RESEARCH NETWORK FOR LARGE-SCALE SEQUENCING OF THE HUMAN GENOME

Release Date:  January 9, 1998

RFA:  HG-98-002

P.T.

National Human Genome Research Institute

Letter of Intent Receipt Date:  July 1, 1998
Application Receipt Date:  October 9, 1998

PURPOSE

The purpose of this Request for Applications (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 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, 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: 1) sequence production centers; 2) specialized sequencing projects,
and 3) a quality control center. 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: 1) up to five years for sequence production centers, 2)
up to three years for specialized sequencing projects and 3) up to three years
for the quality control center. 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

The 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%) 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%) 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:

A.  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.

B.  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:

o  testing one or more new sequencing technologies or strategies that have the
potential, when implemented at large scale before 2005, to surpass the
performance of those currently being used for large-scale production sequencing. 
These projects could be undertaken with the intent of exporting the technology
or strategy, once it has been demonstrated to be robust, to a production center
or of scaling it up to production levels at the test site with the intent of
becoming a sequence production center;

o  serving as a service center to, for example, sequence difficult regions or
close gaps.

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 format available at
http://www.nhgri.nih.gov/DER/Announcements/progress_reports.html.  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.

C.  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 at
http://www.nhgri.nih.gov/Grant_info/Funding/Statements/RFA/.  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 PI 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 PI 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 web
site: http://www.nhgri.nih.gov/Grant_info/Funding/Statements/RFA/).

Data Release.  Finished mapping sequence and data: The U.S. HGP has adopted 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  (see
http://www.nhgri.nih.gov/Grant_info/Funding/Statements/RFA/).

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 http://www.nhgri.nih.gov/Grant_info/Funding/Statements/RFA/). 
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 (see
http://www.nhgri.nih.gov/Grant_info/Funding/Statements/RFA/).  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 http://www.nhgri.nih.gov/Grant_info/Funding/Statements/RFA/).  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
(http://www.nhgri.nih.gov/Grant_info/Funding/Statements/RFA/) 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; this progress report form is available at
http://www.nhgri.nih.gov/DER/Announcements/progress_reports.html.  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
(http://www.nhgri.nih.gov/Grant_info/Funding/Statements/RFA/), 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 PI in the progress report.  During the course of the project
period, the assessment will be done by the quality control center.

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% 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 PI of the project.  Accordingly, he or she is expected to
devote at least 30% 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

I.  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 (PI):  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 PI 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 PIs of a cooperative agreement involved in the Research
Network. The AC will meet at least annually.

II.  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:

1.  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).

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 a sequence production center will:

o  Determine experimental approaches, design protocols, set project milestones
and conduct experiments
o  Produce genomic sequence to meet a quality standard and cost agreed upon at
the time of  award
o  Release data according to NHGRI policies and publish results
o  Submit data for quality assessment by the quality control center or in any
other manner specified by the Steering Committee and the Advisory Committee.
o  Submit periodic progress reports in a standard format, as agreed upon by the
Steering Committee and the Advisory Committee
o  Adhere to the NHGRI policies regarding intellectual property, data release and
human subjects and other policies as might be established during the course of
this activity
o  Accept and implement the common guidelines and procedures approved by the
Steering Committee
o  Accept and participate in the cooperative nature of the group
o  Attend Steering Committee meetings

The PI of a specialized sequencing center will:

o  Determine experimental approaches, design protocols, set project milestones
and conduct experiments
o  If appropriate, produce genomic sequence to meet a quality standard and cost
agreed upon at the time of  award
o  Release data according to NHGRI policies and publish results
o  If appropriate, submit data for quality assessment by the quality control
center or in any other manner specified by the Steering Committee and the
Advisory Committee.
o  Submit periodic progress reports in a standard format, as agreed upon by the
Steering Committee and the Advisory Committee
o  Adhere to the NHGRI policies regarding intellectual property, data release and
human subjects and other policies as might be established during the course of
this activity
o  Accept and participate in the cooperative nature of the group
o  Accept and implement the common guidelines and procedures approved by the
Steering Committee
o  Attend Steering Committee meetings

The PI of the quality control center will:

o  In collaboration with the research network, determine experimental approaches,
design protocols, and conduct quality assessment of the genomic sequence produced
by the research network
o  Release results of the quality assessment to NHGRI and back to each PI
o  Submit periodic progress reports in a standard format, as agreed upon by the
Steering Committee and the Advisory Committee
o  Accept and participate in the cooperative nature of the group
o  Accept and implement the common guidelines and procedures approved by the
Steering Committee
o  Attend Steering Committee meetings

3.  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:

o  Participate (with the other Steering Committee members) 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(s) will assist and facilitate the group
process and not direct it.

o  Serve as liaison, helping to coordinate activities among the awardees; act as
a liaison to the NHGRI, and as an information resource about extramural genome
research activities.

o  Attend the Steering Committee meetings as a voting member, assist in
developing operating guidelines, quality control procedures, and consistent
policies for dealing with recurrent situations that require coordinated action. 
The Program Director(s) must be informed of all major interactions of members of
the Steering Committee.  The NHGRI Program Director(s) will be responsible for
scheduling the time and preparing concise (3 to 4 pages) minutes or a summary of
the Steering Committee meetings, 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 Advisory Committee and the
Steering Committee.

o  Serve as liaison between the Steering Committee and the Advisory Committee,
attending Advisory Committee meetings in a non-voting liaison member role.

o  Serve on subcommittees of the Steering Committee and the Advisory Committee,
as appropriate.

o  Provide advice in the management and technical performance of the
investigation.

o  The Program Director(s) will 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 from
any project within the Research Network that substantially fails to achieve its
sequencing goals at the quality stated in the NHGRI sequence quality standard and
at a cost agreed at the time the goals are set for the next year, fails to remain
state of the art in its production sequencing capabilities, fails to release data
according to the Terms and Conditions of the award, or fails to comply with any
other term of the award.

o  Participate in data analyses, interpretations, and where warranted, co-
authorship of the publication of results of studies conducted through the
Research Network.

4.  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 PI 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 PIs 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.

5. 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.

6.  Arbitration Process

Any disagreement that may arise on scientific/programmatic matters (within the
scope of the award), between award recipients and the NHGRI may be brought to
arbitration.  An Arbitration Panel, 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.

7.  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.

Public Briefing on the Research Network For Large-Scale Sequencing of the Human
Genome

Prospective 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.

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
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 is to be sent to:

Dr. Jane L. Peterson
Large Scale Sequencing
National Human Genome Research Institute
Building 38A, Room 614, MSC 6050
Bethesda, MD  20892-6050

APPLICATION PROCEDURES

The research grant application form PHS 398 (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, 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 38A, Room 609, MSC 6050
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

A.  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 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.

B.  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:
o  prior demonstrated success and quality of the proposed plan for a) producing
high quality sequence and b) increasing throughput, including both upstream map
production and sequence finishing
o  prior demonstrated success and quality of the proposed plan for decreasing
cost, including efficiency improvements due to technology development or other
factors
o  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:
o  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:
o  Merit of sequence quality assessment plans, including validation of fidelity
to the genome, monitoring and minimizing sequencing errors, and other QA/QC plans
o  Results from NHGRI sequence quality assessment exercises
o  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 PI 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 PI 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 PI 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 from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Dr. Jane L. Peterson or Dr. Adam Felsenfeld
Division of Extramural Research
National Human Genome Research Institute
Building 38A, Room 614, MSC 6050
Bethesda, MD  20892-6050
Telephone:  (301) 496-7531
FAX:  (301) 480-2770
Email:  Jane_Peterson@nih.gov
Email:  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, , MSC 6050
Bethesda, MD  20892-6050
Telephone:  (301) 402-0733
FAX:  (301) 402-1951
Email:  Jean_Cahill@nih.gov

Schedule

Public Briefing at Cold Spring Harbor, NY:  May 13, 1998
Letter of Intent Receipt Date:              July 1, 1998
Application Receipt Date:                   October 9, 1998
Scientific Review Date:                     Feb/Mar 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.



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