DETERMINATION OF ALL FUNCTIONAL ELEMENTS IN HUMAN DNA RELEASE DATE: February 21, 2003 RFA: HG-03-003 National Human Genome Research Institute (NHGRI) (http://www.genome.gov/) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER: 93.172 LETTER OF INTENT RECEIPT DATE: April 13, 2003 APPLICATION RECEIPT DATE: May 13, 2003 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism(s) 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 The purpose of this RFA is to solicit applications to participate in a Research Network that will conduct a pilot project to test and compare methods for identifying all of the functional elements in a limited (~1%) region of the human genome. The emphasis during this initial phase will be on the identification and verification of transcription units, including associated cis-regulatory elements, but projects using existing methods for the identification of other sequence-based functional elements are also encouraged. Both computational and experimental approaches will be critical components of the project. This RFA is being issued in conjunction with a second RFA, HG-03-004 "Technologies to Find Functional Elements in Genomic DNA" which will support the development of new and improved high-throughput and efficient technologies for the comprehensive identification and verification of a larger variety of functional elements. RESEARCH OBJECTIVES Background In April 2003, the sequence of the human genome will be essentially complete. For the scientific community now to make the best use of that fundamental information resource, the identity and precise location of all sequence-based functional elements in the genome must be determined. While many of the protein-coding genes are already known, many others remain to be identified. Beyond open reading frames, non-protein-coding genes, transcriptional regulatory elements and determinants of chromosome structure and function remain largely unknown. A comprehensive encyclopedia of all of these features is needed to utilize fully the sequence of the human genome to understand human biology better, to predict potential disease risks, and to stimulate the development of new therapies and other interventions to prevent and treat disease. One of the primary reasons for the success of the Human Genome Project has been the development and use of high-throughput strategies for data generation, and the placement of the data immediately in the public domain. Most of the sequence data, the underlying maps and the sequence assemblies were generated through the use of large-scale automated processes. Now, methods such as sequence analysis of whole genomes, DNA microarray technology and mass spectrometry have been or are being developed as high-throughput approaches for additional types of genomic analyses, such as determining the parameters of gene expression or the location of gene products by the thousands at a time instead of individually. High-throughput methods to determine the location of cis-regulatory elements and, to a lesser extent, other sequence elements, are also beginning to be developed. However, at present, there is no single approach or compilation of approaches known to identify accurately and efficiently every sequence feature in genomic DNA. While determining the identity and function of all of the sequence elements in human DNA is a daunting challenge, it is appropriate at this time to begin to consider such a project. On July 23-24, 2002, the NHGRI held a workshop, the Comprehensive Extraction of Biological Information from Genomic Sequence, to discuss a proposal to initiate a new public research consortium to test and compare existing and new methods for exhaustive identification and verification of functional sequence elements as a pilot project focused on a limited region of human genomic DNA. The report of this meeting is available at http://www.genome.gov/page.cfm?pageID=10005115. Based on the recommendations of this workshop, the NHGRI has decided to launch the Encyclopedia of DNA Elements (ENCODE) project. The goal of this project is to comprehensively identify functional elements in the human genome sequence. The ENCODE project will begin as a pilot project that will test and compare methods for the exhaustive identification and verification of functional sequence elements in 30 Mb of human genomic DNA. This will require access to information, resources, ideas, expertise, and technology beyond the scope of what any single group can currently provide. Therefore, the pilot will be carried out by a consortium of investigators with diverse backgrounds and expertise working cooperatively to (1) evaluate rigorously the relative merits of each of a varied set of techniques, technologies, and strategies for identifying all of the functional elements in human genomic sequence, (2) test the abilities of such methods to be scaled up efficiently so that ultimately, it will be feasible to use them to analyze all of the functional elements encoded in the entire human genome sequence, and (3) identify and fill gaps in our ability to annotate genomic sequence. The ENCODE project is intended to characterize the tools needed for mining genomic sequence and, where necessary, improve them, and define a clear path for the determination of all of the functional elements in the entire human genome sequence. A fully annotated human genome sequence will be an integrated information resource that will enable the efforts of the entire research community in both basic and clinical research. It is obvious, however, that current technology is not capable of achieving all of the aims of even the initial phase of the ENCODE project. Therefore, at the same time that high-throughput efforts are being initiated using well-developed technologies, a parallel effort is being started to develop new or improved high-throughput and efficient technologies. The companion RFA, HG-03-004, "Technologies To Find Functional Elements in Genomic DNA", is intended to expand the repertoire of tools that can be applied to the ENCODE, or similar projects, in the future. Research Scope The aim of the ENCODE pilot project is to determine the best way to generate a comprehensive catalog of all sequence-based functional elements in human DNA. The pilot will test and compare a combination of available methods, seek to improve current methods, and develop new methods using, as a test bed, a defined 30 Mb of human genome sequence. Both computational and experimental approaches will be involved. A prime criterion by which any method or combination of methods will be evaluated will be its potential for being efficiently applied at large enough scale to characterize the entire human genome. The sequence-based functional elements that will be targeted include, but are not limited to: o Transcribed sequences, including both protein-coding and non- protein-coding. A description of the gene structure with transcriptional start sites, polyadenylation sites, along with all alternative transcripts, is an example. o Conserved non-coding sequences that may represent functional elements. o Cis-acting elements that regulate transcription and/or chromatin structure. These elements include promoters, enhancers, and insulators. o Sequence features that affect/control chromosome biology. Examples include origins of replication and hot spots for recombination. o Epigenetic changes, such as DNA methylation and chromatin modifications. If the ENCODE project is to be successful, it will be critical to balance the desire for complete information about genome features with the practical ability to obtain a useful amount of information in a reasonable and affordable manner. Therefore, the scope for this RFA will be limited to the initial identification and verification of sequence-based elements. This limitation has a number of consequences: o Although a minimum amount of functional analysis may be required in the process of identification, in-depth study of the biological function of genes and gene products, e.g., functional studies in vitro or in vivo, is beyond the scope of this RFA. o NHGRI recognizes that the function and activity of sequence elements will vary in different cell types. As this RFA is being issued in support of the ENCODE project's pilot phase, proposals should only include as many different cells types as necessary to demonstrate feasibility of the approaches proposed in the application. The NHGRI will not specify cells or tissues to be used for this project; however, proposals must clearly define the cells or tissues to be studied along with a justification for their use. o The goal of the pilot project is to test methods for identifying functional elements in the human genome. Experimental work should be restricted to human tissues and cells unless a compelling argument can be made for the use of model organisms. The functional analysis of sequences from other species that are homologous to the selected target regions is beyond the scope of this solicitation. The ENCODE consortium will be open to all academic, government and private sector scientists interested in participating in an open process to facilitate the comprehensive interpretation of the human genome sequence. It is expected that groups with funding from other sources will participate in the ENCODE project and therefore, funding through this initiative is not a prerequisite for participation in the consortium. Participants will be expected to design experiments that apply high throughput methods to identify, with high accuracy, functional elements in the selected target sequences in the human genome. In the application, the P.I. should describe the functional element to be identified, the specific assay(s) to be used, the plans for scaling the assay(s) for high-throughput analyses, and the collection and processing of data from the experiments. In addition, applicants should describe how the biological authenticity of the identified elements could be validated, and plans to validate the technical approach should be included. The large datasets from these experiments will be deposited in the ENCODE database(s), and other appropriate public databases, as described in the data release policy (see below). Through interactions within the ENCODE consortium, the P.I.s may modify their experimental approach, either incorporating modified or new methods or using new information supplied to the ENCODE consortium, such as improved computer predictions of functional elements. To help plan certain initial aspects of the ENCODE pilot project, NHGRI convened an Organizing Committee which identified a set of target regions of the genome for study (see below) and recommended a proposed set of data release policies. Once the project has been initiated, it will be organized as a Research Network with a Coordinating Committee (see Terms and Conditions), which will guide the operations of the consortium. A Scientific Advisory Panel, comprised of scientists not directly working on the project, will be convened to provide advice to the Director, NHGRI regarding the progress of the project. Target Regions. The 30 Mb target regions to be analyzed in the ENCODE pilot project include representative features of the entire genomic landscape. There are forty-four regions altogether, ranging in size from 500 Kb to 2 Mb. Approximately 50% of the 30Mb of sequence was chosen manually, based upon two criteria: 1) the existence of an extensive amount of comparative sequence data for a region, and 2) interesting gene(s) or other sequence features residing in a region. The remaining 15Mb were selected randomly using a computer algorithm that stratified the human genome based upon two criteria gene density and non-exonic conservation with mouse sequence and then selected regions representative of each stratum. The list of target regions, as well as a more detailed description of the selection process, can be found at http://www.genome.gov/page.cfm?pageID=10005107. Applicants must propose to study the entire set of target regions rather than focus on only one or a subset of regions. Comparative sequence analysis of regions homologous to the selected target regions will undoubtedly provide valuable information for discerning functional sequence elements and it is anticipated that these sequences will be determined for a number of species during the course of the ENCODE pilot project. The de novo generation of additional sequence information by standard methods will not be supported under this RFA, but comparative sequences will be made available through the consortium's database. Data Release. The ENCODE project aims to function openly by making all data available to the scientific community in a timely manner. The ENCODE project is a community resource project. It is expected that the consortium will establish a common data release policy and that all participants will agree to abide by that policy. The Organizing Committee has recommended to NHGRI a set of practices for data release. Taken together with other considerations, the NHGRI deems that the following data release policy would be appropriate: 1. Participants would submit data to the consortium database(s) as soon as the data have been determined to be reliable. The timing of data submission may differ for different types of data. The consortium's Coordinating Committee in conjunction with the Scientific Advisory Panel would establish appropriate data release standards for each data type. Approval for participation in the consortium will be predicated on agreement to abide by these data release standards. Applicants should propose what they consider to be appropriate data release practices in the application, and a policy acceptable to the investigator, the consortium and NHGRI will be negotiated at the time of award. 2. Consortium participants would submit data to the consortium databases in the specified format. 3. Upon submission, all data would be made freely available to the entire research community in a form that would allow for redisplay and reanalysis, so that maximal utility of this community resource could be achieved. It is NHGRI's expectation that users of these data would respect the legitimate interests of the producers to analyze and publish their results by treating the data as unpublished information, until otherwise indicated. As with any unpublished data, it would be expected that users would provide proper citation of the source of the data. The best interests of all are served when all act responsibly to promote the highest standards of respect for scientific work. In some cases, this might best be done by discussion or coordination with the resource producers. 4. The individual investigators within the consortium may publish the results of their own work that have been submitted to the ENCODE project's database(s) in the course of that work. Neither these individual publications nor any consortium publications should hold up the other's publications. 5. The consortium intends to publish global analyses of the results of the pilot project. At the same time, the consortium recognizes that it has the responsibility to do so in a timely manner. While it is not possible, at present, to predict an appropriate time for any such publication(s), the consortium, with guidance from the Scientific Advisory Panel, will establish a timeframe once the project has been launched and there is a better understanding of the timeframe and scope of the project. 6. Publicly funded consortium participants would fully disclose algorithms, software source code, and experimental methods to the other members of the consortium for purposes of scientific evaluation and will be strongly encouraged to make them available to the broad research community. Applicants should address data release in their applications either by agreeing to abide by the proposed ENCODE data release policy stated above or by proposing alternative approaches to make the ENCODE data available for the consortium to consider. Ultimately, the ENCODE consortium will develop a common data release policy for all participants. Funding of any award under this RFA will be contingent on negotiation of a data release policy that is acceptable to the applicant, to the consortium and to the NHGRI. Resources for the ENCODE project. To facilitate the project, the storage, display and release of data generated by the consortium will be coordinated through a central database. Ultimately, this database will become a knowledgebase that will be a central repository for information about the selected genome regions. This database will not be supported by this RFA. During the course of the ENCODE pilot project, it may be necessary or efficient for the NHGRI to provide common sets of reagents and resources in support of the consortium's research activities. It is not possible, however, to anticipate what resources may be needed prior to the establishment of the consortium and the funding of specific projects. Therefore, each applicant should propose to develop or procure the resources needed for the research project and request the necessary funds to do so. The costs for these resources should be clearly described in the budget justification section of the application. If common reagents and resources are developed through the course of the project, NHGRI will negotiate any appropriate changes to the award's budget. All common reagents developed for the consortium, including clones, microarrays, and software, would be made available to the entire scientific community. Training. The applicant is strongly encouraged to propose a plan in response to NHGRI's Action Plan for increasing the number of underrepresented minorities in genome research. Please see http://www.genome.gov/page.cfm?pageID=10003996 for a description of the Action Plan. In summary, applicants for awards under this RFA: 1. should provide plans to study the entire set of target regions; 2. should provide a detailed cost breakout for the development or procurement of specialized resources; 3. should provide specific plans for data release; 4. are strongly encouraged to provide a plan for training underrepresented minorities. MECHANISM OF SUPPORT This RFA will use the NIH U01 Research Project Cooperative Agreement, the U19 Research Program Cooperative Agreement, and the U41 Biotechnology Resource Cooperative Agreement award mechanisms in which the Principal Investigators retain the primary responsibility and dominant role for planning, directing, and executing their components of the ENCODE pilot project, with NIH staff being substantially involved as a partner with the Principal Investigators, as described under the section "Cooperative Agreement Terms and Conditions of Award". This RFA is a one-time solicitation, and uses just-in-time concepts. The earliest anticipated award date is September 30, 2003. Applications that are not funded in the competition described in this RFA may be resubmitted as NEW investigator-initiated applications using the standard receipt dates for NEW applications described in the instructions to the PHS 398 application. FUNDS AVAILABLE The NIH intends to commit approximately $10 million total costs in FY 2003 to fund five to fifteen awards in response to this RFA. An applicant may request a project period of up to three years. Awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. At this time, it is not known if this RFA will be reissued. ELIGIBLE INSTITUTIONS You may submit (an) application(s) 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 or foreign 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 FOR COOPERATIVE AGREEMENTS Cooperative Agreement Terms and Conditions of Award The following terms and conditions will be incorporated into the award statement of each cooperative agreement awarded under RFA HG-03-003 and will be provided to the Principal Investigators and the appropriate institutional officials at the time of award. The following special terms of award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, DHHS grant administration regulations at 45 CFR Parts 74 and 92, as are other DHHS, NIH, and (NHGRI) grant administration policies: 1. Cooperative Agreement The administrative and funding instruments used for this program will be the NIH U01 Research Project Cooperative Agreement, the U19 Research Program Cooperative Agreement, or the U41 Biotechnology Resource Cooperative Agreement award mechanisms. The cooperative agreement is an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH scientific and programmatic involvement with the awardee is anticipated during the performance of the activity. Under the Cooperative Agreement, the NIH purpose is to support and stimulate the recipient's activity by involvement in and otherwise working jointly with the award recipient in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Consistent with this concept, the dominant role and prime responsibility for the project as a whole will reside with the awardees, although specific tasks and activities in carrying out the study will be shared among the awardees and the NIH Program Director. 2. P.I. Rights and Responsibilities The P.I. will have the primary responsibility for defining the details for the project within the guidelines of RFA HG-03-003 and for performing the scientific activities. The P.I. will agree to accept close coordination, cooperation, and participation of NIH staff in those aspects of scientific and technical management of the project as described under "NIH Program Staff Responsibilities". The P.I. of an ENCODE pilot project component will: o Determine experimental approaches, design protocols, set project milestones, and conduct experiments. o Analyze the entire set of selected regions and not just a subset of the target sequences; OR, lead a research group composed of several individuals with a shared experimental approach with each individual examining a part of the target sequences, provided that the group as a whole will gather data on the entire set of target regions and that the P.I. will take responsibility for this. o Share results according to the data sharing policy developed for and by this project. o Participate in group activities, including attending periodic workshops to discuss the project's progress and coordinating the publication of research results. o Fully disclose all algorithms, software source code, and experimental methods to the other members of the consortium for purposes of scientific evaluation. o Not disclose confidential information obtained from other members of the consortium. o Adhere to NHGRI policies regarding intellectual property and other policies that might be established during the course of this activity. o Submit periodic progress reports in a standard format, as agreed upon by the Coordinating Committee and Scientific Advisory Panel. o Accept and implement the common guidelines and procedures approved by the Coordinating Committee, Scientific Advisory Panel and NHGRI. 3. NIH Program Staff Responsibilities The NIH Program Director is a scientist of the NHGRI extramural staff who will provide normal stewardship of the award and, in addition, will have substantial scientific and programmatic involvement during the conduct of this activity through technical assistance, advice, and coordination. However, the role of NIH staff will be to facilitate and not to direct the activities. It is anticipated that decisions in all activities will be reached by consensus of the ENCODE Research Network Coordinating Committee and that NIH staff will be given the opportunity to offer input to this process. One NHGRI Program Director will participate as a member of the Coordinating Committee and will have one vote. The Program Director will have the following substantial involvement: o Participate with the other Coordinating Committee members in the group process of setting research priorities, 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 a liaison, helping to coordinate activities among and for the awardees, including acting as a liaison to the NHGRI, and as an information resource about extramural genome research activities. The Program Director will also coordinate the efforts of the Research Network with groups participating in the ENCODE consortium. o Attend all Coordinating Committee meetings as a 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 the Coordinating Committee. The NIH Program Director will be responsible for scheduling the time and preparing concise minutes or summaries of the Coordinating Committee meetings, which will be delivered to members of the group within 30 days after each meeting. o Report periodically on the progress of the ENCODE pilot project to the Director, NHGRI. o Provide relevant expertise and overall knowledge of NIH-sponsored research to facilitate the selection of scientists not affiliated with the awardee institutions to serve on the Scientific Advisory Panel. o Serve as a liaison between the Coordinating Committee and the Scientific Advisory Panel, attending Scientific Advisory Panel meetings in a non-voting liaison member role. o Serve on subcommittees of the Coordinating Committee and the Scientific Advisory Panel, as appropriate. o Assist awardees in the development, if needed, of policies for dealing with situations that require coordinated action. o Provide advice in the management and technical performance of the investigation. o Assist in promoting the availability of the ENCODE and related resources developed in the course of this project to the scientific community at large. o Participate in data analyses, interpretations, and, where warranted, co-authorship of the publication of results of studies conducted through the ENCODE Research Network. 4. Collaborative Responsibilities The Coordinating Committee will serve as the main governing board of the ENCODE Research Network established under this RFA. It is anticipated that additional coordination mechanisms will be set up with other U.S. and international groups that may join this effort. The Coordinating Committee membership will include one NIH Program Director and the P.I. from each awarded cooperative agreement. The Coordinating Committee may add additional members. Other government staff may attend the Coordinating Committee meetings, if their expertise is required for specific discussions. The Coordinating Committee will be responsible for coordinating the activities being conducted by the ENCODE Research Network. To address particular issues, the Coordinating Committee may establish working groups as needed, which will include representatives from the Research Network and the NHGRI and possibly other experts. Such groups might include ones to: 1) develop a list of common reagents needed for the pilot project; 2) address data management issues; 3) analyze the pilot project data; 4) develop quality standards and methods to assess data quality; and 5) handle communication issues and develop principles for reporting findings. 5. Scientific Advisory Panel A Scientific Advisory Panel will be established by the NHGRI to evaluate the progress of the ENCODE Research Network. The Scientific Advisory Panel will provide recommendations to the Director, NHGRI about the progress and scientific direction of all components of the program. The Scientific Advisory Panel will be composed of six to eight senior scientists with relevant expertise, although the membership may be enlarged permanently or on an ad hoc basis as needed. The Scientific Advisory Panel will meet at least twice a year; some meetings may be conducted by telephone conference. At least once a year, there will be a joint meeting with the Coordinating Committee to allow the members of the both the Scientific Advisory Panel and the Coordinating Committees to interact directly with each other. Twice a year the Scientific Advisory Panel will make recommendations regarding progress of the ENCODE Research Network and present advice to the Director of NHGRI about changes, if any, that may be necessary in the ENCODE Research Network program. 6. Arbitration Process Any disagreement that may arise on scientific or programmatic matters within the scope of the awards between award recipients and the NIH may be brought to arbitration. An Arbitration Panel will be convened, which will be composed of three members: (1) a designee of the awardee, (2) an NIH designee, and (3) a third designee with relevant expertise who is chosen by the other two. The Arbitration Panel will help resolve scientific or programmatic issues that develop during the course of work that restrict progress. This special arbitration procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with NIH regulations 42 CFR Part 50, Subpart D and HHS regulation at 45 CFR Part 16. 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 your questions about scientific/research issues to: Elise Feingold, PhD or Peter Good, PhD Program Directors Division of Extramural Research NHGRI Building 31, Room B2B07 Bethesda, MD 20892-2033 Telephone: (301) 496-7531 FAX: (301) 480-2770 Email: Elise_Feingold@nih.gov or GoodP@mail.nih.gov o Direct your questions about peer review issues to: Rudy Pozzatti, PhD Scientific Review Administrator Division of Extramural Research NHGRI Building 31, Room B2B37 Bethesda, MD 20892-2032 Telephone: (301) 402-0838 FAX: (301) 435-1580 Email: pozzattr@mail.nih.gov o Direct your questions about financial or grants management matters to: Jean Cahill Chief, Grants Administration Branch Division of Extramural Research NHGRI Building 31, Room B2B34 Bethesda, MD 20892-2031 Telephone: (301)435-7858 FAX: (301) 402-1951 Email: cahillj@mail.nih.gov 7. Prospective applicant meeting. There will be a combined meeting at the Natcher Conference Center on the NIH campus from 9:00 a.m. to approximately 2:00 p.m. on March 7, 2003 to launch the ENCODE project and to answer questions about the RFA from prospective applicants. Attendance at this meeting is not a prerequisite for responding to the RFA or for participation in the ENCODE consortium. For more information about this meeting, see http://www.genome.gov/Pages/Research/ENCODE/ or email: encode@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 IC 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: Elise Feingold, PhD Program Director, Genome Analysis Program Division of Extramural Research NHGRI Building 31, Room B2B07 Bethesda, MD 20892-2033 Telephone: (301) 496-7531 FAX: (301) 480-2770 Email: Elise_Feingold@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) 710-0267, 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 THE NIH: 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: Rudy Pozzatti, PhD Scientific Review Administrator Division of Extramural Research NHGRI Building 31, Room B2B37 Bethesda, MD 20892-2032 Telephone: (301) 402-0838 FAX: (301) 435-1580 Email: pozzattr@mail.nih.gov APPLICATION PROCESSING: Applications must be received on or before 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. Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within 8 weeks. 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. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to an RFA, it is to be prepared as a NEW application. That is the application for the RFA must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes. While the investigator may still benefit from the previous review, the RFA application is not to state explicitly how. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NHGRI. Incomplete 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 NHGRI 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 Council for Human Genome Research. 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. The application must be directed toward attaining the programmatic goals as stated under RESEARCH OBJECTIVES. The following criteria will be used by peer review groups to evaluate these applications: (1) SIGNIFICANCE: Does the application address the problem outlined in this RFA? (2) APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project as outlined in this RFA? Are potential problem areas acknowledged and alternative tactics considered? Does the applicant propose to study the entire set of target regions? Does the technical approach have the potential to be applied efficiently and cost-effectively at large scale? Will the experiments proposed demonstrate that potential? (3) INNOVATION: Does the project employ novel concepts, approaches, or methods for identifying and verifying sequenced-based functional elements? Does the project develop new methods or technologies to reduce costs or increase quality or throughput? (4) INVESTIGATOR: Are the principal investigator, key personnel, and any collaborators appropriately trained and well suited to carry out this work? Is the work proposed appropriate for the experience of the P.I., key personnel, and any collaborators? (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? Are any collaborative arrangements appropriate? Is there evidence of institutional support? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following items will be considered in the determination of scientific merit and the priority score: o PROTECTIONS: 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 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. o DATA RELEASE: The adequacy of the proposed plan to release data in concert with the guidelines stated in this RFA. o BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: April 13, 2003 Application Receipt Date: May 13, 2003 Peer Review Date: July 2003 Council Review: September 2003 Earliest Anticipated Start Date: September 30, 2003 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit, as determined by peer review o Plans for data release and intellectual property o Variety in scientific approaches o Efficiency of scientific approach o Availability of funds o Programmatic priorities 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 Grant0s 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. HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at http://grants.nih.gov/grants/stem_cells.htm and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see http://escr.nih.gov). It is the responsibility of the applicant to provide the official NIH identifier(s)for the hESC line(s)to be used in the proposed research. Applications that do not provide this information will be returned without review. 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 at http://www.cfda.gov/ 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. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm. 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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