and Human Services
9000 Rockville Pike
Bethesda, Maryland 20892
LARGE-SCALE GENOTYPING FOR THE HAPLOTYPE MAP OF THE HUMAN GENOME
RELEASE DATE: March 26, 2002
RFA: HG-02-005
National Human Genome Research Institute (NHGRI)
(http://www.nhgri.nih.gov/)
National Cancer Institute (NCI)
(http://www.nci.nih.gov/)
National Eye Institute (NEI)
(http://www.nei.nih.gov/)
National Institute on Aging (NIA)
(http://www.nia.nih.gov/)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
(http://www.niaaa.nih.gov/)
National Institute of Allergy and Infectious Diseases (NIAID)
(http://www.niaid.nih.gov/)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
(http://www.niams.nih.gov/)
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
(http://www.nibib.nih.gov/)
National Institute on Deafness and Other Communication Disorders (NIDCD)
(http://www.nidcd.nih.gov/)
National Institute of Dental and Craniofacial Research (NIDCR)
(http://www.nidr.nih.gov/)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
(http://www.niddk.nih.gov/)
National Institute on Drug Abuse (NIDA)
(http://www.nida.nih.gov/)
National Institute of Environmental Health Sciences (NIEHS)
(http://www.niehs.nih.gov/)
National Institute of General Medical Sciences (NIGMS)
(http://www.nigms.nih.gov/)
National Institute of Mental Health (NIMH)
(http://www.nimh.nih.gov/)
National Institute of Neurological Disorders and Stroke (NINDS)
(http://www.ninds.nih.gov/)
Fogarty International Center (FIC)
(http://www.nih.gov/fic/)
LETTER OF INTENT RECEIPT DATE: April 25, 2002
APPLICATION RECEIPT DATE: May 29, 2002
THIS RFA CONTAINS THE FOLLOWING INFORMATION
o Purpose of this RFA
o Research Objectives
o Mechanism of Support
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Special Requirements
o Where to Send Inquiries
o Letter of Intent
o Submitting an Application
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations
PURPOSE OF THIS RFA
This is a joint initiative among several Institutes and Centers at NIH to
develop a haplotype map of the human genome. This RFA solicits cooperative
agreement applications for the large-scale genotyping across the genome of
samples from three populations. The data will be used to develop a map of the
haplotype patterns and of the genetic variants that are most informative for
detecting these patterns. The haplotype map is expected to be a key resource
for finding genes affecting health, disease, and response to drugs and
environmental factors, and for beginning to understand the pattern of human
genetic variation. It is anticipated that this initiative will become part of
an international collaboration to produce a human haplotype map.
RESEARCH OBJECTIVES
Background
Biomedical researchers have developed highly successful positional cloning
methods to find the genetic basis of rare diseases that are strongly affected by
single genes. However, many common diseases, such as diabetes, cancer, stroke,
Alzheimer's disease, Parkinson's disease, psychiatric disorders, alcoholism,
heart disease, deafness, arthritis, and asthma, are influenced by multiple
genetic and environmental factors. Linkage strategies that have worked well for
single-gene Mendelian disorders lack power to map such polygenic susceptibility
loci, and, far too often, such studies have yielded only weak linkages that fail
to be confirmed in follow-up studies. Thus, relatively little is known about
the genetic basis of these common diseases, or of the factors that determine
individual risk of disease, clinical course, or response to treatment.
Discovering the particular DNA sequence variants that contribute to common
disease risk offers one of the best opportunities for illuminating pathways of
disease causation in humans.
There is increasing support for the "common variant – common disease hypothesis",
which proposes that most of the genetic contributions to disease susceptibility
arise from variants that are relatively common in the susceptible population. A
growing list of examples (ApoE4 in Alzheimer's disease, Factor V Leiden in deep
vein thrombosis, MTHFR in heart disease, PPARgamma in type 2 diabetes) supports
this hypothesis, which is also based on the history of our species. According
to this hypothesis, a systematic case-control analysis of all common variants in
the human genome would reveal the major causative genetic contributions to a
disease with considerably greater statistical power than provided by the linkage
approach.
Sites in the genome where individuals differ in their DNA sequence by a single
base are called single nucleotide polymorphisms (SNPs). Recent work has shown
that there are about 10 million SNPs that are common in human populations. SNPs
are not inherited independently; rather, sets of adjacent SNPs are inherited in
blocks. The specific pattern of particular SNP alleles in a block is called a
haplotype. Recent studies show that most haplotype blocks in the human genome
have been transmitted through many generations without recombination.
Furthermore, each block has only a few common haplotypes. This means that
although a block may contain many SNPs, it takes only a few SNPs to uniquely
identify or "tag" each of the haplotypes in the block.
Recent studies show that most common haplotypes occur in all human populations,
though the frequencies may vary. Initial studies also indicate that the
boundaries between the blocks are remarkably similar among the populations
studied, although some of the blocks found in European or Asian populations are
subdivided into separate blocks in populations of African ancestry, as would be
expected based on the more recent history of European and Asian populations
compared with African ones. These data provide strong support for the idea that
a human haplotype map built with samples from populations of African, Asian, and
European ancestry would apply to most populations in the world, although further
testing of this conclusion is needed. Although the block boundaries seem to be
similar in the various populations, the frequencies of the haplotypes and the
associations between blocks do differ among populations, so the optimum choice
of tag SNPs will need to be based on information from a number of populations.
The present initiative will support the development of the haplotype map,
abbreviated the HapMap, which will be a description of the set of haplotype
blocks and the SNPs that tag them. The HapMap is expected to be valuable by
reducing the number of SNPs required to examine the entire genome for
association with a phenotype from 10 million SNPs to roughly 300,000 tag SNPs.
This should make genome scan approaches to finding regions with genes that
affect diseases much more efficient and comprehensive, since effort will not be
wasted typing more SNPs than necessary and all regions of the genome can be
included.
In addition to its use in studying genetic associations with disease, the HapMap
is expected to be a powerful resource for studying the genetic factors
contributing to variation in response to environmental factors, in
susceptibility to infection, in host immune responses, and in the effectiveness
of and adverse responses to drugs and vaccines. All such studies will be based
on the expectation that there will be higher frequencies of the contributing
genetic components in a group of people with a disease or particular response to
a drug, vaccine, pathogen, or environmental factor than in a group of similar
people without the disease or response. Using just the tag SNPs, researchers
should be able to find chromosome regions that have different haplotype
distributions in the two groups of people, those with a disease or response,
and those without. Each region would then be studied in more detail to
discover which variants in which genes in the region contribute to the disease
or response. This, in turn, is expected to contribute to an understanding of
the complex biological processes involved in the disease or response, leading to
more effective interventions or control measures. This should also allow the
development of tests to predict which drugs or vaccines would be most effective
in individuals with particular genotypes for genes affecting drug metabolism.
Haplotype methods have already been used successfully for finding genes
contributing to disease. Examples include some rare single-gene disorders such
as cystic fibrosis, diastrophic dysplasia, and Hirschsprung's disease, as well
as more common diseases such as Crohn's disease, type 2 diabetes, psoriasis, and
migraine.
An initial meeting to discuss the HapMap Project was held in July 2001; the
report of this meeting is available at
http://www.nhgri.nih.gov/About_NHGRI/Der/haplotype/index.html. Since then, working
groups have been discussing the experimental design, the populations to include,
and the ethical, legal, and social issues (ELSI) that must be addressed when
collecting samples from identified populations.
Pilot studies have already shown sufficient differences in haplotype frequencies
among Yoruban, CEPH (Western and Northern European ancestry), and
Japanese/Chinese samples to warrant beginning to develop the HapMap with
large-scale analysis of haplotypes in these populations. NHGRI is arranging for
additional sample collection for these populations. These populations were
chosen based on a sampling of ancestral geography, and they are not to be
considered typical, special, or well defined. In addition, a few non-human
primate samples may be included because they define the ancestral allele and
thus help in the interpretation of human SNP patterns. It is anticipated that
the international HapMap Project will study roughly 200 samples from these three
populations across the genome. NIH-funded researchers are expected to
contribute 30-50% of this effort. Support from other public and private sources
is expected to be forthcoming.
Research Scope
The goal of the HapMap Project is to develop a genome-wide haplotype map by
identifying the haplotype blocks and the common haplotypes in the human genome,
and to define a set of tag SNPs, using the population samples discussed above.
This RFA is intended to solicit research proposals for the large-scale
genotyping and analysis of SNPs needed to create the first-generation HapMap.
About 600,000 informative SNPs will need to be genotyped across the genome in
all the samples in order to find the roughly 300,000 tag SNPs of the HapMap.
Each research group will be responsible for the genotyping of particular regions
of the genome, in all of the samples. Each research group will choose which
known SNPs in those regions will be genotyped, will obtain more SNPs in those
regions if needed, and will genotype the SNPs. Each research group will
participate in the analysis group that will develop methods to analyze the
genotype data to find haplotypes and haplotype blocks and to choose tag SNPs.
The data will be deposited quickly in public databases.
Projects supported by this RFA will be part of a HapMap Network set up with the
funded groups. Coordination of the overall project will be through a
Coordinating Committee composed of the investigators and representatives of the
funding agencies. This network may also coordinate with related projects funded
by other organizations.
The Coordinating Committee will be responsible for a number of components of the
HapMap Project, including advising the NHGRI about which populations to study
and the number of samples from each population to be studied, in consultation
with the ELSI/Population working group; and recommending which chromosome
regions each awardee will be responsible for, taking into account the awardees'
preferences and capacities. To address particular issues, the Coordinating
Committee may establish groups as needed, which will include representatives
from the grantees, the funding agencies, and possibly other experts. Such
groups might include an analysis group to develop methods to analyze the data; a
quality group to develop methods to assess data quality; and a communication
group for explaining the project. The awardees will be expected to cooperate
closely with each other and the funding agencies.
Other Components of the HapMap Project (not part of this RFA)
This RFA deals only with the large-scale genotyping and analysis for the HapMap.
However, the overall project will have several other components: 1) Study of
the haplotype patterns on a small scale (in a few dozen regions) in several
populations in addition to those to be included in the initial large-scale
analysis. NHGRI is arranging for the community engagement and sample collection
for about 10 populations; more populations may be included in the future. Based
on the results of these small-scale studies, some of these populations may also
be studied on a large scale in the future. 2) Obtaining more SNPs, which will
be used for developing the HapMap and will be studied when particular regions
are identified by the use of the HapMap as potentially affecting a disease or
response. 3) Developing better and cheaper genotyping methods, to allow
average-sized laboratories to use the HapMap to study many diseases and
responses. 4) Developing better statistical methods to analyze data on SNPs,
haplotypes, environments, and disease associations. 5) Addressing the ethical,
legal, and social issues raised by the HapMap.
MECHANISM OF SUPPORT
This RFA will use the NIH U54 Specialized Center Cooperative Agreement and the
U01 Research Project Cooperative Agreement award mechanisms, in which the
Principal Investigators retain the primary responsibility and dominant role for
planning, directing, and executing the HapMap Project, with NIH staff being
substantially involved as a partner with the Principal Investigators, as
described under the section "Cooperative Agreement Terms and Conditions of
Award". This RFA is a one-time solicitation, and uses just-in-time concepts.
The earliest anticipated award date is September 20, 2002.
FUNDS AVAILABLE
The NIH intends to commit approximately $16 million total costs in FY 2002 to
fund two to four awards in response to this RFA; a similar amount is expected to
be committed for the second year of the awards. An applicant may request a
project period of up to two years. Although the financial plans of the ICs
provide support for this program, awards pursuant to this RFA are contingent
upon the availability of funds and the receipt of a sufficient number of
meritorious applications. Each research group will be subject to a semi-annual
evaluation of progress by the Scientific Advisory Panel of the HapMap Network
(see below for details). Based on this evaluation, adjustments may be made in
funding levels if any groups fail to meet their goals.
ELIGIBLE INSTITUTIONS
Domestic organizations may submit applications if they have any of the following
characteristics:
o For-profit or non-profit organizations.
o Public or private institutions, such as universities, colleges, hospitals, and
laboratories.
o Units of State and local governments.
o Eligible agencies of the Federal government.
(Foreign organizations are not eligible to submit applications, but are eligible
to receive subcontracts in applications submitted by domestic organizations.)
INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS
Individuals with the skills, knowledge, and resources necessary to carry out the
proposed research are invited to work with their institutions to develop
applications for support. Individuals from underrepresented racial and ethnic
groups as well as individuals with disabilities are always encouraged to apply
for NIH programs.
In order to complete the large-scale aspect of the HapMap within two years and
at reasonable cost, only investigators who have demonstrated experience with
large-scale SNP genotyping will be eligible to apply. Applicants should have
genotyped at the rate of 100,000 high-quality genotypes per month for at least
three months. Each applicant should have the capability to do at least 10% of
the genotyping for this project in two years.
SPECIAL REQUIREMENTS
NHGRI POLICIES CONCERNING INTELLECTUAL PROPERTY, DATA RELEASE, AND DATA QUALITY
Over the past several years, NHGRI has established a number of policies related
to large-scale data production
(http://www.nhgri.nih.gov/Grant_info/Funding/Statements/RFA/intellectual_property.html,
http://www.nhgri.nih.gov:80/Grant_info/Funding/Statements/RFA/data_release.html,
http://www.nhgri.nih.gov/Grant_info/Funding/Statements/data_release.html). Similar
policies related to this initiative are under development. NHGRI is currently
consulting with a number of advisors, including haplotype producers and users as
well as the National Advisory Council for Human Genome Research, to develop
policies that will ensure the timely public release of genotype and
haplotype-related data produced under this initiative. The intent is for
research supported under this RFA to produce a haplotype map that will be freely
available to all investigators. Applicants will need to describe their plans
for releasing data to public databases, including dbSNP. However, precise terms
and conditions will be negotiated when the awards are made.
An important component of the NHGRI's large-scale production programs has been
the establishment of quality standards and the assessment of the quality of the
data produced. NHGRI intends to establish a process to assess the quality of
the genotyping data produced by the HapMap Network, based on quality measure
developed by the Coordinating Committee. Since the quality of the genotyping
data that a research group has produced over the last year is likely to be a
reasonable general indicator of the quality of the genotyping data that it will
produce, applicants should describe the quality of their genotyping data and
how it was assessed.
SPECIAL REQUIREMENTS FOR COOPERATIVE AGREEMENTS
Cooperative Agreement Terms and Conditions of Award
The following terms and conditions will be incorporated into the award statement
of each cooperative agreement awarded under RFA HG-02-005 and will be provided
to the Principal Investigators and the appropriate institutional officials at
the time of award. The following special terms of award are in addition to, and
not in lieu of, otherwise applicable OMB administrative guidelines, DHHS grant
administration regulations at 45 CFR Parts 74 and 92, as are other DHHS, NIH,
and NIH grant administration policies:
1. Cooperative Agreement
The administrative and funding instruments used for this program will be the
Specialized Center Cooperative Agreement (U54) and the Research Project
Cooperative Agreement (U01). The cooperative agreement is an "assistance"
mechanism (rather than an "acquisition" mechanism), in which substantial NIH
scientific and programmatic involvement with the awardee is anticipated during
the performance of the activity. Under the Cooperative Agreement, the NIH
purpose is to support and 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 project as a whole will reside with the awardees,
although specific tasks and activities in carrying out the study will be shared
among the awardees and the NIH Program Director.
2. P.I. Rights and Responsibilities
The P.I. will have the primary responsibility for defining the details for the
project within the guidelines of RFA HG-02-005 and for performing the scientific
activities. The P.I. will agree to accept close coordination, cooperation, and
participation of NIH staff in those aspects of scientific and technical
management of the project as described under "NIH Program Staff
Responsibilities".
The P.I. of a HapMap genotyping research group will:
o Determine experimental approaches, design protocols, set project milestones,
and conduct experiments.
o Ensure that the amount of genotyping agreed upon is accomplished.
o Ensure that the genotyping meets or betters the cost agreed upon.
o Submit data for quality assessment in any manner specified by the Coordinating
Committee or the Scientific Advisory Panel.
o Ensure that the genotyping quality meets or exceeds the standards agreed to by
the Coordinating Committee and the Scientific Advisory Panel.
o Ensure that the choice of SNPs to genotype is done by the methods agreed to by
the Coordinating Committee and the Scientific Advisory Panel.
o Ensure that the analyses of haplotypes, haplotype blocks, and tag SNPs is done
by the methods agreed to by the Coordinating Committee or the Scientific
Advisory Panel.
o Ensure that the data resources developed as part of this project, including
individual genotypes, haplotypes, haplotype blocks, and tag SNPs, are released
according to NHGRI policies, by procedures developed by the Coordinating
Committee, and that results are submitted to dbSNP.
o Adhere to the NHGRI policies regarding intellectual property and other
policies that might be established during the course of this activity.
o Submit periodic progress reports in a standard format, as agreed upon by the
Coordinating Committee and the Scientific Advisory Panel.
o Accept and implement the common guidelines and procedures approved by the
Coordinating Committee.
o Accept and participate in the cooperative nature of the group.
o Attend Coordinating Committee meetings.
o Coordinate and collaborate with other U.S. and international groups producing
the HapMap.
3. NIH Program Staff Responsibilities
The NIH Program Director is a scientist of the NHGRI extramural staff who will
provide normal stewardship of the award and, in addition, will have substantial
scientific and programmatic involvement during the conduct of this activity
through technical assistance, advice, and coordination. However, the role of
NIH staff will be to facilitate and not to direct the activities. It is
anticipated that decisions in all activities will be reached by consensus of the
HapMap Network and that NIH staff will be given the opportunity to offer input
to this process. One NIH Program Director will participate as a member of the
Coordinating Committee and will have one vote. The Program Director will have
the following substantial involvement:
o Participate with the other Coordinating Committee members in the group process
of setting research priorities, deciding optimal research approaches and
protocol designs, and contributing to the adjustment of research protocols or
approaches as warranted. The Program Director will assist and facilitate the
group process and not direct it.
o Serve as a liaison, helping to coordinate activities among and for the
awardees, including acting as a liaison to the NHGRI and the other Institutes
and Centers of the NIH, and as an information resource about extramural genome
research activities. The Program Director will also coordinate the efforts of
the HapMap Network with other U.S. and international groups participating in
the HapMap Project.
o Attend all Coordinating Committee meetings as a voting member and assist in
developing operating guidelines, quality control procedures, and consistent
policies for dealing with recurrent situations that require coordinated action.
The Program Director must be informed of all major interactions of members of
the Coordinating Committee. The NIH Program Director will be responsible for
scheduling the time and preparing concise minutes or summaries of the
Coordinating Committee meetings, which will be delivered to members of the
group within 30 days after each meeting.
o Report periodically on the progress of the HapMap Project to the Directors of
the NHGRI and other NIH Institutes and Centers.
o Provide relevant expertise and overall knowledge of NIH-sponsored research to
facilitate the selection of scientists not affiliated with the awardee
institutions who are to serve on the Advisory Panel and the Coordinating
Committee.
o Serve as a liaison between the Coordinating Committee and the Advisory Panel,
attending Advisory Panel meetings in a non-voting liaison member role.
o Serve on subcommittees of the Coordinating Committee and the Advisory Panel,
as appropriate.
o Assist awardees in the development, if needed, of policies for dealing with
situations that require coordinated action.
o Provide advice in the management and technical performance of the
investigation.
o Assist in promoting the availability of the HapMap and related resources
developed in the course of this project to the scientific community at large.
o Retain the option to recommend, with the advice of the Scientific Advisory
Panel, the withholding or reduction of support from any project within the
HapMap Network that substantially fails to achieve its genotyping goals at the
cost agreed to or the quality agreed upon by the Coordinating Committee, fails
to remain state of the art in its genotyping capabilities, or fails to comply
with the Terms and Conditions of the award.
o Participate in data analyses, interpretations, and, where warranted, co-
authorship of the publication of results of studies conducted through the
HapMap Network.
4. Collaborative Responsibilities
The Coordinating Committee will serve as the main governing board of the HapMap
Network established under this RFA. It is anticipated that additional
coordination mechanisms will be set up with other U.S. and international groups
that may join this effort. The Coordinating Committee membership will include
one NIH Program Director and the P.I. from each awarded cooperative agreement.
The Coordinating Committee may add additional members. Other government staff
may attend the Coordinating Committee meetings, if their expertise is required
for specific discussions.
The Coordinating Committee will be responsible for coordinating with other
groups working on the HapMap and for advising NIH as to how the HapMap Network
can help complete the first phase of the HapMap within the stated goals of time
and accuracy, and within budget. To address particular issues, the Coordinating
Committee may establish groups as needed, which will include representatives
from the grantees and the funding agencies, and possibly other experts. Such
groups might include an analysis group to develop uniform methods to choose SNPs
for study, define haplotype blocks and haplotypes, and choose the tag SNPs, as
well as develop overall analyses of the data; a quality group to develop quality
standards and methods to assess data quality; and a communication group to
develop principles for explaining the project and reporting findings. The
Coordinating Committee will develop procedures for data flow to ensure quality
checks of the data and deposition in public databases. Members of the
Coordinating Committee will be required to accept and implement the common
guidelines and procedures approved by the Coordinating Committee.
5. Scientific Advisory Panel
A Scientific Advisory Panel may be established to evaluate the progress of the
HapMap Network toward producing the first phase of the HapMap by October 2004.
The Scientific Advisory Panel will provide recommendations to the Directors of
NHGRI and the other participating Institutes and Centers about continued support
of all components of the program. The Scientific Advisory Panel will be
composed of three to five senior scientists with relevant expertise, although
the membership may be enlarged permanently or on an ad hoc basis as needed.
The Scientific Advisory Panel will meet at least twice a year; some meetings may
be by telephone conference. The first part of the meeting will be a joint
meeting with the Coordinating Committee to allow the members of the two
committees to interact directly with each other. Twice a year the Scientific
Advisory Panel will make recommendations regarding progress of the HapMap
Network and present advice to the Directors of NHGRI and the other participating
Institutes and Centers about changes, if any, that may be necessary in the
HapMap Network program. If other funding agencies fund projects with the same
goal as this RFA, the Advisory Panel may be modified to accommodate this
situation by mutual consent of the agencies involved.
6. Arbitration Process
Any disagreement that may arise on scientific or programmatic matters within the
scope of the awards between award recipients and the NIH may be brought to
arbitration. An Arbitration Panel will be convened, which will be composed of
three members: (1) a designee of the awardee, (2) an NIH designee, and (3) a
third designee with relevant expertise who is chosen by the other two. The
Arbitration Panel will help resolve scientific or programmatic issues that
develop during the course of work that restrict progress. This special
arbitration procedure in no way affects the awardee's right to appeal an adverse
action that is otherwise appealable in accordance with NIH regulations 42 CFR
Part 50, Subpart D and HHS regulation at 45 CFR Part 16.
7. Semi-Annual Milestones
All awardees participating in the HapMap Network will be asked to define semi-
annual milestones at the time of the award and to update these milestones every
six months. These will be made a condition of the award. In accord with the
procedures described above, NIH may withhold or reduce funds for projects that
substantially fail to meet their milestones or to maintain the state of the art.
WHERE TO SEND INQUIRIES
We encourage inquiries concerning this RFA and welcome the opportunity to answer
questions from potential applicants. Inquiries may fall into three areas:
scientific or research, peer review, and financial or grants management issues:
o Direct your questions about scientific and research issues to:
Lisa Brooks, Ph.D.
National Human Genome Research Institute
Building 31, Room B2B07
Bethesda, MD 20892-2033
Telephone: (301) 435-5544
Fax: (301) 480-2770
lisa_brooks@nih.gov
Wendy Wang, Ph.D.
National Cancer Institute
6130 Executive Blvd., EPN 3138
Bethesda, MD 20852-7362
Telephone: (301) 594-7607
wangw@mail.nih.gov
Peter Dudley, Ph.D.
National Eye Institute
6120 Executive Blvd., EPS Suite 350
Bethesda, MD 20892-7164
Telephone: (301) 451-2020
pad@nei.nih.gov
Anna McCormick, Ph.D.
Chief, Biology Branch
Biology of Aging Program
National Institute on Aging
Gateway Building, Suite 2C231
Bethesda, MD 20892-9205
Telephone: (301) 496-6402
FAX: (301) 402-0010
Email: am38k@nih.gov
Maria Giovanni, Ph.D.
National Institute of Allergy and Infectious Diseases
6700-B Rockledge Drive, Room 3146
Bethesda, MD 20892-7630
Telephone: (301) 496-1884
mg37u@nih.gov
Alison Deckhut, Ph.D.
National Institute of Allergy and Infectious Diseases
6700-B Rockledge Drive, Room 5138
Bethesda, MD 20892-7630
Telephone: (301) 496-7551
adeckhut@niaid.nih.gov
Lisa A. Neuhold, Ph.D.
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Blvd., Suite 402
Bethesda, MD 20892-7003
Telephone: (301) 594-6228
lneuhold@willco.niaaa.nih.gov
William J. Sharrock, Ph.D.
National Institute of Arthritis and Musculoskeletal and Skin Diseases
45 Center Drive, Room 5AS-37A
Bethesda, MD 20892-6500
Telephone: (301) 594-5055
SharrocW@mail.nih.gov
Richard Swaja, Ph.D.
National Institute of Biomedical Imaging and Bioengineering
6707 Democracy Blvd., Suite 920
Bethesda, MD 20892-5469
Telephone: (301) 451-4779
swajar@mail.nih.gov
Thomas M. Johnson, Ph.D.
National Institute on Deafness and Other Communication Disorders
6120 Executive Blvd., EPS Suite 400C
Bethesda, MD 20892-7180
Telephone: (301) 402-3461
tj65y@nih.gov
Rochelle Small, Ph.D.
National Institute of Dental and Craniofacial Research
45 Center Drive, Room 4AN-18D
Bethesda, MD 20892-6402
Telephone: (301) 594-9898
rochelle.small@nih.gov
Catherine McKeon, Ph.D.
National Institute of Diabetes and Digestive and Kidney Diseases
Room 6103 Democracy 2
6707 Democracy Blvd.
Bethesda, MD 20892-5460
Telephone: (301) 594-8810
McKeonC@ep.niddk.nih.gov
Jonathan Pollock, Ph.D.
National Institute on Drug Abuse
6001 Executive Blvd., Room 4282
Bethesda, MD 20892-9555
Telephone: (301) 443-6300
jpollock@mail.nih.gov
Jose Velazquez, Ph.D.
National Institute of Environmental Health Sciences
P.O. Box 12233, Mail Drop EC-21
Research Triangle Park, NC 27709
Telephone: (919) 541-4998
velazqu1@niehs.nih.gov
Richard Anderson, M.D., Ph.D.
National Institute of General Medical Sciences
45 Center Drive, Room 2AS-25B
Bethesda, MD 20892-6200
Telephone: (301) 594-0943
andersor@nigms.nih.gov
Steven Moldin, Ph.D.
National Institute of Mental Health
6001 Executive Blvd., Room 7189
Bethesda, MD 20892-9643
Telephone: (301) 443-2037
smoldin@mail.nih.gov
Danilo A. Tagle, Ph.D.
National Institute of Neurological Disorders and Stroke
Neuroscience Center, Room 2133
6001 Executive Boulevard
Bethesda, MD 20892-9527
Telephone: (301) 496-5745
tagled@ninds.nih.gov
Karen Hofman, M.D.
Fogarty International Center
16 Center Drive, Room 202
Bethesda, MD 20892-6705
Telephone: (301) 496-1491
hofmank@mail.nih.gov
o Direct your questions about peer review issues to:
Rudy Pozzatti, Ph.D.
Scientific Review Branch
National Human Genome Research Institute
Building 31, Room B2B37
Bethesda, MD 20892-2032
Telephone: (301) 402-8739
Fax: (301) 435-1580
rudy_pozzatti@nih.gov
o Direct your questions about financial or grants management matters to:
Ms. Jean Cahill
Grants Administration Branch
National Human Genome Research Institute
Building 31, Room B2B34
Bethesda, MD 20892-2031
Telephone: (301) 402-0733
Fax: (301) 402-1951
jean_cahill@nih.gov
LETTER OF INTENT
Prospective applicants are asked to submit a letter of intent that includes the
following information:
o Descriptive title of the proposed research
o Name, address, e-mail, and telephone number of the Principal Investigator
o Names of other key personnel
o Participating institutions
o Number and title of this RFA
Although a letter of intent is not required, is not binding, and does not enter
into the review of a subsequent application, the information it contains allows
NIH staff to estimate the potential review workload and plan the review.
The letter of intent should be e-mailed by April 25, 2002, to:
Lisa Brooks, Ph.D.
Program Director
Genetic Variation Program
National Human Genome Research Institute
Building 31, Room B2B07
Bethesda, MD 20892-2033
Telephone: (301) 435-5544
Fax: (301) 480-2770
lisa_brooks@nih.gov
SUBMITTING AN APPLICATION
Applications must be prepared using the PHS 398 research grant application
instructions and forms (rev. 5/2001). The PHS 398 is available at
http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format.
For further assistance contact GrantsInfo at (301) 435-0714 or GrantsInfo@nih.gov.
SUPPLEMENTAL INSTRUCTIONS
SPECIAL APPLICATION GUIDANCE FOR PRODUCTION GENOTYPING
Applicants should address the following when preparing applications for the
genotyping production projects called for in this RFA. Items A–D in the
application should not exceed 25 pages.
I. Prior Experience (as part of item C in the application)
In order to complete the large-scale aspect of the HapMap within two years and
at reasonable cost, only investigators who have demonstrated experience with
large-scale SNP genotyping will be eligible to apply. Applicants should have
genotyped at the rate of 100,000 high-quality genotypes per month for at least
three months.
The NHGRI has conducted several competitions for large-scale projects during the
past few years. Our experience has been that specific information items are
central to the review of large-scale production proposals, and that the most
highly rated applications provided that information clearly and succinctly.
Brief, concise answers are encouraged. Please focus these answers on your past
accomplishments.
How do your group's past efforts support its ability to successfully
contribute to the HapMap? Discussion should include, but not be limited to:
Prior experience in SNP genotyping: How much genotyping per month has your
group done in the last three (or more) months? How much genotyping did your
group do in the last year? What proportion of the genotyping reactions
worked successfully?
Prior experience with genotype quality: Describe the quality of the
genotypes your group produced, how your group checked this quality, and how
the quality information was used to improve the genotyping quality.
Prior experience with increasing throughput and reducing costs: Describe how
your group managed to increase capacity and decrease costs for large-scale
genotyping, sequencing, or other large-scale genomic projects.
Prior experience in attaining milestones: What examples can you provide that
you have proposed milestones for genotyping, sequencing, or other large-scale
genomic projects and met them on schedule? What internal metrics have you
used to evaluate progress?
II. Research Proposal (as part of item D in the application)
Genotyping capacity: Although the actual numbers may vary, assume for this
application that the total amount of genotyping in the first phase of the HapMap
will be 600,000 informative SNPs in each of about 200 individuals. Each
applicant should have the capability to do at least 10% of the genotyping for
this project in two years. Applicants should propose the amount of genotyping
they wish to carry out; the actual amounts will be negotiated when the awards
are made. Applicants may propose the chromosome regions they wish to genotype
and analyze. Allocations of the regions will be negotiated among the groups and
the Coordinating Committee after the awards are made.
Genotyping platform: Applicants should propose and justify the genotyping
platform they wish to use. It is desirable to have a variety of platforms used
for this project, and a common platform is not expected to be chosen.
Genotype production plan: The applicant should present a plan to implement
large-scale genotyping, and propose milestones for achieving the proposed
genotyping production. This plan should thoroughly discuss and justify the
applicant's specific choices for all phases of the genotyping pipeline,
including choosing SNPs to study, obtaining needed SNPs in regions, developing
genotyping assays, producing primers, genotyping, assessing quality, finding
blocks and haplotypes, choosing tag SNPs, and depositing genotype and haplotype
data in dbSNP. It will be important to discuss potential bottlenecks or other
problems that may be anticipated and how they will be addressed. Applicants
should make clear how much of a ramp-up the proposed production plans are from
their current production capacity.
Genotyping costs: Include all costs for genotyping production. The calculated
costs of genotyping should take into account all the expenses associated with
large-scale high-quality genotyping, including choosing SNPs, obtaining needed
SNPs, developing genotyping assays, producing primers, genotyping, repeating
failed genotyping reactions, assessing quality, analyzing the data, and
depositing the data. The total costs should also include any production-related
technology development that will be supported by the project. Applicants should
also provide a breakdown of costs so that the reviewers can evaluate the
contribution of different cost elements, such as personnel, equipment, reagents
and consumables, and production-related technology development, to the reported
total cost. Applicants should explain how they anticipate reducing costs in the
first and second years of the awards. Cost analyses should be presented in
terms of both direct costs and total costs, which include indirect costs.
Applicants should explain how they monitor costs internally.
Analysis costs: Costs for the analysis of the genotypes to find haplotypes,
haplotype blocks, and tag SNPs should be included.
Other costs: Costs for the PI and another individual to attend two meetings a
year of the HapMap Network should be included.
Obtaining SNPs: Most of the common SNPs needed for developing the HapMap should
be available by the time the awards under this RFA start. More SNPs may still
be needed in particular regions, however, and applicants should describe how
they would obtain additional SNPs.
Genotype quality: Applicants should describe how they would monitor the quality
of the genotypes they propose to produce. Internal quality control programs
should be described, including quality assessment criteria. Applicants should
be prepared to submit genotyping data produced in the last six months, including
success rates, quality measures, and information about data tracking, prior to
review if NHGRI and the reviewers decide that data quality needs to be assessed
in more detail. This decision will be made after the reviewers have seen the
applications.
Data analysis: It is anticipated that an analysis group will be formed and that
there will be a coordinated approach to data analysis and definition of blocks,
haplotypes, and tag SNPs. Applicants should describe the expertise and
experience their groups have with these sorts of analyses and how they would
approach them.
Data release: Applicants should describe their proposed data release policy.
Management plan: Applicants should describe how this project would be managed.
Since the management of this project would require a significant time
commitment, a P.I. is expected to devote at least 30% effort to this project.
III. Human Subjects (as part of item E in the application)
Applicants should address human subjects issues. The samples to be used for
this project will have been collected after a process of community engagement
and individual informed consent for participation in the HapMap Project. The
samples to be used will be publicly available through the NIGMS Human Genetic
Cell Repository at the Coriell Institute. Thus, while the research funded under
this RFA will involve Human Subjects, NHGRI expects that most IRBs will find
that exemption 4 applies (the study of existing samples in which the human
subjects are not identifiable, directly or through identifiers linked to the
subjects).
Applicants should address inclusion issues. Of the samples to be studied, at
least one-quarter will come from African populations and at least one-quarter
will come from Asian populations, so there will be a large minority
representation. Roughly equal numbers of females and males will be studied.
Children from ages 18 to 21 will be included.
USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001)
application form must be affixed to the bottom of the face page of the
application. Type the RFA number on the label. Failure to use this label could
result in delayed processing of the application such that it may not reach the
review committee in time for review. In addition, the RFA title and number must
be typed on line 2 of the face page of the application form and the YES box must
be marked. The RFA label is also available at:
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf.
SENDING AN APPLICATION TO THE NIH: Submit a signed original of the application,
including the Checklist, and three signed photocopies, in one package to:
Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD 20892-7710
Bethesda, MD 20817 (for express/courier service)
At the time of submission, send two additional copies of the application to:
Rudy Pozzatti, Ph.D.
Scientific Review Branch
National Human Genome Research Institute
Building 31, Room B2B37
Bethesda, MD 20892-2032
Telephone: (301) 402-8739
Fax: (301) 435-1580
rudy_pozzatti@nih.gov
APPLICATION PROCESSING: Applications must be received by May 29, 2002. If an
application is received after that date, it will be returned to the applicant
without review.
The Center for Scientific Review (CSR) will not accept any application in
response to this RFA that is essentially the same as one currently pending
initial review, unless the applicant withdraws the pending application. The CSR
will not accept any application that is essentially the same as one already
reviewed. This does not preclude the submission of substantial revisions of
applications already reviewed, but such applications must include an
Introduction addressing the previous critique.
PEER REVIEW PROCESS
Upon receipt, applications will be reviewed for completeness by the CSR and
responsiveness by the NHGRI. Incomplete or non-responsive applications will be
returned to the applicant 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. As part of the initial merit review, all applications:
o Will receive a written critique;
o May undergo a process in which only those applications deemed to have the
highest scientific merit, generally the top half of the applications under
review, will be discussed and assigned a priority score;
o Will receive a second level review by the National Advisory Council for Human
Genome Research.
REVIEW CRITERIA
The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health. In the
written comments, reviewers will be asked to discuss the following aspects of
your application in order to judge the likelihood that the proposed research
will have a substantial impact on the pursuit of these goals:
o Significance
o Approach
o Innovation
o Investigator
o Environment
The scientific review group will address and consider each of these criteria in
assigning your application's overall score, weighting them as appropriate for
each application. Your application does not need to be strong in all categories
to be judged likely to have major scientific impact and thus deserve a high
priority score. For example, you may propose to carry out important work that
by its nature is not innovative but is essential to move a field forward.
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:
(1) SIGNIFICANCE: Does the application address the problem outlined in this
RFA?
(2) APPROACH: Are the conceptual framework, design, methods, and analyses
adequately developed, well integrated, and appropriate to the aims of the
project as outlined in this RFA? Are potential problem areas acknowledged and
alternative tactics considered? Are the plans for scaling up production
adequate? Are the costs appropriate and are the plans for reducing costs
adequate? Are the plans for assessing data quality adequate? Is the proposed
effort likely to produce an adequate amount of high-quality genotype and
haplotype information?
(3) INNOVATION: Does the project employ novel concepts, approaches, or methods
for genotyping, haplotyping, or analysis of SNP, genotype, or haplotype data, if
appropriate? Does the project develop new methods or technologies to reduce
costs or increase quality or throughput?
(4) INVESTIGATOR: Are the principal investigator, key personnel, and any
collaborators appropriately trained and well suited to carry out this work? Is
the work proposed appropriate for the experience of the P.I., key personnel, and
any collaborators? Does the prior experience section provide sufficient
evidence that the research group can carry out its part of the project? Are the
management plan and P.I. experience with management sufficient for this project?
(5) ENVIRONMENT: Does the scientific environment in which the work will be done
contribute to the probability of success? Do the proposed experiments take
advantage of unique features of the scientific environment? Are any
collaborative arrangements appropriate? Is there evidence of institutional
support?
ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your application
will also be reviewed with respect to the following:
o PROTECTIONS: The adequacy of the proposed protection for humans, animals, or
the environment, to the extent they may be adversely affected by the project
proposed in the application.
o INCLUSION: The adequacy of plans to include subjects from both genders, all
racial and ethnic groups (and subgroups), and children as appropriate for the
scientific goals of the research.
o DATA SHARING: The adequacy of the proposed plan to share data in a timely
manner.
o BUDGET: The reasonableness of the proposed budget and the requested period of
support in relation to the proposed research.
RECEIPT AND REVIEW SCHEDULE
Letter of Intent Receipt Date: April 25, 2002
Application Receipt Date: May 29, 2002
Peer Review Date: July 2002
Council Review: September 2002
Earliest Anticipated Start Date: September 25, 2002
AWARD CRITERIA
Award criteria that will be used to make award decisions include:
o Scientific merit, as determined by peer review.
o Plans for data release and intellectual property.
o Variety in genotyping platforms, if appropriate.
o Cost-effectiveness.
o Availability of funds.
o Programmatic priorities.
REQUIRED FEDERAL CITATIONS
PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The
Office of Management and Budget (OMB) Circular A-110 has been revised to provide
public access to research data through the Freedom of Information Act (FOIA)
under some circumstances. Data that are (1) first produced in a project that is
supported in whole or in part with Federal funds and (2) cited publicly and
officially by a Federal agency in support of an action that has the force and
effect of law (i.e., a regulation) may be accessed through FOIA. It is
important for applicants to understand the basic scope of this amendment.
NIH has provided guidance at:
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.
Applicants may wish to place data collected under this RFA in a public archive,
which can provide protections for the data and manage the distribution for an
indefinite period of time. If so, the application should include a description
of the archiving plan in the study design and include information about this in
the budget justification section of the application. In addition, applicants
should think about how to structure informed consent statements and other human
subjects procedures given the potential for wider use of data collected under
this award.
URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals
for NIH funding must be self-contained within specified page limitations.
Internet addresses (URLs) should not be used to provide information necessary
to the review because reviewers are under no obligation to view the Internet
sites. Furthermore, we caution reviewers that their anonymity may be
compromised when they directly access an Internet site.
HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to achieving
the health promotion and disease prevention objectives of "Healthy People 2010,"
a PHS-led national activity for setting priority areas. This RFA is related to
one or more of the priority areas. Potential applicants may obtain a copy of
"Healthy People 2010" at http://www.health.gov/healthypeople.
AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal
Domestic Assistance No. 93.172, 93.394, 93.867, 93.866, 93.855, 93.856, 93.891,
93.846, 93.287, 93.173, 93.121, 93.848, 93.847, 93.849, 93.279, 93.114, 93.862,
93.242, 93.853, 93.989 and is not subject to the intergovernmental review
requirements of Executive Order 12372 or Health Systems Agency review. Awards
are made under authorization of Sections 301 and 405 of the Public Health
Service Act as amended (42 USC 241 and 284) and administered under NIH grants
policies described at http://grants.nih.gov/grants/policy/policy.htm
and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92.
The PHS strongly encourages all grant recipients to provide a smoke-free
workplace and discourage the use of all tobacco products. In addition, Public
Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain
facilities (or in some cases, any portion of a facility) in which regular or
routine education, library, day care, health care, or early childhood
development services are provided to children. This is consistent with the PHS
mission to protect and advance the physical and mental health of the American
people.
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