Release Date:  January 22, 1999

PA NUMBER:  PAR-99-047


National Human Genome Research Institute

Letter of Intent Receipt Dates:  February 15 and July 15
Application Receipt Dates:  April 26 and September 21


The National Human Genome Research Institute (NHGRI) invites applications to
support the Advanced Development of high-throughput technologies for genomic
research. This program will address technologies for which proof-of-principle
already has been demonstrated, but for which additional support is needed for
development into robust, efficient tools for use in publicly supported,
high-throughput genomics laboratories.  This program will support Advanced
Development for methods, hardware (instrumentation), and software.  The initial
emphasis of the program will be on DNA sequencing technologies.


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 Program Announcement (PA), Advanced
Development Of Genomic Technologies, is related to one or more of the priority
areas.  Potential applicants may obtain a copy of "Healthy People 2000" at


Applications may be submitted by domestic, for-profit and non-profit
organizations, public and private, such as universities, colleges, companies,
hospitals, laboratories, units of State and local governments, and eligible
agencies of the Federal government.  Racial/ethnic minority individuals, women,
and persons with disabilities are encouraged to apply as principal investigators.
Applications from foreign institutions will not be accepted, however,
subcontracts to foreign institutions will be considered.


This PA will use the National Institutes of Health (NIH) resource-related
research project (R24) award mechanism. Responsibility for the planning,
direction, and execution of the proposed project will be solely that of the
applicant. Applicants may request up to five years of funding, but only with the
strongest justification will awards under this program exceed three years.


NHGRI anticipates having available $5-10 million for this program in fiscal year
1999 and an additional $10 million in each of the next two fiscal years.  It is
anticipated that the complexity and scope of awards made under this program will
vary, as will, therefore, the size of awards. NHGRI anticipates that several
projects per year will be funded, contingent upon availability of funds and
receipt of a sufficient number of high quality applications. The anticipated
award dates are December 1 and April 1. This program announcement will be in
effect for three years; additional announcements to continue this program may be
issued in the future.



The NHGRI is currently engaged, along with several other federal, private, and
international organizations, in a multi-year research program called the Human
Genome Project (HGP). The goals of the HGP are to characterize the genomes of the
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.  The genetic and physical mapping goals for both the human and the
mouse have been met.  There has also been good progress toward meeting the
sequencing goals.  The complete DNA sequence of the E. coli, S. cerevisiae (and
several other microorganisms), and C. elegans genomes has been determined, and
the complete DNA sequence of D. melanogaster is expected to be finished shortly.

Producing a complete reference human DNA sequence by 2003 is now the HGP's
primary goal.  In 1996, NHGRI funded six pilot projects to develop and test
approaches to the full-scale production sequencing of human DNA.  Under the pilot
project program, several different strategies, a number of new technologies, and
new informatics tools have been implemented.  In the course of developing their
sequencing capabilities, the pilot projects and other NHGRI grantees had
contributed, by December 1998, a substantial portion of the more than 230 Mb of
high-quality human genomic DNA sequence in GenBank.

In parallel with the scale-up of DNA sequencing capacity, NHGRI has continued to
support the improvement of current, and development of novel, DNA sequencing
technologies.  As a result, technology developers are now demonstrating the
feasibility of their ideas, resulting in the possibility that these technologies
could be introduced into production sequencing laboratories.  However, a
significant gap exists between the demonstration of feasibility that is required
to publish the results of an academic technology development project, and that
which is needed to implement that technology effectively in a high-throughput
data production setting.  The sequencing laboratories involved in the HGP have
become complex and integrated data production facilities in which processes must
be controlled more precisely, and changes in procedures made more carefully, than
in typical research laboratories.  To be useful in such a high-throughput
laboratory, a technology must have been thoroughly tested, shown to be extremely
robust under production conditions, and must offer substantial improvements in
the production process.  However, few technology developers possess the
infrastructure, the production experience, or access to a production facility
that are needed to demonstrate these achievements.  Furthermore, the investment
needed to support these tasks exceeds that which is provided by a typical NIH
research grant.

To address these problems, NHGRI is initiating an Advanced Development program,
which is intended to promote the implementation of new technologies in
large-scale data production laboratories engaged in the public HGP effort,
through adequately supported collaborations between teams of investigators having
appropriate expertise.  Discussions leading to the establishment of this program
occurred at a meeting held in May 1998
(  and the NIH/DOE HGP
five-year plan for 1998-2003 ( explicitly
recognized the need for such a program.  At present, DNA sequencing is the
process that has been scaled up most effectively to production levels and
therefore this program will focus on DNA sequencing technologies.  As other
processes, such as the discovery and scoring of DNA sequence variation, are
scaled up, NHGRI will consider accepting applications for Advanced Development
projects for these processes.


To be suitable for support under this program, a technology must have been
developed to the stage that proof-of-principle has been demonstrated, but
additional effort will be needed to make it robust, reliable and capable of
producing high quality data in one or more data production centers engaged in the
public HGP effort.  To warrant the investment that will be needed to accomplish
the goals of the Advanced Development program, the technologies involved must be
able to contribute to decreasing the cost and to increasing the throughput of the
production process, while maintaining the requisite data accuracy, relative to
the state-of-the-art when the application was submitted, and to improvements in
that state-of-the-art that are anticipated to arise from other quarters.

This program will support the range of activities required to drive technologies
from the proof-of-principle stage to their implementation in one or more of the
public HGP large-scale sequencing facilities.  These activities include (this
list is not intended to be exhaustive):

o  designing and fabricating prototype instruments and/or software, based on
existing breadboard devices;

o testing of methods, software, and prototypes at appropriate, increasing scale,
using appropriate 'control' and 'real' biological samples or data;

o  engineering refinements to address robustness, reliability, cost, and

o redesign and fabrication of pre-commercial, functional prototypes that can be
used in production laboratories; and

o acquisition of the data needed to demonstrate that the technology can be
exported effectively to other centers.

Accomplishing these activities will require the participation of
multidisciplinary teams that will include expertise such as technology
developers, engineers, computer scientists, and users of related technologies who
have extensive experience in high-volume data production.  In particular, it is
essential that the collaborative team must include a group of users who are
experienced in high-throughput data production.  To achieve maximum flexibility,
NHGRI will not specify the organization of the projects; the Principal
Investigator (P.I.) may be a technology developer, user, etc., and the
application may be organized into one or multiple projects.  The P.I. should
present a cost-effective plan to recruit and apply the appropriate expertise as
it is needed to meet project goals, and to shift resources as requirements
change.  For example, substantial engineering capacity may be required early in
the project, but not later, while device testing may be modest at the beginning,
but ramp to high throughput later.  The research plan must describe how effective
communication between the various components will be established and maintained,
the information flow by which input from various perspectives will be gathered
and used to implement the research plan, and how decisions will be made on
resource deployment.

NHGRI anticipates that an Advanced Development project will not result directly
in a commercial-grade product.  Therefore, applicants must present a plan to
support/maintain the hardware and software that results from the project, while
it remains pre-commercial but in use in the publicly supported laboratories. 
Also, a plan for technology dissemination beyond a small number of selected
publicly-supported production centers would strengthen the application.  NIH will
not provide the substantial amount of funding that will likely be required to
support the commercialization that must occur if these tools are to be
disseminated beyond a few expert centers.  Because such additional investment is
likely to come from the private sector, and more generally, because of the
important expertise available in the private sector to accomplish the tasks
required of such projects, the participation of the private sector in Advanced
Development projects is encouraged, although not required.

Advanced Development projects are likely to be design-directed rather than
hypothesis-driven research.  Therefore, rather than presenting an hypothesis and
an experimental plan to test it, applicants should address the following:

o design goals (a quantitative statement of what the device/method is supposed
to accomplish, e.g., 10,000 sequencing lanes per day, 1500 bases per lane at
99.5% accuracy, $0.01/lane);

o design tasks (enumeration of the designs that will have been completed before
funding begins, and those that must be done during the grant);

o program plan (includes the overall plan, with a timetable, for accomplishing
and coordinating the design, fabrication, and testing; achieving robust operation
and high data quality; and incorporating the technology into a production

o anticipated barriers (critical technologies) and approaches for overcoming
them; and

o milestones to guide and measure progress toward ambitious goals.

The primary intent of this Advanced Development program is to develop tools that
will reduce the cost of NHGRI-supported data production projects.  Projects
funded under this program are expected to reach significant endpoints during the
initial period of support (approximately three years).  Thus, it is essential
that applicants set ambitious short-term milestones to ensure that projects will
reach their endpoints on time.  Applicants should propose multiple milestones per
year, associated with key events in their development plans.  These milestones
must be defined precisely and clearly, and be quantifiable, to allow both the
P.I. and NHGRI to make a realistic assessment of progress.  The P.I. will use the
assessment of progress toward milestones to guide future work and resource
deployment.  NHGRI will use the accomplishment of milestones to trigger the
release of funds needed for the achievement of subsequent tasks.  Given the
ambitious nature of the projects, it will not be practical to conduct full-scale
technical reviews at each point where critical decisions must be made during the
project period.  However, the complexity of the tasks to be accomplished in this
program will require funding at levels that are higher than typical research
grants, and that funds can be used flexibly.  Therefore, mechanisms are required
so that NHGRI can ensure that those funds are provided only in response to
continued progress toward ambitious goals.  The enumeration of quantifiable
milestones is the responsibility of the applicant.  Evaluation of the stated
milestones and their appropriateness as triggers for the release of funds needed
to continue the project will be an important review criterion.  Prior to making
an award, NHGRI will negotiate the milestones with the P.I. and incorporate them
into the award notice.  During performance of the research, the P.I. will be
responsible for documenting and reporting to NHGRI the accomplishment of


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 and 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, and
other HHS, PHS, and NIH grant administration policies:

1.  The milestones that will serve as measures of progress, and that must be met
prior to releasing funds for the next step in development, will become a
condition of the award.  (The milestones will be proposed by the applicant,
reviewed by the peer review group and the National Advisory Council for Human
Genome Research, and finally negotiated between the applicant and NIH staff). 
Before and during the project period, staff will have the option of using
consultants to aid in the evaluation of the milestones themselves, the grantee's
progress toward milestones, and the possibility of setting additional milestones. 
The P.I. will be required to submit timely progress reports to coincide with the
schedule for evaluation of milestones.  NHGRI will have the option of reducing
funds or terminating a grant that fails to meet milestones, or of re-negotiating
the schedule for meeting the milestones, with corresponding changes in the level
of funding.

2.  P.I.s will be required to participate in one workshop per year, at which the
P.I.s and key personnel of the various awards made under this program will
exchange information concerning lessons learned in the course of the projects. 
The purpose of these workshops will be for the P.I.s to help each other to climb
the learning curve for accomplishing the overall tasks of
implementation/testing/hardening of technologies for genomics; communicating with
developers of related technologies that might be incorporated into their
projects; communicating with other potential users of their technology; or
conferring with consultants having expertise relevant to advanced development
projects.  Participation in these workshops will be a condition of the award. 
Applicants may request up to $1200 per person for up to three people, per year,
to defray the costs of participating in these meetings.

3.  Projects will be required to remain at the state-of-the-art.  The
state-of-the-art for technologies that are relevant to each project funded under
this program will be evaluated periodically by NHGRI staff, possibly in
conjunction with consultants.  Failure to remain at the state-of-the-art would
be grounds for early termination or renegotiation of the project budget if the
P.I./grantee and NHGRI were unable to reach accommodation.


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, Vol. 23, No.
11, March 18, 1994, available on the web at


It is the policy of NIH that children (i.e., individuals under the age of 21)
must be included in all human subjects research, conducted or supported by the
NIH, unless there are scientific and ethical reasons not to include them.  This
policy applies to all initial (Type 1) applications submitted for receipt dates
after October 1, 1998.

All investigators proposing research involving human subjects should read the
"NIH Policy and Guidelines on the Inclusion of Children as Participants in
Research Involving Human Subjects" that was published in the NIH Guide for Grants
and Contracts, March 6, 1998, and is available at

Investigators also may obtain copies of these policies from the program staff
listed under INQUIRIES.  Program staff may also provide additional relevant
information concerning the policy.


Prospective applicants are asked to submit a letter of intent that includes a
descriptive title of the proposed research, the name address, and telephone
number of the Principal Investigator, names of other key personnel and, if
applicable, participating institutions, and the number and title of this PA. 
Although a letter of intent is not required, is not binding, and does not enter
into the review of subsequent applications, the information that it contains
allows NHGRI staff to estimate the potential review workload and to avoid
possible conflict of interest in the review.

The letter of intent is to be sent to:

Jeffery A. Schloss, Ph.D.
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


Applications are to be submitted on the grant application form PHS 398 (rev.
4/98, accepted at the application deadlines listed at the beginning of this
program announcement.  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, email:  Application kits also are available at

Applicants planning to submit a new, competing continuation, competing
supplement, or any amended/revised version of the preceding grant application
types requesting $500,000 or more in direct costs for any year are advised that
he or she must contact the NHGRI  program staff member listed under INQUIRIES,
below, before submitting the application, i.e., as plans for the study are being
developed.  Furthermore, the applicant must obtain agreement from NHGRI staff
that the NHGRI will accept the application for consideration for award.  Finally,
the applicant must identify, in a cover letter sent with the application, the
NHGRI staff member who agreed to accept assignment of the application.  This
policy requires an applicant to obtain agreement for acceptance of both any such
application and any such subsequent amendment.  Refer to the NIH Guide for Grants
and Contracts, March 20, 1998, at

The title and number of this program announcement 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:

BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

At the time of submission, two additional copies of the application, including
all appendices, must be sent to:

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

The Center for Scientific Review (CSR) will not accept any application in
response to this PA that is essentially the same as one currently pending initial
review, unless the applicant withdraws the pending application.  The CSR will not
accept any application that is essentially the same as one already reviewed. 
This does not preclude the submission of substantial revisions of applications
already reviewed, but such applications must include an introduction addressing
the previous critique.


Upon receipt, applications will be reviewed for completeness by CSR and for
responsiveness by the NHGRI.  Incomplete applications will be returned to the
applicant without further consideration.  Applications that are complete and
responsive to the program announcement will be evaluated for scientific and
technical merit by an appropriate peer review group, convened by the NHGRI in
accordance with the standard NIH peer review procedures. The applications will
receive a second-level review by the National Advisory Council for Human Genome

To ensure that applications for this Advanced Development of Genomic Technologies
Program are evaluated appropriately, the standard NIH review criteria have been
adapted to be more appropriate for proposals that are design- rather than
hypothesis-driven.  The score should reflect the overall impact that the award
would have on the accomplishment of Human Genome Project goals, based on
consideration of the five criteria.  Each of these criteria will be addressed and
considered in assigning the overall score, weighting them as appropriate for each
application.  Note that the application does not need to be strong in all
categories to be judged likely to have major scientific impact and thus deserve
a high priority score.  For example, an investigator may propose to carry out
important work that by its nature is not innovative but is essential to move an
important new technology forward.  In the written comments reviewers will be
asked to discuss the following aspects of the application in order to judge the
likelihood that the proposed research will have a substantial impact on the
pursuit of the goals of this program.

(1)  Significance:  Does this proposal address an important problem?  If the aims
of the application are achieved, will the new technology result in more efficient
and cost-effective accomplishment of HGP goals in publicly-supported centers? 
Will this study contribute to the ability of other groups to accomplish parallel
goals for other Advanced Development projects (e.g., is the collaborative model

(2)  Approach:   Is the proposed approach likely to yield the desired results? 
Has proof-of-principle of the underlying technology been achieved? Are the
advantages of the proposed technology over competing technologies clearly
articulated?  Are the design principles clearly articulated and likely to be
achieved?  Does the applicant acknowledge potential problem areas and consider
alternative tactics?  Are the milestones and evaluation procedures appropriate? 
Are plans in place to monitor and document the quality of the products?  Is there
a plan to manage the conflicting pulls toward further optimization, on the one
hand, versus building and testing the device, on the other?  Are plans clearly
in evidence and appropriate for establishing and maintaining effective
partnership between technology developers and experienced users?  Is the cost of
the Advanced Development project justified relative to projected savings of
production costs?  Is the project timely and likely to remain at the
state-of-the-art throughout the period of requested support?  Is there an
adequate plan to assemble the data that will be needed to allow other genomic
data production centers to evaluate the technology?  Is there an adequate plan
to support the instrumentation/software while it is in use in the production
center?  Are plans for information dissemination and technology transfer

(3)  Innovation:  Does the project employ novel concepts, approaches or method?
Are extant concepts, approaches or methods applied in novel ways?  Note that
novelty and innovation are not required for this program.

(4)  Investigator:  Are the experience of the P.I. and team members appropriate
to the tasks and well balanced, and is there evidence of firm commitment to the
project from each of the key parties of the collaboration?  Is the P.I. capable
of coordinating and managing the proposed project?  Is there evidence that the
team members can work together effectively?  Do the P.I. and team members have
a track record of developing useful technology?

(5)  Environment:  Does the scientific and technological environment in which the
work will be done contribute to the probability of success?  Do the proposed
experiments take advantage of unique features of the scientific environment or
employ useful collaborative arrangements?  Is there evidence of institutional

In addition to the above criteria, in accordance with NIH policy, all
applications will also be reviewed with respect to the following, to the extent
that these issues pertain to a particular application:

o The adequacy of plans to include both genders, minorities and their subgroups,
and children for the scientific goals of the research.  Plans for the recruitment
and retention of subjects will also be evaluated.

o The reasonableness of the proposed budget and duration in relation to the
proposed research.

o The adequacy of the proposed protection for humans, animals or the environment,
to the extent they may be adversely affected by the project  proposed in the

Provisions for the safety of the research environment.


Applications will compete for available funds with all other approved
applications.  The following will be considered in making funding decisions: 
Quality of the proposed project as determined by peer review, availability of
funds, contribution to program goals, and overall program balance.


Inquiries are encouraged.  The opportunity to clarify any issues or questions
from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Jeffery A. Schloss, Ph.D.
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

Direct inquiries regarding fiscal matters to:

Ms. Jean M. 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

Direct inquiries regarding review matters to:

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


This program is described in the Catalog of Federal Domestic Assistance No.
93.172.  Awards are made under authorization of the Public Health Service Act,
Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241
and 285) and administered under PHS grants policies and Federal Regulations 42
CFR 52 and 45 CFR Part 74.  This program is not subject to the intergovernmental
review requirements of Executive Order 12372 or Health Systems Agency review.

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, and 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

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