INCREASING THE EFFICIENCY OF BUILDING PHYSICAL MAPS FROM CLONE LIBRARIES FOR GENOMIC STUDIES RELEASE DATE: March 21, 2002 RFA: HG-02-004 National Human Genome Research Institute (NHGRI) ( National Center for Research Resources (NCRR) ( National Institute of Mental Health (NIMH) ( LETTER OF INTENT RECEIPT DATE: April 23, 2002 APPLICATION RECEIPT DATE: May 23, 2002 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 Where to Send Inquiries o Letter of Intent o Submitting an Application o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations: PURPOSE OF THIS RFA: The NHGRI, NCRR and NIMH invite applications for research projects to improve the capability for rapidly and efficiently producing a contiguous physical map of a genome from libraries of genomic clones and to reduce the cost of physical mapping so that the NIH can afford to increase the number of genomes that will have physical maps available for use in genomic approaches to sequencing and other problems in biomedical and biological research. RESEARCH OBJECTIVES Background In the past three decades, a number of different vector systems have been developed and tested for use in constructing the large-insert chromosomal DNA libraries required for genomic analysis. Over the past several years, the bacterial artificial chromosome (BAC) has emerged as the vector system of choice, although it is certainly not the only one. The BAC cloning system allows the isolation of genomic DNA fragments that are large enough (80 to >200 kilobases [kb]) to be useful for both genomic sequence determination and for a variety of functional studies. At the same time, BAC clones are less prone to artifacts than other available vector systems for large-fragment cloning, e.g. cosmids and yeast artificial chromosomes (YACs). In this RFA, the objectives for developing new or improved technology to build physical maps are described in terms of BAC clone libraries. However, this RFA is NOT limited to technology for producing BAC clone-based maps. Any vector system or clone library that can be used in a highly efficient, low cost way to produce physical maps that may be used in complete genomic sequencing or other genomic studies may be proposed and will be considered responsive to this RFA. To date, the complete sequencing of all large eucaryotic genomes has involved large-insert clones. The initial eucaryotic genome sequencing projects (including those for the S. cerevisiae, C. elegans, and A. thaliana genomes) were guided by carefully constructed clone-based physical maps. Mapped BAC clones continue to play a critical role, even as whole genome shotgun sequencing has come to be an important component of genome-scale sequencing projects. In the case of the human sequence, for example, both of the published draft sequences were based on a mixed strategy that involved both clone-based and whole genome shotgun sequence data. Similarly, a mixed strategy is now being used in the sequencing of both the mouse and rat genomes, and a clone- based component has been introduced for finishing the sequence of the D. melanogaster genome. A clone map that allows sequence contigs to be correctly located and regions containing large repeated sequences to be properly assembled will be a necessity for the foreseeable future in the determination of a high quality, complete sequence of a large, repeat-rich genome. BAC clones and BAC libraries are also important in other types of studies, particularly those that require isolation of a specific region of a genome for analysis and genetic manipulation. However, the broader use of BACs in biomedical and biological research is currently limited by several factors. The NHGRI, along with the NCRR and NIMH have attempted to address one bottleneck, the supply of BAC libraries, by establishing a research network designed to expand the national capacity for BAC library making. Another objective of that research network is to improve library construction technology and reduce the cost of making libraries. This effort should greatly expand the number of organisms, strains, and individuals for which representative BAC libraries will become available over the course of the next two to three years. While uncharacterized BAC libraries are useful, more extensive characterization of the clones in a library and organization of the library clones into a physical map significantly widen the range of uses to which the BAC clones can be put. At present, the standard methods for constructing physical maps from BAC clones involve insert end sequencing and restriction enzyme fingerprinting. However, as a few hundred thousand clones are needed to make a library that provides an adequate representation of a mammalian-sized genome, both techniques are currently relatively expensive to implement for the complete characterization of a large library. For example, for 200,000 clones, end sequencing currently costs at least $1.5 million, while fingerprinting costs more than $2 million. Thus, in parallel with the expansion of the capacity for BAC library production, it would also be advantageous to increase the efficiency of constructing physical maps from BACs (e.g., by reducing costs) and to expand the capacity for doing so. This RFA therefore solicits proposals for research projects that will improve the technology or develop new technology, reduce the cost, and ultimately increase the capacity for characterizing BAC libraries and using them to make contiguous physical maps of a genome. Research Objectives Because of the present limitations on throughput and cost, NHGRI currently funds only the limited amount of physical mapping that is directly associated with, and needed for, constructing maps that are required for committed genomic sequencing efforts. The purpose of this RFA is to increase the throughput and decrease the cost for characterizing a sufficient number of BACs from a library to produce a physical map of overlapping clones with few gaps. If map construction could be made sufficiently inexpensive, it would be possible to construct useful maps even for genomes that were not likely to be sequenced soon. Proposals that address either significant improvement in the efficiency of presently used methods or new and better methods for clone characterization and map construction will be considered to be responsive to this solicitation. Improving current methods: At present, the organization of a BAC library into a physical map uses both BAC-end sequence and restriction enzyme-based fingerprint map data. Insufficient effort has been given to the optimization of either of these techniques at high throughput, and proposals to improve either or both approaches would be responsive to this RFA. Paired BAC end sequence sets are among the data that are now routinely used for constructing sequence scaffolds during a genomic sequencing project. The utility of a BAC-end sequence data set increases as the depth of the set (the number of clones for which paired end sequences have been determined) increases. However, the depth of the BAC end sequence set is often limited by cost, as sequencing BAC ends is presently nearly three times more expensive than sequencing other substrates. There are apparently a number of reasons for this difference. It is difficult to obtain good yields of BAC DNA for sequencing, and the lower amounts of DNA per sample leads to a requirement for higher concentrations of expensive sequencing reagents. Furthermore, appropriate DNA preparation is difficult and automated preparation systems have not been developed. As for restriction enzyme-based fingerprinting, only in the last few years has the methodology become reliable enough at high throughput levels to generate the amount of high quality data needed to build maps that are accurate enough and of high enough resolution to guide the choice of clones for sequencing. The costs of constructing a fingerprint-based map have decreased somewhat recently, but remain high. Additional automation may be one way to reduce this cost. Applications that propose research to significantly increase the efficiency of current BAC-end sequence and/or restriction enzyme fingerprinting production lines are encouraged in response to this RFA. Developing new methods: Alternatively, completely new methods or strategies for constructing physical maps from large-insert clones may provide a better solution to decreasing the cost and increasing the throughput of methods for constructing physical maps. Proposals for research into such new approaches are encouraged. Applications in response to this RFA may address one or more than one physical mapping technology. As noted above, BAC clone libraries are specified as the reagents for developing new or improved technology to build physical maps in this RFA. However, applications responding to this RFA are NOT limited to proposing technology for producing BAC-based maps. Any clone library that can be used in a highly efficient, low cost way to produce a physical map that may be used in sequencing or other genomic studies may be proposed in response to this RFA. In order to ultimately attain the objectives of this program, a map generated by any new or improved technology must be utilized by a sequencing center as part of its sequencing strategy. NIH recognizes that applicants to this RFA may not necessarily be associated with a sequencing center that could rapidly test or implement a new technology. However, to ensure that any technology developed under this program can actually be useful to the NHGRI sequencing program, the applicant must discuss the issue of how the proposed new technology, if successful, would be implemented. This application should also include evidence from at least one of the current sequencing centers, of its willingness to consider implementing the new technology in the event that the technology were to attain its goals. Funds provided under this RFA are intended to support technology development and proof of principle for building a physical map for a genome of moderate to large size. If the technology successfully reduces cost of physical mapping, such a proof of principle should be possible with the funds allocated. Any issues relevant to the application of the technology to a genome of considerably larger size than those used to demonstrate proof of principle must be discussed. A critical component of any high throughput production method is the quality of the product. Therefore, the issues of quality assessment of the resources produced during the proof of principle stage by the proposed technology improvements must be addressed in the application. Finally, applicants should describe their plans for the release and dissemination of the physical mapping data that will be produced in the proof of principle stage of these research projects. NHGRI and the other participating institutes strongly believe in the value of rapid data and materials release in the case of genomic resources. For an example, the NHGRI policy on release of sequence data is available at ase.html. Responses to this RFA should propose a plan for data release, as this will be a criterion in the review of the application. Appropriate data release plans will be made a condition of the awards made as a result of this RFA. Applicants should also be familiar with the NIH statements regarding intellectual property of resources developed with Federal funds ( In summary, applicants for awards under this RFA: o should address the approach(es) they propose to take to improve the technology for producing physical maps from BAC libraries for use in genomic sequencing or other genomic applications, such approaches may involve either significant improvements to current methods for library characterization or development of novel technologies, o should explicitly describe the goals of the proposed technology development effort and the milestones that will be used to evaluate progress toward those goals, o should address the issue of physical mapping costs (both current and projected) and explain in detail how the proof of principle phase will demonstrate the proposed technology"s potential to scale for rapidly and efficiently mapping large genomes, o should discuss the issues involved in implementation of the new technology, o should provide information about the applicant"s prior experience in physical mapping and/or technology development for physical mapping, o should propose a quality assessment plan, o should propose a data release plan. MECHANISM OF SUPPORT This RFA will use the NIH Cooperative Agreement (U01) award mechanism. This RFA is a one-time solicitation. Future unsolicited, competing- continuation applications based on this project will compete with all investigator-initiated applications and will be reviewed according to the customary peer review procedures. The anticipated award date is December 2002. The NIH (U01) is a cooperative agreement award mechanism in which the Principal Investigator retains the primary responsibility and dominant role for planning, directing, and executing the proposed project, with NIH staff being substantially involved as a partner with the Principal Investigator, as described under the section "Cooperative Agreement Terms and Conditions of Award" FUNDS AVAILABLE The participating Institutes and Centers intend to commit approximately $3 million in FY 03 to fund three to six new grants in response to this RFA. An applicant may request a project period of up to three years. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the IC(s) provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. 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 In describing the research plan, the applicant must address the following issues and questions: o Methodology - Will the proposed new or improved technology produce physical maps that support different sequencing strategies, e.g. clone-based sequence assemblies, whole genome shotgun assemblies? o Usability and transportability - Will the maps that will be produced with the proposed new or improved technology be widely useable? Will the proposed new technology be portable to other centers? If not, please explain how the new technology or the maps will be made available for use by other scientists. o Integration into sequence or other maps - Will the maps produced with the proposed new or improved technology be able to be integrated? Will your new maps be easily compared to maps from other organisms or to maps that have been produced by other methods? o Depth of clones- What depth of clones will be needed for maps produced with the proposed new or improved technology? o Cost and throughput- How do you expect the proposed new or improved technology to change the cost and throughput of your maps as compared to current mapping costs? o Complexity of the genome being mapped- How will the size and complexity of the genome being mapped affect the ability of the proposed new or improved technology to assemble a map? o Propose specific, quantitative milestones for the project. I. 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-02-004 and will be provided to the Principal Investigator, as well as the appropriate institutional official, 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 [Part 92 are applicable when State and local Governments are eligible to apply], as are other DHHS, NIH, and NIH grant administration policies: 1. The administrative and funding instrument used for this program will be the Cooperative Agreement (U01). The cooperative agreement is an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during the performance of the activity. Under the Cooperative Agreement, the NIH purpose is to support and/or 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 physical mapping technology project as a whole will reside with the awardee(s), although specific tasks and activities in carrying out the study will be shared among the awardee(s) and the NHGRI Program Director. 2. P.I. Rights and Responsibilities: The P.I. will have the primary responsibility for defining the details for the physical mapping project within the guidelines of RFA HG-02-004 and for performing the scientific activities. The P.I. will agree to accept close coordination, cooperation, and participation of NHGRI staff in those aspects of scientific and technical management of the project as described under "NIH Program Staff Responsibilities." The P.I. of a physical mapping technology center will: o Determine experimental approaches, design protocols, set project milestones and conduct experiments, o Ensure that the technology developed for physical mapping and the resources produced meet the quality standards and cost agreed upon at the time of award, o Ensure that the technology and resources developed as part of this project are made publicly available and that results are published in a timely manner, o Ensure that the decisions about the technologies and resources developed under NIH funding meet the needs of the Institute/Centers" programs, as determined at the time of initiation of the project, o Coordinate and collaborate with other U.S. and international groups developing technology for producing physical maps, o Be required to accept and implement any common guidelines and procedures developed for the physical mapping technology program. 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 between the Principal Investigator and NHGRI staff. NHGRI will consult with NIH staff from the other Institutes contributing to this RFA to keep them apprised of progress and issues arising. The Program Director will have the following substantial involvement: o Participate in discussing research priorities, deciding optimal research approaches and protocol designs (including quality assessment), and contributing to any necessary adjustment of research protocols or approaches, o Serve as 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, o Coordinate the efforts of the awardees with the BAC library makers, the NHGRI sequence production program, with other U.S. large-scale sequencing efforts and with the international sequencing community as well as the biological community, o Assist awardees in the development, if needed, of policies for dealing with situations that require coordinated action, o Periodically report on the progress of the physical mapping technology program to the NHGRI Director, the Sequencing Advisory Panel and other NIH Institutes and Centers supporting this research, o Assist in promoting the availability of the 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 BAC Resources Steering Panel, the withholding or reduction of support from any cooperative agreement that substantially fails to achieve its goals of improving technology according to the milestones agreed to at the time of award, fails to remain state of the art in its library- making capabilities, or fails to comply with the Terms and Conditions of the award. 4. Joint Responsibilities. The awardees and Program Director will be jointly responsible for: o Discussing progress in meeting the research community"s need for physical maps, o Helping to develop uniform procedures for quality assessment of resources produced, o Accepting and implementing the common guidelines and procedures approved by the awardees, program director and CRSP. 5. Clone Resources Steering Panel (CRSP) The Clone Resources Steering Panel will be responsible for reviewing and evaluating the progress of the awards for developing and implementing technology for physical map construction, and the coordination of that program with the BAC library production and large- scale genomic sequencing programs. The CRSP will be composed of five senior scientists with relevant expertise. The membership of the CRSP may be enlarged permanently, or on an ad hoc basis, as needed. At least once a year, there will be an opportunity, either in a meeting or by conference call, for the CRSP members to interact directly with the awardees. Annually, the CRSP will make recommendations regarding progress of the physical mapping technology effort and present advice about any changes to the program that may be necessary to the Director, NHGRI. 6. Arbitration Process: Any disagreement that may arise on scientific/programmatic matters (within the scope of the award), between award recipients and the NHGRI may be brought to arbitration. An Arbitration Panel will be composed of three members: one selected by the awardee, one selected by the NHGRI, and a third selected by the two prior selected members. This special arbitration procedure in no way affects the awardee"s right to appeal an adverse action that is otherwise appealable in accordance with NIH regulations 42 CFR Part 50, Subpart D and HHS regulation at 45 CFR Part 16. 7. Yearly Milestones: All awardees participating in the physical mapping technology program will be asked to define yearly milestones at the time of the award and to update these milestones annually at the anniversary date. These will be made a condition of the award. In accord with the procedures described above, NHGRI may withhold or reduce funds for any project that substantially fails to meet its 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: Direct inquiries regarding programmatic issues to: Dr. Jane L. Peterson Division of Extramural Research National Human Genome Research Institute National Institutes of Health Building 31, Room B2B07 MSC 2033 Bethesda, MD 20892-2033 Telephone: (301) 496-7531 FAX: (301) 480-2770 E-mail: Dr. John D. Harding Division of Comparative Medicine National Center for Research Resources 6705 Rockledge Drive, Suite 6050, MSC 7965 Bethesda, MD 20892-7965 Telephone: (301) 435-0776 FAX: (301) 480-3819 E-mail: NIMH Dr. Hemin Chin National Institute of Mental Health National Institutes of Health 6001 Executive Blvd. Room 7190 MSC 9643 Bethesda, MD 20892-9643 Telephone: (301) 443-9869 Fax: (301) 443-9890 E-mail: Direct inquiries regarding review issues to: Dr. Rudy Pozzatti Scientific Review Administrator Office of Scientific Review National Human Genome Research Institute National Institutes of Health Building 31, Room B2B37, MSC 2032 Bethesda, MD 20982-2032 Telephone: (301) 402-0838 Fax: (301) 435-1580 E-mail: Direct inquiries regarding fiscal matters to: Ms. Jean Cahill Grants Administration Branch National Human Genome Research Institute Building 31, Room B2B34, MSC 2031 Bethesda, MD 20892-2031 Telephone: (301) 402-0733 FAX: (301) 402-1951 E-mail: 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: Dr. Jane L. Peterson Division of Extramural Research National Human Genome Research Institute National Institutes of Health Building 31, Room B2B07 MSC 2033 Bethesda, MD 20892-2033 Telephone: (301) 496-7531 FAX: (301) 480-2770 E-mail: 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 in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: 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: 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: Dr. Rudy Pozzatti Scientific Review Administrator Office of Scientific Review National Human Genome Research Institute National Institutes of Health Building 31, Room B2B37, MSC 2032 Bethesda, MD 20982-2032 Telephone: (301) 402-0838 Fax: (301) 435-1580 E-mail: APPLICATION PROCESSING: Applications must be received by the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an Introduction addressing the previous critique. 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. And, if the application is not responsive to the RFA, CSR staff may contact the applicant to determine whether to return the application to the applicant or submit it for review in competition with unsolicited applications at the next appropriate NIH review cycle. 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 Human Genome Advisory Council. REVIEW CRITERIA The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to discuss the following aspects of your application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals: o Significance o Approach o Innovation o Investigator o Environment The scientific review group will address and consider each of these criteria in assigning your application"s overall score, weighting them as appropriate for each application. Your application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, you may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. (1) SIGNIFICANCE: Does your proposal address the problem outlined in this RFA? How much will your proposed approach increase the efficiency of the constructing physical maps beyond current practices? Will a larger number of physical maps for entire genomes become available for use in research as a result of the introduction of your proposed technology? (2) APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Do you acknowledge potential problem areas and consider alternative tactics? Are the proposed milestones reasonable? Is the planning for evaluating readiness for proof of principle acceptable? (3)INNOVATION: Does your project employ novel concepts, approaches or methods to improve technology for characterization of BAC libraries, and to reduce the costs, or increase the efficiency of producing physical maps? Does your project challenge existing paradigms or develop new methodologies or technologies? (4) INVESTIGATOR: Are you appropriately trained and well suited to carry out this work? (5) ENVIRONMENT: Does the scientific environment in which your work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your application will also be reviewed with respect to the following: o DATA SHARING: Are the plans for release of information about new technology and resources appropriate? 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 23, 2002 Application Receipt Date: May 23, 2002 Peer Review Date: July 2002 Council Review: September 2002 Earliest Anticipated Start Date: December 2002 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit (as determined by peer review) o Availability of funds o Programmatic priorities. o Likelihood that any proposed technology development effort will lead to significant improvement in the scientific quality of using BAC libraries to make physical maps and/or to a reduction in the cost of using BAC libraries to produce physical maps of a genome. o General applicability of the technology to generate characterized BAC libraries applicable to physical map making and to other problems in genomic research. REQUIRED FEDERAL CITATIONS INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of the NIH that women and members of minority groups and their sub- populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the AMENDMENT "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (, a complete copy of the updated Guidelines are available at 01.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 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 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 Applicants may wish to place data collected under this PA 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 AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance No. 93.172_, 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 and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. The PHS strongly encourages all grant recipients to provide a smoke- free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

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