Release Date:  September 21, 2001

RFA:  RFA-MH-02-009

National Institute of Mental Health

Letter of Intent Receipt Date:  November 15, 2001
Application Receipt Date:       December 14, 2001



The National Institute of Mental Health (NIMH) invites research grant 
applications that apply recent advances in cognitive and affective science, 
measurement theory, and psychometrics to identify and assess biological and 
behavioral indicators related to the onset, progression, and treatment 
responsiveness of major mental disorders such as schizophrenia, bipolar 
disorder, unipolar major depression, and obsessive-compulsive disorder.  The 
results of this effort are expected to assist in future evaluations of novel 
pharmacologic and psychosocial interventions for mental illness symptoms and 
disabilities.  This Request for Applications (RFA) encourages research that 
will: (1) dissect currently defined mental disorder syndromes into component 
symptom clusters or dimensions; (2) select a specific symptom cluster or 
dimension (i.e., an illness module) for intensive analysis; (3) model the 
pathological mechanisms that underlie the selected clinical phenomenon; and 
(4) develop and test methods for assessing the sensory, cognitive, affective, 
and/or behavioral systems thought to underpin symptoms and functional 
impairments.  For these studies, measures of component symptoms and 
intermediate biological and behavioral processes must be psychometrically 
sound, interval-level, time-efficient, and suitable for tracking changes in 
functioning as a repeated measure over time, or in response to therapeutic 
intervention.  Collaborations are encouraged among researchers examining basic 
behavioral processes (e.g., cognition, emotion, motivation); clinical 
investigators studying the etiology, course, and psychosocial treatment of 
mental and behavioral disorders; psychopharmacologists; and experts in 
contemporary measurement theory.    


The Public Health Service (PHS) is committed to achieving the health promotion 
and disease prevention objectives of "Healthy People 2010," a PHS-led national 
activity for setting priority areas.  This RFA, Modular Phenotyping for Major 
Mental Disorders, is related to one or more of the priority areas.  Potential 
applicants may obtain a copy of "Healthy People 2010" at


Applications may be submitted by domestic and foreign, for-profit and non-
profit organizations, public and private, such as universities, colleges, 
hospitals, laboratories, units of State and local governments, and eligible 
agencies of the Federal government.  Racial/ethnic minority individuals, 
women, and persons with disabilities are encouraged to apply as Principal 


This RFA will use the National Institutes of Health (NIH) Research Project 
Grant (R01) award mechanism.  Responsibility for the planning, direction, and 
execution of the proposed project will be solely that of the applicant.  The 
total project period for an application submitted in response to this RFA may 
not exceed 5 years.  This RFA is a one-time solicitation.  Future unsolicited 
competing continuation applications will compete with all investigator-
initiated applications and be reviewed according to the customary peer review 
procedures.  The anticipated award date is July 1, 2002.

Specific application instructions have been modified to reflect "MODULAR 
GRANT" and "JUST-IN-TIME" streamlining efforts that have been adopted by the 
NIH.  Complete and detailed instructions and information on Modular Grant 
applications have been incorporated into the PHS 398 (rev. 5/2001).  
Additional information on Modular Grants can be found at


The NIMH intends to commit approximately $1,500,000 in FY 2002 to fund 4 to 6 
new and/or competitive continuation grants in response to this RFA.  An 
applicant may request a project period of up to 5 years and a budget for 
direct costs of up to $500,000 per year.  Because the nature and scope of the 
research proposed may vary, it is anticipated that the size of each award will 
also vary.  Although the financial plans of the NIMH provide support for this 
program, awards pursuant to this RFA are contingent upon the availability of 
funds and the receipt of a sufficient number of meritorious applications.

Applicants requesting up to $250,000 will use the modular grant application 


The past two decades have witnessed substantial progress in the diagnosis and 
treatment of mental disorders such as unipolar major depression, bipolar 
illness, and schizophrenia.  Current syndromal definitions of these disorders, 
which emphasize observable signs and symptoms, have improved the reliability 
of diagnoses in both treatment and research settings.  However, existing DSM-
IV criteria permit considerable heterogeneity within diagnostic cohorts, 
resulting in research samples that vary widely according to presenting 
features, chronicity, levels of disability, and treatment response.  Such 
within-group heterogeneity has been cited as a source of "noise" in studies 
that search for subtle genetic or neurobiological influences on mental illness 
vulnerability, onset, and progression.  Similarly, it has become evident that 
neither pharmacological nor psychosocial treatments target DSM categories 
broadly, but rather impact specific domains of symptoms that may cut across 
several diagnostic entities.  Progress in research areas like the genetics of 
mental disorders and experimental therapeutics would accelerate if methods 
were available to increase the phenotypic homogeneity of diagnostic samples 
and to define clinical treatment targets more precisely.  For example, 
alternative phenotypes based on circumscribed biological or behavioral 
deficits are more likely to represent a single gene effect than clinical 
syndromes themselves, and will serve as more powerful targets for genetic 
analysis than phenotypes based on clinical diagnoses.  Likewise, more 
effective pharmacologic and psychosocial treatments might be developed if 
interventions were targeted at the specific biobehavioral mechanisms that 
produced a particular symptom or functional impairment.  

A modular approach to illness phenotyping has been proposed as one method for 
reducing diagnostic heterogeneity within psychiatric samples.  This strategy 
calls for dissecting currently defined syndromes into simpler behavioral or 
biological components, thereby creating enriched samples for studying 
mechanisms that account for discrete symptoms or behavioral difficulties.  
Alternative phenotypes could be based on clinical subgroups within a syndrome, 
single traits found within an illness (e.g., mood dysregulation in affective 
disorders), or neurobiological deficits that correlate with clinical symptoms 
(e.g., disturbed attention regulation in schizophrenia).  To be useful for 
either genetic or treatment development studies, alternative phenotypes must 
be reproducible across different research sites, using identical measures and 
assessment methods to establish construct validity.  An important component of 
the validation process will be to utilize hypothesis-driven, experimental 
methods to discern and map the biobehavioral mechanisms and neurobiological 
systems that account for disturbed behavior.  

This RFA encourages studies that will apply modular phenotyping concepts to 
better understand and measure the component behavioral and/or biological 
subtypes that exist within and across clinical syndromes.  To be considered 
responsive to this RFA, applications must dissect currently defined 
psychiatric syndromes into component symptom dimensions, select a single 
illness module for intensive analysis, and propose a testable model for 
clarifying putatively pathogenic mechanisms.  A variety of research projects 
are permissible, ranging from studies that develop reliable and valid modular 
symptom rating scales, to investigations that measure the sensory, cognitive, 
affective, and other behavioral processes thought to underlie psychiatric 
symptoms and functional disabilities.  Of particular interest are studies that 
validate markers of aberrant behavioral or neurobiological processes in well-
defined clinical and comparison samples.  Equally important are studies that 
adapt experimental measures of symptoms and intermediate mechanisms for use in 
intervention development projects.  To be useful as an intermediate outcome 
marker in treatment development studies, modular symptom rating scales and 
biobehavioral measures must meet the demands of the clinical trial 
environment.  That is, candidate outcome measures must be: (1) 
psychometrically sound vis-a-vis validity and reliability indices; (2) scaled 
at an interval level to permit assessment of incremental change; (3) resistant 
to repeated testing effects; and (4) time efficient.  One goal of this RFA is 
to produce intermediate treatment outcome measures that are suitable for 
tracking changes in symptomatic or neurobiological functioning as a repeated 
measure over time, or in response to therapeutic intervention.  

Recent advances in cognitive and affective science suggest strategies that may 
illuminate the neural circuitry and intermediate biobehavioral operations that 
underpin disturbed perceptual, cognitive, and emotional functioning in 
schizophrenia, unipolar major depression, and bipolar disorder.  Likewise, new 
methodologies from quantitative and measurement sciences offer strategies for 
developing psychometrically sound tools for measuring these basic behavioral 
processes in clinical populations.  To capitalize on these advances, this RFA 
encourages collaborations among scientists who examine basic behavioral 
processes such as cognition, emotion, and motivation in normal individuals; 
clinical investigators who study the etiology, course, and psychosocial 
treatment of mental and behavioral disorders; psychopharmacologists; and 
experts in contemporary measurement theory.  Applications must feature the 
types of translational partnerships described in the report of the National 
Advisory Mental Health Council’s Behavioral Science Workgroup, "Translating 
Behavioral Science into Action" (

Below are examples of research areas and questions that could advance 
scientific knowledge of alternative phenotypes and the biobehavioral 
mechanisms that underpin DSM-IV symptom dimensions.  The list is not 
exhaustive, and it is expected that additional important research topics may 
be identified.
o  The validity of employing symptom complexes or traits, rather than 
diagnoses, as appropriate targets for genetic or treatment development studies 
must be demonstrated.  Construct validation strategies, such as empirical 
tests of convergent and discriminant validity, could be utilized for this 

o  Different strategies could be explored for deconstructing DSM-IV disorders 
into component modules.  Examples of illness modules that could be studied 
within diagnostic categories include laboratory-based measures of attention in 
attention-deficit/hyperactivity disorder and agitation in Alzheimer’s disease.  
Examples of symptom targets that cut across diagnostic entities include 
attention dysregulation, distractibility, and disturbed concentration in 
schizophrenia and affective disorders, and disturbed hedonic tone in 
schizophrenia and depression.  

o  New rating scales are required for assessing the component symptoms that 
have been proposed for affective disorders, e.g., mood lability, guilt and 
worthlessness, and loss of the capacity to experience pleasure (i.e., 
anhedonia).  Measurement development studies should incorporate recent 
advances in measurement theory and methods when evaluating a rating 
instrument’s psychometric characteristics (i.e., construct validity, internal 
consistency, inter-rater reliability, and test-retest stability), and 
screening properties (i.e., sensitivity, specificity, and predictive power).  

o  The mechanisms that control affect regulation in major depression and 
bipolar disorder are not well-understood.  Investigations that incorporate 
neuroscience methods for studying activation and termination of positive and 
negative mood states in normal individuals might illuminate how affect control 
processes fail in persons with mood disorders.  

o  Anhedonia, or the loss of the capacity to experience pleasure, is a core 
feature of schizophrenia.  The neurobiological basis for abnormal emotional 
processing in schizophrenia has not been explored in depth, but might be 
illuminated by applying neurocognitive tests and imaging procedures used to 
study hedonic experiences in normal individuals. 
o  Recent advances in the neuroscience of goal-directed behavior have helped 
to model the cognitive and motivational processes that underlie purpose and 
initiative in normal individuals.  These models could be applied to explore 
and test the neurobehavioral basis of avolition and apathy in schizophrenia.  

o  Further research is required to discern the pathophysiological processes 
that characterize disabling schizophrenia features like hallucinations, 
delusions, language disturbance, attention and memory deficits, and emotional 
blunting.  Better understanding of, and enhanced ability to measure, these 
phenomena would suggest new intermediate biological and behavioral targets for 
pharmacologic and psychosocial intervention.


It is the policy of the NIH that women and members of minority groups and 
their sub-populations must be included in all NIH-supported biomedical and 
behavioral research projects involving human subjects, unless a clear and 
compelling rationale and justification are provided indicating 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 
UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in 
Clinical Research," published in the NIH Guide for Grants and Contracts on 
August 2, 2000 (; 
a complete copy of the updated Guidelines are available at  The 
revisions relate to NIH defined Phase III clinical trials and require: a) all 
applications or proposals and/or protocols to provide a description of plans 
to conduct analyses, as appropriate, to address differences by sex/gender 
and/or racial/ethnic groups, including subgroups if applicable; and b) all 
investigators to report accrual, and to conduct and report analyses, as 
appropriate, by sex/gender and/or racial/ethnic group differences.


It is the policy of NIH that children (i.e., individuals under the age of 21) 
must be included in all human subjects research, conducted or supported by the 
NIH, unless there are scientific and ethical reasons not to include them.  
This policy applies to all initial (Type 1) applications 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 the following URL 

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


NIH policy requires education on the protection of human subject participants 
for all investigators submitting NIH proposals for research involving human 
subjects.  This policy announcement is found in the NIH Guide for Grants and 
Contracts Announcement dated June 5, 2000, at the following website:


All applications and proposals for NIH funding must be self-contained within 
specified page limitations.  Unless otherwise specified in an NIH 
solicitation, internet addresses (URLs) should not be used to provide 
information necessary to the review because reviewers are under no obligation 
to view the Internet sites.  Reviewers are cautioned that their anonymity may 
be compromised when they directly access an Internet site.


The Office of Management and Budget (OMB) Circular A-110 has been revised to 
provide public access to research data through the Freedom of Information Act 
(FOIA) under some circumstances.  Data that are (1) first produced in a 
project that is supported in whole or in part with Federal funds and (2) cited 
publicly and officially by a Federal agency in support of an action that has 
the force and effect of law (i.e., a regulation) may be accessed through FOIA.  
It is important for applicants to understand the basic scope of this 
amendment.  NIH has provided guidance at

Applicants may wish to place data collected under this RFA in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time.  If so, the application should 
include a description of the archiving plan in the study design and include 
information about this in the budget justification section of the application. 
In addition, applicants should think about how to structure informed consent 
statements and other human subjects procedures given the potential for wider 
use of data collected under this award.


Prospective applicants are asked to submit 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 IC staff to 
estimate the potential review workload and plan the review.

The letter of intent is to be sent to Dr. Robert Heinssen at the address 
listed under INQUIRIES by the letter of intent receipt date listed.

The PHS 398 research grant application instructions and forms (rev. 5/2001) at are to be used in 
applying for these grants.  This version of the PHS 398 is available in an 
interactive, searchable PDF format.  Although applicants are strongly 
encouraged to begin using the 5/2001 revision of the PHS 398 as soon as 
possible, the NIH will continue to accept applications prepared using the 
4/1998 revision until January 9, 2002.  Beginning January 10, 2002, however, 
the NIH will return applications that are not submitted on the 5/2001 version.  
For further assistance contact GrantsInfo, Telephone 301/710-0267, Email:


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 NIH staff.  
The research grant application form PHS 398 (rev. 5/2001) at is to be used in 
applying for these grants, with modular budget instructions provided in 
Section C of the application instructions.  Applicants are permitted, however, 
to use the 4/1998 revision of the PHS 398 for scheduled application receipt 
dates until January 9, 2002.  If you are preparing an application using the 
4/1998 version, please refer to the step-by-step instructions for Modular 
Grants available at  
Additional information about Modular Grants is also available on this site.

The RFA label available in the PHS 398 (rev. 5/2001) application form must be 
affixed to the bottom of the face page of the application.  Type the RFA 
number on the label.  Failure to use this label could result in delayed 
processing of the application such that it may not reach the review committee 
in time for review.  In addition, the RFA title and number must be typed on 
line 2 of the face page of the application form and the YES box must be 
marked. The RFA label is also available at:

Submit a signed, typewritten original of the application, including the 
Checklist, and three signed, photocopies, in one package to:

BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

At the time of submission, two additional copies of the application must be 
sent to:

Jean Noronha, Ph.D.
Division of Extramural Activities
National Institute of Mental Health
6001 Executive Boulevard, Room 6154, MSC 9609
Bethesda, MD  20892-9609
Bethesda, MD  20817 (for express/courier service)

Applications must be received by the application receipt date listed in the 
heading of this RFA.  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.


Upon receipt, applications will be reviewed for completeness by the CSR and 
responsiveness by NIMH staff.  Incomplete and/or non-responsive applications 
will be returned to the applicant without further consideration.

Applications that are complete and responsive to the RFA will be evaluated for 
scientific and technical merit by an appropriate peer review group convened by 
the NIMH in accordance with the review criteria stated below.  As part of the 
initial merit review, 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 the applications under review, 
will be discussed, assigned a priority score, and receive a second level 
review by the National Advisory Mental Health Council of the participating 

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 comments reviewers will be asked to discuss the following aspects 
of the application 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 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 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.

(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 

In addition to the above criteria, in accordance with NIH policy, all 
applications will also be reviewed with respect to the following:

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

o  The reasonableness of the proposed budget and duration in relation to the 
proposed research.

o  The adequacy of the proposed protection for humans, animals or the 
environment, to the extent they may be adversely affected by the project  
proposed in the application.

o  The adequacy of the proposed plan to share data, if appropriate.


Letter of Intent Receipt Date:    November 15, 2001
Application Receipt Date:         December 14, 2001
Peer Review Date:                 February 2002
Council Review:                   May 2002
Earliest Anticipated Start Date:  July 1, 2002


Award criteria that will be used to make award decisions include:

o  scientific merit (as determined by peer review)
o  availability of funds
o  programmatic priorities


Inquiries concerning this RFA are encouraged.  The opportunity to clarify any 
issues or answer questions from potential applicants is available.

Direct inquiries regarding programmatic issues to:

Robert Heinssen, Ph.D.
Division of Mental Disorders, Behavioral Research and AIDS
National Institute of Mental Health, NIH
6001 Executive Boulevard, Room 6181, MSC 9625
Bethesda, MD  20892-9625
Rockville, MD  20892 (for express/courier service)
Telephone:	(301) 435-0371
FAX:  (301) 443-4611

Direct inquiries regarding fiscal matters to:

Diana S. Trunnell
Grants Management Branch
Division of Extramural Activities
National Institute of Mental Health
6001 Executive Boulevard, Room 6115, MSC 9605
Bethesda, MD  20892-9605
Telephone:	(301) 443-2805
FAX:  (301) 443-6885


This program is described in the Catalog of Federal Domestic Assistance No. 
93.242.  Awards are made under authorization of Sections 301 and 405 of the 
Public Health Service Act as amended (42 USC 241 and 284) and administered 
under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 
74 and 92.  This program is not subject to the intergovernmental review 
requirements of Executive Order 12372 or Health Systems Agency review.

The PHS strongly encourages all grant recipients to provide a smoke-free 
workplace and promote the non-use of all tobacco products.  In addition, 
Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain 
facilities (or in some cases, any portion of a facility) in which regular or 
routine education, library, day care, health care, or early childhood 
development services are provided to children.  This is consistent with the 
PHS mission to protect and advance the physical and mental health of the 
American people.

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