GENETICS OF NEUROBEHAVIORAL DISORDERS IN EXISTING SAMPLES

Release Date:  June 23, 1999

PA NUMBER:  PA-99-120

National Institute of Mental Health
National Institute of Child Health and Human Development

THIS PA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS.  THIS PA INCLUDES
DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED
WHEN PREPARING AN APPLICATION IN RESPONSE TO THIS PA.

PURPOSE

The purpose of this Program Announcement (PA) is to encourage applications for
multidisciplinary, collaborative genetic research projects, employing state-
of-the-art diagnostic procedures and analytic methods, to integrate different
pedigree data sets that have already been collected for the study of a given
neurobehavioral disorder.  Applications will implement the assembling of data
from multiple research groups for combined analysis, and will focus on one of
the following: attention-deficit hyperactivity disorder, bipolar disorder or
other related mood disorders, recurrent early-onset depression, eating
disorders, obsessive-compulsive disorder or other anxiety disorders, panic
disorder, schizophrenia or other psychotic disorders, personality disorders,
or Tourette's syndrome.

The goal will be to assemble a large data set that has adequate statistical
power for identifying genomic regions that may harbor loci conferring
susceptibility to the neurobehavioral disorder under investigation.  Projects
are solicited to: (1) uniformly apply the same standardized diagnostic
criteria and assessment procedures across the pooled pedigree sets, in order
to establish lifetime best estimate final diagnoses and comprehensively assess
psychopathology in previously ascertained affected individuals and their
relatives; and (2) conduct genome-wide analyses to establish the chromosomal
localization of disease susceptibility loci.  Data and biological materials
collected and produced in projects funded under this PA will augment pre-
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 PA, Genetics of Neurobehavioral
Disorders in Existing Samples, is related to the priority area of Mental
Health and Mental Disorders.  Potential applicants may obtain a copy of
"Healthy People 2000" at http://odphp.osophs.dhhs.gov/pubs/hp2000/.

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 creation and analysis of clinically well-
characterized samples of sufficient size for linkage analyses and for linkage
disequilibrium mapping studies in genetically isolated populations studied
previously 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 PA will use the National Institutes of Health (NIH) research project
grant (R01), conceptualized either as a single R01 project or as a multi-site
collaborative R01 research project. Further information on collaborative R01
research project application procedures, which will apply to both NIMH and
NICHD, may be found in a program announcement (PAR-98-017) entitled,
"Collaborative R01s for Clinical Studies of Mental Disorders" in the December
19, 1997 issue of the NIH Guide at
http://www.nih.gov/grants/guide/pa-files/PAR-98-017.html, and also below under
APPLICATION PROCEDURES.

The total project period for an application submitted in response to this PA
may not exceed 5 years.  Because the nature and scope of the research proposed
in response to this PA may vary, it is anticipated that the size of an award
will also vary.

Specific application instructions have been modified to reflect "MODULAR
GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH.
Complete and detailed instructions and information on Modular Grant
applications can be found at
http://www.nih.gov/grants/funding/modular/modular.htm

RESEARCH OBJECTIVES

Background

Genes contribute to virtually every human disease by conferring susceptibility
or resistance, affecting the severity or progression of disease, and
interacting with environmental factors that modify disease course and
expression.  Much of current biomedical research is based upon the expectation
that understanding the genetic basis of disease will revolutionize diagnosis,
treatment, and prevention.  Tremendous advances have occurred in mapping and
cloning genes for diseases that follow Mendelian patterns in families.  In
contrast, the discovery of genes that influence susceptibility to more common
neurobehavioral disorders like attention-deficit hyperactivity disorder,
schizophrenia, and bipolar disorder has proceeded more slowly.  The etiologies
of these disorders are highly complex, with disease susceptibility likely
influenced by multiple genes of small relative effect and environmental
factors.

Such complexities present considerable challenges for genetic inquiry.  While
molecular genetic studies have implicated several chromosomal regions as
harboring loci that confer susceptibility to several neurobehavioral
disorders, the magnitude of the statistical evidence and the failure to
convincingly replicate demonstrate that these are clearly not confirmed,
convincing findings.  Given the magnitude of the gene effects that likely
influence susceptibility to complex diseases like neurobehavioral disorders,
chromosomal localization of a given gene may not be possible in data sets of
the size collected in most individual research projects.

Collaborative research by consortia of investigators, as well as ad hoc meta-
analyses of some pooled data sets, have been conducted but thus far have
yielded inconclusive results.  This may reflect one or more of the following:
methodologic differences in ascertaining patients and pedigrees across
different populations, varying diagnostic criteria, locus heterogeneity,
alternative procedures for typing markers in different laboratories,
genotyping differences across laboratories, or a persistent lack of
statistical power.  Researchers have not yet undertaken the assembly of
multiple data sets from all or most of the data collection efforts for a
particular neurobehavioral disorder conducted worldwide, in order to uniformly
apply the same phenotyping and genotyping procedures and conduct a genome-wide
search for disease susceptibility genes.

Objectives and Scope

Many family-genetic studies of neurobehavioral disorders have been or are
currently being conducted by groups of investigators who separately analyze
their data.  Scientific advancement and ultimate success in identifying
disease susceptibility loci likely will require integration of data to obtain
samples of sufficient size that have high power for the detection of
susceptibility loci of small relative effect.  This PA will support
collaborative efforts by a single principal investigator, or by self-selected
teams of principal investigators working collaboratively, to achieve state-of-
the-art clinical characterization and assembly of an integrated data set on a
scale unprecedented in molecular genetic studies of neurobehavioral disorders. 
This will include establishment of lifetime best estimate final diagnoses,
comprehensive assessment of psychopathology including the developmental
assessment of disorders, and the application of high-throughput genotyping
efforts.

Applications will permit the assembling and coding of data from multiple
research groups for combined analysis, and will focus on one of the following:
attention-deficit hyperactivity disorder, bipolar disorder or other related
mood disorders, recurrent early-onset depression, eating disorders, obsessive-
compulsive disorder or other anxiety disorders, panic disorder, schizophrenia
or other psychotic disorders, personality disorders, or Tourette syndrome.

Inclusion of all (or most) genetic research groups worldwide who have
collected pedigrees for analysis of a given disease - in order to minimize the
bias that results from the preferential selection of groups with positive
findings - is highly desirable.  State-of-the-art, whole-genome analyses in
such assembled data sets will be supported under this PA, and will have
tremendous potential for identifying chromosomal regions that harbor
susceptibility loci.

This PA will support assembly of independent datasets of pedigrees containing
multiple affected individuals that were collected for a family-genetic or
linkage study in an outbred population, or a linkage disequilibrium mapping
study in a genetically isolated population.  This also may include small
nuclear families (affected individuals and their parents) that were collected
for use in family-based association analyses.  The scope of the proposed
research will likely include a multidisciplinary team comprised of clinicians,
diagnosticians, molecular geneticists, and statistical geneticists.

Research activities to be supported include, but are not limited to, the
following: phenotypic re-classification of subjects across data sets using the
same diagnostic instrument and sets of objective criteria; drawing of blood
for the creation of cell lines and extraction of DNA; re-consenting of
subjects, to inform them of the investigator's data sharing plans (see below);
statistical genetic analyses of a large assembled data set; and high-
throughput genotyping on a common marker set, as conducted by a single,
centralized laboratory.

It is scientifically desirable to avoid the creation of a series of partially
overlapping pedigree data sets.  A major difficulty is that this would
frustrate efforts to attempt independent replications of preliminary findings. 
Thus, it is expected that a given pedigree set will be represented in only one
application submitted under this PA.  Schizophrenia or bipolar disorder
pedigrees already collected for the NIMH Human Genetics Initiative (see below
in Plan for Dissemination of Data and Biomaterials under SPECIAL REQUIREMENTS)
may be included in an application, but it is expected that these will
represent no more than 15 percent of pedigrees in the assembled data set.

This PA will not support the ascertainment of new pedigrees.  In addition,
genetic analyses to be conducted in projects funded under this PA will
exclusively 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.

Research topics of interest include, but are not limited to, the following:

o  Integration of extended pedigree data sets collected in genetically
isolated populations, for linkage disequilibrium mapping studies.

o  Integration of pedigrees data sets containing affected sibling pairs (ASPs)
or multiple affected individuals, for linkage analyses.

o  Integration of data sets comprised of small nuclear families that have an
affected individual and his two parents, especially those also containing at
least one ASP, for family-based association analyses.

The assembly of data sets from multiple research studies, including the re-
contacting of subjects for clinical characterization and blood draws, presents
numerous complexities.  Several methodological problems could significantly
reduce the power to detect linkage or linkage disequilibrium, and thwart
efforts to identify disease susceptibility loci.  For example, efforts to
replicate results and combine data across different samples may be hampered if
diagnostic criteria are widely variable across pooled pedigree data sets. 
Applications will minimize such problems by simultaneously incorporating
several methodologic strengths that include, but are not limited to, the
following:

o  Application of structured diagnostic criteria to establish a final best
estimate lifetime diagnosis.  State-of-the-art methods permit the synthesis of
information collected from a structured diagnostic interview, medical records,
and multiple family informants.  Subjects may be diagnosed in any one of
multiple systems (e.g., ICD-10), but a DSM-IV diagnosis also should be
established to permit pooling of these data with other pre-existing NIMH
resources.

o  Comprehensive clinical characterization through the use of a highly
reliable diagnostic instrument, e.g., the Diagnostic Interview of Children and
Adolescents-DSM-IV (DICA-IV) or the Diagnostic Interview for Genetic Studies
(DIGS).  The DIGS was developed in the NIMH Human Genetics Initiative (blank
forms and training and code manuals are available at 
http://zork.wustl.edu/nimh/digs/newpage11.htm).

o  Entry of comprehensive phenotypic data into a computerized database that
may be easily shared among collaborators.  For example, all of the data
collected from the DIGS interview may be input into such a database via a
Windows 95 operating system graphical user interface (available at 
http://zork.wustl.edu/nimh/digs/newpage11.htm).

o  Creation of lymphoblastoid cell lines, in order to establish an infinitely
renewable source of DNA for current and future genetic analyses.  If requested
by the investigator, NIMH will provide no-cost access to a cell repository to
facilitate data sharing; high-quality cell lines will be created upon receipt
of blood samples, and DNA will be extracted and provided to applicants at no
cost.

SPECIAL REQUIREMENTS

Application to NIH Genotyping Facility

One resource available to applicants is the Center for Inherited Disease
Research (CIDR), a centralized facility established to provide high-throughput
genotyping and statistical genetics services.  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).  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 and NICHD are supporting NIH Institutes, research
projects funded under this PA are eligible for CIDRs special introductory rate
of no-cost genotyping.  Further information about CIDR may be found 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, and to obtain the results
of the CAC evaluation prior to submission of an application in response to
this PA.  An approval letter from the CAC may then be included in the
application.  Regardless of the CAC evaluation, investigators may 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 the 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 or less per genotype, appears
reasonable.  It is anticipated that technologies will improve and the rate of
work and associated cost will change.

Plan for Dissemination of Data and Biomaterials

The sharing of biomaterials, 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, located at
https://grants.nih.gov/grants/guide/notice-files/not96-184.html). 
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 (http://zork.wustl.edu/nimh/
NIMH_initiative/NIMH_initiative_link.html).

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 PA to develop and propose detailed plans for sharing the data
and biomaterials 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 PA should be placed in common, public
cell repositories and databases that are widely accessible by investigators in
the scientific community.  A data management facility and cell repository
maintained by an NIMH contractor are such resources.

The NIMH Human Genetics Initiative employs procedures by which data and
biomaterials 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%20Access%20Information.htm.  It is preferable that the
procedures for determining access and for disseminating data and biomaterials
are comparable to those currently employed in the NIMH Human Genetics
Initiative.  This is essential to pooling of data and biomaterials collected
and produced in grants funded under this PA with pre-existing resources
widely distributed to the scientific community.

It is expected that the investigator's data sharing plan will specify 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 biomaterials (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 biomaterials; (5) a
timetable for distribution; and (6) an assurance that data and biomaterials
are disseminated in a manner comparable to pre-existing protocols and
procedures for distributing such data and biomaterials 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
methodology for carrying out the research and, as such, the adequacy of the
plan will be considered by NIH 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
biomaterial 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
at http://www.nhgri.nih.gov/Grant_info/Funding/Statements/data_release.html

Adherence with the time frame recommended by the NAMHC 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.

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, cell lines and DNA are expected to be included in
the investigator's data sharing plan.

Adequate Informed Consent Procedures

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 for use in projects funded under this PA.  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 biomaterials (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.  NIH intends to review the consent forms and IRB approval for all
projects prior to funding under this PA.

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 at
http://www.nih.gov/grants/guide/1994/94.03.18/notice-nih-guideline008.html.

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 at
http://www.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.

APPLICATION PROCEDURES

Research grant application form PHS 398 (rev. 4/98) is to be used in applying
for these grants.  Application kits 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) 710-0267, Email:
[email protected].  Applications are also available at
http://www.nih.gov/grants/forms.htm.

The modular grant concept establishes specific modules in which direct costs
may be requested as well as a maximum level for requested budgets.  Only
limited budgetary information is required under this approach.  The
just-in-time concept allows applicants to submit certain information only when
there is a possibility for an award.  It is anticipated that these changes
will reduce the administrative burden for the applicants, reviewers and
Institute staff.  The research grant application form PHS 398 (rev. 4/98) is
to be used in applying for these grants, with the modifications noted below.

BUDGET INSTRUCTIONS

Modular Grant applications will request direct costs in $25,000 modules, up to
a total direct cost request of $250,000 per year.  (Applications that request
more than $250,000 direct costs in any year must follow the traditional PHS
398 application instructions.)  The total direct costs must be requested in
accordance with the program guidelines and the modifications made to the
standard PHS 398 application instructions described below:

PHS 398

o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in
$25,000 increments up to a maximum of $250,000) and Total Costs [Modular Total
Direct plus Facilities and Administrative (F&A) costs] for the initial budget
period Items 8a and 8b should be completed indicating the Direct and Total
Costs for the entire proposed period of support.

o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4
of the PHS 398.  It is not required and will not be accepted with the
application.

o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the
categorical budget table on Form Page 5 of the PHS 398.  It is not required
and will not be accepted with the application.

o NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative
page.  (See http://www.nih.gov/grants/funding/modular/modular.htm for sample
pages.)  At the top of the page, enter the total direct costs requested for
each year.  This is not a Form page.

o Under Personnel, List key project personnel, including their names, percent
of effort, and roles on the project.  No individual salary information should
be provided.  However, the applicant should use the NIH appropriation language
regarding the salary cap and the NIH policy for graduate student compensation
in developing the budget request.

For Consortium/Contractual costs, provide an estimate of total costs (direct
plus facilities and administrative) for each year, each rounded to the nearest
$1,000.  List the individuals/organizations with whom consortium or
contractual arrangements have been made, the percent effort of key personnel,
and the role on the project.  Indicate whether the collaborating institution
is foreign or domestic.  The total cost for a consortium/contractual
arrangement is included in the overall requested modular direct cost amount. 
Include the Letter of Intent to establish a consortium.

Provide an additional narrative budget justification for any variation in the
number of modules requested.

o BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by
reviewers in the assessment of each individual's qualifications for a specific
role in the proposed project, as well as to evaluate the overall
qualifications of the research team.  A biographical sketch is required for
all key personnel, following the instructions below.  No more than three pages
may be used for each person.  A sample biographical sketch may be viewed at:
http://www.nih.gov/grants/funding/modular/modular.htm

- Complete the educational block at the top of the form page;
- List position(s) and any honors;
- Provide information, including overall goals and responsibilities, on
research projects ongoing or completed during the last three years.
- List selected peer-reviewed publications, with full citations;

o CHECKLIST - This page should be completed and submitted with the
application.  If the F&A rate agreement has been established, indicate the
type of agreement and the date.  All appropriate exclusions must be applied 
in the calculation of the F&A costs for the initial budget period and all
future budget years.

o The applicant should provide the name and phone number of the individual to
contact concerning fiscal and administrative issues if additional information
is necessary following the initial review.

APPLICATION PROCEDURES FOR COLLABORATIVE R01 PROJECTS

Applicants submitting a collaborative R01 project 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 at
http://www.nih.gov/grants/guide/pa-files/PAR-98-017.html.  In these cases,
this PA title and number must be typed in section 2 of the face page of the
application form, in addition to the PA title and number of the current PA
("PA-99-120: Genetics of Neurobehavioral Disorders in Existing Samples").

The collaborative R01 project requires more than one applicant
organization, although multiple campuses of a single institution are also
eligible (e.g., among the multiple campuses of a state university system).

It is conceivable that one or more collaborative R01 applications may be
continuations of currently funded IRPGs or separate (i.e., previously non-
collaborative) grants, with others being new (Type 1) R01s, all seeking
support to come under the umbrella of the collaborative R01 program.  In such
cases, the competing renewal (Type 2) applications will keep the same grant
number as usual. However, it is essential that the following information be
incorporated identically into all collaborative R01 applications:

1.  The application from each site must contain an OVERVIEW that is no longer
than two pages.  It should list the individual participating sites and provide
justification for applying as collaborative R01s.  This section should also
make clear the roles of each participating site.

2.  RESEARCH PLAN - Section 2 A - D, should describe those aspects of the
project that are common to all sites of the collaboration. Investigators
should use this section to describe the research procedures or protocol, the
study population from which samples are drawn, resources, data analyses, and
any other characteristics that support each site's importance to the overall
project.  Where there are even minor variations in the research plan, these
should be highlighted in a subsection of Section 2 D with the heading
"ELEMENTS UNIQUE TO THIS SITE."

3.  Applications must describe a feasible mechanism for scientific integration
of research procedures, overall managerial and administrative
responsibilities, and cross-site comparability of training to assure
reliability and quality control.  The PIs may or may not wish to designate a
Steering Committee or other decision making body, or identify one individual
as the contact person for the group as a whole, for purposes of NIH
correspondence. Plans for ensuring access to data by all sites, analytic
resources, publication and authorship rights, the possibility of public use
research materials and data, or other means of distributing research materials
to the wider scientific community, and a means of arbitrating disagreements on
publication and other issues should be found in this section of the
application.

4.  Any site that contracts out some portions of this work should list this
fact under "ELEMENTS UNIQUE TO THIS SITE," and provide a full description of
the nature, purpose and oversight of this contractual arrangement.  As per
instruction in the PHS 398 kit, the application may also contain an APPENDIX,
including up to 10 publications or other printed material; surveys,
questionnaires, data collection sets and clinical protocols; and original
glossy photographs provided that photocopies are also included within the 25
page limit of the research plan.

In accordance with NIH policy, incomplete applications will be returned by
CSR.

Revised collaborative R01 applications must include an Introduction and
highlight the changes made in the Research Plan in response to the previous
critique and describe in item (I) how the delay in initiating the
collaboration will be managed.  This is particularly important if some
projects in the collaborative R01 group were awarded and research on those
projects has already begun.

Applications not conforming to these guidelines will be considered
unresponsive to this PA and will be returned without further review.

The PA title and number, "PA-99-120: Genetics of Neurobehavioral Disorders in
Existing Samples," must be typed on line 2 of the face page of the application
form, and the YES box must be marked.

Investigators who submit an individual R01 application requesting direct costs
of $500,000 or more for any one year, and investigators as a group who submit
a collaborative R01 application requesting an overall total direct cost budget
of $500,000 or more for any one year, must contact Institute program staff
before submitting the application, i.e., as plans for the study are being
developed (See INQUIRIES, below).  Furthermore, the applicant must obtain
agreement from Institute staff that the Institute will accept the application
for consideration for award.  Finally, the applicant must identify, in a cover
letter sent with the application, the staff member and Institute who agreed to
accept assignment of the application.  This policy requires an applicant to
obtain agreement for acceptance of both any such application and any
subsequent amendment.  Refer to the NIH Guide for Grants and Contracts, March
20, 1998 on the World Wide Web at
http://www.nih.gov/grants/guide/notice-files/not98-030.html.

Submit a completed original application, including the Checklist, and five
legible 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)

REVIEW CONSIDERATIONS

Applications will be assigned on the basis of established PHS referral
guidelines.  Applications that are complete will be evaluated for scientific
and technical merit by an appropriate peer review group convened in accordance
with the standard NIH peer review procedures.  As part of the initial merit
review, all applications will receive a written critique and undergo a process
in which only those applications deemed to have the highest scientific merit,
generally the top half of applications under review, will be discussed,
assigned a priority score, and receive a second level review by the
appropriate national advisory council or board, when applicable.

Review Criteria

The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health.  In
the written review, comments on the following aspects of the application will
be made in order to judge the likelihood that the proposed research will have
a substantial impact on the pursuit of these goals.  Each of these criteria
will be addressed and considered in the assignment of the overall score:

(1) Significance.  Does this study address an important problem? If the aims
of the application are achieved, how will scientific knowledge be advanced?
What will be the effect of these studies on the concepts or methods that drive
this field?

(2) Approach.  Are the conceptual framework, design, methods, and analyses
adequately developed, well integrated, and appropriate to the aims of the
project? Does the applicant acknowledge potential problem areas and consider
alternative tactics?

(3) Innovation.  Does the project employ novel concepts, approaches or method?
Are the aims original and innovative? Does the project challenge existing
paradigms or develop new methodologies or technologies?

(4) Investigator.  Is the investigator appropriately trained and well suited
to carry out this work? Is the work proposed appropriate to the experience
level of the principal investigator and other researchers (if any)?

(5) Environment.  Does the scientific environment in which the work will be
done contribute to the probability of success? Do the proposed experiments
take advantage of unique features of the scientific environment or employ
useful collaborative arrangements? Is there evidence of institutional support?

In addition, the adequacy of plans to include both genders, minorities and
their subgroups, and children as appropriate for the scientific goals of the
research will be reviewed.  Plans for the recruitment and retention of
subjects will also be evaluated.

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.

AWARD CRITERIA

Applications will compete for available funds with all other recommended
applications. 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 assembling of data from multiple pre-existing
pedigree sets, to form a large sample of sufficient statistical power for the
genetic analysis of a given neurobehavioral disorder;

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

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

o  Adequacy of plans to make all data and biomaterials 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 PA 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 Neuroscience and Basic Behavioral Science
National Institute of Mental Health
6001 Executive Boulevard, Room 7189, MSC 9643
Bethesda, MD 20892-9643
Telephone: (301) 443-2037
Fax: (301) 443-9890
Email: [email protected]

Dr. Lisa Freund
Child Development and Behavior Branch
National Institute of Child Health and Human Development
Building 6100, Room 4B05D
9000 Rockville Pike, MSC 7510
Bethesda, MD 20892-7510
Telephone:  (301) 435-6879
Fax:  (301) 480-7773
Email:  [email protected]

Direct inquiries regarding fiscal matters to:

Ms. Diana S. Trunnell
Grants Management Branch
National Institute of Mental Health
6001 Executive Blvd., Room 6115, MSC 9605
Bethesda, MD 20892-9605
Telephone: (301) 443-2805
Fax: (301) 443-6885
Email:  [email protected]v

Mr. Douglas E. Shawver
Grants Management Branch
National Institute of Child Health and Human Development
Building 6100, Room 8A17F
9000 Rockville Pike, MSC 7510
Bethesda, MD 20892-7510
Telephone:  (301) 435-6999
Fax:  (301) 402-0915
Email:  [email protected]

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.242 (NIMH) and 93.865 (NICHD).  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.

Return to Volume Index

Return to NIH Guide Main Index

	Office of Extramural Research (OER)			National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892			Department of Health and Human Services (HHS)