CENTER FOR COLLABORATIVE GENETIC STUDIES ON MENTAL DISORDERS RELEASE DATE: March 28, 2002 RFA: MH-03-003 National Institute of Mental Health (NIMH) (http://www.nimh.nih.gov) PRE-APPLICATION MEETING: May 15, 2002 LETTER OF INTENT RECEIPT DATE: September 16, 2002 APPLICATION RECEIPT DATE: October 16, 2002 THIS RFA CONTAINS THE FOLLOWING INFORMATION: o Purpose of this RFA o Research Objectives o Mechanism of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirements o Where to Send Inquiries o Letter of Intent o Submitting an Application o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations PURPOSE OF THIS RFA The National Institute of Mental Health (NIMH) invites applications for support of a Center for Collaborative Genetic Studies on Mental Disorders, which will contribute to the improvement and enrichment of research resources to be distributed for genetic studies of mental disorders under the rubric of the NIMH Human Genetics Initiative (http://zork.wustl.edu/nimh/NIMH _initiative/NIMH_initiative_link.html). The Center, which will function as a integrated team of investigators with expertise in molecular biology, statistical genetics, bioinformatics and psychiatric genetics within a single institution or across institutions, will facilitate and accelerate free and open sharing among researchers in the scientific community by providing on a fee-for-service basis: DNA, cell lines, electronic data files, and services for the genetic analysis of mental disorders. The goal of this initiative will be to enrich and distribute clinical information, genotypic data, DNA samples, and cell lines from large numbers of unrelated affected individuals and from pedigrees of affected individuals and their relatives. Such research resources will provide adequate statistical power for discovering genes that produce vulnerability to mental disorders. Data and biomaterials collected and produced by the Center will augment pre-existing resources in the NIMH Human Genetics Initiative for genetic analyses by the wider scientific community. RESEARCH OBJECTIVES Background The free and open sharing of genetic material and clinical data among researchers has been essential in accelerating discoveries in human genetics. A recent national survey of life scientists found that over 70% of geneticists felt that lack of data sharing detracted from the level of communication in science and slowed the rate of progress in their field; the major conclusion was that the impact of data withholding in academic genetics is widespread and adversely affects essential scientific activities such as the ability to confirm published results. For mental disorders and other genetically complex diseases in which gene effects are modest, sharing is often absolutely necessary to achieve sample sizes that have adequate statistical power for gene mapping. Other specific scientific advantages of sharing research resources include facilitating the rapid replication of new findings, stimulating multidisciplinary research among clinical and basic scientists, providing needed clinical resources to promising young investigators, avoiding duplicative data collection efforts and laboratory work, and facilitating the rapid application of state-of-the-art genomic technologies and analytic methods to clinical data sets. These advantages are expected to facilitate our understanding of disease pathophysiology, and accelerate the development of new therapeutic compounds and diagnostic tests. In the late 1980s, NIMH launched a Human Genetics Initiative (http://zork.wustl.edu/nimh/NIMH_initiative/NIMH_initiative_link.html) to study the genetic basis of vulnerability to schizophrenia, Alzheimer's disease, and bipolar disorder. The main goal of this effort was to accelerate gene discovery through the sharing of electronic databases of clinical information, DNA samples, and cell lines as a national resource for the scientific community. In 1997, a workgroup of the National Advisory Mental Health Council reviewed the NIMH genetics research portfolio and recommended that NIMH continue to fund large-scale data collection efforts and to maintain a repository of DNA and clinical data for sharing with the scientific community (see the report summary at http://www.nimh.nih.gov/research/ genetics.htm). The Workgroup also discussed future expansion of these efforts to include other mental disorders. At a joint meeting in September 2000, the National Advisory Councils of the NIMH and the National Institute of Neurological Disorders and Stroke strongly recommended that data sharing for the genetic analysis of complex diseases supported by these Institutes continue to be strongly encouraged. In order to enhance and enrich research resources in the NIMH Human Genetics Initiative for free and open sharing with the scientific community, the NIMH plans to fund one Center under this RFA. An example of the benefits of data sharing expected from Center activities is the recent successful effort to promote collaboration across investigators involved in the collection of families with Crohn disease. Whereas individual data sets reporting linkage to three different chromosomes did not have sufficient power alone to yield conclusive evidence, pooling the data from investigators in 13 countries provided unequivocal replication of linkage for Crohn disease to a marker on chromosome 16. The long-term objective of data sharing and research resource enrichment under this RFA is to accelerate gene discovery in mental disorders that include Alzheimer's disease, attention-deficit hyperactivity disorder, autism and related spectrum disorders, bipolar disorder and other related mood disorders, recurrent early-onset depression, eating disorders, obsessive- compulsive disorder and other anxiety disorders, panic disorder, schizophrenia, and other psychotic disorders. Research Objectives The NIMH will utilize the U24 Resource-Related Research Projects – Cooperative Agreements funding mechanism to establish one Center for Collaborative Genetic Studies on Mental Disorders to serve as a national and international resource to the scientific community. The Center funded under this RFA will be directed by a Principal Investigator (PI) and will receive guidance from NIMH program staff to assist with identification and implementation of appropriate strategies and priorities. It is expected that the Center will be comprised of an integrated team of investigators (within a single institution or across institutions) with expertise in molecular biology, statistical genetics, bioinformatics and psychiatric genetics. Regardless of how many institutions are involved, it is expected that the efforts of the Center will be strategically and functionally coordinated such that the Center will function as a single, national resource. It is expected that the principal investigator and the proposed collaborative team have direct experience in providing to the scientific community research resources and services for genetic studies. Specific areas of scientific expertise required by the Center include the following: o Molecular biology, with a primary focus on the Epstein-Barr virus transformation of lymphocytes from fresh blood samples received from national and international sites to create contaminant-free cell lines, and the extraction of high-quality DNA from these cell lines. o Bioinformatics, with a primary focus on the receipt and production of pedigree, clinical (including information obtained from structured psychiatric interviews), genotypic and other genetic data for the establishment of documented web-based data files for the genetic analysis of mental disorders. This work will also encompass the development and application of novel technological or computational methods for the production and analysis of comprehensive genomic data sets. o Statistical genetics of complex diseases, with a primary focus on the development of algorithms and well-documented software for meta-analytic genetic studies and clustering and other classification techniques in genetic analysis. This work will also encompass the development of novel statistical approaches by which linkage findings from multiple genomic scans may be jointly analyzed to fine map disease susceptibility loci. o Analysis of psychiatric family data, with a primary focus on the development of analytic methods by which psychiatric diagnostic information can be analyzed to identify biologically meaningful phenotypes and clinical subtypes. Coordination of the Center's activities will be accomplished through close collaboration between the Center scientific staff, NIMH program staff, and a scientific steering committee (Genetics Steering Committee (GSC)). A Genetics Advisory Panel (GAP), composed of experts not affiliated with the Centers or the GSC, also will be formed to provide scientific oversight of the Center and to address long-term strategic issues and policies related to the gene discovery and characterization of the genetic basis of mental disorders. GSC, GAP, PI, and NIMH responsibilities are described under SPECIAL REQUIREMENTS. Specific functions and services to be performed by the Center for the scientific community include: o Resolution of the discrepancies in linkage findings obtained in multiple data sets for mental disorders. o Exploration of explanations for discrepancies - either at the level of the phenotype definition, characterization of DNA markers, or statistical methods - which would provide a stronger base for a priori testing of particular candidate regions in future genetic studies. o Development of analytic approaches for the pooling of data on therapeutic drug response, in order to accelerate gene discovery. o Development of novel statistical approaches by which linkage findings from multiple genomic scans may be jointly analyzed to fine map disease susceptibility loci. o Receipt from national and international research projects supported under the NIMH Human Genetics Initiative of blood samples for cell line immortalization and of clinical and genetic data files. This includes blood samples drawn from unrelated affected individuals in NIMH-supported large- scale clinical trials. o Creation and maintenance of contaminant-free lymphoblastoid cell lines, immortalized from fresh whole blood samples with a success rate of greater than 98% (for samples shipped from both domestic and foreign sites), and extraction of high-quality DNA. o Verification of sample identity, gender, and pedigree relationships on blood samples received from research projects supported under the NIMH Human Genetics Initiative. o Distribution of datafiles and biomaterials (cell lines and DNA) to the scientific community, according to the unique needs of investigators. o Consultation on the experimental design of pharmacogenomic and other genetic studies, and development of analytic methods by which clinical and genotypic data may be pooled for meta-analytic genetic studies of mental disorders. o Provision of algorithms and well-documented software for meta-analytic studies of genotypic data, and consultation on applying clustering and other classification techniques in genetic analysis. o Consultation on the analysis of psychiatric family study data obtained from diagnostic interviews. o Establishment and distribution of pedigree datasets, in which non- Mendelian inheritances and other errors determined from genome scans and other genetic analyses are resolved. o Receipt, production and distribution of databases of genotypic information received from multiple laboratories, in which genotyping inconsistencies are reconciled. o Provision of novel technological or computational methods for the production and analysis of comprehensive genomic data sets. These services and research resources will be provided to the scientific community by the Center on a fee-for-service basis. Fees charged will recover costs and service delivery costs. Applications in response to this RFA should include detailed plans for the advisory, research and development, and other fee-for-service functions of the Center. MECHANISM OF SUPPORT This RFA will use the NIH Resource-Related Research Projects – Cooperative Agreements award mechanism (U24). As an applicant, you will be solely responsible for planning, directing, and executing the proposed project. This RFA is a one-time solicitation. The earliest anticipated award date is July 1, 2003. The NIH U24 is a cooperative agreement award mechanism in which the Principal Investigator retains the primary responsibility and dominant role for planning, directing, and executing the proposed project, with NIH staff being substantially involved as a partner with the Principal Investigator, as described under the section "Cooperative Agreement Terms and Conditions of Award." FUNDS AVAILABLE The NIMH intends to commit approximately $4.7 million in FY 2003 to fund one new cooperative agreement in response to this RFA. An applicant may request a project period of up to 5 years. 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 sufficiently meritorious application. At this time, it is not known if this RFA will be reissued. ELIGIBLE INSTITUTIONS You may submit an application if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Domestic INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs. SPECIAL REQUIREMENTS I. Definitions ARBITRATION PANEL: A panel that would be formed to arbitrate scientific or programmatic disagreement, should any arise, between award recipients and the NIMH within the scope of the award. AWARDEE: The institution to which a cooperative agreement is awarded. COOPERATIVE AGREEMENT: An assistance mechanism in which there is anticipated substantial NIMH programmatic involvement with the recipient organization during the performance of the planned activity. PRINCIPAL INVESTIGATOR (PI): The researcher who assembles the project, submits an application in response to this RFA, and assumes responsibility for the overall performance of the project. The PI will coordinate project activities scientifically and administratively. NIH PROGRAM DIRECTOR: A scientist of the NIMH program staff who has substantial scientific/programming involvement. GENETICS STEERING COMMITTEE (GSC): The main governing board of the Center funded under this RFA, through which the NIMH formally interacts with the Center. Membership includes the NIMH Program Director, the PI, and two extramural scientists with relevant expertise who are not affiliated with the funded project. GENETICS ADVISORY PANEL (GAP): A panel of extramural researchers who provide scientific oversight of the Center. GAP evaluates the goals and objectives of the NIMH Human Genetics Initiative, the progress of the Center in relation to the ongoing needs of the scientific community in genetic studies of mental disorders, and the inclusion of state-of-the-art genomic tools and technologies in Center activities. II. Pre-Application Meeting Prospective applicants are invited to attend a pre-application meeting on May 15, 2002, at the NIMH in Rockville, MD. This meeting will provide the opportunity for NIH staff to clarify any requirements of the RFA. At the pre-application meeting, NIH staff will explain the purpose of this RFA, provide detailed instructions about the application process, and answer questions. Interested scientists should contact the NIMH program staff contact listed under WHERE TO SEND INQUIRIES to obtain further information. Potential applicant institutions are urged to send a representative to this meeting. Anyone who cannot attend this meeting will be provided with any distributed materials and with a summary of the discussion within two weeks of the meeting. III. Program Income Fees charged by the Center will constitute Program Income. Program Income is gross income earned by the awardee that is directly generated by a supported activity or earned as a result of the award (see 45 CFR 74.2 and 74.24 for additional information). An estimate of the amount and source of Program Income that will be generated as a result of the award must be included on the Checklist Page of all competing and non-competing continuation applications. Net program income earned during a budget period must be reported on the annual Financial Status Report (FSR) (except for Program Income earned as a result of inventions, to which special rules apply). Costs incident to the generation of Program Income may be deducted from gross income to determine Program Income to be reported on the FSR, provided that these costs have not been charged to the award. Program Income earned during the project period shall be retained by the award recipient and is to be deducted from the total project or program allowable costs in determining the net allowable costs on which the federal share of costs is based. The NIMH may offset a future award by this amount or reauthorize it for expenditure on a future award. IV. Quarterly Meetings The GSC will meet quarterly at the NIMH. Applications in response to this RFA should include a request for funds to cover the expense of attending these meetings in Rockville, MD. V. Data Sharing 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. NIH policy requires that investigators make unique research resources produced with DHHS funding available for research purposes to qualified individuals within the scientific community (NIH Grants Policy Statement - March 2001, Part II Subpart A, Availability of Research Results: Publications, Intellectual Property Rights, and Sharing Biomedical Research Resources, page 120-122, "Sharing Biomedical Research Resources," available at http://grants.nih.gov/grants/policy/nihgps_2001/nihgps_2001.pdf); see also PHS policy relating to the distribution of unique research resources produced with PHS funding at http://grants.nih.gov/grants/guide/notice-files/not96- 184.html). Principles and guidelines for sharing biomedical research resources also can be found in online NIH reports at http://www.nih.gov/science/models/sharing.html and http://www.nih.gov/news/researchtools/index.htm. A draft NIH Statement on sharing research data that extends these policies has recently been published (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-035.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, the NIMH requires applicants who respond to this RFA to develop and propose detailed plans for sharing and disseminating the data and biomaterials produced and received through the Center. It is expected that the information to be shared includes clinical, diagnostic, and pedigree structure information, in addition to cell lines and DNA. Policies and procedures in the NIMH Human Genetics Initiative specify that DNA, cell lines, and datafiles be widely accessible by investigators in the scientific community. The NIMH Human Genetics Initiative employs procedures by which data and biomaterials are widely disseminated to qualified investigators in the scientific community (http://zork.wustl.edu/nimh/NIMH_initiative/NIMH%20Human%20Genetics%20 Initiative%20Access%20Information.htm). It is preferable that the procedures for sharing data and biomaterials are comparable to those currently employed in the NIMH Human Genetics Initiative. It is expected that the investigator's data sharing plan will specify the following elements: (1) the production of comprehensive and verified databases that contain clinical, diagnostic, pedigree structure, and genotypic information collected and produced by the Center; (2) the establishment of cell lines, from which DNA will be extracted and stored, for all subjects studied from whom blood samples have been received by the Center; (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 free and open sharing of these data and biomaterials; and (5) an assurance that data and biomaterials are shared in a manner comparable to pre-existing protocols and procedures for sharing such research resources in the NIMH Human Genetics Initiative. The Scientific Review Group will comment on the proposed plan for sharing and data access. The plan will be considered as an important part of the methodology for carrying out the research and, as such, the adequacy of the plan will be considered by NIMH staff in determining whether the grant shall be awarded. The sharing plan as approved, after negotiation with the applicant when necessary, will be a condition of the award. VI. Cooperative Agreement Terms and Conditions of Award The following special Terms and Conditions will be incorporated into the cooperative agreement award statement and are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), and other HHS and NIH grant administration policies: The administrative and funding instrument used for this program will be the U24, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH scientific and/or programmatic involvement with the awardees is anticipated during performance of the activities. Under the cooperative agreement, the NIH purpose is to support and/or stimulate the recipient's activities by involvement in and otherwise working jointly with the award recipients in a partnership role. The NIH purpose is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardee for the project as a whole, although specific tasks and activities will be shared among the awardee, GSC, and NIMH program staff. 1. Awardee Rights and Responsibilities The awardee, as Center PI, will coordinate project activities scientifically and administratively at the awardee institution, and will have primary responsibility for performing all scientific and fee-for-service activities. The Center PI must agree to participate with NIMH program staff and GSC in coordinating the activities of the Center, with the result that all investigators included in the application function as a single functioning Center. The PI agrees to accept the close coordination, cooperation, and participation of the Program Director, GSC, and GAP in those aspects of scientific and technical management of the project as described below. Specifically, the PI will: o Determine experimental approaches, design protocols, oversee the provision of services and research resources to the scientific community, and work cooperatively to set project milestones, in consultation with NIMH program staff, GSC, and GAP. o Distribute biomaterials and datafiles for researchers granted access by the NIMH to research resources in the NIMH Human Genetics Initiative. Access determinations will be made by the NIMH with input as required from GAP. o Maintain a log of Center usage that records the products and services provided and the fees charged. o Prior to each non-competing renewal, submit progress reports in a standard format, as agreed upon by GSC. The progress report will describe the activities and accomplishments of the Center for the preceding award period, and the goals to be accomplished during the renewal period. The progress report will include the log of Center usage. The contents of the progress report will be used by NIMH program staff, along with other information, to determine the amount of funding the Center will receive for the renewal period. o Accept and implement the common guidelines and procedures approved by GSC and GAP. o Attend and participate in GSC meetings (budget requests should include travel funds for the PI and other critical staff to attend GSC meetings at the NIMH in Rockville, MD, on a quarterly basis). The awardee will have one vote on GSC and will accept any modification, deletion, or addition of Center activities approved by GSC. 2. NIMH Program Staff Responsibilities The NIMH Program Director will have substantial scientific/ programmatic involvement during the conduct of this activity through technical assistance, advice, and coordination. This includes functioning as a peer with the PIs, facilitating the partnership relationship between the NIMH and the Center, helping to maintain the overall scientific balance in the program commensurate with new research and emerging research opportunities, and ensuring that the activities of the Center are consistent with the scientific mission of the NIMH Human Genetics Initiative (http://zork.wustl.edu/nimh/NIMH_initiative/NIMH%20Human%20Genetics%20 Initiative%20Mission.htm). The role of the NIMH will be to facilitate and not to direct activities. Access to research resources maintained in the NIMH Human Genetics Initiative will be determined by NIMH staff, with input as required from GAP. The NIMH Program Director shall participate as a member of GSC and will have one vote. Specifically, the NIMH Program Director will: o Provide relevant scientific expertise and overall knowledge. o Recruit and select the members of GSC, who will each serve a three-year term. The Program Director will also have the responsibility of replacing GAP or GSC members that choose to leave. The Program Director may, but is not required to, consult with Center PIs, GSC members, GAP members, or other outside advisors when recruiting GSC and GAP members. o Attend GSC meetings as one voting member and assist in developing operating guidelines, quality control procedures, and consistent policies for dealing with recurrent situations that require coordinated action. The Program Director must be informed of all major interactions of members of GSC. The Program Director will be responsible for preparing within 30 days a concise summary of each GSC meeting. o Participate with other GSC members in the group process of setting research priorities and milestones, deciding optimal research approaches and protocol designs, and contributing to the adjustment of research protocols or approaches as warranted. The Program Director will assist and facilitate the group process and not direct it. o Serve as administrative liaison to GAP, attending GAP meetings as a non- voting member, to help coordinate Center activities with the development of evolving tools and technologies in genomic and genetic science. The Program Director will also coordinate Center activities with the scientific mission and evolving goals of the Human Genetics Initiative, with input as required from GAP. The Program Director will also coordinate Center activities with other US and international efforts that focus on sharing research resources for genetic analyses of complex diseases. o Appoint the GSC and GAP Chairs, based on recommendations from GSC and GAP members. o Serve as scientific liaison between the Center and other NIH staff. o Assist in promoting and encouraging the sharing of unique research resources for genetic studies of mental disorders by the scientific community at large. o Develop timetables for the timely, open, and free sharing of research resources received and produced by the Center to the scientific community. o Coordinate Center activities to ensure the efficient long-term storage of research resources. o Retain the option to recommend re-allocating NIMH support provided to the Center, as scientific goals evolve. o Determine the amount of support that will be awarded to the Center as a non-competing renewal. The progress report received from each Center, along with other information, will be used to make this determination. The criteria used for this decision will include, but not be limited to, Center production, customer satisfaction, and successful performance of the Center as a member of the consortium. 3. Collaborative Responsibilities - Genetics Steering Committee (GSC) All collaborative activities of the awardee and NIMH staff will occur through the activities of GSC, which will serve as the governing board of the Center. The NIMH will formally interact and collaborate with the Center through GSC, which will include the PI, the NIMH Program Director, and two researchers (advisors) with relevant scientific expertise who are not affiliated with the Center. These advisors will be appointed by the NIMH Program Director. One of the two advisors will be appointed by the Program Director to be GSC's chair, after consideration of recommendations made by GSC. After appointment by the Program Director, the GSC Chair will be responsible for developing meeting agendas and chairing meetings. GSC will meet quarterly. Additional GSC members may be added by action of GSC or GAP. Other NIH staff may attend GSC meetings, when their expertise is required for specific discussions. The Program Director, PI, and each advisor will have one vote each. In cases where members do not agree, any member may ask the chairperson to solicit a vote. In order for a decision or course of action to be finalized by GSC, a majority of the possible votes must be cast in favor of the decision or course of action. The GSC will coordinate the activities of the Center and the distribution of data, biomaterials, and services to the wider scientific community. GSC will discuss scientific progress, make recommendations regarding the enhancement of research resources and facilitation of free and open sharing. GAP recommendations will be addressed by GSC. The awardee will be required to accept and implement the common protocol and procedures approved by GSC. 4. Scientific Oversight - Genetics Advisory Panel (GAP) The GAP will meet at least once each year and will oversee Center activities to assure that the needs of the broader scientific community for research resources necessary for the genetic analysis of mental disorders are being met. GAP will provide oversight of the Center, and scientific advice to GSC and NIMH. GAP members will provide scientific and operational oversight concerning both long-term developments and distribution activities at the Center. GAP also will consult on the incorporation of emerging genomic and genetic tools and technologies into Center activities. The GAP will consist of about 10 scientists (advisors) who are not affiliated with the Center, and who are not members of any advisory committee of the Center. GAP members will be appointed by the NIMH Program Director and will be selected for their broad expertise in relevant topics such as molecular biology, molecular genetics, genomics, pharmacogenomics, statistical genetics, bioinformatics and psychiatric genetics. The NIMH will select one member to be GAP's chair, after considering GAP recommendations. Additional GAP members may be added by an action of GAP. The NIMH Program Director will attend GAP meetings as a non-voting member and will act as a representative of GSC. Other NIH staff and GSC members may attend GAP meetings, when their expertise is required for specific discussions. GAP members will not vote on GSC but may be invited to attend GSC meetings if attendance would significantly facilitate GSC business. Periodically, at intervals determined by GSC, a formal request for advice on specific subjects will be submitted to GAP. The GAP will convene to consider and formulate opinions on the questions submitted to it. NIMH program staff will consider GAP opinions with regard to overall Center functioning and when making determinations for renewal funding. 5. Arbitration Any disagreement that may arise on scientific/programmatic matters (within the scope of the award), between award recipients and the NIMH may be brought to arbitration. An arbitration panel will be composed of three members – one chosen by GSC (with NIMH not voting) or by the awardee in the event of an individual disagreement, a second member selected by the NIMH, and the third member with expertise in the relevant area who is selected by the two prior selected members. This special arbitration procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with the PHS regulations at 42 CFR Part 50, Subpart D and HHS regulation at 45 CFR Part 16. 6. Milestones and Evaluations Applicants should define yearly milestones in their applications, and the selected awardee will have the opportunity to modify these milestones at the time of award. The awardee's milestones will be reviewed by GSC and GAP. It is expected that the milestones should be adjusted annually at the award anniversary dates, both to incorporate a group's scientific accomplishments and progress in the field in general, as well as to reflect GSC and GAP recommendations. Following the evaluation of milestones, NIMH program staff may recommend augmenting any activity or reducing or withholding funds for an activity that substantially fails to meet its milestones or to remain state- of-the-art. Augmentation of funds must be in the scope of work of the Center's activities and subject to approval by the NIMH and the National Advisory Mental Health Council. WHERE TO SEND INQUIRIES We encourage inquiries concerning this RFA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues: o Direct questions about scientific/research issues to: Steven O. Moldin, Ph.D. Genetics Research Branch 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: smoldin@mail.nih.gov o Direct questions about peer review issues to: Camilla Day, Ph.D. Chief, Genetic Sciences IRG Center for Scientific Review 6701 Rockledge Drive, Room 2212, MSC 7890 Bethesda, MD 20892-7890 Telephone: (301) 435-1037 FAX: (301) 480-2067 Email: dayc@csr.nih.gov o Direct questions about financial or grants management matters to: Carol J. Robinson Grants Management Branch Division of Extramural Activities National Institute of Mental Health 6001 Executive Boulevard, Room 6118, MSC 9605 Bethesda, MD 20892-9605 Telephone: (301) 443-3858 FAX: (301) 443-6885 Email: crobinso@mail.nih.gov LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o Number and title of this RFA Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows NIMH staff to estimate the potential review workload and plan the review. The letter of intent is to be sent by the date listed at the beginning of this document. The letter of intent should be sent to: Steven O. Moldin, Ph.D. Genetics Research Branch Division of Neuroscience & 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: smoldin@mail.nih.gov SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). The PHS 398 is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 435-0714, Email: GrantsInfo@nih.gov. USING THE RFA LABEL: 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. SENDING AN APPLICATION TO NIH: Submit a signed, typewritten original of the application, including the Checklist, and five 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) APPLICATION PROCESSING: 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. 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. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by CSR and responsiveness by NIMH. 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 CSR in accordance with the review criteria stated below. As part of the initial merit review, all applications will: o Receive a written critique o 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 and assigned a priority score o Receive a second level review by the National Advisory Mental Health Council. REVIEW CRITERIA The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to discuss the following aspects of your application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals: o Significance o Approach o Innovation o Investigator o Environment The scientific review group will address and consider each of these criteria in assigning your application's overall score, weighting them as appropriate for each application. Your 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, you may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. (1) SIGNIFICANCE: If the aims of the application are achieved and research resources for genetics studies are freely shared with the scientific community, how will knowledge on the genetic basis of mental disorders be advanced? What will be the effect of these research resources on other scientific activities that drive this field? (2) APPROACH: Are the conceptual framework, design, and methods to be used for the receipt and sharing of research resources and provision of services to the scientific community adequately developed, well-integrated, and appropriate? Will the meta-analytic methods to be developed, and the statistical genetic services to be provided, succeed in accelerating the discovery of genes producing vulnerability to mental disorders? Does the applicant utilize state-of-the-art methods to create efficient web-based databases of clinical and genotypic data? Does the investigator utilize appropriate molecular biological techniques to assure a high rate of success (98% or greater) in establishing cell lines from both domestic and foreign sites? (3) INNOVATION: Does the project employ novel concepts, approaches, or methods for the production and sharing of research resources, for the development of analytic methods for meta-analytic studies, and for resolution of the discrepancies in linkage findings obtained in multiple data sets for mental disorders? Does the project employ novel methods by which linkage findings from multiple genomic scans may be jointly analyzed to fine map disease susceptibility loci? (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)? Does the principal investigator have demonstrated experience in providing high-quality research resources and services for genetic studies on mental disorders to the scientific community? Is the principal investigator highly committed to the principals of free and open sharing of research resources for genetic studies of mental disorders? (5) ENVIRONMENT: Does the scientific environment in which the work will be done contribute to the probability of success? Does the proposed work take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your application will also be reviewed with respect to the following: o PROTECTIONS: The adequacy of the proposed protection for humans or the environment, to the extent they may be adversely affected by the project proposed in the application. o INCLUSION: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria included in the section on Federal Citations, below) o DATA SHARING: The adequacy of the proposed plan to share data, and to provide research resources and scientific services to the community. o BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. o OTHER REVIEW CRITERIA: The adequacy of the proposed fee-for-service plan, including administration and funds management. RECEIPT AND REVIEW SCHEDULE Pre-Application Meeting: May 15, 2002 Letter of Intent Receipt Date: September 16, 2002 Application Receipt Date: October 16, 2002 Peer Review Date: February/March 2003 Council Review: May 2003 Early Anticipated Start Date: July 1, 2003 AWARD CRITERIA 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 and program balance o Commitment to the long-term scientific mission, goals, and objectives of the NIMH Human Genetics Initiative REQUIRED FEDERAL CITATIONS INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: 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 clinical research projects unless a clear and compelling justification is 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 clinical research should read the AMENDMENT "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (http://grants.nih.gov/grants/guide/notice- files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must 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) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy 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 is available at http://grants.nih.gov/grants/funding/children/children.htm. 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. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. 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. 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. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. 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 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. AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance No. 93.242, and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. 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 described at http://grants.nih.gov/grants/policy/policy.htm and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the 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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