A QUALITY ASSESSMENT CENTER FOR GENOMIC DNA SEQUENCE Release Date: December 15, 1999 RFA: HG-00-001 National Human Genome Research Institute Letter of Intent Receipt Date: January 12, 2000 Application Receipt Date: March 14, 2000 PURPOSE The objective of this RFA is to establish an independent DNA sequence quality assessment center (QAC) to evaluate the quality of the DNA sequence being produced with NHGRI support. On a regular basis, the QAC will conduct assessments of the quality of the genomic sequence data being produced by each of the NHGRI-funded centers involved in the production of human and/or mouse genomic DNA sequence. Regular assessments of genomic sequence data are essential to assure the scientific community and the public that the quality of the sequence being deposited in the public databases meets the international standards and provides a reliable basis for further biomedical research. Assessments will also provide fundamental data about the quality characteristics of the sequence data, which can be used by the scientific community as an aid to interpreting the sequence data and using it to design further experiments and improved analyses. As a secondary goal, the QAC will be a resource to the sequencing centers, and to the National Human Genome Research Institute (NHGRI) for technical advice about sequence quality assessment. The NHGRI is also open to the possibility that the QAC will undertake, as an additional, but secondary objective, a research and development effort to improve methods of quality assessment for genomic sequence. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This RFA, A Quality Assessment Center for Genomic DNA Sequence, is related to several priority areas including cancer, heart disease and stroke, diabetes and chronic disability conditions, and maternal and infant health. Potential applicants may obtain a copy of "Healthy People 2000" at http://odphp.osophs.dhhs.gov/pubs/hp2000. 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 and local governments, and eligible agencies of the Federal government. Applications from foreign institutions will not be accepted; however subcontracts to foreign institutions will be considered. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. A principal investigator submitting an application for the QAC must be able to demonstrate independence from any NHGRI-funded large-scale sequencing center whose data are to be evaluated by the QAC. MECHANISM OF SUPPORT The administrative and funding mechanism to be used to support this program will be the Cooperative Agreement (U01), an "assistance" mechanism, which is distinguished from a regular research grant in that substantial scientific and/or programmatic involvement by NHGRI staff with the awardee is anticipated. The cooperative agreement is used when participation by NIH staff is warranted to support and/or stimulate the recipient's activity by involvement in and otherwise working jointly with the award recipient in a partner role; NIH staff will not assume direction, primary responsibility, or a dominant role in the activity. Details of the responsibilities, relationships, and governance of the studies funded under cooperative agreement(s) are discussed later in this document under the section Terms and Conditions of Award. The initial award for this RFA will be for three years; it is anticipated that the need for a QAC will persist as long as NHGRI funds large-scale sequence production. FUNDS AVAILABLE The estimated funds available for the first year of support for awards under this RFA will be $2.8 million per year (total costs). One award will be made. The usual NIH policies governing grants administration and management will apply. This level of support is dependent on the receipt of a sufficient number of applications of high scientific merit. Beyond the first year, the funding level of the QAC will be based on an annual evaluation. The primary criterion for evaluation will be whether the QAC is adequately performing regular quality assessments of the NHGRI-funded sequence production centers and fulfilling the long- and short-term needs of the human and mouse genomic sequencing programs, as determined by the scientific consultants to the large- scale sequencing program, NHGRI staff and the National Advisory Council for Human Genome Research (NACHGR). The funding level for the QAC will also be dependent upon the availability of funds as well as the number of sequence production centers. RESEARCH OBJECTIVES Background The National Human Genome Research Institute (NHGRI) is currently engaged, along with several other federal, private, and international organizations, in a fifteen-year research program called the Human Genome Project (HGP). The HGP started in 1990 and significant progress toward completing its goals has been achieved. The genetic and physical mapping goals for both the human and the mouse have been met. There has also been good progress toward meeting the sequencing goals. The DNA sequence of both the E. coli and S. cerevisiae genomes has been determined (as have those of several other microorganisms), the sequence of the C. elegans genome was completed in 1998, and it is anticipated that the complete DNA sequence of the D. melanogaster genome will be finished by 2001. The HGP's primary goal is now the completion of an index human DNA sequence (see http://www.nhgri.nih.gov/98plan). To effect its part of the sequencing program, NHGRI initiated a three-year pilot sequencing program in 1996. This was followed in the first half of 1999 by scale up to a full production mode, and NHGRI now supports seven cooperative agreements for sequencing the human genome. As of the end of September 1999, the world-wide public genome sequencing effort had deposited over 460 Mb of finished human sequence in the public databases, plus more than 400 Mb of working draft quality sequence. During the past five years, advances and refinements in DNA sequencing have led to a rapid acceleration in the level of sequencing capacity. First, technological advances (e.g., capillary sequencing machines) have progressed even more rapidly than anticipated. Second, the degree of cooperation among the public sequencing laboratories has increased significantly. Accordingly, the schedule for attaining the Human Genome Project's goal of completing an index human DNA sequence has been advanced several times. Completion is now projected by 2003. Furthermore, a working draft version is anticipated by Spring 2000, and until then, most of the capacity for human sequencing will be devoted to working draft production. Although primarily an intermediate in the generation of a high quality finished human DNA sequence, the working draft will itself be useful for many types of biological analyses. The primary objective of the sequencing phase of the Human Genome Project is to generate a very high quality index sequence of human DNA that will be usable as the basis for a wide variety of biological studies for the foreseeable future. After extensive discussion with the scientific community, including both sequencers and users of sequence data, the HGP has developed a set of standards for the quality of the finished human genomic sequence data. The full text of the sequence quality policy that has been adopted by NHGRI in light of these community determinations is available at http://www.nhgri.nih.gov/Grant_info/Funding/Statements/RFA/quality_standard.html. In summary, o the sequence must be at least 99.99% accurate (i.e, fewer than one error per 10,000 bases); and o the sequence should be contiguous (i.e. with no gaps, other than those few areas that cannot be cloned in current vectors). These standards are very stringent, and it has been recognized that they may not be achievable in some regions of the genome. In those cases, any deviations from the standard must be documented, including the location and size of gaps, the orientation of flanking regions, and a description of the efforts made to close the gaps. These standards may be applied to genomic sequence from other organisms as NHGRI undertakes to sequence them. It is critical for the scientific community to be able to rely on, and be informed about, the quality of the genomic sequence. Objective data must be available to assure the scientific and general public that the sequence data meet the standards. Quantitative information about sequence quality is also required for designing further experiments. For example, studies on genetic variation, analysis of disease-causing mutations, protein structure prediction, comparative sequence analysis, sequence annotation, and sequence assembly are all increasingly utilizing information about genomic sequence quality. Before the final adoption of the sequence quality standards, the NHGRI carried out a set of experiments designed to test whether the quality of DNA sequence data could be assessed and whether the standards could be achieved. The results of the first two quality assessment exercises (results published in Genome Research 9:1-4, 1999; also available at http://www.nhgri.nih.gov/Grant_info/Funding/Statements/RFA/quality_standard.html) indicated both that evaluation was feasible and that high quality DNA sequence data could be generated at a reasonable cost. Since then, two additional exercises have been carried out, with similar results. These four sequence assessment exercises were conducted by the same laboratories that are the primary producers of human sequence data, in a 'round-robin' manner, in which each center’s data was checked by two other centers. While the round-robin format was very useful, both for the NHGRI in assessing sequence quality and for the individual centers in monitoring their processes, it has several disadvantages for ongoing quality control. Since the assessments were done by several centers, there was the possibility of a lack of consistency. The exercises were also time- and resource- consuming for the sequencing laboratories and, as a result , placed a burden on them that undoubtedly reduced their productivity. With the major increase in the rate of data production that will be required to meet the new HGP goals, sequence data will have to be assessed in greater quantity and/or at greater frequency than in the past. Continuing the round-robin format would thus impose an increasing burden on the sequence production centers. Finally, groups that were, in effect, competing with each other for resources conducted the previous exercises. This is less than desirable within the new NHGRI management structure for the human and mouse sequencing programs, which relies on a high degree of cooperation among the participating centers for their success. A dedicated Quality Assessment Center (QAC) will address all of these issues. In addition, a dedicated QAC will also be able to advance the methods used to assess sequence quality as this rapidly moving field progresses. The recent introduction of an intermediate goal for the HGP of "working draft" quality sequence has also had ramifications for sequence data quality assessment, and NHGRI believes that a QAC will also be useful for checking working draft data. The current provisional standard for working draft data is that the number of phred 20 bases divided by the total project length (calculated both as a sum of fingerprint fragments and as a sum of sequence contigs over 1 kb) should be no lower than 3 for any individual project, and at least 4 as an average of all a producer’s working draft projects. Since production of working draft sequence is a recent endeavor, these standards may be re-evaluated. It is anticipated that the quality of working draft can be adequately assessed against this standard by purely computational methods. In September 1999, NHGRI began a new initiative to sequence the mouse genome. Nine groups were funded for sequence production; five of these were new groups that are not part of the Human Sequencing Research Network, bringing the total number of NHGRI-funded genome sequence production groups to 12. The Mouse Sequencing Research Network will also produce both working draft and finished sequence. The precise quality standard for mouse genomic sequence is still a matter of community discussion, but it is likely that the working draft standard and the finished sequence single-base error rate will be similar to that for human. Research objectives and scope Applications are sought to support one cooperative agreement for a Quality Assessment Center (QAC) to evaluate, on an ongoing basis, the quality of both the finished and the working draft DNA sequence data being produced by the NHGRI-funded human and mouse sequence production centers. NHGRI expects that the QAC will encompass three principal activities: 1) routine quality assessment exercises on finished and working draft sequence produced by NHGRI- funded large-scale sequencers; 2) regular reports of results to the public and to NHGRI; and 3) coordination with the internal quality control programs at the sequence production centers. NHGRI is willing to support a fourth activity, research on questions about sequence quality, if funds are available. 1. Quality assessment a. Finished data The most important activity of the QAC will be the routine assessment of the quality of finished and working draft data produced by the NHGRI-funded human and mouse sequence production centers. During the pilot project period, several sequence quality assessment exercises were completed; a description of the methods used is available at http://www.nhgri.nih.gov/Grant_info/Funding/Statements/RFA/quality_standard.html. The methods proposed by an applicant responding to this RFA need not be identical to those used in the previous exercises. However, any new methods proposed must be robust, well-justified, and be an improvement over existing methods. In any QAC proposal, the sampling methods (e.g., schedule of quality assessments, how much material will be sampled) should be addressed. In order to perform an effective quality assessment, t is expected that the QAC will stay abreast of developments and standards in large-scale genomic sequencing and incorporate these advances into a QA program. The QAC should be able to use all basecalling and data assembly programs that are used by the sequence production centers. Moreover, the software used by the QAC for checking sequence quality should be compatible with that used by the sequencing centers to ensure that the file formats used by the sequence production centers are readily and reliably transferable to the QAC, and to ensure that results are comparable between sequence production centers. The NHGRI expects that the data from the sequence production centers will be checked on at least a semi-annual basis, and that first assessment of the quality of finished sequence should be completed no later than four months after funding of the QAC. Applicants should propose a plan that addresses this schedule or, with appropriate justification, propose a plan that involves a better schedule. In any particular round of evaluation, the emphasis should be on data that has been produced in the interval since the most recent previous assessment. The raw sequencing data and the bacterial isolates containing large insert clones corresponding to the genomic sequence are maintained by the individual sequencing centers. Insofar as these materials will be required for the QAC to perform a quality assessment exercise, NHGRI will be responsible for ensuring that they are provided to the QAC. It is expected that the QAC will maintain adequate communication with NHGRI and the sequencing centers so that the logistical aspects of the QA program will be accomplished smoothly. b. Working draft data Applicants responding to this RFA should also propose methods to efficiently assess the quality of working draft sequence from each production center. For assessment of working draft sequence, a schedule and sampling protocols appropriate to the amount of data produced should be proposed. For the human sequence, the NHGRI-funded sequence production centers will produce most of the working draft sequence as soon as Spring 2000 (they will also produce a smaller amount of finished sequence during this time). The rate of conversion of the working draft to finished sequence will then increase very rapidly in order to meet the NHGRI-DOE five-year goals. At the same time, production of working draft and finished mouse sequencing will be increasing during 2000 and 2001. Applicants should take this anticipated schedule into account, including the increasing demand for checking capacity, and propose a distribution between the assessment of working draft and of finished sequence. At present, there are three larger, and four smaller, NHGRI-funded human sequencing centers, and four new mouse sequencing centers; most are producing both draft and finished sequence. Although the NHGRI will not provide support for checking data from centers funded by other agencies, it is not unreasonable to expect that there will be a need for the QAC to assess data from at least two other large sequence production centers (the Sanger Centre and the Joint Genome Institute). Opportunities for assessment of other large-scale sequence products may arise in the future. Ideally, the QAC should have sufficient eventual capacity to assess this data as well. However, support for the assessment of data from non-NHGRI centers must be negotiated separately. 2. Reporting The primary purpose of the regular quality assessment exercises is for the QAC to gather data that will enable it to provide the public, the production centers and NHGRI with information about the quality of the sequence data being produced. . It is anticipated that the QAC will publish significant findings, based on aggregate quality assessment results, about the quality of the human genome sequence in the appropriate peer-reviewed literature, within the terms and conditions of the Cooperative Agreement. In addition, as part of the large-scale sequencing research network, the QAC is also expected to provide reports to each of the sequence production centers and to NHGRI about the results of quality assessments. Information about the quality of the sequence gathered by the QAC under Item 1 above must be handled equitably, expeditiously, and with discretion by the QAC. The details of the elements of these reports will be negotiated with the successful applicant after the award is made. However, reports from previous QA exercises have identified the following elements as being informative: o the procedures used to perform the assessment, including an indication of statistical significance of the result; o the general quality of underlying sequence data (read lengths, quality of reads, etc.); o results pertaining to the verification of assembly (e.g. restriction analysis, PCR, computational reassembly results); the likely origin of any misassemblies; o the number, location and type of discrepancies between the QAC's assembly and the GenBank accession; o how discrepancies were resolved by the QAC; o the number of gaps and ambiguities, and (if readily resolvable) whether and how these were resolved; o the overall analysis of quality of finished sequence, including a brief narrative assessing the quality of the finished sequence, strengths, weaknesses, and an assessment of whether the overall sequence meets the community standards; and o recommendations to the sequence production center to improve any deficiencies. Applicants should propose any additional items that they believe should be incorporated into the quality assessment report. A report format will also be developed for working draft data, in consultation with the QAC and NHGRI staff. In addition to the report on the individual assessments, it is expected that the QAC will periodically report on the aggregate quality assessment data obtained from all sequence producers. Such a report could contain, for example, a brief summary of the results from each sequencing production center (anonymously), a summary of the aggregate data, comparisons to previous aggregate analysis reports, a summary of the kinds of errors or weaknesses in the data that were revealed, analysis of the aggregate data that may reveal trends of error, sources of error, etc., recommendations to improve the quality of the sequence produced by the sequence production centers assessed, and recommendations for improving the methods for data quality assessment. The aggregate analyses will likely form the basis for a public report on the quality of sequence data produced by the HGP, for example by publication in the peer-reviewed scientific literature, within the terms and conditions of the Cooperative Agreement award. 3. Outreach/coordination It is expected that the QAC will interact productively with the production centers, both to maintain the state of the art and to provide advice about sequencing quality. QAC investigators are encouraged to visit the production centers at regular intervals to maintain close familiarity with the state of the art in genomic DNA sequencing, and support for such travel will be allowable. The P.I. of the QAC will be expected to participate in meetings of the principal investigators of the sequence centers, for both human and mouse sequencing. These will be held up to three times per year. It is expected that the successful applicant will be productively integrated into the sequencing research networks for the human and mouse, to be better able to provide advice and information about quality of genomic sequence data. 4. Sequence quality research and development It is likely that methods for assessing the quality of genomic sequence will evolve rapidly. Because large-scale genomic sequencing is a relatively new activity, few methods have been developed to assess the quality of the data produced. NHGRI encourages applicants to include in their application a program of research and development to investigate new methods, or to improve existing methods, to measure and characterize the quality of genomic DNA sequence data. For example, there are few methods available to routinely assess the fidelity of the deposited sequence to the target genome(s), (i.e., to verify long or short-range assemblies, or to assess the frequency of deletions or rearrangements in deposited sequence relative to the target genome); NHGRI believes that assessing these quality parameters will become increasingly important over the next two years. Other suitable topics for research and development include statistical optimization of sampling for quality assessment exercises; computerized methods for rapid error detection in, and assessment of the quality of genomic data; genomic sequencing error types, trends and origins; and novel or improved methods of annotating errors in genomic sequence databases. Incorporation of new or improved methods into routine quality assessment should be made in consultation with NHGRI. If limitations in staffing, space or other factors arise, or NHGRI funds are limited, the quality assessment activity will take precedence over QA research and development. It is expected that QA research projects will occupy no more than about 15% of the budget and effort for the project. SPECIAL REQUIREMENTS FOR COOPERATIVE AGREEMENTS Terms and conditions of award The following terms and conditions will be incorporated into the award statement 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, HHS grant administration regulations at 45 CFR Parts 74 and 92 [Part 92 is applicable when State and local Governments are eligible to apply], and other HHS, and NIH grant administration policies: 1. Mechanism The administrative and funding instrument used for this program will be the Cooperative Agreement (U01), 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 activity resides with the awardee(s) for the project as a whole, although specific tasks and activities in carrying out the study will be shared among the awardee(s) and the NHGRI Program Director. 2. PI Rights and Responsibilities The PI will have the primary responsibility for defining the details for the project within the guidelines of the RFA and for performing the scientific activity. The PI 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 "NHGRI Program Staff Responsibilities". The PI of the quality control center will: o Determine experimental approaches, design protocols, and conduct quality assessment of the genomic sequence produced by the sequence production centers, o Conduct regular quality assessments of finished and working draft data produced by the NHGRI-funded sequence production centers, sufficient to allow a reliable and independent assessment of the data quality, o Coordinate with NHGRI and respond to sequencing center P.I. comments about the results of individual quality assessments; publish or otherwise publicize results of individual quality assessments with the agreement of the sequencing production centers and the NHGRI, o Publish significant findings on the quality of the aggregate genomic sequence, o Submit periodic progress reports in a standard format, as agreed upon by the scientific consultants to the large-scale sequencing program, o Accept and implement the common guidelines and procedures approved by the scientific consultants to the large-scale sequencing program and NHGRI, including future decisions about sequence quality standards, and o Attend meetings of the scientific consultants to the large-scale sequencing program. 3. NHGRI Program Staff Responsibilities: The NHGRI Program Director will have substantial scientific/programmatic involvement during the conduct of this activity through technical assistance, advice and coordination such as participating in the design of the collective activities of the sequence production centers, advising in the selection of sources or resources, coordinating or participating in collection and/or analysis of data, advising in management and technical performance, or participating in the preparation of publications. However, the role of NHGRI 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 sequence production centers and that NHGRI staff will be given the opportunity to offer input to this process. This substantial involvement is in addition to normal stewardship provided for the award by NHGRI. The Program Director will: o Participate in the group process-setting research priorities, deciding optimal research approaches and protocol designs, and contributing to the adjustment of research protocols or approaches as warranted. The Program Director will assist and facilitate the group process and not direct it, o Serve as liaison, helping to coordinate activities among the members of the scientific consultants to the large-scale sequencing program, act as a liaison to the NHGRI, and as an information resource about extramural genome research activities, o Attend the meetings of the scientific consultants to the large-scale sequencing program, assist in developing operating guidelines, quality control procedures, and consistent policies for dealing with recurrent situations that require coordinated action. The Program Director must be informed of all major interactions of the scientific consultants to the large-scale sequencing program. The NHGRI Program Director will be responsible for scheduling the time and preparing concise (3 to 4 pages) minutes or a summary of the meetings of the scientific consultants to the large-scale sequencing program, which will be delivered to members of the group within 30 days after each meeting, o Lend his/her relevant expertise and overall knowledge of the NHGRI- and NIH- sponsored research to facilitate the selection of scientists not affiliated with the awardee institutions who are to serve on the scientific consultants to the large-scale sequencing program, o Serve on subcommittees of the scientific consultants to the large-scale sequencing program as appropriate, o Provide advice in the management and technical performance of the investigation, o Serve as scientific liaison between the awardees and other program staff at NHGRI, o Assist in promoting the availability of the human genome sequence and related resources to the scientific community at large, o Retain the option to recommend the withholding or reduction of support if the QAC fails to carry out routine QA exercises in such a way as to ensure that the quality of sequence produced by the production centers is adequately monitored, and o Participate in data analyses, interpretations, and where warranted, co- authorship of the publication of results of studies conducted by the QAC. 4. Scientific consultants to the large-scale sequencing program The scientific consultants to the large-scale sequencing program are responsible for discussing progress within the collective organization of the sequence production centers funded under RFA HG-98-002 and RFA HG-98-003, and for advising NHGRI as to how the human and mouse DNA sequence can be completed within the stated goals of time and accuracy, and within budget. As part of their role in advising NHGRI, the scientific consultants will provide counsel to the NHGRI about developing uniform procedures for data quality assessment. The scientific consultants will be senior scientists with relevant expertise. The Director, NHGRI, will select the scientific consultants. The scientific consultants will meet as a group at least once a year. The first part of this meeting will be joint with the PI’s of the sequence production centers and the QAC. Annually, the scientific consultants will make recommendations regarding progress of the QAC, along with recommendations about progress at the sequence production centers, and offer recommendations to the Director, NHGRI about any changes which may be necessary in the program. 5. Arbitration Process Any disagreement that may arise on scientific/programmatic matters (within the scope of the award), between the award recipient and the NHGRI may be brought to arbitration. An Arbitration Panel, composed of three members - one QAC designee, one NHGRI designee, and a third designee with expertise in the relevant area and chosen by the other two designees, will be convened. This special arbitration procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulations 42 CFR Part 50, Subpart D and HHS regulation at 45 CFR Part 16. 6. Yearly Milestones The awardee will be asked to define yearly milestones, including information about expected progress on sequence quality research and development, at the time of the award and to adjust these milestones annually at the anniversary date. In accord with the procedures described above, NHGRI may withhold or reduce funds if the QAC substantially fails to meet its milestones or to maintain the center at the state of the art. A mandatory yearly milestone for the QAC is that regular QA exercises will be carried out on all NHGRI-funded sequencing production centers, sufficient to constitute an independent evaluation of the quality of finished and working draft data. At a minimum, the data must be assessed from each center twice per year. Failure to meet this milestone will result in a programmatic finding that progress is inadequate. LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of the RFA in response to which the application may be submitted. 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 avoid conflict of interest in the review. The letter of intent is to be sent to the program staff listed under INQUIRIES by the letter of intent receipt date listed in the heading of this RFA. APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 4/98). These forms are available at most institutional offices of sponsored research; from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email: [email protected]; and on the internet at http://grants.nih.gov/grants/funding/phs398/phs398.html and from the program administrator listed under INQUIRIES. Because of the multi- component scope of the RFA, applicants will likely require more than the usual space allowed by the page limits for the Research Plan described in form PHS 398 to address the four components described in the Research Objectives and Scope above. Therefore, the page limit for the application Research Plan for the first three components taken together (Quality assessment, Reporting, and Outreach/Coordination) is 25 pages. If a proposal for sequence quality research and development is included, an additional 25 pages will be allowed in the application Research Plan for this fourth component. The RFA label available in the PHS 398 (rev. 4/98) application form must be affixed to the bottom of the face page of the application. 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. The RFA number must be on the label. 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 sample RFA label is available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to allow for this change. Please note this is in pdf format. 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, SUITE 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 also be sent to: Dr. Rudy Pozzatti Office of Scientific Review National Human Genome Research Institute Building 31, Room B2B37, MSC 6050 Bethesda, MD 20982-6050 Telephone: (301) 402-0838 Applications must be received by March 14, 2000. 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. Applicants must consider and address the following in preparing an application for the QAC: General. The applicant must be able to carry out an independent assessment of the sequence data produced by the production centers. This does not preclude the QAC from being in the same institution as an NHGRI-funded production center. In such a situation, however, it must be clear that the QAC will be completely independent of the production center and that no personnel of the QAC are funded in any part by a grant that funds a production center. QA exercise plan. Applicants should propose and justify a method for carrying out the routine assessments of data produced by the human and mouse production centers. The proposal must include a plan, including a schedule, to accomplish these assessments in a timely manner. The applicant must also provide sufficient information to justify the ability of the plan and personnel to meet the organizational challenges of conducting routine quality assessments on the scale requested in this RFA. Applications that can demonstrate cost efficiencies in carrying out the QA exercises (for example, from approach, scale, automation, organization, etc.) will be at an advantage. Applications that do not adequately address the QA exercise component for finished and working draft sequence will be considered non-responsive to this RFA. Applications should address the potential for growth in capacity of the QAC to be able to account for growth in the production of sequence data by NHGRI- funded sequence production centers, as outlined above. Outreach/coordination. It is extremely important that the QAC be able to interact in a positive and productive way with the other participants in the Research Network. The information generated by the QAC will potentially be made public, used in making funding decisions and remedying quality concerns, should they arise, in the sequence production centers. Applicants should provide information that indicates their willingness and ability to integrate successfully and productively with the cooperative organization of the sequence production centers. Sequence quality research. Applicants who choose to request funds for this component should provide a detailed research plan for the entire grant period. Examples of areas suitable for sequence quality assessment research include (but are not limited to) methods to assess fidelity of the deposited sequence to the target genome(s); statistical optimization of sampling for Quality Assessment exercises; computerized methods for rapid error detection in, and assessment of the quality of genomic data; genomic sequencing error types, trends and origins; novel or improved methods of annotating errors in genomic sequence databases. It is anticipated that successful methods developed in the research component will be applied to routine quality assessment exercises as appropriate. Applicants should justify the utility and relevance of the proposed research, in addition to addressing novelty and feasibility. REVIEW CONSIDERATIONS A. General Upon receipt, applications will be reviewed for completeness by CSR and for responsiveness by the NHGRI. Incomplete applications will be returned to the applicant without further consideration. If NHGRI staff find that the application is not responsive to the RFA, it will be returned without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the (IC) in accordance with the review criteria stated below. As part of the initial merit review, a process will be used by the initial review group in which applications receive a written critique and 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, assigned a priority score, and receive a second level review by the (IC) National Advisory Council or Board. The second level of review will be provided by the National Advisory Council for Human Genome Research. All applications will be judged on the basis of the scientific and technical merit of the proposed projects and the documented ability of the investigators to meet the RESEARCH OBJECTIVES of the RFA. B. Review criteria In the written comments, reviewers will be asked to discuss the following aspects of the application in order to judge the likelihood that the proposed work will accomplish the goals of this RFA. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. For the Quality assessment, Reporting, and Outreach/Coordination components: o Quality of the plan to assess the quality of the finished DNA sequence being produced by the production sequencing centers. o Quality of the plan to assess whether working draft sequence data produced by the production sequencing centers meets the NHGRI standards. o Ability of the PI to integrate productively with the collective organization of the sequence production centers. o Track Record of the PI and other key personnel. o Quality of the management plan, including organization, integration and allocation of personnel and equipment, and plans for attaining cost efficiencies. o Availability of the facilities, resources, expertise and technology necessary to perform the research, and the level of institutional commitment. o Appropriateness of the proposed budget, schedule and time-line in relation to the proposed quality assessment program. For the Sequence Quality Research and Development component: Quality of the proposed plan, if any, for sequence quality research and development; including significance, probability of success, innovation of approach, and relevance to future genomic sequencing QA needs. 1. Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? Is the proposed work relevant to the current and projected needs for assessing quality of genomic sequence produced at large scale? 2. Approach: Are the conceptual framework, design (including composition of study population), methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? 3. Innovation: Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? 4. Investigator: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? PLEASE DO NOT INCLUDE descriptive biographical information unless important to the evaluation of merit. 5. Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o The reasonableness of the proposed budget and duration in relation to the proposed research o The adequacy of the proposed protection for humans, animals or the environment, to the extent they may be adversely affected by the project proposed in the application. o The initial review group will also examine the provisions for the protection of human subjects and the safety of the research environment. The second level review will be conducted by the National Advisory Council for Human Genome Research. AWARD CRITERIA Awards will be made on the basis of scientific and technical merit as determined by peer review and the availability of funds. INQUIRIES Written and telephone inquiries concerning this RFA are encouraged. The opportunity to clarify issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Dr. Adam Felsenfeld Division of Extramural Research National Human Genome Research Institute Building 31, Room B2B07, MSC 6050 Bethesda, MD 20892-6050 Telephone: (301) 496-7531 FAX: (301) 480-2770 Email: [email protected] Direct inquiries regarding fiscal matters to: Ms. Jean Cahill Grants Management Office National Human Genome Research Institute Building 38A, Room B2B34 , MSC 6050 Bethesda, MD 20892-6050 Telephone: (301) 402-0733 FAX: (301) 402-1951 Email: [email protected] AUTHORITY AND REGULATIONS This program is described in the catalog of Federal Domestic Assistance No. 93.172. Awards are made under the authority 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 Part 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 122372 or Health Systems Agency review. The PHS strongly encourages all grant and contract recipients to provide a smoke- free workplace and promote the non-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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