ADDITIONAL GENOTYPING FOR THE HUMAN HAPLOTYPE MAP 

RELEASE DATE:  April 16, 2004
 
RFA Number:  RFA-HG-04-005

EXPIRATION DATE:  June 26, 2004

Department of Health and Human Services (DHHS)
 
PARTICIPATING ORGANIZATION: 
National Institutes of Health (NIH)
 (http://www.nih.gov/)

COMPONENTS OF PARTICIPATING ORGANIZATION: 
National Human Genome Research Institute (NHGRI) 
 (http://www.genome.gov/) 
National Cancer Institute (NCI)
 (http://www.nci.nih.gov/)
National Center for Research Resources (NCRR)
 (http://www.ncrr.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 on Deafness and Other Communication Disorders (NIDCD)
 (http://www.nidcd.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.fic.nih.gov/)

CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBERS: This program is described in the 
Catalog of Federal Domestic Assistance No. 93.172, 93.394, 93.389, 93.866, 
93.273, 93.173, 93.848, 93.847, 93.849, 93.279, 93.114, 93.862, 93.242, 93.853, 
and 93.989.

LETTER OF INTENT RECEIPT DATE:  May 28, 2004 
APPLICATION RECEIPT DATE:       June 25, 2004
 
THIS RFA CONTAINS THE FOLLOWING INFORMATION

o Purpose of this RFA
o Research Objectives
o Mechanisms 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 Supplementary Instructions
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations

PURPOSE OF THIS RFA 

This RFA solicits applications for a cooperative agreement to augment the 
International HapMap Project by supporting the genotyping of approximately 2.25 
million single nucleotide polymorphisms (SNPs) across the genome in 270 samples 
from four populations, at high quality and at a cost of about 1 cent per 
genotype.  The data from this effort will contribute to the development of a 
map, called the HapMap, of the haplotype patterns in the human genome and of a 
set of SNPs that are informative about these patterns and the associations among 
the SNPs.  The HapMap is expected to be a key resource that researchers will use 
to find genes that affect health, disease, and response to drugs and 
environmental factors.  The genotyping supported by this RFA will augment the 
current efforts of the HapMap Project by substantially increasing the number of 
SNPs that will be studied, thereby increasing the quality of the HapMap and its 
usefulness as a resource for understanding human genetic variation and its role 
in health and disease.  This RFA builds on a previous RFA, HG-02-005 
Large-Scale Genotyping for the Haplotype Map of the Human Genome 
(http://grants.nih.gov/grants/guide/rfa-files/RFA-HG-02-005.html).  
 
RESEARCH OBJECTIVES
 
Background

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.  Relatively little is known about the genetic bases 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. 

Sites in the genome where individuals differ in their DNA sequence by a single base 
are called single nucleotide polymorphisms (SNPs).  About 10 million SNPs are common 
in human populations.  SNPs are not inherited independently.  Rather, sets of 
adjacent SNP alleles are generally associated because they are inherited together.  A 
specific set of such associated SNP alleles is called a haplotype.  Most chromosome 
regions have only a few common haplotypes.  This means that although a region may 
contain many SNPs, it can be characterized by a few SNPs that uniquely identify, or 
“tag”, each of the haplotypes in the region.  Most common haplotypes occur in all 
human populations, although their frequencies may vary among populations.  Thus, the 
optimal choice of tag SNPs will need to be based on information from several 
populations.  

The goal of the International HapMap Project is to produce a resource that describes 
the haplotypes in the human genome and the SNPs that tag them.  It is estimated that 
roughly 300,000 to 500,000 tag SNPs can be chosen that contain most of the 
information on the patterns of variation of the 10 million common SNPs in the human 
genome.  By using the HapMap tag SNPs, researchers will be able to examine candidate 
regions or even the entire genome for association with a phenotype in an efficient 
and comprehensive way.  

The International HapMap Consortium is a collaboration among researchers in six 
countries:  Japan, the United Kingdom, Canada, China, Nigeria, and the U.S.  An 
earlier RFA (http://grants.nih.gov/grants/guide/rfa-files/RFA-HG-02-005.html) 
solicited research proposals for genotyping SNPs in the chromosomes that are to be 
done by U.S. researchers for the Project, which is almost one-third of the genome.  
The HapMap Project is studying a set of 270 samples with geographic ancestry from 
four populations:  30 trios (both parents and an adult child) from the Yoruba people 
of Ibadan, Nigeria, 45 unrelated Japanese living in the Tokyo area, 45 unrelated Han 
Chinese living in Beijing, and 30 trios from U.S. donors with ancestry from Northern 
and Western Europe, originally collected by the Centre d’Etude du Polymorphisme 
Humain (CEPH).  The living CEPH donors provided consent for the use of their samples 
for this Project; the IRB approved the use of samples from the deceased donors.  The 
samples from Nigeria, Japan, and China were collected after a process of community 
engagement and individual informed consent; these samples are stored as cell lines at 
the non-profit Coriell Institute for Medical Research, as part of the NIH NIGMS Human 
Genetic Cell Repository (http://locus.umdnj.edu/nigms/).  More information is at the 
Project website http://www.hapmap.org, and in the paper Nature 426: 789-796 (2003) 
http://www.nature.com/nature/.

Since the start of the HapMap Project in October of 2002, six million SNPs have been 
added to public databases, the new samples have been collected and are almost ready 
for use, much of the scientific strategy has been refined, and the genotyping of 
about 600,000 SNPs in all the samples is expected to by done by the fall of 2004.  
The Consortium has established working groups to address ethical and cultural issues, 
data flow, quality control, analysis, data release, intellectual property issues, and 
communications.  The data produced by the Consortium are rapidly released, with some 
of the data available from the public database dbSNP 
(http://www.ncbi.nlm.nih.gov/SNP/), and some available from the HapMap Data 
Coordination Center at the Cold Spring Harbor Laboratory under the terms of a 
clickwrap license that requires only that users must not restrict the ability of 
others to use the data (http://www.hapmap.org/downloads/datarelease.html).  Ongoing 
assessment of the genotype data quality is being done; the data are estimated to be 
about 98% complete and 99.5% accurate.

The initial plan for producing the HapMap was to genotype the samples for about 1 to 
1.5 million SNPs, of which about 300,000 to 500,000 would be chosen as the tag SNPs.  
There was, however, some uncertainty about whether this coverage of the genome would 
be adequate to develop the HapMap, especially in chromosome regions with low linkage 
disequilibrium (LD).  There was also concern about whether this would provide 
adequate coverage for the Yoruba samples, which are expected to have less LD than 
samples from the other populations (Gabriel SB, et al. Science 296: 2225-2229 
(2002)).  

This RFA is being issued in response to recent technology improvements that have led 
to a large reduction in the cost of genotyping.  NHGRI estimates that it should now 
be possible to do large-scale genotyping for about one cent per genotype, which is 
considerably lower than the cost at the start of the HapMap Project, and therefore to 
obtain more genotyping than had been planned initially.  This RFA is designed to 
augment the work that the Consortium is doing and not substitute for genotyping that 
is already planned by the currently funded genotyping centers; this is an opportunity 
to enhance the work by providing more depth of coverage.  When combined with the 
extensive set of genotype data already produced and planned by the current 
Consortium, these additional data will greatly improve the HapMap, providing adequate 
coverage of the genome in all the samples and much better resolution of haplotypes, 
especially in regions with low LD.  The choice of tag SNPs should be much better and 
thus more useful for association studies using the HapMap.

Research Scope

The goal of the HapMap Project is to develop a genome-wide haplotype map by 
identifying the common haplotypes in the human genome and defining a set of tag SNPs 
that best describes the pattern of variation and association among the SNPs, using 
the population samples discussed above.  This RFA is intended to solicit research 
proposals for the large-scale SNP genotyping needed to properly complete the HapMap.  
Genotyping is to be done successfully for at least 2.25 million SNPs in the 270 
HapMap samples (plus 15 duplicates and 3 blank controls) in less than one year.  The 
genotyping is to be done at a total cost of about 1 cent or less per successful 
genotype, at quality standards agreed on by the International HapMap Consortium, of 
at least 99.5% accuracy and 98% completeness.
 
It is anticipated that the group supported by this RFA will become a member of the 
International HapMap Consortium.  Coordination of the overall Project is through the 
International HapMap Consortium Steering Committee, which is composed of the 
investigators, chairs of the working groups, and the representatives of the funding 
agencies.  The awardee will be expected to cooperate closely with the other HapMap 
groups and the funding agencies.    

The awardee will choose which SNPs to genotype, will genotype the SNPs, will release 
the genotype data and related data quickly to the HapMap Data Coordination Center, 
and will participate in quality assessment exercises, following the procedures and 
policies agreed on by the International HapMap Project Steering Committee, and in 
consultation with the NHGRI and the HapMap Analysis Group.  Assay information for new 
SNPs not already in dbSNP will be sent to dbSNP.  It is anticipated that the Project 
will end by the fall of 2005.  To meet this goal, the Project’s Analysis Group will 
need the summer to produce the HapMap from the genotype data.  The genotype data will 
be most useful if they are produced as soon as possible; thus, most of the genotyping 
supported by this RFA should be done by March of 2005.

MECHANISM OF SUPPORT

This RFA will use the NIH U54 Specialized Center Cooperative Agreement award 
mechanism.  The applicant will be solely responsible for planning, directing, and 
executing the proposed project.  The anticipated award date is September 17, 2004.  

This RFA uses just-in-time concepts.  It uses the non-modular budgeting format (see 
http://grants.nih.gov/grants/funding/modular/modular.htm).  This program does not 
require cost sharing as defined in the current NIH Grants Policy Statement at 
http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part2.htm.  

The NIH U54 Specialized Center is a cooperative agreement award mechanism.  In the 
cooperative agreement mechanism, the Principal Investigator retains the primary 
responsibility and dominant role for planning, directing, and executing the proposed 
project, with NIH staff being substantially involved as a partner with the Principal 
Investigator, as described under the section "Cooperative Agreement Terms and 
Conditions of Award".  There are no plans to reissue this RFA.

FUNDS AVAILABLE 

The NHGRI intends to commit approximately $6.5 million in total costs in FY 2004, and 
anticipates funding one new award in response to this RFA.  An applicant should 
request a project period of one year.  Although the financial plans of the NHGRI 
provide support for this program, any awards pursuant to this RFA are contingent upon 
the availability of funds and the receipt of a sufficient number of meritorious 
applications.

The funded research group will become a participant in the HapMap Research Network, 
and be subject to a semi-annual evaluation of progress by the Scientific Advisory 
Panel of the HapMap Network (see below for details).  
 
ELIGIBLE INSTITUTIONS
 
You may submit an application if your institution has 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  
o Domestic or foreign institutions/organizations
 
INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS   

Any individual with the skills, knowledge, and resources necessary to carry out the 
proposed research is invited to work with his or her institution to develop an 
application 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 achieve the goals of this RFA, to generate large amounts of genotype data 
within one year at the target cost and quality levels, only investigators who have 
demonstrated experience with large-scale low-cost SNP genotyping will be eligible to 
apply.  

SPECIAL REQUIREMENTS 

NHGRI AND INTERNATIONAL HAPMAP CONSORTIUM POLICIES CONCERNING DATA RELEASE, 
INTELLECTUAL PROPERTY, AND DATA QUALITY

NIH supports the goals of the International HapMap Project to release the genotype 
and related data produced by the International HapMap Consortium in a timely manner, 
and to ensure that the HapMap will be freely available to all researchers.  The NHGRI 
thus has adopted the International HapMap Consortium’s policies and procedures for 
data submission and release, which were designed to ensure the access of researchers 
to the HapMap data (Nature 426: 789-796 (2003), 
http://www.hapmap.org/downloads/datarelease.html , 
http://www.hapmap.org/cgi-perl/registration ). These procedures are:

o All new SNPs identified by the Project are sent directly to the NIH public 
database dbSNP (http://www.ncbi.nlm.nih.gov/SNP/).  
o Genotype data are submitted to the HapMap Data Coordination Center (DCC) at the 
Cold Spring Harbor Laboratory on a monthly basis (http://www.hapmap.org).  
o The DCC calculates SNP allele and genotype frequencies and submits them to dbSNP, 
which releases them publicly in the next dbSNP build.  
o The individual genotype data are released by the DCC on a monthly basis.  To 
obtain access to these data, a user must agree to the terms of a license 
(http://www.hapmap.org/downloads/datarelease.html), which requires only that users 
not restrict the access of others to the data, and that they share the data only 
with others who have agreed to the same terms.  
o When a sufficient density of SNPs has been genotyped in a chromosome region to 
determine haplotypes, the individual genotype data and the haplotype data will be 
sent to dbSNP for public release, at which time the license restrictions will be 
removed for those data.  
o At the end of the Project, all remaining data will be released to dbSNP, and 
license restrictions will no longer apply.  

The International HapMap Consortium members have also agreed that their own 
laboratories will access the data only through the DCC and under the license terms, 
to ensure that all scientists have equal access to the data for research in which the 
HapMap is used.  The Consortium believes that SNP, genotype, and haplotype data in 
the absence of specific utility do not constitute appropriately patentable 
inventions; however, this policy does not block users from filing for appropriate 
intellectual property on associations they have found relating SNPs or haplotypes to 
particular phenotypes, as long as any ensuing patent is not used to prevent others' 
access to the basic HapMap data, in accordance with the terms of the license.

Applicants are required to explain their plans for data sharing and exercising their 
intellectual property rights.  If the plans differ from what the International HapMap 
Consortium has adopted, the applicant should discuss the differences and explain how 
the proposed approaches meet the Consortium’s objective of ensuring rapid access to 
the Project’s data.  The reviewers and NHGRI staff will evaluate the adequacy of 
these plans.  Plans acceptable to NHGRI and the applicant will need to be arrived at 
before an award can be made.

The International HapMap Consortium has developed processes to assess the quality of 
genotyping data produced by its members.  Applicants will need to agree to 
participate in the data quality assessment exercises established by the Consortium 
and adopted by the NHGRI.  As 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 in detail the quality of their genotyping data and how it was assessed.  
Instructions for presenting these data are given below.  

It will be particularly useful for the reviewers, as they evaluate the quality of the 
genotyping, to have results from a standard set of SNPs and samples.  NHGRI has 
identified a standard set of 200 SNPs (see http://www.genome.gov/11511477).  
Applicants are strongly encouraged to genotype these SNPs in the set of 90 HapMap 
CEPH samples plus 5 duplicates (available from the Coriell Institute for Medical 
Research, http://locus.umdnj.edu/ccr/), and to submit these data to the NHGRI Program 
Director by July 6, 2004, for analysis by NHGRI and the reviewers.  

It is anticipated that the awardee from this RFA will become a member of the 
International HapMap Consortium.  

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-04-005 and will be provided to the 
Principal Investigator 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, and other DHHS, NIH, and NIH grant 
administration policies.  These terms and conditions are the same as for RFA HG-02-
005, released in March of 2002; in practice the role of the Coordinating Committee is 
played by the International HapMap Project Steering Committee. 

1.  Cooperative Agreement

The administrative and funding instruments used for this program will be the 
Specialized Center Cooperative Agreement (U54).  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-04-005 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 and 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 and 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.  The NIH Program Director will participate as a member of the 
Coordinating Committee and will have one vote.  The NIH 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 NIH 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 NIH 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 NIH 
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 Scientific Advisory 
Panel, attending Advisory Panel meetings in a non-voting liaison member role. 

o  Serve on subcommittees of the Coordinating Committee and the Scientific 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 continue to 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 the 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 Consortium can 
complete 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 HapMap.  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/research, peer review, and financial or grants management issues:

o Applicants are strongly encouraged to consult with the Program Director early in 
the process of preparing an application.  Direct your questions about scientific and 
research issues to:

Michael Shi, M.D., Ph.D.
National Human Genome Research Institute
31 Center Dr., Room B2B07
Bethesda, MD  20892-2033
Telephone:  (301) 451-1340
Fax:  (301) 480-2770
michael.shi@nih.hhs.gov

Lisa Brooks, Ph.D.
National Human Genome Research Institute
31 Center Dr., Room B2B07
Bethesda, MD  20892-2033
Telephone:  (301) 435-5544
Fax:  (301) 480-2770
lisa.brooks@nih.hhs.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
 
Marjorie Tingle, Ph.D.
National Center for Research Resources
1 Democracy Plaza, Room 958 
Bethesda, MD 20892-4874
Telephone: (301) 435-0772 
TingleM@mail.nih.gov

Anna McCormick, Ph.D.
National Institute on Aging
Gateway Building, Suite 2C231
Bethesda, MD 20892-9205
Telephone:  (301) 496-6402
am38k@nih.gov
 
Zhaoxia Ren, M.D., Ph.D.
National Institute on Alcohol Abuse and Alcoholism
5635 Fishers Lane, Room 2052
Bethesda, MD 20892-9304
Telephone: (301) 443-5733
zren@mail.nih.gov
 
Bracie Watson, Jr., Ph.D.
National Institute on Deafness and Other Communication Disorders
6120 Executive Blvd., EPS Suite 400C
Bethesda, MD  20892-7180
Telephone:  (301) 402-3458
watsonb@nidcd.nih.gov 
 
Catherine McKeon, Ph.D.
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Blvd., Room 6103
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
 
Gwen Collman, Ph.D.
National Institute of Environmental Health Sciences
P.O. Box 12233, Mail Drop EC-21
Research Triangle Park, NC  27709
Telephone:  (919) 541-4980
collman@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 7191
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
6001 Executive Boulevard, Room 2133
Bethesda, MD  20892-9527 
Telephone:  (301) 496-5745
tagled@ninds.nih.gov
 
Flora Katz, Ph.D.
Fogarty International Center
31 Center Drive, Room B2C39Q
Bethesda, MD 20892-2220 
Telephone:  (301) 402-9591
katzf@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
31 Center Dr., MSC 2032
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. Cheryl Chick
Grants Administration Branch
National Human Genome Research Institute 
Building 31, Room B2B34
31 Center Dr., MSC 2032
Bethesda, MD  20892-2031
Telephone:  (301) 402-0733
Fax:  (301) 402-1951
cheryl.chick@nih.hhs.gov

LETTER OF INTENT
 
Prospective applicants are strongly encouraged to submit a letter of intent that 
includes the following information:

o Descriptive title of the proposed research
o Name, address, 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 that it contains allows IC 
staff to estimate the potential review workload and plan the review.
 
The letter of intent is to be sent by May 28, 2004.  The letter of intent should be 
e-mailed to:

Michael Shi, M.D., Ph.D.
Program Director
Genetic Variation Program
National Human Genome Research Institute 
31 Center Dr., 31 / B2B07
Bethesda, MD  20892-2033
Telephone:  (301) 451-1340
Fax:  (301) 480-2770
michael.shi@nih.hhs.gov 

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001).  Applications must have a DUN and Bradstreet 
(D&B) Data Universal Numbering System (DUNS) number as the Universal Identifier when 
applying for Federal grants or cooperative agreements.  The DUNS number can be 
obtained by calling (866) 705-5711 or through the web site at 
http://www.dunandbradstreet.com/.  The DUNS number should be entered on line 11 of 
the face page of the PHS 398 form.  The PHS 398 document is available at 
http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format.  
For further assistance contact GrantsInfo, Telephone (301) 435-0714, Email: 
GrantsInfo@nih.gov.
 
SUPPLEMENTARY INSTRUCTIONS 

SPECIAL APPLICATION GUIDANCE FOR PRODUCTION GENOTYPING

Applicants should address the following when preparing applications for the 
genotyping production 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 genotyping for the HapMap within one year and at the 
target cost, only investigators who have demonstrated experience with large-scale 
low-cost SNP genotyping will be eligible to apply.  

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 have provided that information clearly and succinctly.  

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 large-scale SNP genotyping:  How many unique SNP assays 
did your group develop and use in the last year?  What proportion of the 
assays worked successfully?  How much genotyping per month did your group do 
in the last three (or more) months?  How much genotyping did your group do in 
the last year?  

Prior experience with genotyping quality:  Describe the quality 
(completeness, concordance, accuracy) of the genotypes your group has 
produced recently, how your group estimated these quality measures, and how 
the quality information was used to improve the genotyping process. 

Prior experience with low-cost genotyping:  Describe the cost of the 
genotyping that your group has produced recently.  The total costs should be 
described, including equipment, personnel, and Fiscal and Administrative 
costs (F&A, indirect costs), not just reagent costs.

Prior experience in attaining milestones:  What examples can you provide that 
you have proposed milestones for genotyping and met them on schedule?  What 
internal metrics do you use to evaluate progress? 

II. Research Proposal (as part of item D in the application)

Genotyping platform:  The applicant should justify the genotyping platform 
proposed for use.  If the platform does not perform uniformly across the entire 
genome or for all types of samples, describe any differences in how well it works 
in certain types of genomic regions or for certain types of samples.  Explain how 
the efforts of the current HapMap genotyping centers could coordinate with the 
proposed effort to maximize the overall information provided by the Project.

Genotype production plan:  The applicant should present a plan to implement 
large-scale genotyping, and propose milestones for achieving the proposed 
genotyping production within the specified time frame.  This plan should 
thoroughly discuss and justify the applicant's specific choices for all phases of 
the genotyping pipeline, including choosing SNPs to study, producing primers, 
genotyping, assessing genotype quality, and depositing genotype data in the DCC.  
It will be important to discuss potential bottlenecks or other problems that may 
be anticipated and how they will be addressed.  The applicant should make clear 
how much of a ramp-up the proposed production plans are from the current 
production capacity.

Genotyping costs:  Include all costs for genotyping production.  The calculated 
costs of genotyping should take into account all of the expenses associated with 
large-scale high-quality genotyping, including obtaining the samples from the 
Coriell Institute, choosing SNPs (in cooperation with the Analysis Group), 
developing genotyping assays, obtaining primers, genotyping SNPs, repeating 
failed genotyping reactions, genotyping additional SNPs to compensate for those 
that failed, assessing genotype quality, analyzing the data to guide future 
production, and depositing the data.  Applicants should also provide a breakdown 
of costs so that the reviewers can evaluate the contribution of different cost 
elements, such as personnel, equipment, and reagents and consumables to the 
reported total cost.  Cost analyses should be presented in terms of both direct 
costs and of total costs, which include Fiscal and Administrative (F&A) costs.  
Applicants should explain how they monitor costs internally. 

Analysis costs:  Costs for the analysis to choose the SNPs to genotype, to assess 
the SNP coverage of the genome, and to coordinate with the efforts of other 
genotyping groups should be included.  
     
Other costs:  Costs should be included for the PI and up to two additional 
individuals to attend five meetings of the International HapMap Consortium before 
the end of calendar year 2005; probably three of these meetings will be at non-
U.S. sites.

All components of total costs, including genotyping costs, failed genotyping 
costs, analysis costs, other costs, and indirect costs, should be counted in the 
cost goal of about 1 cent per genotype.

Genotype quality:  The applicant should describe the plan for monitoring the 
quality of the genotyping process.  Internal quality control programs should be 
described, including quality assessment criteria.  

It will be particularly useful for the reviewers, as they evaluate the quality of 
the genotyping, to have results from a standard set of SNPs and samples.  NHGRI 
has identified a standard set of 200 SNPs (see http://www.genome.gov/11511477).  
Applicants are strongly encouraged to genotype these SNPs in the set of 90 HapMap 
CEPH samples plus 5 duplicates (available from Coriell 
http://locus.umdnj.edu/ccr/), and to submit these data to the NHGRI Program 
Director by July 6, 2004, for analysis by NHGRI and the reviewers.    

Data sharing plan and intellectual property plan:  Applicants are required to 
explain their plans for data sharing and exercising their intellectual property 
rights.  If the plans differ from what the International HapMap Consortium has 
adopted, the applicant should discuss the differences and explain how the 
proposed approaches meet the Consortium’s objective of ensuring rapid access to 
the Project’s data.  The reviewers and NHGRI staff will evaluate the adequacy of 
these plans.  Plans acceptable to NHGRI and the applicant will need to be arrived 
at before an award can be made.  

Management plan:  The applicant should describe how this project would be 
managed, including decision-making processes and oversight for attaining 
milestones.  Since the management of this project would require a significant 
time commitment, the P.I. is expected to devote at least 25% effort to this 
project.  

III. Human Subjects (as part of item E in the application)

The applicant should address human subjects issues.  The samples to be used for 
this project were collected with individual informed consent for participation in 
the HapMap Project; the new samples were also collected after a process of 
community engagement.  The samples to be used will be publicly available through 
the NIGMS Human Genetic Cell Repository at the Coriell Institute 
(http://locus.umdnj.edu/ccr/).  Thus, while NHGRI considers that 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 270 samples to be studied, 90 
will come from a Yoruba population in Nigeria, 45 will come from a Japanese 
population, and 45 will come from a Han Chinese population, so there will be a 
large minority representation.  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/labels.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, two additional copies of the application and 5 copies of 
the appendix material must be sent to:

Rudy Pozzatti, Ph.D.
Scientific Review Branch
National Human Genome Research Institute
Building 31, Room B2B37
31 Center Dr., MSC 2032
Bethesda, MD  20892-2032
Telephone:  (301) 402-8739
Fax:  (301) 435-1580
rudy_pozzatti@nih.gov
 
APPLICATION PROCESSING:  Applications must be received on or before June 25, 2004.  
If an application is received after that date, it will be returned to the applicant 
without review. 

Although there is no immediate acknowledgement of the receipt of an application, 
applicants are generally notified of the review and funding assignment within 8 
weeks.
 
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.  However, when a previously unfunded 
application, originally submitted as an investigator-initiated application, is to be 
submitted in response to an RFA, it is to be prepared as a NEW application.  That is, 
the application for the RFA must not include an Introduction describing the changes 
and improvements made, and the text must not be marked to indicate the changes from 
the previous unfunded version of the application.  

PEER REVIEW PROCESS  
 
Upon receipt, applications will be reviewed for completeness by the CSR and 
responsiveness by the NHGRI.  Incomplete and/or nonresponsive applications will not 
be reviewed.  

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, all applications will:

o 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 Receive a written critique;
o 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 evaluate the application in order to judge the 
likelihood that the proposed research will have a substantial impact on the pursuit 
of these goals.  The scientific review group will address and consider each of the 
following criteria in assigning the application’s overall score, weighting them as 
appropriate for each application. 

o Significance 
o Quality, quantity, and cost of genotyping
o Approach 
o Innovation
o Investigator
o Environment
o Data sharing plans
o Intellectual property plans 
o Budget
  
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 a field forward.

SIGNIFICANCE:  Does the application address the problem outlined in this RFA?  

QUALITY, QUANTITY, AND COST OF GENOTYPING:  Will the applicant be able to produce the 
amount of genotype data at the cost and quality levels requested in this RFA?  Are 
the plans for genotype production adequate?  Are the plans for assessing data quality 
adequate?

APPROACH:  Are the conceptual framework, design, methods, and analyses adequately 
developed, well integrated, and appropriate for the aims of the project as outlined 
in this RFA?  Are potential problem areas acknowledged and alternative tactics 
considered?  

INNOVATION:  Does the project employ novel approaches or methods for genotyping that 
result in significant reductions in cost or increases in data quality or throughput?  
The emphasis of this RFA is on proven methods for producing high-quality genotype 
data at low cost; credible methods for doing this will be considered to represent 
sufficient innovation for this RFA.  

INVESTIGATOR:  Are the principal investigator and key personnel appropriately trained 
and well suited to carry out this work?  Is the work proposed appropriate for the 
experience of the P.I. and key personnel?  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 the P.I.’s experience with management sufficient for this 
project?

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?  Is there evidence of institutional 
support?  

ADDITIONAL REVIEW CRITERIA:  In addition to the above criteria, the following items 
will be considered in the determination of scientific merit and the priority score:

DATA SHARING PLANS:  The adequacy of the proposed plans to share data in a timely 
manner. 

INTELLECTUAL PROPERTY PLANS:  The adequacy of the proposed plans to maintain access 
to data. 

BUDGET:  The reasonableness and cost-effectiveness of the proposed budget and the 
requested period of support in relation to the proposed research.  

PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK:  The involvement of human subjects 
and protections from research risk relating to their participation in the proposed 
research will be assessed.  (See criteria included in the section on Federal 
Citations, below).
 
INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH:  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.  (See Inclusion 
Criteria in the sections on Federal Citations, below).

RECEIPT AND REVIEW SCHEDULE

Letter of Intent Receipt Date:  May 28, 2004
Application Receipt Date: June 25, 2004
Supplemental Genotyping Data Report Receipt Date:  July 6, 2004
Peer Review Date:  Late July or early August 2004
Council Review:  September 13-14, 2004
Earliest Anticipated Start Date:  September 17, 2004   

AWARD CRITERIA

Award criteria that will be used to make award decisions include:

o Scientific merit (as determined by peer review)
o Data quality and quantity
o Cost-effectiveness
o Plans for data release
o Plans for intellectual property
o Programmatic priorities
 o Availability of funds

REQUIRED FEDERAL CITATIONS 

HUMAN SUBJECTS PROTECTION:  Federal regulations (45CFR46) require that applications 
and proposals involving human subjects must be evaluated with reference to the risks 
to the subjects, the adequacy of protection against these risks, the potential 
benefits of the research to the subjects and others, and the importance of the 
knowledge gained or to be gained.
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm 

SHARING RESEARCH DATA:  Investigators submitting an NIH application seeking $500,000 
or more in direct costs in any single year are expected to include a plan for data 
sharing or state why this is not possible. 
http://grants.nih.gov/grants/policy/data_sharing   Investigators should seek guidance 
from their institutions, on issues related to institutional policies, local IRB 
rules, as well as local, state and Federal laws and regulations, including the 
Privacy Rule.  

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS:  The NIH 
maintains a policy 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.  

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 is available at 
http://grants.nih.gov/grants/funding/children/children.htm

REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS:  NIH policy 
requires education on the protection of human subject participants for all 
investigators submitting NIH proposals for research involving human subjects.  You 
will find this policy announcement in the NIH Guide for Grants and Contracts 
Announcement, dated June 5, 2000, at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.
 
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.

URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals for NIH 
funding must be self-contained within specified page limitations.  Unless otherwise 
specified in an NIH solicitation, 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.healthypeople.gov/.

AUTHORITY AND REGULATIONS:  This program is described in the Catalog of Federal 
Domestic Assistance at http://www.cfda.gov/ and is not subject to the 
intergovernmental review requirements of Executive Order 12372 or Health Systems 
Agency review.  Awards are made under the authorization of Sections 301 and 405 of 
the Public Health Service Act as amended (42 USC 241 and 284) and under Federal 
Regulations 42 CFR 52 and 45 CFR Parts 74 and 92.  All awards are subject to the 
terms and conditions, cost principles, and other considerations described in the NIH 
Grants Policy Statement.  The NIH Grants Policy Statement can be found at 
http://grants.nih.gov/grants/policy/policy.htm .

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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