MODULAR PHENOTYPING FOR MAJOR MENTAL DISORDERS Release Date: September 21, 2001 RFA: RFA-MH-02-009 National Institute of Mental Health (http://www.nimh.nih.gov/) Letter of Intent Receipt Date: November 15, 2001 Application Receipt Date: December 14, 2001 THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. MODULAR INSTRUCTIONS MUST BE USED FOR RESEARCH GRANT APPLICATIONS REQUESTING LESS THAN $250,000 PER YEAR IN ALL YEARS. MODULAR BUDGET INSTRUCTIONS ARE PROVIDED IN SECTION C OF THE PHS 398 (REVISION 5/2001) AVAILABLE AT http://grants.nih.gov/grants/funding/phs398/phs398.html. PURPOSE 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. HEALTHY PEOPLE 2010 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 http://www.health.gov/healthypeople/. ELIGIBILITY REQUIREMENTS 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 Investigators. MECHANISM OF SUPPORT 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 http://grants.nih.gov/grants/funding/modular/modular.htm. FUNDS AVAILABLE 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 procedures. RESEARCH OBJECTIVES Background 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" (http://www.nimh.nih.gov/tbsia/tbsiatoc.cfm). 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 purpose. 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. 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 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 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html), a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm. 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. 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 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 address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html. 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. REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS 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: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. URLS IN NIH GRANT APPLICATIONS OR APPENDICES 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. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT 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 http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. 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. LETTER OF INTENT 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. APPLICATION PROCEDURES The PHS 398 research grant application instructions and forms (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html 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: GrantsInfo@nih.gov. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS 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 http://grants.nih.gov/grants/funding/phs398/phs398.html 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 http://grants.nih.gov/grants/funding/modular/modular.htm. 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: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. Submit a signed, typewritten original of the application, including the Checklist, and three signed, 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) 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. REVIEW CONSIDERATIONS 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 Institutes. 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 support? 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 evaluated. 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. Schedule 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 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 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 Email: rheinsse@mail.nih.gov 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 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 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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