ADDITIONAL GENOTYPING FOR THE HUMAN HAPLOTYPE MAP RELEASE DATE: April 16, 2004 RFA Number: RFA-HG-04-005 EXPIRATION DATE: June 26, 2004 Department of Health and Human Services (DHHS) PARTICIPATING ORGANIZATION: National Institutes of Health (NIH) (http://www.nih.gov/) COMPONENTS OF PARTICIPATING ORGANIZATION: National Human Genome Research Institute (NHGRI) (http://www.genome.gov/) National Cancer Institute (NCI) (http://www.nci.nih.gov/) National Center for Research Resources (NCRR) (http://www.ncrr.nih.gov/) National Institute on Aging (NIA) (http://www.nia.nih.gov/) National Institute on Alcohol Abuse and Alcoholism (NIAAA) (http://www.niaaa.nih.gov/) National Institute on Deafness and Other Communication Disorders (NIDCD) (http://www.nidcd.nih.gov/) National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (http://www.niddk.nih.gov/) National Institute on Drug Abuse (NIDA) (http://www.nida.nih.gov/) National Institute of Environmental Health Sciences (NIEHS) (http://www.niehs.nih.gov/) National Institute of General Medical Sciences (NIGMS) (http://www.nigms.nih.gov/) National Institute of Mental Health (NIMH) (http://www.nimh.nih.gov/) National Institute of Neurological Disorders and Stroke (NINDS) (http://www.ninds.nih.gov/) Fogarty International Center (FIC) (http://www.fic.nih.gov/) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBERS: This program is described in the Catalog of Federal Domestic Assistance No. 93.172, 93.394, 93.389, 93.866, 93.273, 93.173, 93.848, 93.847, 93.849, 93.279, 93.114, 93.862, 93.242, 93.853, and 93.989. LETTER OF INTENT RECEIPT DATE: May 28, 2004 APPLICATION RECEIPT DATE: June 25, 2004 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanisms 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 Supplementary Instructions o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations PURPOSE OF THIS RFA This RFA solicits applications for a cooperative agreement to augment the International HapMap Project by supporting the genotyping of approximately 2.25 million single nucleotide polymorphisms (SNPs) across the genome in 270 samples from four populations, at high quality and at a cost of about 1 cent per genotype. The data from this effort will contribute to the development of a map, called the HapMap, of the haplotype patterns in the human genome and of a set of SNPs that are informative about these patterns and the associations among the SNPs. The HapMap is expected to be a key resource that researchers will use to find genes that affect health, disease, and response to drugs and environmental factors. The genotyping supported by this RFA will augment the current efforts of the HapMap Project by substantially increasing the number of SNPs that will be studied, thereby increasing the quality of the HapMap and its usefulness as a resource for understanding human genetic variation and its role in health and disease. This RFA builds on a previous RFA, HG-02-005 Large-Scale Genotyping for the Haplotype Map of the Human Genome (http://grants.nih.gov/grants/guide/rfa-files/RFA-HG-02-005.html). RESEARCH OBJECTIVES Background Many common diseases, such as diabetes, cancer, stroke, Alzheimer’s disease, Parkinson’s disease, psychiatric disorders, alcoholism, heart disease, deafness, arthritis, and asthma, are influenced by multiple genetic and environmental factors. Relatively little is known about the genetic bases of these common diseases, or of the factors that determine individual risk of disease, clinical course, or response to treatment. Discovering the particular DNA sequence variants that contribute to common disease risk offers one of the best opportunities for illuminating pathways of disease causation in humans. Sites in the genome where individuals differ in their DNA sequence by a single base are called single nucleotide polymorphisms (SNPs). About 10 million SNPs are common in human populations. SNPs are not inherited independently. Rather, sets of adjacent SNP alleles are generally associated because they are inherited together. A specific set of such associated SNP alleles is called a haplotype. Most chromosome regions have only a few common haplotypes. This means that although a region may contain many SNPs, it can be characterized by a few SNPs that uniquely identify, or tag , each of the haplotypes in the region. Most common haplotypes occur in all human populations, although their frequencies may vary among populations. Thus, the optimal choice of tag SNPs will need to be based on information from several populations. The goal of the International HapMap Project is to produce a resource that describes the haplotypes in the human genome and the SNPs that tag them. It is estimated that roughly 300,000 to 500,000 tag SNPs can be chosen that contain most of the information on the patterns of variation of the 10 million common SNPs in the human genome. By using the HapMap tag SNPs, researchers will be able to examine candidate regions or even the entire genome for association with a phenotype in an efficient and comprehensive way. The International HapMap Consortium is a collaboration among researchers in six countries: Japan, the United Kingdom, Canada, China, Nigeria, and the U.S. An earlier RFA (http://grants.nih.gov/grants/guide/rfa-files/RFA-HG-02-005.html) solicited research proposals for genotyping SNPs in the chromosomes that are to be done by U.S. researchers for the Project, which is almost one-third of the genome. The HapMap Project is studying a set of 270 samples with geographic ancestry from four populations: 30 trios (both parents and an adult child) from the Yoruba people of Ibadan, Nigeria, 45 unrelated Japanese living in the Tokyo area, 45 unrelated Han Chinese living in Beijing, and 30 trios from U.S. donors with ancestry from Northern and Western Europe, originally collected by the Centre d Etude du Polymorphisme Humain (CEPH). The living CEPH donors provided consent for the use of their samples for this Project; the IRB approved the use of samples from the deceased donors. The samples from Nigeria, Japan, and China were collected after a process of community engagement and individual informed consent; these samples are stored as cell lines at the non-profit Coriell Institute for Medical Research, as part of the NIH NIGMS Human Genetic Cell Repository (http://locus.umdnj.edu/nigms/). More information is at the Project website http://www.hapmap.org, and in the paper Nature 426: 789-796 (2003) http://www.nature.com/nature/. Since the start of the HapMap Project in October of 2002, six million SNPs have been added to public databases, the new samples have been collected and are almost ready for use, much of the scientific strategy has been refined, and the genotyping of about 600,000 SNPs in all the samples is expected to by done by the fall of 2004. The Consortium has established working groups to address ethical and cultural issues, data flow, quality control, analysis, data release, intellectual property issues, and communications. The data produced by the Consortium are rapidly released, with some of the data available from the public database dbSNP (http://www.ncbi.nlm.nih.gov/SNP/), and some available from the HapMap Data Coordination Center at the Cold Spring Harbor Laboratory under the terms of a clickwrap license that requires only that users must not restrict the ability of others to use the data (http://www.hapmap.org/downloads/datarelease.html). Ongoing assessment of the genotype data quality is being done; the data are estimated to be about 98% complete and 99.5% accurate. The initial plan for producing the HapMap was to genotype the samples for about 1 to 1.5 million SNPs, of which about 300,000 to 500,000 would be chosen as the tag SNPs. There was, however, some uncertainty about whether this coverage of the genome would be adequate to develop the HapMap, especially in chromosome regions with low linkage disequilibrium (LD). There was also concern about whether this would provide adequate coverage for the Yoruba samples, which are expected to have less LD than samples from the other populations (Gabriel SB, et al. Science 296: 2225-2229 (2002)). This RFA is being issued in response to recent technology improvements that have led to a large reduction in the cost of genotyping. NHGRI estimates that it should now be possible to do large-scale genotyping for about one cent per genotype, which is considerably lower than the cost at the start of the HapMap Project, and therefore to obtain more genotyping than had been planned initially. This RFA is designed to augment the work that the Consortium is doing and not substitute for genotyping that is already planned by the currently funded genotyping centers; this is an opportunity to enhance the work by providing more depth of coverage. When combined with the extensive set of genotype data already produced and planned by the current Consortium, these additional data will greatly improve the HapMap, providing adequate coverage of the genome in all the samples and much better resolution of haplotypes, especially in regions with low LD. The choice of tag SNPs should be much better and thus more useful for association studies using the HapMap. Research Scope The goal of the HapMap Project is to develop a genome-wide haplotype map by identifying the common haplotypes in the human genome and defining a set of tag SNPs that best describes the pattern of variation and association among the SNPs, using the population samples discussed above. This RFA is intended to solicit research proposals for the large-scale SNP genotyping needed to properly complete the HapMap. Genotyping is to be done successfully for at least 2.25 million SNPs in the 270 HapMap samples (plus 15 duplicates and 3 blank controls) in less than one year. The genotyping is to be done at a total cost of about 1 cent or less per successful genotype, at quality standards agreed on by the International HapMap Consortium, of at least 99.5% accuracy and 98% completeness. It is anticipated that the group supported by this RFA will become a member of the International HapMap Consortium. Coordination of the overall Project is through the International HapMap Consortium Steering Committee, which is composed of the investigators, chairs of the working groups, and the representatives of the funding agencies. The awardee will be expected to cooperate closely with the other HapMap groups and the funding agencies. The awardee will choose which SNPs to genotype, will genotype the SNPs, will release the genotype data and related data quickly to the HapMap Data Coordination Center, and will participate in quality assessment exercises, following the procedures and policies agreed on by the International HapMap Project Steering Committee, and in consultation with the NHGRI and the HapMap Analysis Group. Assay information for new SNPs not already in dbSNP will be sent to dbSNP. It is anticipated that the Project will end by the fall of 2005. To meet this goal, the Project’s Analysis Group will need the summer to produce the HapMap from the genotype data. The genotype data will be most useful if they are produced as soon as possible; thus, most of the genotyping supported by this RFA should be done by March of 2005. MECHANISM OF SUPPORT This RFA will use the NIH U54 Specialized Center Cooperative Agreement award mechanism. The applicant will be solely responsible for planning, directing, and executing the proposed project. The anticipated award date is September 17, 2004. This RFA uses just-in-time concepts. It uses the non-modular budgeting format (see http://grants.nih.gov/grants/funding/modular/modular.htm). This program does not require cost sharing as defined in the current NIH Grants Policy Statement at http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part2.htm. The NIH U54 Specialized Center is a cooperative agreement award mechanism. In the cooperative agreement mechanism, 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". There are no plans to reissue this RFA. FUNDS AVAILABLE The NHGRI intends to commit approximately $6.5 million in total costs in FY 2004, and anticipates funding one new award in response to this RFA. An applicant should request a project period of one year. Although the financial plans of the NHGRI provide support for this program, any awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. The funded research group will become a participant in the HapMap Research Network, and be subject to a semi-annual evaluation of progress by the Scientific Advisory Panel of the HapMap Network (see below for details). 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 or foreign institutions/organizations 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 his or her 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. In order to achieve the goals of this RFA, to generate large amounts of genotype data within one year at the target cost and quality levels, only investigators who have demonstrated experience with large-scale low-cost SNP genotyping will be eligible to apply. SPECIAL REQUIREMENTS NHGRI AND INTERNATIONAL HAPMAP CONSORTIUM POLICIES CONCERNING DATA RELEASE, INTELLECTUAL PROPERTY, AND DATA QUALITY NIH supports the goals of the International HapMap Project to release the genotype and related data produced by the International HapMap Consortium in a timely manner, and to ensure that the HapMap will be freely available to all researchers. The NHGRI thus has adopted the International HapMap Consortium’s policies and procedures for data submission and release, which were designed to ensure the access of researchers to the HapMap data (Nature 426: 789-796 (2003), http://www.hapmap.org/downloads/datarelease.html , http://www.hapmap.org/cgi-perl/registration ). These procedures are: o All new SNPs identified by the Project are sent directly to the NIH public database dbSNP (http://www.ncbi.nlm.nih.gov/SNP/). o Genotype data are submitted to the HapMap Data Coordination Center (DCC) at the Cold Spring Harbor Laboratory on a monthly basis (http://www.hapmap.org). o The DCC calculates SNP allele and genotype frequencies and submits them to dbSNP, which releases them publicly in the next dbSNP build. o The individual genotype data are released by the DCC on a monthly basis. To obtain access to these data, a user must agree to the terms of a license (http://www.hapmap.org/downloads/datarelease.html), which requires only that users not restrict the access of others to the data, and that they share the data only with others who have agreed to the same terms. o When a sufficient density of SNPs has been genotyped in a chromosome region to determine haplotypes, the individual genotype data and the haplotype data will be sent to dbSNP for public release, at which time the license restrictions will be removed for those data. o At the end of the Project, all remaining data will be released to dbSNP, and license restrictions will no longer apply. The International HapMap Consortium members have also agreed that their own laboratories will access the data only through the DCC and under the license terms, to ensure that all scientists have equal access to the data for research in which the HapMap is used. The Consortium believes that SNP, genotype, and haplotype data in the absence of specific utility do not constitute appropriately patentable inventions; however, this policy does not block users from filing for appropriate intellectual property on associations they have found relating SNPs or haplotypes to particular phenotypes, as long as any ensuing patent is not used to prevent others' access to the basic HapMap data, in accordance with the terms of the license. Applicants are required to explain their plans for data sharing and exercising their intellectual property rights. If the plans differ from what the International HapMap Consortium has adopted, the applicant should discuss the differences and explain how the proposed approaches meet the Consortium’s objective of ensuring rapid access to the Project’s data. The reviewers and NHGRI staff will evaluate the adequacy of these plans. Plans acceptable to NHGRI and the applicant will need to be arrived at before an award can be made. The International HapMap Consortium has developed processes to assess the quality of genotyping data produced by its members. Applicants will need to agree to participate in the data quality assessment exercises established by the Consortium and adopted by the NHGRI. As the quality of the genotyping data that a research group has produced over the last year is likely to be a reasonable general indicator of the quality of the genotyping data that it will produce, applicants should describe in detail the quality of their genotyping data and how it was assessed. Instructions for presenting these data are given below. It will be particularly useful for the reviewers, as they evaluate the quality of the genotyping, to have results from a standard set of SNPs and samples. NHGRI has identified a standard set of 200 SNPs (see http://www.genome.gov/11511477). Applicants are strongly encouraged to genotype these SNPs in the set of 90 HapMap CEPH samples plus 5 duplicates (available from the Coriell Institute for Medical Research, http://locus.umdnj.edu/ccr/), and to submit these data to the NHGRI Program Director by July 6, 2004, for analysis by NHGRI and the reviewers. It is anticipated that the awardee from this RFA will become a member of the International HapMap Consortium. 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-04-005 and will be provided to the Principal Investigator 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, and other DHHS, NIH, and NIH grant administration policies. These terms and conditions are the same as for RFA HG-02- 005, released in March of 2002; in practice the role of the Coordinating Committee is played by the International HapMap Project Steering Committee. 1. Cooperative Agreement The administrative and funding instruments used for this program will be the Specialized Center Cooperative Agreement (U54). 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-04-005 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 a HapMap genotyping research group will: o Determine experimental approaches, design protocols, set project milestones, and conduct experiments. o Ensure that the amount of genotyping agreed upon is accomplished. o Ensure that the genotyping meets or betters the cost agreed upon. o Submit data for quality assessment in any manner specified by the Coordinating Committee and the Scientific Advisory Panel. o Ensure that the genotyping quality meets or exceeds the standards agreed to by the Coordinating Committee and the Scientific Advisory Panel. o Ensure that the choice of SNPs to genotype is done by the methods agreed to by the Coordinating Committee, and the Scientific Advisory Panel. o Ensure that the analyses of haplotypes, haplotype blocks, and tag SNPs is done by the methods agreed to by the Coordinating Committee and the Scientific Advisory Panel. o Ensure that the data resources developed as part of this project, including individual genotypes, haplotypes, haplotype blocks, and tag SNPs, are released according to NHGRI policies, by procedures developed by the Coordinating Committee, and that results are submitted to dbSNP. o Adhere to the 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 the Scientific Advisory Panel. o Accept and implement the common guidelines and procedures approved by the Coordinating Committee. o Accept and participate in the cooperative nature of the group. o Attend Coordinating Committee meetings. o Coordinate and collaborate with other U.S. and international groups producing the HapMap. 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 HapMap Network and that NIH staff will be given the opportunity to offer input to this process. The NIH Program Director will participate as a member of the Coordinating Committee and will have one vote. The NIH 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 NIH 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 the other Institutes and Centers of the NIH, and as an information resource about extramural genome research activities. The NIH Program Director will also coordinate the efforts of the HapMap Network with other U.S. and international groups participating in the HapMap Project. 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 NIH 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 HapMap Project to the Directors of the NHGRI and other NIH Institutes and Centers. o Provide relevant expertise and overall knowledge of NIH-sponsored research to facilitate the selection of scientists not affiliated with the awardee institutions who are to serve on the Advisory Panel and the Coordinating Committee. o Serve as a liaison between the Coordinating Committee and the Scientific Advisory Panel, attending 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 HapMap and related resources developed in the course of this project to the scientific community at large. o Retain the option to recommend, with the advice of the Scientific Advisory Panel, the withholding or reduction of support from any project within the HapMap Network that substantially fails to achieve its genotyping goals at the cost agreed to or the quality agreed upon by the Coordinating Committee, fails to remain state of the art in its genotyping capabilities, or fails to comply with the Terms and Conditions of the award. o Participate in data analyses, interpretations, and, where warranted, co-authorship of the publication of results of studies conducted through the HapMap Network. 4. Collaborative Responsibilities The Coordinating Committee will continue to serve as the main governing board of the HapMap Network established under this RFA. It is anticipated that additional coordination mechanisms will be set up with the 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 with other groups working on the HapMap and for advising NIH as to how the HapMap Consortium can complete the HapMap within the stated goals of time and accuracy, and within budget. To address particular issues, the Coordinating Committee may establish groups as needed, which will include representatives from the grantees and the funding agencies, and possibly other experts. Such groups might include an analysis group to develop uniform methods to choose SNPs for study, define haplotype blocks and haplotypes, and choose the tag SNPs, as well as develop overall analyses of the data; a quality group to develop quality standards and methods to assess data quality; and a communication group to develop principles for explaining the project and reporting findings. The Coordinating Committee will develop procedures for data flow to ensure quality checks of the data and deposition in public databases. Members of the Coordinating Committee will be required to accept and implement the common guidelines and procedures approved by the Coordinating Committee. 5. Scientific Advisory Panel A Scientific Advisory Panel may be established to evaluate the progress of the HapMap Network toward producing the HapMap. The Scientific Advisory Panel will provide recommendations to the Directors of NHGRI and the other participating Institutes and Centers about continued support of all components of the program. The Scientific Advisory Panel will be composed of three to five 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 by telephone conference. The first part of the meeting will be a joint meeting with the Coordinating Committee to allow the members of the two committees to interact directly with each other. Twice a year the Scientific Advisory Panel will make recommendations regarding progress of the HapMap Network and present advice to the Directors of NHGRI and the other participating Institutes and Centers about changes, if any, that may be necessary in the HapMap Network program. If other funding agencies fund projects with the same goal as this RFA, the Advisory Panel may be modified to accommodate this situation by mutual consent of the agencies involved. 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. 7. Semi-Annual Milestones All awardees participating in the HapMap Network will be asked to define semi- annual milestones at the time of the award and to update these milestones every six months. These will be made a condition of the award. In accord with the procedures described above, NIH may withhold or reduce funds for projects that substantially fail to meet their milestones or to maintain the state of the art. 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 Applicants are strongly encouraged to consult with the Program Director early in the process of preparing an application. Direct your questions about scientific and research issues to: Michael Shi, M.D., Ph.D. National Human Genome Research Institute 31 Center Dr., Room B2B07 Bethesda, MD 20892-2033 Telephone: (301) 451-1340 Fax: (301) 480-2770 michael.shi@nih.hhs.gov Lisa Brooks, Ph.D. National Human Genome Research Institute 31 Center Dr., Room B2B07 Bethesda, MD 20892-2033 Telephone: (301) 435-5544 Fax: (301) 480-2770 lisa.brooks@nih.hhs.gov Wendy Wang, Ph.D. National Cancer Institute 6130 Executive Blvd., EPN 3138 Bethesda, MD 20852-7362 Telephone: (301) 594-7607 wangw@mail.nih.gov Marjorie Tingle, Ph.D. National Center for Research Resources 1 Democracy Plaza, Room 958 Bethesda, MD 20892-4874 Telephone: (301) 435-0772 TingleM@mail.nih.gov Anna McCormick, Ph.D. National Institute on Aging Gateway Building, Suite 2C231 Bethesda, MD 20892-9205 Telephone: (301) 496-6402 am38k@nih.gov Zhaoxia Ren, M.D., Ph.D. National Institute on Alcohol Abuse and Alcoholism 5635 Fishers Lane, Room 2052 Bethesda, MD 20892-9304 Telephone: (301) 443-5733 zren@mail.nih.gov Bracie Watson, Jr., Ph.D. National Institute on Deafness and Other Communication Disorders 6120 Executive Blvd., EPS Suite 400C Bethesda, MD 20892-7180 Telephone: (301) 402-3458 watsonb@nidcd.nih.gov Catherine McKeon, Ph.D. National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Blvd., Room 6103 Bethesda, MD 20892-5460 Telephone: (301) 594-8810 McKeonC@ep.niddk.nih.gov Jonathan Pollock, Ph.D. National Institute on Drug Abuse 6001 Executive Blvd., Room 4282 Bethesda, MD 20892-9555 Telephone: (301) 443-6300 jpollock@mail.nih.gov Gwen Collman, Ph.D. National Institute of Environmental Health Sciences P.O. Box 12233, Mail Drop EC-21 Research Triangle Park, NC 27709 Telephone: (919) 541-4980 collman@niehs.nih.gov Richard Anderson, M.D., Ph.D. National Institute of General Medical Sciences 45 Center Drive, Room 2AS-25B Bethesda, MD 20892-6200 Telephone: (301) 594-0943 andersor@nigms.nih.gov Steven Moldin, Ph.D. National Institute of Mental Health 6001 Executive Blvd., Room 7191 Bethesda, MD 20892-9643 Telephone: (301) 443-2037 smoldin@mail.nih.gov Danilo A. Tagle, Ph.D. National Institute of Neurological Disorders and Stroke Neuroscience Center 6001 Executive Boulevard, Room 2133 Bethesda, MD 20892-9527 Telephone: (301) 496-5745 tagled@ninds.nih.gov Flora Katz, Ph.D. Fogarty International Center 31 Center Drive, Room B2C39Q Bethesda, MD 20892-2220 Telephone: (301) 402-9591 katzf@mail.nih.gov o Direct your questions about peer review issues to: Rudy Pozzatti, Ph.D. Scientific Review Branch National Human Genome Research Institute Building 31, Room B2B37 31 Center Dr., MSC 2032 Bethesda, MD 20892-2032 Telephone: (301) 402-8739 Fax: (301) 435-1580 rudy_pozzatti@nih.gov o Direct your questions about financial or grants management matters to: Ms. Cheryl Chick Grants Administration Branch National Human Genome Research Institute Building 31, Room B2B34 31 Center Dr., MSC 2032 Bethesda, MD 20892-2031 Telephone: (301) 402-0733 Fax: (301) 402-1951 cheryl.chick@nih.hhs.gov LETTER OF INTENT Prospective applicants are strongly encouraged 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 May 28, 2004. The letter of intent should be e-mailed to: Michael Shi, M.D., Ph.D. Program Director Genetic Variation Program National Human Genome Research Institute 31 Center Dr., 31 / B2B07 Bethesda, MD 20892-2033 Telephone: (301) 451-1340 Fax: (301) 480-2770 michael.shi@nih.hhs.gov SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). Applications must have a DUN and Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the Universal Identifier when applying for Federal grants or cooperative agreements. The DUNS number can be obtained by calling (866) 705-5711 or through the web site at http://www.dunandbradstreet.com/. The DUNS number should be entered on line 11 of the face page of the PHS 398 form. The PHS 398 document 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. SUPPLEMENTARY INSTRUCTIONS SPECIAL APPLICATION GUIDANCE FOR PRODUCTION GENOTYPING Applicants should address the following when preparing applications for the genotyping production called for in this RFA. Items A D in the application should not exceed 25 pages. I. Prior Experience (as part of item C in the application) In order to complete the genotyping for the HapMap within one year and at the target cost, only investigators who have demonstrated experience with large-scale low-cost SNP genotyping will be eligible to apply. The NHGRI has conducted several competitions for large-scale projects during the past few years. Our experience has been that specific information items are central to the review of large-scale production proposals, and that the most highly rated applications have provided that information clearly and succinctly. How do your group's past efforts support its ability to successfully contribute to the HapMap? Discussion should include, but not be limited to: Prior experience in large-scale SNP genotyping: How many unique SNP assays did your group develop and use in the last year? What proportion of the assays worked successfully? How much genotyping per month did your group do in the last three (or more) months? How much genotyping did your group do in the last year? Prior experience with genotyping quality: Describe the quality (completeness, concordance, accuracy) of the genotypes your group has produced recently, how your group estimated these quality measures, and how the quality information was used to improve the genotyping process. Prior experience with low-cost genotyping: Describe the cost of the genotyping that your group has produced recently. The total costs should be described, including equipment, personnel, and Fiscal and Administrative costs (F&A, indirect costs), not just reagent costs. Prior experience in attaining milestones: What examples can you provide that you have proposed milestones for genotyping and met them on schedule? What internal metrics do you use to evaluate progress? II. Research Proposal (as part of item D in the application) Genotyping platform: The applicant should justify the genotyping platform proposed for use. If the platform does not perform uniformly across the entire genome or for all types of samples, describe any differences in how well it works in certain types of genomic regions or for certain types of samples. Explain how the efforts of the current HapMap genotyping centers could coordinate with the proposed effort to maximize the overall information provided by the Project. Genotype production plan: The applicant should present a plan to implement large-scale genotyping, and propose milestones for achieving the proposed genotyping production within the specified time frame. This plan should thoroughly discuss and justify the applicant's specific choices for all phases of the genotyping pipeline, including choosing SNPs to study, producing primers, genotyping, assessing genotype quality, and depositing genotype data in the DCC. It will be important to discuss potential bottlenecks or other problems that may be anticipated and how they will be addressed. The applicant should make clear how much of a ramp-up the proposed production plans are from the current production capacity. Genotyping costs: Include all costs for genotyping production. The calculated costs of genotyping should take into account all of the expenses associated with large-scale high-quality genotyping, including obtaining the samples from the Coriell Institute, choosing SNPs (in cooperation with the Analysis Group), developing genotyping assays, obtaining primers, genotyping SNPs, repeating failed genotyping reactions, genotyping additional SNPs to compensate for those that failed, assessing genotype quality, analyzing the data to guide future production, and depositing the data. Applicants should also provide a breakdown of costs so that the reviewers can evaluate the contribution of different cost elements, such as personnel, equipment, and reagents and consumables to the reported total cost. Cost analyses should be presented in terms of both direct costs and of total costs, which include Fiscal and Administrative (F&A) costs. Applicants should explain how they monitor costs internally. Analysis costs: Costs for the analysis to choose the SNPs to genotype, to assess the SNP coverage of the genome, and to coordinate with the efforts of other genotyping groups should be included. Other costs: Costs should be included for the PI and up to two additional individuals to attend five meetings of the International HapMap Consortium before the end of calendar year 2005; probably three of these meetings will be at non- U.S. sites. All components of total costs, including genotyping costs, failed genotyping costs, analysis costs, other costs, and indirect costs, should be counted in the cost goal of about 1 cent per genotype. Genotype quality: The applicant should describe the plan for monitoring the quality of the genotyping process. Internal quality control programs should be described, including quality assessment criteria. It will be particularly useful for the reviewers, as they evaluate the quality of the genotyping, to have results from a standard set of SNPs and samples. NHGRI has identified a standard set of 200 SNPs (see http://www.genome.gov/11511477). Applicants are strongly encouraged to genotype these SNPs in the set of 90 HapMap CEPH samples plus 5 duplicates (available from Coriell http://locus.umdnj.edu/ccr/), and to submit these data to the NHGRI Program Director by July 6, 2004, for analysis by NHGRI and the reviewers. Data sharing plan and intellectual property plan: Applicants are required to explain their plans for data sharing and exercising their intellectual property rights. If the plans differ from what the International HapMap Consortium has adopted, the applicant should discuss the differences and explain how the proposed approaches meet the Consortium’s objective of ensuring rapid access to the Project’s data. The reviewers and NHGRI staff will evaluate the adequacy of these plans. Plans acceptable to NHGRI and the applicant will need to be arrived at before an award can be made. Management plan: The applicant should describe how this project would be managed, including decision-making processes and oversight for attaining milestones. Since the management of this project would require a significant time commitment, the P.I. is expected to devote at least 25% effort to this project. III. Human Subjects (as part of item E in the application) The applicant should address human subjects issues. The samples to be used for this project were collected with individual informed consent for participation in the HapMap Project; the new samples were also collected after a process of community engagement. The samples to be used will be publicly available through the NIGMS Human Genetic Cell Repository at the Coriell Institute (http://locus.umdnj.edu/ccr/). Thus, while NHGRI considers that the research funded under this RFA will involve Human Subjects, NHGRI expects that most IRBs will find that exemption 4 applies (the study of existing samples in which the human subjects are not identifiable, directly or through identifiers linked to the subjects). Applicants should address inclusion issues. Of the 270 samples to be studied, 90 will come from a Yoruba population in Nigeria, 45 will come from a Japanese population, and 45 will come from a Han Chinese population, so there will be a large minority representation. Equal numbers of females and males will be studied. Children from ages 18 to 21 will be included. 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/labels.pdf. SENDING AN APPLICATION TO THE NIH: Submit a signed 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 and 5 copies of the appendix material must be sent to: Rudy Pozzatti, Ph.D. Scientific Review Branch National Human Genome Research Institute Building 31, Room B2B37 31 Center Dr., MSC 2032 Bethesda, MD 20892-2032 Telephone: (301) 402-8739 Fax: (301) 435-1580 rudy_pozzatti@nih.gov APPLICATION PROCESSING: Applications must be received on or before June 25, 2004. 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 from the previous unfunded version of the application. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NHGRI. Incomplete and/or nonresponsive applications will not be reviewed. 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 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 written critique; 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 evaluate the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. The scientific review group will address and consider each of the following criteria in assigning the application’s overall score, weighting them as appropriate for each application. o Significance o Quality, quantity, and cost of genotyping o Approach o Innovation o Investigator o Environment o Data sharing plans o Intellectual property plans o Budget The application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. SIGNIFICANCE: Does the application address the problem outlined in this RFA? QUALITY, QUANTITY, AND COST OF GENOTYPING: Will the applicant be able to produce the amount of genotype data at the cost and quality levels requested in this RFA? Are the plans for genotype production adequate? Are the plans for assessing data quality adequate? APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate for the aims of the project as outlined in this RFA? Are potential problem areas acknowledged and alternative tactics considered? INNOVATION: Does the project employ novel approaches or methods for genotyping that result in significant reductions in cost or increases in data quality or throughput? The emphasis of this RFA is on proven methods for producing high-quality genotype data at low cost; credible methods for doing this will be considered to represent sufficient innovation for this RFA. INVESTIGATOR: Are the principal investigator and key personnel appropriately trained and well suited to carry out this work? Is the work proposed appropriate for the experience of the P.I. and key personnel? Does the prior experience section provide sufficient evidence that the research group can carry out its part of the project? Are the management plan and the P.I.’s experience with management sufficient for this project? 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? 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: DATA SHARING PLANS: The adequacy of the proposed plans to share data in a timely manner. INTELLECTUAL PROPERTY PLANS: The adequacy of the proposed plans to maintain access to data. BUDGET: The reasonableness and cost-effectiveness of the proposed budget and the requested period of support in relation to the proposed research. PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed. (See criteria included in the section on Federal Citations, below). INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: 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. (See Inclusion Criteria in the sections on Federal Citations, below). RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: May 28, 2004 Application Receipt Date: June 25, 2004 Supplemental Genotyping Data Report Receipt Date: July 6, 2004 Peer Review Date: Late July or early August 2004 Council Review: September 13-14, 2004 Earliest Anticipated Start Date: September 17, 2004 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit (as determined by peer review) o Data quality and quantity o Cost-effectiveness o Plans for data release o Plans for intellectual property o Programmatic priorities o Availability of funds REQUIRED FEDERAL CITATIONS HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained. http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm SHARING RESEARCH DATA: Investigators submitting an NIH application seeking $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible. http://grants.nih.gov/grants/policy/data_sharing Investigators should seek guidance from their institutions, on issues related to institutional policies, local IRB rules, as well as local, state and Federal laws and regulations, including the Privacy Rule. 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. 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. 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.healthypeople.gov/. 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 the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) 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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