy, efficiency and
cost of creating, maintaining, and documenting electronic databases as stipulated
in their data sharing plan (see below, section 7) for dissemination to qualified
investigators in the scientific community will be comparable to what could be
achieved by using the resource to which NIMH provides no-cost access.

5) Lymphoblastoid Cell Lines and DNA Samples

Creation of lymphoblastoid cell lines from blood samples establishes an
infinitely renewable source of DNA for subsequent genetic analyses.  In addition,
these biological materials will be invaluable source for future studies that
employ genetic maps of much higher density  (e.g., those with SNPs as a basis)
and that employ efficient technologies to study gene function and expression. 
Therefore, it is expected that permanent cell lines will be established for
subjects studied in projects funded under this RFA.  The creation of cell lines
and extraction of DNA for genetic analyses requires provision of blood samples
to a cell repository.  It is expected that investigators shall obtain blood
samples to establish cell lines and extract DNA samples for wide dissemination
to qualified investigators in the scientific community for use in genetic
analyses, in accordance with a data sharing plan developed by the investigator
(see below, section 7).  If requested by the investigator, NIMH will provide no-
cost access to a cell repository; high-quality cell lines will be created upon
receipt of blood samples, and DNA will be extracted and provided to applicants
at no cost for their exclusive use.  The quantity of DNA required for genetic
analyses is expected to be precisely specified in the application.  Applicants
may request funds to defray the costs of establishing cell lines and extracting
DNA for distribution to the wider scientific community, with adequate
justification.  If another repository is utilized, it is expected that the
adequacy, efficiency and cost of the procedures for establishing cell lines and
extracting DNA for wide dissemination to qualified investigators in the
scientific community as stipulated in their data sharing plan will be comparable
to what could be achieved by using the resource to which NIMH provides no-cost
access.

6) Molecular and Statistical Genetic Analyses

Identification and cloning of a disease susceptibility locus first requires
chromosomal localization.  Genetic analyses to be conducted in projects funded
under this RFA will focus on genome-wide scans and statistical analyses to
identify chromosomal regions that may harbor disease susceptibility loci.  Fine
mapping studies (including the saturation of regions of interest with multiple
markers), gene sequencing, mutation analysis, and other steps in the positional
cloning process will not be supported by this RFA.

One resource currently available to applicants is the Center for Inherited
Disease Research (CIDR), a centralized facility established to provide high-
throughput genotyping and statistical genetics services for investigators seeking
to identify genes that contribute to human disease. CIDR utilizes automated
fluorescent microsatellite analysis using a standard marker set (Weber Screening
Set 8), consisting of 387 primer pairs spaced approximately 10 CentiMorgans
throughout the genome.  Current capacity is approximately 120,000 genotypes per
month.  CIDR was established in 1996 as a joint effort of eight NIH Institutes,
and is supported through a contract to Johns Hopkins University.

CIDR is available to all investigators through competitive peer review by a
chartered CIDR Access Committee (CAC).  The CAC is a standing NIH committee
comprised of scientists who have expertise in gene mapping and the genetic
dissection of complex diseases.  Projects are evaluated on the need for high
throughput genotyping and the likelihood that genotyping will lead to successful
mapping of genes contributing to that disease.  Given that NIMH is one of the
supporting NIH Institutes, research projects funded under this RFA are eligible
for CIDR's special introductory rate of no-cost genotyping.  Further information
about CIDR may be found on the World Wide Web at http://www.cidr.jhmi.edu. 
Submission deadlines for applications requesting CIDR access are November 1,
March 1 and July 1.  Applicants are expected to request access to CIDR.

Applicants will not learn the outcome of the CAC evaluation in time to include
an approval letter from the CAC in their application.  Thus, investigators are
expected to include in their application a scientific plan to accomplish a high
throughput genome-wide scan at a single, centralized laboratory and statistical
analyses, as well as budgeted genotyping and analysis costs. It is expected that
the time frame and costs for their genomic scan and statistical analyses will be
generally comparable to what could be achieved at CIDR or at academic or
commercial facilities.  A time frame for completion of a genome wide scan within
one year, at a cost of approximately $1 per genotype, appears reasonable.  It is
anticipated that technologies will improve and the rate of work and associated
cost will change.

7) Data and Biological Materials Dissemination

The sharing of materials, data, and software in a timely manner has been an
essential element in the rapid progress that has been made in the genetic
analysis of human diseases.  PHS policy requires that investigators make unique
research resources readily available for research purposes to qualified
individuals within the scientific community when they have been published (PHS
Grants Policy Statement in the July 12, 1996 issue of the NIH Guide to Grants and
Contracts).  Providing access to data collected in human genetic studies for
qualified investigators in the wider scientific community has been a guiding
principle of the NIMH Human Genetics Initiative, which funded data collection and
genetic analysis for schizophrenia, bipolar disorder, and late-onset Alzheimer
disease.  Information for this Initiative is available on the Web at 
http://zork.wustl.edu/nimh/NIMH_initiative/NIMH_initiative_link.html.
Data and materials collected and produced in projects funded by this RFA will
be distributed to qualified scientific investigators in the wider research
community, and will augment these existing resources.

To address the joint interests of the government in the availability of, and
access to, the results of publicly funded research and in the opportunity for
economic development based on these results, NIMH requires applicants who respond
to this RFA to develop and propose detailed plans for sharing the data and
materials generated through the grant.  It is expected that the information to
be shared includes all clinical, diagnostic, and pedigree structure information,
in addition to cell lines and DNA.  For this purpose, it is the opinion of the
NIH that dissemination of such data and materials via individual laboratories and
Web sites is not sufficient, as it would force interested investigators to have
to search several different data collections to make use of the results of this
initiative.  In addition, differences in protocols across projects for creating
databases, establishing cell lines, and extracting DNA may make it impossible for
researchers to combine information for integrated genetic analyses.  It is
preferable that data and materials generated in grants funded under this RFA
should be placed in common, public cell repositories and databases that are
widely accessible by investigators in the scientific community.  The data
management facility and cell repository supported by NIMH contractors are such
resources.

The NIMH Human Genetics Initiative employs procedures by which data and
biological materials are widely disseminated to qualified investigators in the
scientific community.  These are described on the Web at http://
zork.wustl.edu/nimh/NIMH_initiative/NIMH%20Human%20Genetics%20Initiative%20
Access%20Information.htm.  It is preferable that the procedures for
determining access and for disseminating data and materials are comparable to
those currently employed in the NIMH Human Genetics Initiative.  This is
essential to pooling of data and materials collected and produced in grants
funded under this RFA with existing resources widely distributed to the
scientific community.

It is expected that the investigator's data sharing plan will include the
following elements: (1) the creation of comprehensive and verified databases that
contain all clinical, diagnostic, pedigree structure, and genotypic information
collected and produced in the grant; (2) the establishment of cell lines, from
which DNA will be extracted and stored, for all subjects studied from whom blood
samples have been obtained; (3) mechanisms by which all databases and biological
materials (DNA samples, cell lines) are widely distributed to qualified
investigators in the scientific community; (4) a protocol and criteria for wide
dissemination of these data and materials; (5) a timetable for distribution; and
(6) an assurance that data and biological materials are disseminated in a manner
comparable to existing protocols and procedures for distributing such data and
materials in the NIMH Human Genetics Initiative.  The initial review group will
comment on the proposed plan for sharing and data access.  The plan will be
considered part of the scientific methodology for carrying out the research and,
as such, the adequacy of the plan will be considered by NIMH staff in determining
whether the grant shall be awarded.  The sharing plan as approved, after
negotiation with the applicant when necessary, will be a condition of the award. 
Evaluation of renewal applications will include assessment of the effectiveness
of data and biological material release.

After extensive discussion with mental health and human genetics researchers and
advocacy members, the Genetics Workgroup of the National Advisory Mental Health
Council (NAMHC) recommended that NIMH should draft a policy that provides for the
sharing of genetic materials after a 12- to 18-month proprietary period.  It was
also recommended that this policy include all elements of the guidelines
developed by the NIH and the Department of Energy (DOE) to address the special
needs of genome research.  These guidelines call for material and information
from genome research to be made available within six months of the time the data
or materials are collected, and are available on the Web at
http://www.nhgri.nih.gov/Grant_info/Funding/Statements/data_release.html.

Adherence with the time frame recommended by the NAMHC's Genetics Workgroup is
highly desirable.  This is expected to result in all data being released to the
scientific community by the end of the four-year award period, even if a
competing renewal application is submitted.  More rapid sharing is encouraged. 
Requests for exemptions or extensions will require compelling justification and
will be fully evaluated through peer review and by program staff. 

8) Quality Control

The verification of family structure and updating of diagnostic and other
clinical information is essential to the conduction of genetic analyses. 
Applicants are expected to maintain an electronic database of clinical, family
structure, and diagnostic information that will be verified and updated
throughout the project.  Rigorous quality control procedures will permit the
applicant to create up-to-date diagnostic and pedigree structure information. 
An essential element of the quality control procedure is to verify this family
structure and diagnostic information.  Final information - consisting of family
structure information obtained after genotyping, updated final best estimate
diagnostic data, and other updated clinical information - is expected to be
included in the investigator's data sharing plan.  In addition, high-quality cell
lines and DNA are expected to be included in the investigator's data sharing
plan.

9) Human Subjects Issues

Proper safeguards are required to protect the welfare and rights of subjects who
participate in genetic research.  Subjects who participate in research projects
funded under this RFA need to be fully informed that data collected from them
will be rendered anonymous and will be distributed by NIMH to qualified
scientific investigators in the wider research community.  Subjects also need to
be informed that some of these qualified investigators may have commercial
interests.  As a result of research supported under this RFA and of research
subsequently conducted on these data, it is possible that enough information
eventually might be developed to allow individuals to be identified and,
consequently, become subject to any risk(s) that might arise as a result of that
identification.  Applicants should address any special human subjects issues that
arise as a result of the proposed research.

NIMH, in consultation with the NIH Office of the General Counsel (OGC) and the
Office for Protection From Research Risks (OPRR), has developed a model consent
form for human genetic research.  This form will be provided to applicants whose
projects are funded under this RFA.  This may then serve as a template that is
subject to modification and/or approval by local institutional review boards. 
It is expected that the applicant's approved consent form address the following:
(1) disclosure that biological materials (DNA and cell lines) and clinical data
will be stored at a central data management/laboratory facility, as part of a
national resource of data and materials distributed by NIMH for the genetic
analysis of the disease under investigation; (2) assurance that such data will
be provided to a central facility without personal identifiers; (3) disclosure
that analyses of these data will be conducted by other scientists currently not
included within the current research team; and (4) disclosure that there is no
plan to provide subjects with any financial benefits from commercial products
derived from the data.  NIMH intends to review the consent forms and IRB approval
for all projects prior to funding under this RFA.

Post-Award Management

During the course of the project period, while the original approved scope of
work must be maintained, it is anticipated that technologies will improve and the
rate of progress and focus of work supported by the grant(s) may change. 
Accordingly, it is expected that the principal investigator(s) will make many
necessary adjustments in scientific direction to accommodate such changes.  Most
importantly, it is essential to the achievement of the study aims for recruitment
to proceed as rapidly and efficiently as possible.  Thus, principal investigators
may need to be flexible in modifying recruitment strategies to assure that the
targeted sample size is achieved within a three-year period.  During the course
of the award period, the principal investigators may be invited to meet with NIMH
program staff in the Washington, D.C. area, to review scientific progress.  Other
scientists external to and knowledgeable about these studies may also be invited
to participate.  Budget requests should include travel funds for the principal
investigator to meet annually in the Washington, D.C. area, should such meetings
be advisable. 

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
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 was published in the Federal Register of March 28, 1994 (FR 59
14508-14513) and in the NIH Guide for Grants and Contracts, Vol. 23, No. 11,
March 18, 1994, available on the web at:
http://grants.nih.gov/grants/guide/notice-files/not94-105.html

NIH POLICY AND GUIDELINES ON THE INCLUSION OF CHILDREN AS PARTICIPANTS IN
RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of NIH that children (i.e., individuals under the age of 12)
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 submitted for receipt dates
after October 1, 1998.

All investigators proposing research involving human subjects should read the
"NIH Policy and Guidelines on the Inclusion of Children as Participants in
Research Involving Human Subjects" that was published in the NIH Guide for Grants
and Contracts, March 6, 1998, and is available on the World Wide Web at
http://grants.nih.gov/grants/guide/notice-files/not98-024.html.

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.

LETTER OF INTENT

Prospective applicants are asked to submit, by January 22, 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 NIMH staff to
estimate the potential review workload and avoid conflicts of interest in the
review.

The letter of intent is to be sent to:

Dr. Steven O. Moldin
Division of Basic and Clinical Neuroscience Research
National Institute of Mental Health
5600 Fishers Lane, Room 10C-26
Rockville, MD  20857
Telephone:  (301) 443-2037
FAX:  (301) 443-9890
Email:  smoldin@nih.gov

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 5/95) is to be used in applying
for these grants.  These forms are available at most institutional offices of
sponsored research and from the Division of Extramural Outreach and Information
Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910,
Bethesda, MD 20892-7910; telephone (301) 435-0714; fax (301) 480-0525; E-mail:
GrantsInfo@nih.gov.

The RFA label available in the PHS 398 (rev. 5/95) 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, "Molecular Genetics of Schizophrenia and Depression: RFA MH-99-005," must
be typed in section 2 of the face page of the application form and the YES box
marked.

Applicants submitting a collaborative R01 application must follow the
instructions and application procedures described in PAR-98-017, "Collaborative
R01s for Clinical Studies of Mental Disorders," which appeared in the December
19, 1997 issue of the NIH Guide on the Web at http://grants.nih.gov/grants/guide/pa-
files/PAR-98-017.html.  In these cases, this program announcement title and
number must also be typed in section 2 of the face page of the application form.

Submit a signed, typewritten original of the application, including the
checklist, and four 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)

One additional copy of the application must be sent directly to:

Dr. Steven O. Moldin
Division of Basic and Clinical Neuroscience Research
National Institute of Mental Health
5600 Fishers Lane, Room 10C-26
Rockville, MD  20857

Applications must be received by February 23, 1999.  One additional copy of the
application must be received by program staff at the address above by February
23, 1999.  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.  The applicants
should also ensure that their revised applications respond to the review criteria
by which applications in response to this RFA will be evaluated.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by CSR and for
responsiveness to this RFA by NIMH staff.  Incomplete applications will be
returned to the applicant without further consideration.  If the application is
not responsive to the RFA, NIH staff will 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.

Those applications that are complete and responsive to this RFA will be evaluated
for scientific and technical merit in accordance with the criteria stated below
by an appropriate peer review group.  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 will be
discussed and assigned a priority score.  All applications will receive a second
level of review by the NIMH National Advisory Council.

Review Criteria

The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health.  The
reviewers will comment on the following aspects of the application in their
written critiques in order to judge the likelihood that the proposed research
will have a substantial impact on the pursuit of these goals.  Each of the
criteria will be addressed and considered by the reviewers in assigning the
overall score weighting them as appropriate for each application.  Note that the
application does not need to be strong in all categories to be judged likely to
have a major scientific impact and thus deserve a high priority score.  For
example, an investigator may propose to carry out important work that by its
nature is not innovative but is essential to move a field forward. 

o Significance:  Does this study specify the large-scale data collection effort
needed to determine the chromosomal localization of genes that confer
susceptibility to schizophrenia or early-onset recurrent unipolar depression? 
Does the applicant propose to collect a new pedigree sample, and not one that has
been previously studied?  Is the scope of work for the molecular genetic studies
focused exclusively on efforts to establish the chromosomal locations of
susceptibility loci, and not focused on fine mapping (including the saturation
of regions of interest with multiple markers), sequencing, or mutation analyses?

o  Approach:  Are the conceptual framework, design, ascertainment strategy,
assessment/ diagnostic procedures, and targeted sample size adequate,
appropriate, and feasible to accomplish the specific aims of the project?  Does
the applicant have access to sufficient resources to obtain the targeted sample
size?  Is the projected sample size sufficient to identify chromosomal regions
that harbor genes conferring susceptibility to the disorder under investigation? 
Does the applicant acknowledge potential problems in recruitment and consider
alternatives?  Is the scientific and technical merit of the proposed research
sufficient to advance the objectives of the RFA?  Is phenotyping being done in
a highly reliable, rigorous and comprehensive fashion, permitting the
establishment of diagnoses in multiple systems?  Is the applicant collecting data
on a broad range of symptoms and psychopathology, which may form the basis for
future studies that correlate phenotypic characteristics (and not just existing
diagnoses) to underlying genotypes?  Will genotyping be accomplished in a rapid
and cost-effective fashion?

o  Innovation and originality:  Does the project employ novel and creative
concepts and approaches for large-scale pedigree ascertainment and collection? 
Does the applicant employ novel methods for integrating data from multiple
sources to establish best estimate psychiatric diagnoses?  Does the project
foster new analytic approaches for identifying chromosomal regions of interest?

o Investigator:  Are the principal investigator and staff 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?  Is there
a multidisciplinary, collaborative research effort that includes representation
of the scientists needed for large-scale data collection and genetic analysis
(e.g., clinicians, diagnosticians, molecular geneticist, statistical geneticist,
bioinformatics specialist)?

o Scalability:  What is the likelihood that the data collected in the project
will be rapidly collected and available for analysis by a broad range of
biomedical investigators?

o Integration with other resources:  Are the plans adequate to integrate the data
and materials collected with those collected in the NIMH Human Genetics
Initiative?  Are comprehensive diagnostic assessment instruments and software
currently available utilized in the project?  Are DSM-IV criteria used to define
a minimum number of affected individuals with the core phenotype, for the purpose
of pedigree ascertainment?

o Exportability and accessibility:  Will the applicant's data management plans
permit creation of a highly efficient and organized electronic database?  Will
these plans facilitate the creation of databases containing final best estimate
diagnostic data, family structure information, and clinical data, as well as the
establishment of cell lines and DNA samples, that will be widely disseminated to
qualified investigators in the scientific community?  Are data provided to a data
management facility and cell repository at frequent and regular intervals, in a
highly exportable format that will permit rapid integration with comparable
resources maintained by NIMH?  Does the investigator's quality control plans
assure that databases provided to the scientific community are accurate and up-
to-date, and that high-quality cell lines and DNA samples may be created?

o  Environment:  Does the scientific environment in which the work will be done
contribute to the probability of success?  Do the proposed methods take advantage
of unique features of the scientific environment or employ useful
multidisciplinary, collaborative arrangements?  Is there evidence of
institutional support?  Does the applicant have access to sufficient clinical
resources to obtain the targeted sample size?

o  Budget and duration:  Are the proposed budget and duration appropriate in
relation to the proposed research?  Are the costs and time frames for molecular
and statistical analyses generally comparable to those at CIDR and other high-
throughput genotyping facilities?  Are the costs, time frames, and abilities to
widely distribute data and materials to qualified investigators in the scientific
community for the cell repository and data management facility chosen by the
applicant to create databases, establish cell lines, and extract DNA generally
comparable to those that would be obtained by using existing NIMH resources?

o Adequacy of plans to include both genders and minorities and their subgroups: 
Are both genders and minority groups represented, or is their exclusion
scientifically justified?

o Adequacy of plans to include children:  Are children represented, or is their
exclusion scientifically justified?

The initial review group will also examine the provisions for the protection of
human and animal subjects, the safety of the research environment, and
conformance with the NIH Guidelines for the Inclusion of Women and Minorities as
Subjects in Clinical Research.

The availability of special opportunities for furthering methods development
through the use of unusual talent resources or environmental conditions in other
countries which are not readily available in the United States, or which provide
augmentation of existing U.S. resources, will be considered in the review.

In addition, the following specific issues will be evaluated in an application
for a Collaborative R01 for the Clinical Studies of Mental Disorders (CMSD):

o  The scientific rationale for the overall collaborative CSMD, including
scientific, technical, or medical significance, originality, and innovativeness
of proposed interactive program.

o  The plan for management (e.g., steering committee or other governing body) of
the project across sites, including coordination, decision making, quality
control, and resolution of disagreements.

o  Availability of the resources at each site necessary to carry out the
research.

o  Appropriateness of the proposed budget and duration at each site.

o  Procedures to ensure access to data, sharing of data and resources (both
within and outside the collaborative CSMD group), publication rights, and means
of arbitrating and resolving publication disagreements among the participating
investigators.

o  Adequacy of plans to include both genders and minorities and their subgroups
as appropriate for the scientific goals of the research.  Plans for the
recruitment and retention of subjects will also be evaluated.

AWARD CRITERIA

The earliest anticipated date of award is September 30, 1999.  Subject to the
availability of funds, and consonant with the priorities of this RFA, NIMH will
provides funds for a project period not to exceed 4 years.  Factors that will be
used to make award decisions are as follows:

o Quality of the proposed project, as determined by rigorous scientific peer
review; 

o Feasibility of the proposed large-scale data collection effort, within a three-
year time frame;

o Cost effectiveness and rapidity of the proposed genotyping work and genetic
analyses;

o Adequacy of plans to assure that data and biological materials collected and
produced in the project can be easily integrated with comparable data and
materials collected in the NIMH Human Genetics Initiative;

o Adequacy of plans to make all data and biological materials collected and
produced as a result of the proposed research widely accessible in a timely
manner to the biomedical research community; 

o Availability of funds.

INQUIRIES

Written, telephone, and E-mail inquiries concerning this RFA are strongly
encouraged.  The opportunity to clarify any issues or questions from potential
applicants is welcome.  Direct inquiries regarding programmatic issues to:

Dr. Steven O. Moldin
Division of Basic and Clinical Neuroscience Research
National Institute of Mental Health
5600 Fishers Lane, Room 10C-26
Rockville, MD  20857
Telephone:  (301) 443-2037
FAX:  (301) 443-9890
Email:  smoldin@nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Diana S. Trunnell
Grants Management Branch
National Institute of Mental Health
5600 Fishers Lane, Room 7C-08
Rockville, MD  20857
Telephone:  (301) 443-2805
FAX:  (301) 443-6885
Email:  Diana_Trunnell@nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.242.  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. 
Awards will be administered under PHS grants policy as stated in the NIH Grants
Policy Statement (October 1, 1998).

PHS strongly encourages all grant and contract recipients to provide a smoke-free
workplace and promote the nonuse 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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