Full Text PAR-94-044 GENOME SCIENCE AND TECHNOLOGY CENTERS NIH GUIDE, Volume 23, Number 10, March 11, 1994 PA NUMBER: PAR-94-044 P.T. 34 Keywords: Human Genome Nucleic Acid Sequencing National Center for Human Genome Research PURPOSE [This Program Announcement supersedes the one that appeared in the NIH Guide for Grants and Contracts, Vol, 22, No. 20, June 4, 1993.] The purpose of this program announcement is to solicit new or renewal applications to the Genome Science and Technology Centers (GESTEC) program, which supports large-scale, multidisciplinary genomic studies. Specifically, the GESTEC program supports research to achieve the mapping and sequencing goals of the Human Genome Project as set forth in the New Five-Year Plan for the U.S. Human Genome Project (Science, Vol. 262, p. 43, October 1, 1993) in order to progress toward the ultimate goal of determining the complete sequence of human DNA. In order to achieve these goals GESTECs should have a central focus that addresses a specific goal of the Human Genome Program and should include the development of new technology needed for genome mapping and/or sequencing, the application of this technology to data production, informatics solutions to data management, and outreach to the scientific community. The development of techniques for identifying and mapping all of the genes and/or other functional elements in a large genomic region may be integral to the projects. Where appropriate, consideration of the ethical, legal and social implications of the Human Genome Project may also be included in a GESTEC. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State or local governments, and eligible agencies of the Federal government. While a single institu- tion must be the applicant, multi-institutional arrangements (consortia) are possible if there is a compelling reason for them and if there is clear evidence of close interaction among the participants. Applications from foreign institutions will not be accepted. However, subcontracts to foreign institutions are allowable, with sufficient justification. Applications from minority individuals and women are encouraged. Industrial/academic collaborations are also encouraged. In such collaborations, the respective contributions should be well- integrated into the design and operation of the center, to encourage cross-fertilization of ideas and rapid application of the research to practical purposes. MECHANISM OF SUPPORT Grants in the GESTEC program may be supported by Specialized Center Grants (P50) or Program Project Grants (P01). The P50 mechanism will be used for broader, more complex, multidisciplinary programs that address the goals of the Human Genome Project. The P01 mechanism will be used for programs that support a minimum of three components with a well-defined central research focus. The term of support for GESTEC projects is normally three to five years. RESEARCH OBJECTIVES Background The National Institutes of Health (NIH) is currently engaged, along with several other federal, private, and international organizations, in a 15-year research program designed to characterize the human genome and the genomes of selected model organisms. This research program, the Human Genome Project (HGP), has the following interrelated goals: (1) the construction of high-resolution genetic linkage maps; (2) the development of physical maps; (3) the determination of the complete nucleotide sequence of the human genome and the genomes of selected organisms; (4) the development of efficient methods of identifying genes and for placement of known genes on physical maps or sequenced DNA; (5) the development of the capability to collect, store, distribute and analyze the data and materials produced; (6) the development of appropriate new technologies to achieve these goals; and (7) the identification of major issues related to the ethical, legal and social implications (ELSI) of genome research, and the development of policy options to address them. The product of the Human Genome Project will be a set of information and material resources available to the entire research community that will facilitate further research leading to the prevention, diagnosis, and therapy of disease, as well as to further understanding of human biology. In 1990, the NCHGR and the Department of Energy (DOE) jointly published a plan that set out specific goals to be achieved in the first five-year phase of the U.S. human genome program. Anticipating the attainment of much of the initial set of goals, the NCHGR and DOE recently published the above-referenced new five-year plan extending the goals for the U.S. Human Genome Project. At the same time, the NCHGR centers program, which had supported several large-scale, multidisciplinary projects that have made significant contributions to the initial achievements, has undergone transition. As a part of this transition, NCHGR has established a reformulated centers program, the Genome Science and Technology Centers (GESTEC) program, that is intended to build upon the success of the earlier program and the lessons learned from it. This announcement solicits applications for new and continuing research that proposes to address the needs of the project as outlined in the new five year plan, leading toward complete sequencing of the human genome and the genomes of selected model organisms. Progress and Future Needs in Mapping For the genetic linkage map, several current efforts, both genome- wide or on an individual chromosome level, are expected to achieve the timely completion of the 2 to 5 centimorgan genetic map called for in the initial five-year plan. The new five-year plan calls for further development of genetic mapping technologies such as technology for rapid genotying and development of new, easier to use, markers. Similarly, recent progress in physical mapping has been very rapid. A number of contigs for long genomic regions, including two entire human chromosomes and parts of many others, having been assembled; A low resolution map covering a large fraction of the genome has recently been published. The physical mapping goal set forth in the new five-year plan is the attainment of a complete STS map of the human genome at a resolution of 100 kb. Physical maps of even higher resolution will eventually be needed as the substrate for DNA sequencing and for other research purposes. The new plan recognizes that continued technology development will be necessary to produce such maps. New techniques or strategies will be needed to generate physical maps that are accurate enough so that the DNA can be readily sequenced. It is assumed that the nature of the physical maps that will provide the substrate for DNA sequencing will be dependent upon the precise strategy for sequencing. Therefore, proposals to consider development of "sequence-ready" clone sets should be closely associated with an imminent intent to sequence. Progress and Future Needs in DNA Sequencing Progress has also been rapid toward the long-term goal of the Human Genome Program, i.e., determining the complete sequence of the DNA of certain model organisms and the human. In 1990, the cost of sequencing in laboratories devoted to DNA sequencing was estimated to be about $5 per finished base and the rate at which finished sequence could be generated was relatively low. Since its inception, the NCHGR has supported several efforts designed to test and refine current methods in large-scale projects or develop entirely new approaches to DNA sequencing that offer substantial improvements over current methods. Through these efforts, a number of advanced sequencing laboratories are within reach of being able to generate contiguous finished sequence at a rate of a few megabases per year and the cost is now projected to be below $1 per finished base pair. Several interesting regions of both human and non-human DNA have been sequenced in these projects. To build on this significant progress, multidisciplinary centers are needed to develop and implement visionary, integrated strategies that will optimize the several phases of DNA sequencing, including sample preparation, band resolution and detection, sequence assembly and finishing, and annotation. The new five-year plan calls for: development of efficient approaches to sequence one to several megabase regions of DNA in regions of high biological interest; development of technology for high throughput sequencing focusing on system integration of all steps; and building the sequencing capacity to a collective rate of 50 Mb per year by the end of 1998. The efforts in the GESTEC centers will be needed to accomplish these goals and must be carefully balanced between technology development and actual testing in a production mode in order that the new technology developed is effective and well-suited to achieving these ambitious goals. It is expected that, through previous feasibility studies, applicants for GESTEC program grants to support large-scale sequencing projects will have demonstrated their ability to sequence at high throughput in a cost effective manner and to manage a large- scale sequencing effort. Objectives and scope The GESTEC program is intended to foster and support innovative projects in which technology development and cost effectiveness are expected to push the limits of current capabilities. The GESTEC program is NOT intended to fund projects in which existing technology is simply applied to large-scale data production or projects that involve a consortium of investigators whose research interests are only loosely united by a common theme. To achieve the ambitious goals that this program is intended to attain, it is anticipated that a Genome Science and Technology Center must be: o mission-oriented, addressing in a highly integrated way, a major, quantifiable goal(s) of the HGP, and/or going beyond those by addressing the ultimate goal of the HGP ~ the complete sequence of a human genome; o creative and innovative in terms of the proposed strategy and development of new technology for achieving its goal(s); o readily adaptable to new technology and new scientific developments; o focused, on an on-going basis, on issues of increased efficiency as evidenced by a plan for improvements in the rate of output of data and materials; at the same time, attention must be paid to maintaining or improving the quality of the techniques, data, and materials developed; o attentive to the needs of the larger scientific community, as demonstrated by the inclusion of an outreach program that will allow the center to act as a hub for collaboration and as a source for materials and information. The study of ethical, legal and social implications (ELSI) and outreach to the general public through education programs can be a component of such an outreach activity. Applicants interested in conducting research relevant to the NCHGR ELSI program should respond to the program announcement, "Ethical, Legal and Social Implications of Human Genome Research", in the NIH Guide to Grants and Contracts, Vol. 19, No. 4, 1990. Allowable Components of GESTEC Grant Applications Genomic research is defined, in part, by its emphasis on technology development and on a high rate of data production. Because of these inherent characteristics, investigators in the field have occasionally found organizational structures other than those prescribed by traditional multi-component grant mechanisms, i.e., research projects and technical cores each managed by a different principal investigator, to be more effective in managing and effecting large-scale genome research projects. In order to facilitate the most rapid progress and efficient use of limited resources, applicants will not be required to use the standard organizational format. Rather, each applicant is encouraged to organize the proposed program in the manner that will best accomplish the scientific goals of the proposed project. Each proposed organizational component must have an identified leader, although no minimum number of different leaders is required. For example, the Principal Investigator of the entire grant may also serve as leader of several, or even all, of the components, if such an arrangement is scientifically justified and adequate supervision of the project can be assured. The selection of the leader for each component should be justified in terms of the scientific and management needs of that component and the experience of the proposed leader. The following is a discussion of the activities most frequently found in multicomponent genome research projects. Each of these will, in some way, be integral to GESTEC programs and the organizational plan developed by the applicant must address each of these activities (with the exception of alterations and renovations) as well as how the components will interact to achieve the goals efficiently and rapidly. Thus, while the form of the components may differ dramatically among grants in the GESTEC program, it is essential that the scientific and management structure (organizational plan) be clearly presented in the application, both for the overall program and for the individual activities. It is also essential that the requested budget correspond directly to the organizational plan. The proposed plan will be considered as an indication of the quality of the management of the project. Research Activities. There are four primary activities that are usually part of a GESTEC grant: scientific research, technology development, technical support of either of the preceding, and outreach to the scientific community. In a traditionally organized program project or center, research and technology development activities are normally organized as individual "research projects", while technical support and outreach activities are presented as "technical cores". It has been the experience, however, in some large-scale genome projects that it is more efficient and productive to organize and manage efforts in other ways, for example, by combining certain research and support activities into a single unit. In a proposal for a GESTEC project, the applicant may design activities to accomplish the scientific objectives most effectively. A well thought-out data management plan is a critical element in research projects of this size. If data management activities are incorporated into the research activities, it is important that the overall management plan also describe the data management plans for the entire GESTEC. Technology development. The development of new and better technology needed to achieve the objectives of the Human Genome Project is considered to be one of the most important aspects of a GESTEC project. Funds for technology development may be requested to support (1) the design and development of prototypes for equipment needed to increase the rate and efficiency of data production and analysis, (2) pilot projects to take advantage of scientific opportunities that present themselves during the course of the project, and (3) the development of technology to meet unanticipated needs of the research and support activities of the project. When requesting technology development funds, applicants should address the issues of the exportability of and access to the instruments being designed. In some cases, it may be possible to present in the application a detailed description of plans and justification for the particular technology development projects envisioned. Applicants are encouraged to fully describe and justify plans to the extent possible. However, it is also recognized that unanticipated needs may arise as the project develops and, thus, a complete description of all technology development plans may not be possible. In the latter case, the request for technology development funds must be justified by the inclusion of a clear, well-defined strategy for making decisions about the use of such funds, e.g., the planning process for the use of the funds, alternative logistical plans for development of a variety of technologies, and the process for evaluating projects to be supported by technology development activities. In an application for renewal of currently-funded NCHGR grants, the justification for technology development funds must include a description of the use(s) to which such funds were put during the previous grant period. Technical support activities. An applicant may request shared facilities or equipment that will be required by more than one element of the proposed research program. Each applicant should examine the needs of the proposed program and request those technical facilities that would be required to support the proposed research in the most efficient and cost-effective manner. In addition to addressing the specific research, technology development and technical support activities, the applicant should also address the balance among these activities needed to accomplish the major goal of the proposed center. Outreach Activities. GESTEC projects are expected to have an interest in and a sense of responsibility for outreach to the greater scientific community. At a minimum, effective and rapid distribution of data and/or materials generated by a GESTEC project to external investigators is an essential and expected activity of each center. Accordingly, the proposal must include a full description of plans for accomplishing this goal. The joint NIH-DOE Advisory Committee on the Human Genome has recently issued a set of Guidelines for Access to Data and Material Resources, which is available from the NCHGR staff listed below and which would form the basis of an acceptable plan, although investigators are encouraged to go beyond these guidelines whenever possible. Funding to support data and materials distribution may be requested in a GESTEC grant application. Other means of distribution, such as through a commercial vendor are also acceptable. Beyond such distribution activities, GESTEC projects are also encouraged to provide outreach to the larger community by acting as a hub of genomic collaboration through activities such as providing additional services to the community, for example, visitor laboratories or library screening services. In addition to outreach to the scientific community, development of public education outreach programs and demonstration of interest in ELSI issues are also encouraged. Applications for renewal of currently-funded NCHGR center grants must document their accomplishments in the outreach activities as part of their justification for continued support. Administrative and Management Activities. Funds to support overall management of the GESTEC grant may be requested. As the GESTEC program allows for flexibility in management to suit the scientific purpose of the application, it is essential that the applicant adequately describe and justify the overall management strategy proposed and present a plan for the management of each of the components. The leadership and management of a scientific enterprise as complex as a GESTEC center will require a significant amount of attention and effort. Therefore, the proposed center director must serve on a full-time or significant part-time basis. He or she should have authority over appointments and space within the center. The portion of the salaries of the principal investigator and other key individuals corresponding to the percentage of time devoted to center administration can be included as an allowable cost. Costs of advisory committees, steering committees, and/or consultants can also be included as an administrative activity. Such committees are not required, but it is strongly recommended that an effective mechanism be proposed for obtaining independent advice to ensure guidance of the center toward the attainment of its stated goals. In some cases, and at the request of the investigator, NCHGR may appoint an oversight committee for the center in order to monitor progress and the appropriate funding level. It is not necessary for applicants to identify external advisory committee members before review of the application but plans for such a committee should be discussed if one is proposed. Alterations and Renovations. Funds needed for renovation of existing space may be requested, if such space is needed to house core facilities or new or expanded research activities. Costs of equipping renovated laboratories may be included in the request if the items are directly related to the research being conducted in the center. According to the Public Health Service (PHS) Grants Management Policy Statement, detailed justification of the need for, and plans for the use of the renovated space must be provided in the application and renovation plans must be approved by NIH before funds for this purpose can be released. In order to ensure that any renovations or alterations are done in a timely manner, (1) the request for alterations and renovations must include a timetable, (2) the renovation plans must be received by NCHGR no later than three months after the date of funding of the grant, and (3) the work must be finished within one year from the date of NIH approval of the plan. The application must also outline any plans for accommodating the project during the expected renovation period. Such a plan should take into account any need for accommodation of the program in temporary space while the renovations are being done. The institution's commitment to the proposed plan must be well documented. PHS policy also limits the dollar amount for alterations and renovations to the lesser of $150,000 or 25 percent of total direct costs over a three year period. Waivers to exceed this amount may be sought by the NCHGR in exceptional cases. Post Award Management During the course of the grant period and as progress toward the goals of the Human Genome Project is made, the focus of the GESTEC grant will likely change. In order to ensure that GESTEC projects funded for five years remain focused on appropriate goals and make sufficient progress, frequent scientific and programmatic reviews will be conducted. Yearly meetings of the Directors of GESTEC projects and NCHGR staff will be held to discuss recent achievements and expected future directions. It is expected that Principal Investigators of GESTEC grants will make the necessary adjustments in scientific direction and management structure to accommodate to changing requirements. In the case of five-year awards, applications for competitive renewal of support will be due at the first submission date after the beginning of the fourth year. In the event that the review of an application is not favorable, this will allow sufficient time for submission and review of a revised application or for orderly phase-out of the grant. Further support will be for a three- to five-year period. As noted above, GESTEC projects are encouraged to use advisory committees as a means to obtain independent advice. In renewal applications, continued support of this activity must be justified by the demonstration that the advisory committee mechanism has been used effectively. STUDY POPULATIONS SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH STUDY POPULATIONS NIH policy requires that applicants for NIH clinical research grants and cooperative agreements include minorities and women in study populations so that research findings can be of benefit to all persons at risk of the disease, disorder, or condition under study; special emphasis must be placed on the need for inclusion of minorities and subjects of appropriate gender in studies of diseases, disorders, and conditions which disproportionately affect them. This policy is intended to apply to males and females of all ages. If women or minorities are excluded or inadequately represented in clinical research, particularly in proposed population-based studies, a clear, compelling scientific rationale must be provided. The composition of the proposed study population must be described in terms of gender and racial/ethnic group. In addition, gender and racial/ethnic issues should be addressed in developing a research design and sample size appropriate for the scientific objectives of the study. This information must be included in the form PHS 398 (rev. 9/91) in Sections 1-4 of the Research Plan AND summarized in Section 5, Human Subjects. Applicants are urged to carefully assess the feasibility of including the broadest possible representation of minority groups. However, NIH recognizes that it may not be feasible or appropriate in all research projects to include representation of the full array of United States racial/ethnic minority populations (i.e., Native Americans (including American Indians or Alaskan Natives), Asian/Pacific Islanders, Blacks, Hispanics). Rationale must be provided for studies on single minority population groups. For the purpose of this policy, clinical research is defined as human biomedical and behavioral studies of etiology, epidemiology, prevention (and preventive strategies), diagnosis, or treatment of diseases, disorders, or conditions including, but not limited to, clinical trials. The usual NIH policies concerning research on human subjects also apply. Basic research or clinical studies in which human tissues cannot be identified or linked to individuals are excluded. However, every effort should be made to include tissue from women and racial/ethnic minorities when it is important to apply the results of the study broadly, and this should be addressed by applicants. For foreign awards, the policy on inclusion of women applies fully since the definition of minority differs in other countries, the applicant must discuss the relevance of research involving foreign population groups to the United States' populations, including minorities. If the required information is not contained within the application, the review will be deferred until the information is provided. Peer reviewers will address specifically whether the research plan in the application conforms to these policies. If the representation of women or minorities in a study design is inadequate to answer the scientific question(s) addressed AND the justification for the selected study population is inadequate, it will be considered a scientific weakness or deficiency in the study design and will be reflected in assigning the priority score to the application. All applications for clinical research submitted to NIH are required to address these policies. NIH funding components will not award grants or cooperative agreements that do not comply with these policies. LETTER OF INTENT Although it is not required or binding, applicants are strongly urged to contact NCHGR staff by telephone or by letter of intent. This will enable staff to provide clarification of programmatic and budgetary issues regarding these often-complicated applications and will also assist review staff in planning the review workload. Applications received without prior staff contact may be delayed in the review process or may be returned to the applicant without review. This communication will be most useful if it is submitted at least three months before the receipt date on which the application is to be submitted. It need only include the names of the principal investigator and principal collaborators, a descriptive title of the proposed application and identification of the organization(s) involved. This information will not be part of the material that will be peer reviewed and is to be directed to appropriate NCHGR staff member listed under INQUIRIES. APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 9/91) and will be accepted at the application deadlines as indicated in the application kit. Application kits are available from most institutional offices of sponsored research and from the Office of Grants Information, Division of Research Grants, National Institutes of Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone 301/710-0267. The title and number of the program announcement must be typed in Section 2a on the face page of the application. The completed original and five legible copies must be sent or delivered to: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** Additionally, two copies of the full application must be sent to: Office of Scientific Review National Center for Human Genome Research Room 604, Building 38A Bethesda, MD 20892 REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed by DRG staff for completeness and, for those applications assigned to the NCHGR, by NCHGR staff for appropriateness with respect to expressed NCHGR programmatic interests. Incomplete applications will be returned to the applicant without further consideration. The regular NIH receipt dates for center grant and program project applications and renewals are as follows: February 1, June 1 and October 1. Applications will be evaluated for scientific merit by the Genome Research Review Committee (GRRC) or an appropriate review committee constituted for the purpose of evaluating GESTEC grant applications. Site visits are frequently conducted as part of the review process but are not routine. Therefore, applicants should present a complete and well-justified written proposal and not depend on site visits to amplify their application. Review criteria will include the following: o Significance and originality of the research and methodological approaches; o Feasibility of the research and adequacy of the experimental design; o Training, experience, research competence and commitment of the investigator(s); o Adequacy of the facilities and resources; o Provisions for the protection of human subjects, the humane care of animals and biosafety conditions. Subsequent to evaluation by the initial review group, applications will be reviewed by the appropriate National Advisory Council. AWARD CRITERIA For those applications assigned to NCHGR, the following will be considered in making funding decisions: o Quality of the proposed project as determined by peer review; o Value of the proposed research and of the proposed technology development for achieving the goals of the Human Genome Program; o Adequacy of the proposed management structure including the leadership capabilities of the center director; o Nature and extent of the outreach program, including the adequacy of any plans proposed for sharing and distributing data and resources in a timely manner; o Balance among projects within the NCHGR's grant portfolio; o Availability of funds. INQUIRIES Written and telephone inquiries are strongly encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Inquiries regarding the GESTEC Program may be directed to: Jane L. Peterson, Ph.D. Chief, Mammalian Genomics Branch National Center for Human Genome Research Internet: Jane_Peterson@occshost.nlm.nih.gov Specific questions regarding the following programmatic areas may be directed to the staff identified below: Large scale sequencing and mapping of mouse and human genomes: Dr. Jane L. Peterson, Chief Internet: Jane_Peterson@occshost.nlm.nih.gov Dr. Jeffery Schloss, Program Director, Mammalian Genomics Branch Internet: Jeffery_Schloss@occshost.nlm.nih.gov Sequencing technology development and large-scale mapping and sequencing of nonmammalian model organisms: Dr. Robert Strausberg, Acting Chief Internet: Robert_Strausberg@occshost.nlm.nih.gov Dr. Carol Dahl, Program Director, Sequencing Technology Branch Internet: Carol_Dahl@occshost.nlm.nih.gov The address and telephone number for the staff listed above is: National Center for Human Genome Research Building 38A, Room 610 Bethesda, MD 20892 Telephone: (301) 496-7531 Inquiries regarding fiscal matters may be directed to: Ms. Jean Cahill Grants Management Office National Center for Human Genome Research Building 38A, Room 613 Bethesda, MD 20892 Telephone: (301) 402-0733 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.172. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. .
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