Research Network for Large-Scale Sequencing RFA

National Human Genome Research Institute

National Institutes of Health
U.S. Department of Health and Human Services


Research Network for Large-Scale Sequencing of the Human Genome RFA HG-98-002

NIH Guide, January 9, 1998

RFA: HG-98-002

P.T. #:

National Human Genome Research Institute

Letter of Intent Receipt Date: August 1, 1998 *
Application Receipt Date: December 10, 1998 *

January 9, 1998 NIH Guide: RFA HG-98-002
Research Network for Large-Scale Sequencing of the Human

June 19, 1998 NIH Guide: Update to RFA HG-98-002
Change in Submission Date and Scope

September 30, 1998 NIH Guide: Update to RFA HG-98-002
Change in Scope

PURPOSE

The purpose of this RFA is to seek applications to participate in a research network, the goal of which is to make a major contribution to the completion of the first human genome sequence by 2005. This research network will be comprised of sequence production centers, specialized sequencing projects and a quality control center.

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, Research Network for Large-Scale Sequencing of the Human Genome, 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" (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-512-1800).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic non-profit and for-profit organizations, private and public, such as universities, colleges, companies, hospitals, laboratories, units of state or local governments, and eligible agencies of the Federal government. Applications from minority individuals and women are encouraged. Applications from foreign institutions will not be accepted; however subcontracts to foreign institutions will be considered. A principal investigator submitting an application for the sequencing production centers must have demonstrated experience in directing projects that have produced at least 7.5 Mb of high quality finished DNA sequence.

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 National Human Genome Research Institute (NHGRI) staff with the awardee is anticipated. The cooperative agreement is used when participation by the National Institutes of Health (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, prime 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". Each component of the Research Network will be awarded as a separate U01.

The Research Network will be composed of three separate, but complementary, activities:

The objectives of the three types of projects are described below. The project period that may be requested for each type of project is as follows:

Similarly, the sizes of the different types of awards will vary. The earliest anticipated award date is July 1, 1999. It is the intention of NHGRI that the Research Network will continue through Fiscal Year 2005, if needed to complete the human DNA sequence. NHGRI expects to solicit additional specialized sequencing projects during the term of the Research Network if funds are available and if continued activity of this type is warranted. NHGRI is committed to ongoing assessment of the quality of the DNA sequence produced in this project and therefore it is anticipated that there will be a future solicitation to continue a quality control center beyond the three-year term of the center that will be funded under this RFA.

FUNDS AVAILABLE

The estimated funds available for the first year of support for awards under this RFA will be $60 million per year (total costs) for three to five sequence production projects and at least $10 million per year (total costs) for up to four specialized sequencing projects and one quality control center.

The usual PHS 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 each of the centers will be based on an annual evaluation. For the sequencing production centers, the evaluation criteria will be whether progress toward completion of the sequence of the human genome is sufficient and is state-of-the-art, relative to that of the other sequence production centers, as determined by the Advisory Committee (see below), NHGRI staff and the National Advisory Council for Human Genome Research (NACHGR). For the specialized sequencing projects and the quality control center the criteria will be whether the project is meeting its goals and fulfilling the long- and short-term needs of the research network, as determined by the Advisory Committee, NHGRI staff and the NACHGR. The funding level for the research network will also be dependent upon the availability of funds.

RESEARCH OBJECTIVES

Background

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 goals of the HGP are to characterize the genomes of human and selected model organisms through complete mapping and sequencing, to develop technologies for genomic analysis, to examine the ethical, legal, and social implications of human genetics research, and to train scientists who will be able to utilize the tools and resources developed through the HGP to pursue biological studies that will improve human health.

The HGP started in 1990 and significant progress toward completing these goals has been made in the past seven years; several goals have already been achieved. The genetic mapping goals for both the human and the mouse have been met. The human and mouse physical mapping goals are nearly complete. 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 is expected to be finished by 1998, and the complete DNA sequence of D. melanogaster is expected to be finished early in the next century.

Producing the first reference human DNA sequence by 2005 is now the HGP's primary goal. In the early years of the HGP, the focus of the research program was on mapping and technology development because it was recognized that good maps and better technology were needed if the entire human DNA sequence was to be completed within the projected budget and time period. Three years ago, it was concluded that map construction and technology development had progressed sufficiently to warrant initiation of a pilot-scale sequencing program to develop and test approaches to full-scale production sequencing of human DNA. NHGRI funded six pilot projects for this purpose in 1996. Under the pilot project program, several different strategies have been implemented, a number of new technologies have been developed or implemented, and new informatics tools have been implemented to handle the data. In the course of developing their sequence capabilities, the pilot projects have deposited more than 30 Mb of high-quality mammalian genomic DNA sequence in GenBank.

The HGP goals also call for side-by-side sequencing of regions of the mouse genome syntenic with regions of the human genome because these sequences will help to inform the discussion of the use of the mouse sequence in understanding the human sequence. The NHGRI-funded pilot projects have produced a few megabases of sequence from syntenic regions of the mouse genome.

In planning a program that will complete the sequence of the human genome by 2005, the most important component is adequate sequence production capacity. Additional infrastructural/organizational issues that need to be addressed in scaling up the current sequencing program effort have been identified during the pilot project program. It will be critical to ensure that the sequence production groups remain efficient and continue to evolve and become more efficient throughout the term of the program, and a number of additional supportive activities will be required to sustain and increase the productivity of the sequence production efforts over the long term. These include separate research efforts to: 1) evaluate new technology at a production level, 2) address problem regions in DNA (e.g., gaps, closure), 3) provide opportunities for new groups with promising approaches to attain production levels, and 4) evaluate the quality of the DNA sequence produced. It will also be important to facilitate continued and expanded communication and frequent exchange of information among the individual projects and NHGRI staff, as this has been found to provide significant benefits to the overall sequencing effort during the pilot project period.

Through this RFA, the NHGRI proposes to follow up the pilot project program with a Research Network that will make a substantial contribution to the international effort to sequence the human genome. Specifically, the Research Network's goal will be to complete 1.8 billion base pairs (60 percent) of human DNA sequence by 2005 (it is anticipated that the U.S. Department of Energy (DOE) and international partners in the HGP will complete the remaining 1.2 billion base pairs (40 percent) of the human genome sequence). This will require that the NHGRI program produces an annual average of almost 300 Mb of finished sequence, between 1999 and 2005. The coordination of the NHGRI effort by the Research Network is intended to enhance the productivity of the group as a whole, and thus increase the likelihood that the human sequence will be completed on time and within budget.

Completing the human sequence by 2005 will require the commitment of a substantial portion of NHGRI's resources. It is important to note, however, that NHGRI will continue to support the development of novel genomic technologies, including sequencing technology, outside of the Research Network, through its traditional grant program.

Research Objectives and Scope

As stated above, the goal of the Research Network will be to complete 1.8 billion base pairs (60%) of the first human DNA sequence by 2005. This RFA calls for three types of components to make up the Research Network that will accomplish this goal:

Sequence Production Centers: These projects will be the central DNA sequence production units of the network. Acceptable objectives for applications include production of at least 20 Mb of finished human sequence in the first year, at least 40 to 50 Mb in the second year and at least 50 to 100 Mb in each year thereafter, at a cost of no more than $0.40 (total costs) per base pair in the first year and at an average of $0.25 or less per base pair over the life of the Research Network. Applicants for sequence production centers must follow the guidance given in the section below, entitled "Application Guidance for Production Sequencing". Proposals must also address the NHGRI policies for large-scale sequencing outlined below.

Specialized Sequencing Projects: The primary objective of this component of the Research Network is to increase the likelihood that the human DNA sequence will be completed by providing flexibility, capabilities or services that the sequence production centers cannot. Augmenting and complementing the sequence production centers, specialized sequencing projects can contribute to the overall HGP sequencing effort in any of a variety of ways. The following are examples of activities that would be appropriate for specialized sequencing projects:

This list is not intended to be inclusive and other ideas for specialized sequencing projects are welcome. All applications for specialized sequencing projects must present a plan, including a time line, that describes how and when the proposed effort will make a substantial contribution to the completion of the human DNA sequence. If a specialized project proposes to include a moderate-sized sequencing capacity in order to carry out its purpose, evidence of past experience in sequencing should be provided using the progress report format. The unit cost of sequencing in such a project should not exceed twice the average unit cost of sequencing in the production sequencing projects in the previous year. Applicants proposing to sequence at a moderate scale must also address issues listed below under "Application Guidance for Sequence Production Centers."

Quality Control Center: Applications are sought to support one cooperative agreement to evaluate, on an ongoing basis, the quality of the DNA sequence being produced by the sequence production and specialized sequencing centers. This is a new activity in the large-scale sequencing program. During the pilot project period, two sequence quality assessment exercises were completed; a description of the methods used is available. While the methods proposed for the quality control center need not be the same as those used in the previous exercises, applications that propose to carry out quality assessment must provide evidence for the robustness of the method(s) proposed or plans for assessing the validity of the proposed method(s) and of the sampling methods (e.g., how much material will be sampled). The first assessment of the quality of finished sequence must be completed no later than six months after funding of the quality control center, and the applicant should propose a plan for continued semi-annual assessments of data from the production centers and specialized sequencing centers, where needed. It is expected that sequence quality assessment methods will evolve over the period of the grant; therefore the applicant should provide a plan to ensure that the methods being used will be maintained at the state-of-the-art. The quality control center must also include an outreach capability to provide advice to, and assist, the sequence production centers with their in-house quality control programs. The quality control center should also include funds to cover the cost of the Steering and Advisory Committees' activities.

A principal investigator may apply for more than one of the types of centers described above. However, no P.I. will be awarded a production center and a quality control center and it is unlikely that any other combination of two awards will be made to one P.I. although two awards may be made to one institution.

NHGRI POLICIES CONCERNING LARGE-SCALE SEQUENCING

During the past two years, as the pilot projects began to produce significant quantities of human DNA sequence, a number of issues arose that required the development of new policies by NHGRI. These policies will apply during the term of the Research Network. Thus, where appropriate, applicants must present plans to adhere to the policies.

Intellectual Property: In NHGRI's opinion, in the absence of additional biological information, human genomic DNA sequence information should be freely available for use by the entire research community and, therefore, should not be patented but released into the public domain. NHGRI will monitor its grantees' activities with respect to patenting human genomic sequence. (see NHGRI Policy Regarding Intellectual Property of Human Genomic Sequence).

Data Release: Finished mapping sequence and data: The U.S. HGP has adoped a policy of encouraging rapid release of mapping and sequence data into public databases. Guidelines developed by NHGRI and DOE advisors recommend that data be made publicly available within six months of the time they are verified.

Unfinished Sequence Data: Participants in the international human DNA sequencing effort have recommended that early stage human sequence data should be rapidly released. In response, NHGRI determined that its grantees should release all sequence assemblies of 2,000 base pair units or larger within 24 hours of assembly (see NHGRI Policy on Release of Human Genomic Sequence Data). Applicants should fully describe their plans for the release of mapping data and finished and unfinished sequence data.

Human Subjects Protection: Donors whose DNA will be sequenced in the project must give appropriate informed consent, and their confidentiality and anonymity must be ensured to the extent possible (recognizing that, because each individual's DNA sequence is unique, anonymity cannot ultimately be guaranteed). These issues have been addressed in a Guidance for the Use of DNA in Large-Scale Sequencing that was jointly issued by the NHGRI and the DOE human genome program in August, 1996. It is expected sufficient libraries will be available by the anticipated award date of grants funded under this RFA (July 1, 1999); if these libraries are available, human genomic DNA sequence generated under this RFA MUST be determined from resources made according to the NHGRI-DOE Guidance.

Sequence Quality: Quality standards are an important component of this program. After considerable discussion, the NHGRI adopted the goals that the sequence should be 99.99% accurate and there should be no gaps, either within or between clones (see NHGRI Standard for Quality of Human Genomic Sequence). Two sequence quality assessment exercises have been completed and have demonstrated that (1) it is possible to measure sequence quality at a low cost, and (2) that it is possible to produce sequence that meets the standard for accuracy. It is recognized, however, that it may not be possible to sequence all regions of the human genome to this standard. The policy recognizes this by providing that, in such regions, the sequence must be annotated to indicate what efforts were actually made to obtain high quality data. In the case of gaps, the annotation must include the size of the gap and the orientation of sequence fragments.

APPLICATION GUIDANCE FOR PRODUCTION SEQUENCING

Applicants must consider and address the following in preparing applications for sequence production projects called for in this RFA:

Progress Report: In order to achieve the ambitious first-year goal outlined above, applicants must already have a proven record for high-throughput DNA sequencing (At least 7.5 Mb of finished sequence. As the standards for sequence quality are evolving rapidly, for purposes of this RFA, the applicable standard of quality will be posted on the NHGRI Web site as of 7/1/98; see Sequence Quality section below.). NHGRI has developed a progress report submission format that will allow applicants to submit large amounts of mapping and sequencing information electronically and that can be easily examined by the NHGRI staff and reviewers. Evidence of the applicant's past sequencing accomplishments must be provided electronically using this form. The remaining components of the NIH application are not to be submitted through this electronic format and should be sent to NIH in the printed form called for in the NIH application kit. A printed copy of the textual material contained in the electronic progress report (excluding Part B, the graphical and tabular material) should also be included with the application.

Sequence Production Plan: The applicant must present a plan and propose milestones for achieving the proposed level of scale up. This plan must cover all phases of sequence production, starting with construction of a sequence-ready map, through deposition of the finished sequence in GenBank. Issues that should be discussed include: (1) the choice of regions to be sequenced, including any special considerations that may arise specifically because of that choice, (2) the construction of sequence-ready maps, (3) sample preparation, (4) the sequencing process, (5) assembly of the finished sequence from the raw sequence traces and (6) automated annotation. It will be important to discuss bottlenecks or other problems that may be anticipated as the project increases in scale and how they will be addressed.

Sequence Cost: The calculated cost of sequencing (both prior and projected sequencing costs) must take into account all of the expenses associated with sequence production, beginning with construction of a sequence-ready map, through deposition of the finished sequence in GenBank (the costs of the sequence-ready maps must be included whether or not the maps are being produced in-house or at a different site). The total cost of sequencing must also include any production-related technology development (see below) that has been or will be supported by the project. However, the applicant may also provide a break-down of costs so that the reviewers can evaluate the contribution of different cost elements, such as production-related technology development, to the reported total cost.

Sequence Quality: Applicants must agree to submit their data for quality assessment during both the pre-award period (in order to allow the peer reviewers to evaluate this important factor) and during the course of the project period. For sequence data already finished by the application submission date, the assessment will be conducted using the methods employed in the previous NHGRI quality assessment exercises, in which all NHGRI grantees funded for large-scale sequencing cooperated in assessment of each other's data. This evaluation will be conducted after the application is submitted, but prior to the review meeting. The finished sequence to be evaluated will be chosen by NHGRI staff from the list of finished clones submitted by the P.I. in the progress report. During the course of the project period, the assessment will be done by the quality control center.

Internal Quality Control Program: Each sequence production center must also implement an internal quality control program. Applicants must propose an internal quality control program that evaluates sequence accuracy, fidelity to the genome and short-range and long-range contiguity. If a program is already in use in the applicant's project, evidence of its usefulness must be presented in the Progress Report.

Production-Related Technology Development/Implementation: One of the goals of the NHGRI sequencing program is continually to improve the efficiency and decrease the cost of production sequencing. This will facilitate completion of the human genome sequence in the shortest possible time and at the lowest possible cost, as well as build the infrastructure that will be needed to continue sequencing multi-megabase regions of DNA from both the human and other organisms after the first human DNA sequence is completed. Applicants must present a plan to address this issue and discuss how their proposed project will balance further technology development and sequence production. As much as 10% of the requested budget may be budgeted for technology development/implementation for this purpose, but the cost must be included in the total cost of the sequence produced, as discussed above.

Mouse Genomic Sequence: While the focus of activity in the sequence production centers must be on human genomic DNA sequence, as much as 10 percent of the effort may be devoted to sequencing genomic regions of the mouse that are syntenic with regions of the human genome that have already been or are being sequenced. The applicant must present a plan for obtaining the sequence-ready maps for the regions of the mouse to be sequenced and a coherent scientific strategy/rationale as to why the target regions were chosen.

Management Plan: The management of a sequencing center requires a significant commitment by the P.I. of the project. Accordingly, he or she is expected to devote at least 30 percent effort to the project. The applicant must propose a management plan for the project that takes into account the changes that will occur as the project scales up.

SPECIAL REQUIREMENTS FOR COOPERATIVE AGREEMENTS

Definitions

ARBITRATION PANEL: A panel that is formed to review scientific or programmatic disagreement (within the scope of the award) that may arise between award recipients and NHGRI. It will be composed of three members: a designee of the Steering Committee chosen without the NHGRI staff voting, one NHGRI designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of an individual disagreement, the first member may be chosen by the individual awardee. The Arbitration Panel will help resolve both scientific and programmatic issues that develop during the course of work that restrict progress.

AWARDEE: The institution to which the cooperative agreement is awarded.

COOPERATIVE AGREEMENT: An assistance mechanism in which there is anticipated substantial NHGRI programmatic involvement with the recipient organization during the performance of the planned activity.

RESEARCH NETWORK: A group of scientists, each funded by a separate cooperative agreement, working together to complete the DNA sequence of the human genome by 2005.

NHGRI PROGRAM DIRECTOR(S): A scientist(s) of the NHGRI extramural staff who provides normal stewardship for the award and who, in addition, has substantial scientific/programming involvement during conduct of this activity, as defined in the terms and conditions of award. This involvement includes coordinating NHGRI's participation in the Research Network, functioning as a peer with the Principal Investigators, facilitating the partnership relationship between NHGRI and the Research Network, helping to maintain the overall scientific balance in the program commensurate with new research and emerging research opportunities, and ensuring that the Research Network program is consistent with the NHGRI missions and goals.

PRINCIPAL INVESTIGATOR (P.I.): The person who assembles the project, is responsible for submitting the application in response to this RFA, and is responsible for the performance of the project. The Principal Investigator will coordinate project activities scientifically and administratively.

STEERING COMMITTEE (SC): A committee that is the main governing board of the Research Network. Membership includes the NHGRI Program Director(s), the P.I. of each awarded cooperative agreement (including the sequence production centers, specialized sequencing centers and the quality control center), and three research scientists with relevant expertise, but who are not affiliated with any of the projects participating in the Research Network.

SCIENTIFIC ADVISORY PANEL (AC): A committee that evaluates the progress of the Research Network and provides recommendations to the Director, NHGRI about continued support of the components of the Research Network. The Advisory Committee will be composed of four to six senior scientists with relevant expertise and who are not P.I.s of a cooperative agreement involved in the Research Network. The AC will meet at least annually.

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, PHS, and NIH grant administration policies:

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(s).

P.I. Rights and Responsibilities: The P.I. 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 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 "NHGRI Program Staff Responsibilities".

The P.I. of a sequence production center will:

The P.I. of a specialized sequencing center will:

The P.I. of the quality control center will:
In collaboration with the research network,

NHGRI Program Staff Responsibilities: The NHGRI Program Director(s) 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 Research Network activities, 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 Research Network and that NHGRI staff will be given the opportunity to offer input to this process. The NHGRI Program Director(s) shall participate as a member of the Steering Committee having one vote.

The Program Director(s) will:

Collaborative Responsibilities

The Steering Committee will serve as the main governing board of the Research Network. The Steering Committee membership will include the NHGRI Program Director(s), the P.I. from each awarded cooperative agreement (including those of the production centers, the specialized sequencing centers and the quality control center), and three research scientists with relevant expertise, but who are not affiliated with any of the cooperative agreements. The rest of the steering committee will appoint these three members by majority vote. One of these three members will be nominated to serve as the Chair of the Steering Committee and will be appointed by the Program Director(s). Additional members may be added by action of the Steering Committee. Other government staff may attend the Steering Committee meetings, if their expertise is required for specific discussions.

The Steering Committee will be responsible for discussing progress within the Research Network, and for advising NHGRI as to how the Research Network can complete the human DNA sequence within the stated goals of time and accuracy, and within budget. The Steering Committee will work with the quality control center to develop uniform procedures for data quality assessment. Members of the Steering Committee will be required to accept and implement the common guidelines and procedures approved by the Steering Committee.

Within one month after award of the cooperative agreements, the NHGRI Program Director(s) and the P.I.s will meet (perhaps by telephone conference) to select the three outside committee members and to nominate a chair from among those three. The Program Director(s) will appoint the Chair and schedule the first meeting of the Steering Committee once the Chair has been selected. The Chair of the Steering Committee will be responsible for coordinating the Committee's activities, preparing meeting agendas, and chairing meetings. A meeting schedule will be developed at the first meeting. Two meetings will be held each year, either in Bethesda or at one of the sites. One of the meetings will partially overlap with the annual meeting of the Advisory Committee. The purpose of meeting jointly will be to allow direct interaction between members of the Research Network and the Advisory Committee, prior to the latter's annual evaluation of the Research Network's progress. Subcommittees will be established by the Steering Committee as it deems appropriate.

Advisory Committee

The Advisory Committee will be responsible for reviewing and evaluating the progress of the Research Network toward completing that portion of the human DNA sequence for which NHGRI is responsible. The Advisory Committee will be composed of four to six senior scientists with relevant expertise. The Director, NHGRI, will select the members and Chair. The membership of the Advisory Committee may be enlarged permanently, or on an ad hoc basis as needed.

The Advisory Committee will meet at least once a year. The first part of this meeting will be a joint meeting with the Steering Committee to allow the Advisory Committee members to interact directly with the members of the Research Network. Annually, the Advisory Committee will make recommendations regarding progress of the Research Network and present advice about changes which may be necessary in the Research Network program to the Director, NHGRI.

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, composed of three members - one Research Network Steering Committee 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.

Yearly Milestones

Awardees will be asked to define yearly milestones 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 for projects that substantially fail to meet their milestones or to maintain the center at the state of the art.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This new policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43).

All investigators proposing research involving human subjects should read the "NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994. Investigators also may obtain copies of the policy from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy.

LETTER OF INTENT

Prospective applicants are asked to submit, by August 1, 1998, a letter of intent that includes a descriptive title of the overall proposed research, the name, address and telephone number of the Principal Investigator, the number and title of this RFA, and a list of the key investigators and their institution(s) and projects. Any applicant planning to submit an application for more than $500,000 direct cost in any one year must contact the NHGRI staff listed under the INQUIRIES section in order for the application to be accepted by NIH.

The letter of intent should be sent to:

Dr. Jane L. Peterson
Program Director, Large Scale Sequencing
National Human Genome Research Institute
National Institutes of Health
38 Library Drive, MSC 6050 Building 38A, Room 614
Bethesda, MD 20892-6050

PUBLIC BRIEFING ON THE RESEARCH NETWORK FOR LARGE-SCALE SEQUENCING OF THE HUMAN GENOME

Propsective applicants are invited to attend a briefing on this Research Network program on May 13, 1998 in the Plimpton Room of the Beckman Center at the Cold Spring Harbor Laboratory, Cold Spring Harbor, NY. NHGRI staff will explain the purpose of the program, provide detailed instructions about the application process and answer questions. Applicant institutions are urged to send a representative to this briefing. For further information about the meeting or accommodations in the area, please contact the program staff listed in this RFA.

APPLICATION PROCEDURES

The research grant application form PHS 398 [nih.gov] (rev. 5/95) is to be used in applying for these grants. Application kits are available at most institutional offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/435-0714, E-mail: ASKNIH@od.nih.gov; and from the program administrator listed under INQUIRIES.

The RFA label available in the PHS 398 (rev. 5/95) 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. 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.

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, Suite1040 - 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
Scientific Review Administrator, Office of Scientific Review
National Human Genome Research Institute
National Institutes of Health
38 Library Drive, MSC 6050 Building 38A, Room 609
Bethesda, MD 20982-6050
Telephone: (301) 402-0838

Applications must be received by October 9, 1998. 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.

REVIEW CONSIDERATIONS

General Considerations

Upon receipt, applications will be reviewed for completeness by CSR and 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 NHGRI in accordance with the review criteria stated below. As part of the initial merit review, a process (triage) may be used by the initial review group in which applications will be determined to be competitive or non-competitive based on their scientific merit relative to other applications received in response to the RFA. All applications will receive a scientific review and summary statement, although applications judged to be competitive will be discussed and be assigned a priority score. Applications determined to be non-competitive will be withdrawn from further consideration and the principal investigator/program director and the official signing for the applicant organization will be promptly notified. 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.

Review Criteria

The application must be directed toward attaining the programmatic goals as stated under RESEARCH OBJECTIVES. The following criteria will be used by peer review groups to evaluate these applications:

For sequence production centers:

  1. Likelihood that the project will produce a significant fraction of the complete human sequence:

    • Prior demonstrated success and quality of the proposed plan for:
      • producing high quality sequence.
      • increasing throughput, including both upstream map production and sequence finishing.
    • Prior demonstrated success and quality of the proposed plan for decreasing cost, including efficiency improvements due to technology development or other factors.
    • Prior demonstrated success and quality of the proposed plan for identifying and solving critical integration problems, including adequacy of the informatics activities.

  2. Contribution of technology development:
    • Success in incorporating new technologies, with an emphasis on how this has increased productivity and reduced cost, and the merit of the plans for incorporating additional new technologies; the promise of the proposed program of incorporation of new technologies to contribute to sequence production; and evidence that the center has maintained the "state-of-the-art" in sequencing technology.

  3. Sequence quality:
    • Merit of sequence quality assessment plans, including validation of fidelity to the genome, monitoring and minimizing sequencing errors, and other QA/QC plans.
    • Results from NHGRI sequence quality assessment exercises.
    • History of attaining, and proposed measures to improve, overall contiguity, including increasing the length of, and minimizing gaps (including N's) in, the finished sequence; this includes contiguity within and between clones.

  4. Track Record of the P.I. and other key personnel.

  5. Quality of the management plan, including workflow, scale-up, divisions of labor/responsibility among components, coordination between components, appropriate staffing, training, etc.

  6. Past compliance with NHGRI data release policies, and plans for data release.

  7. Availability of the facilities, resources, expertise and technology necessary to perform the research, and the level of institutional commitment.

  8. Appropriateness of the proposed budget and time-line in relation to the proposed research.

For the specialized sequencing projects:

  1. Likelihood that the project will contribute to the completion of the first sequence of the Human Genome.

  2. Value, significance or unique role of the proposed research in contributing to the overall sequencing effort, both as an independent project and as a part of the overall sequencing effort undertaken by the other participants in the Research Network described here.

  3. Quality of the plans to integrate any new technology development into a large-scale sequencing effort.

  4. Track record of the P.I. and other key personnel.

  5. Past compliance and plans for data release.

  6. Availability of the facilities, resources, expertise and technology necessary to perform the research, and the level of institutional commitment

  7. Appropriateness of the proposed budget and time-line in relation to the proposed research.

For the quality control center:

  1. Quality of the plan to assess the accuracy, contiguity and fidelity of the DNA sequence being produced by the production sequencing centers or where appropriate, the specialized sequencing projects.

  2. Quality of the plans to provide assistance to the projects within the Research Network.

  3. Track Record of the P.I. and other key personnel.

  4. Quality of the management plan.

  5. Availability of the facilities, resources, expertise and technology necessary to perform the research, and the level of institutional commitment.

  6. Appropriateness of the proposed budget and time-line in relation to the proposed quality assessment program.

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, including the significance of the projected contribution toward meeting the NHGRI program goal of contributing to the completion of the human DNA sequence by the year 2005, program needs and balance, adherence to NHGRI policies on human subjects, data release and intellectual property, and the availability of funds.

INQUIRIES

Written and telephone inquiries concerning this RFA are encouraged. The opportunity to clarify issues or questions about the RFA from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Dr. Jane L. Peterson
Dr. Adam Felsenfeld
Division of Extramural Research
National Human Genome Research Institute
National Institutes of Health
38 Library Drive, MSC 6050
Building 38A, Room 614
Bethesda, MD 20892-6050
Phone: (301) 496-7531
Fax: (301) 480-2770
E-mail: Jane_Peterson@nih.gov
E-mail: Adam_Felsenfeld@nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Jean Cahill
Grants Management Office
National Human Genome Research Institute
Building 38A, Room 613
38 Library Drive, MSC 6050
Bethesda, MD 20892-6050
Phone: (301) 402-0733
Fax: (301) 402-1951
E-mail: Jean_Cahill@nih.gov

Schedule
Public Briefing at Cold Spring Harbor, NY: May 13, 1998
Letter of Intent Receipt Date: August 1, 1998
Application Receipt Date: December 10, 1998
Scientific Review Date: Feb/March 1999
Advisory Council Date: May 1999
Anticipated Award Date: July 1999

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.

UPDATE TO RFA HG-98-002 CHANGE IN SUBMISSION DATE AND SCOPE

NIH GUIDE, JUNE 19, 1998
RFA: HG-98-002
P.T.
Letter of Intent Receipt Date: August 1, 1998
Application Receipt Date:December 10, 1998

National Human Genome Research Institute

PURPOSE

The purpose of this notice is to inform the scientific community that the National Human Genome Research Institute is revising the RFA Research Network for Large-Scale Sequencing of the Human Genome, which appeared in the NIH Guide on January 9, 1998. NHGRI remains strongly committed to the goal of completing a high quality, complete sequence of the human genome by the year 2005. However, recently there has been discussion in the scientific community of the potential benefit of generating an intermediate rough draft sequence by 2001. During the next three months, NHGRI will be considering this possibility, and will be addressing questions about the utility of and best strategy to develop different types of a rough draft sequence. By the end of this period, NHGRI will decide whether to pursue a rough draft and, if so, what characteristics of that intermediate product would make it most useful and strategically practical. Once a decision is made, another Guide Notice will be published to inform prospective applicants about the NHGRI strategy for obtaining the human genome sequence. It is expected that this Notice will be published no later than September 30, 1998.

NHGRI recognizes that, if the scope of the RFA were to change, applicants would need time to adjust their strategies and to produce preliminary results in support of their applications. Therefore, the submission date for the applications has been changed from October 9, 1998 to December 10, 1998. Applications will be reviewed in March 1999, considered by the National Advisory Council for Human Genome Research at its May 1999 meeting and awards for the cooperative agreements that will participate in the Research Network will be made on July 1, 1999.

The date for the Letter of Intent remains August 1, 1998. The letter of intent should include a descriptive title of the overall proposed research, the name, address and telephone number of the Principal Investigator, the number and title of this RFA and a list of key investigators and their institution(s) and projects. NHGRI recognizes that the nature and perhaps the titles of the projects may change as a result of any changes in the scope of this RFA that may be announced. NHGRI staff plan to contact each investigator submitting a letter of intent during the period between the submission dates for the letter of intent and the application to discuss any changes in the RFA. Any applicant planning to submit an application for more than $500,000 direct cost MUST contact NHGRI staff in order for the application to be accepted by NIH.

The letter of intent should be sent to:

Dr. Jane L. Peterson
Program Director, Large Scale Sequencing
National Human Genome Research Institute
National Institutes of Health
38 Library Drive, MSC 6050
Building 38A, Room 614
Bethesda, MD 20892-6050

INQUIRIES

Direct inquiries regarding programmatic issues to:

Dr. Jane L. Peterson
Dr. Adam Felsenfeld
Division of Extramural Research
National Human Genome Research Institute
National Institutes of Health
38 Library Drive, MSC 6050
Building 38A,Room 614
Bethesda, MD 20892-6050
Phone: (301) 496-7531
Fax: (301) 480-2770
E-mail: Jane_Peterson@nih.gov
E-mail: Adam_Felsenfeld@nih.gov

Direct inquiries regarding fiscal matters to:

Jean Cahill
Grants Management Office
National Human Genome Research Institute
Building 38A, Room 613
38 Library Drive, MSC 6050
Bethesda, MD 20892-6050
Phone: (301) 402-0733
Fax: (301) 402-1951
E-mail: Jean_Cahill@nih.gov

RESEARCH NETWORK FOR LARGE SCALE SEQUENCING OF THE HUMAN GENOME: CHANGE OF SCOPE

Release Date: September 29, 1998
RFA:
HG-98-002 P.T.
Application Receipt Date:
December 10, 1998

National Human Genome Research Institute

PURPOSE

The purpose of this notice is to inform investigators who have expressed an interest in applying for the above-referenced RFA that the National Human Genome Research Institute (NHGRI) is revising the scope of the RFA in light of recent advice from the National Advisory Council for Human Genome Research (NACHGR). The NACHGR has approved a new NIH-DOE plan for the Human Genome Project (HGP) in the U.S. for the years 1999-2003. (The full NIH-DOE five-year plan will be published in the October 23, 1998 issue of Science.) The new plan calls for the completion of a finished, high quality human DNA sequence by 2003; in addition, the plan calls for generation of a 'working draft' of the sequence -- consisting of at least 90% coverage and at least 99% accuracy -- by 2001. The sequence data on which the working draft will be based will be held to quality standards aimed at ensuring that the data can later be directly used in assembling finished genomic sequence. Therefore, assembly of the working draft should not create loss of efficiency or increases in overall cost. Finally, the plan also calls for finishing one-third of the human sequence by 2001, focusing on gene-rich regions of the genome.

Investigators who plan to respond to this RFA must address the new NHGRI sequencing goals in their applications. Applications for large-scale sequencing centers should focus on production of finished sequence, but may also propose to generate additional draft-quality sequence in their research plan.

The primary objective of the specialized centers remains contributing, in any of a variety of ways, to the completion of the human DNA sequence by providing flexibility, capabilities or services that the sequence production centers cannot. The following are examples of activities that would be appropriate for specialized sequencing projects in light of the new goals for the genome project: producing finished and draft-quality sequence, albeit at a smaller scale than the production centers; collaborating with another sequencing center by finishing some portion of the draft-quality data being produced by the collaborating center or by producing draft sequence for finishing by the collaborator. As stated in the original RFA, investigators may also propose to organize specialized sequencing centers around the sequencing of difficult regions of the genome or the testing of a new technology or strategy.

Award criteria for the large-scale sequencing centers and specialized sequencing centers have been revised as follows:

Awards will be made on the basis of scientific and technical merit as determined by peer review, including the significance of the projected contribution toward meeting the NHGRI program goals of: contributing to the completion of the finished, high quality human DNA sequence by the year 2003, generating a draft- quality sequence covering at least 90% of the human genome and at least 99% accuracy by 2001, and completing finished, high quality sequence representing one-third of the human genome by 2001. Award decisions will also take into account program needs and balance; adherence to NHGRI policies on human subjects, data release and intellectual property; and the availability of funds.

It is expected that, under the terms of the Cooperative Agreement as specified in the RFA, there will be effective collaboration and coordination amongst the successful applicants. Applicants should address in the application, the role they will play in the Cooperative Agreement.

Funds Available: It is anticipated that as much as $120 million may be available for support of the Research Network in FY 1999. The funding level will be dependent upon the availability of funds.

Quality Control Center: NHGRI has determined that it will not accept applications for a quality control center as part of this RFA, but will instead issue an RFP for a contract to perform sequence quality assessment in the near future.

Review Schedule: In response to the accelerated timetable for completion of the human genome sequence described in the new NIH-DOE 5-year plan, the NACHGR advised NHGRI to accelerate the review and funding of applications submitted by groups that have already demonstrated the capability to contribute large amounts of finished, high quality human DNA sequence. Therefore, applications from groups that have sequenced and deposited in a public database by December 10, 1998 at least 15 Mb of completed genomic sequence (in contigs greater than 30,000 bp) will be reviewed on an accelerated timetable and considered by the NACHGR at its February 1999 meeting. Approximately one-half of the funds available for the RFA will be available to fund these projects after the February Council meeting. All other applications for large-scale sequencing centers and specialized sequencing centers will be reviewed on the timetable outlined in the original RFA, but should be submitted for the December 10, 1998 receipt date, not October 9, 1998. In July 1999, the remaining funds will be used to support additional efforts that can sequence human genomic DNA rapidly and efficiently, or to increase support for the most efficient production efforts.

Quality Control Exercise for RFA: As announced in the RFA, as part of the review of the applications, NHGRI will conduct a quality control exercise for all applicants who have deposited completed sequence in GenBank. This exercise will commence November 1, 1998. NHGRI staff will contact those who have already submitted letters of intent to discuss the details of the quality control exercise.

Web-based Progress Report: The set of questions that must be addressed by applicants as part of their progress report of their applications has been revised. A new addition to this set is a format for presenting sequencing costs which must be used to report sequencing costs for the previous year and for the years of support requested in the application. The budget should also be submitted in the usual format requested in the Form PHS 398.

INQUIRIES

Direct inquiries regarding programmatic issues to:

Dr. Jane L. Peterson
Dr. Adam Felsenfeld
Division of Extramural Research
National Human Genome Research Institute
38 Library Drive, Room 614, MSC 6050
Bethesda, MD 20892-6050
Telephone: (301) 496-7531
FAX: (301) 480-2770
E-mail: Jane_Peterson@nih.gov
E-mail: Adam_Felsenfeld@nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Jean Cahill
Grants Management Office
National Human Genome Research Institute
38 Library Drive, Room 613, MSC 6050
Bethesda, MD 20892-6050
Telephone: (301) 402-0733
FAX: (301) 402-1951
E-mail: Jean_Cahill@nih.gov


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