DETERMINATION OF ALL FUNCTIONAL ELEMENTS IN HUMAN DNA 

RELEASE DATE:  February 21, 2003
 
RFA:  HG-03-003
 
National Human Genome Research Institute (NHGRI)
(http://www.genome.gov/)

CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER: 93.172

LETTER OF INTENT RECEIPT DATE: April 13, 2003

APPLICATION RECEIPT DATE: May 13, 2003

THIS RFA CONTAINS THE FOLLOWING INFORMATION

o Purpose of this RFA
o Research Objectives
o Mechanism(s) 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

The purpose of this RFA is to solicit applications to participate in a 
Research Network that will conduct a pilot project to test and compare 
methods for identifying all of the functional elements in a limited 
(~1%) region of the human genome.  The emphasis during this initial 
phase will be on the identification and verification of transcription 
units, including associated cis-regulatory elements, but projects using 
existing methods for the identification of other sequence-based 
functional elements are also encouraged.  Both computational and 
experimental approaches will be critical components of the project.  
This RFA is being issued in conjunction with a second RFA, HG-03-004 
"Technologies to Find Functional Elements in Genomic DNA" which will 
support the development of new and improved high-throughput and 
efficient technologies for the comprehensive identification and 
verification of a larger variety of functional elements.  

RESEARCH OBJECTIVES

Background

In April 2003, the sequence of the human genome will be essentially 
complete.   For the scientific community now to make the best use of 
that fundamental information resource, the identity and precise 
location of all sequence-based functional elements in the genome must 
be determined.  While many of the protein-coding genes are already 
known, many others remain to be identified.  Beyond open reading 
frames, non-protein-coding genes, transcriptional regulatory elements 
and determinants of chromosome structure and function remain largely 
unknown.  A comprehensive encyclopedia of all of these features is 
needed to utilize fully the sequence of the human genome to understand 
human biology better, to predict potential disease risks, and to 
stimulate the development of new therapies and other interventions to 
prevent and treat disease.   

One of the primary reasons for the success of the Human Genome Project 
has been the development and use of high-throughput strategies for data 
generation, and the placement of the data immediately in the public 
domain.  Most of the sequence data, the underlying maps and the 
sequence assemblies were generated through the use of large-scale 
automated processes.  Now, methods such as sequence analysis of whole 
genomes, DNA microarray technology and mass spectrometry have been or 
are being developed as high-throughput approaches for additional types 
of genomic analyses, such as determining the parameters of gene 
expression or the location of gene products by the thousands at a time 
instead of individually.  High-throughput methods to determine the 
location of cis-regulatory elements and, to a lesser extent, other 
sequence elements, are also beginning to be developed.  However, at 
present, there is no single approach or compilation of approaches known 
to identify accurately and efficiently every sequence feature in 
genomic DNA.

While determining the identity and function of all of the sequence 
elements in human DNA is a daunting challenge, it is appropriate at 
this time to begin to consider such a project.  On July 23-24, 2002, 
the NHGRI held a workshop, the Comprehensive Extraction of Biological 
Information from Genomic Sequence, to discuss a proposal to initiate a 
new public research consortium to test and compare existing and new 
methods for exhaustive identification and verification of functional 
sequence elements as a pilot project focused on a limited region of 
human genomic DNA.  The report of this meeting is available at 
http://www.genome.gov/page.cfm?pageID=10005115.  

Based on the recommendations of this workshop, the NHGRI has decided to 
launch the Encyclopedia of DNA Elements (ENCODE) project.  The goal of 
this project is to comprehensively identify functional elements in the 
human genome sequence.  The ENCODE project will begin as a pilot 
project that will test and compare methods for the exhaustive 
identification and verification of functional sequence elements in 30 
Mb of human genomic DNA.  This will require access to information, 
resources, ideas, expertise, and technology beyond the scope of what 
any single group can currently provide.  Therefore, the pilot will be 
carried out by a consortium of investigators with diverse backgrounds 
and expertise working cooperatively to (1) evaluate rigorously the 
relative merits of each of a varied set of techniques, technologies, 
and strategies for identifying all of the functional elements in human 
genomic sequence, (2) test the abilities of such methods to be scaled 
up efficiently so that ultimately, it will be feasible to use them to 
analyze all of the functional elements encoded in the entire human 
genome sequence, and (3) identify and fill gaps in our ability to 
annotate genomic sequence.  

The ENCODE project is intended to characterize the tools needed for 
mining genomic sequence and, where necessary, improve them, and define 
a clear path for the determination of all of the functional elements in 
the entire human genome sequence.   A fully annotated human genome 
sequence will be an integrated information resource that will enable 
the efforts of the entire research community in both basic and clinical 
research.

It is obvious, however, that current technology is not capable of 
achieving all of the aims of even the initial phase of the ENCODE 
project.  Therefore, at the same time that high-throughput efforts are 
being initiated using well-developed technologies, a parallel effort is 
being started to develop new or improved high-throughput and efficient 
technologies. The companion RFA, HG-03-004, "Technologies To Find 
Functional Elements in Genomic DNA", is intended to expand the 
repertoire of tools that can be applied to the ENCODE, or similar 
projects, in the future.  

Research Scope

The aim of the ENCODE pilot project is to determine the best way to 
generate a comprehensive catalog of all sequence-based functional 
elements in human DNA.  The pilot will test and compare a combination 
of available methods, seek to improve current methods, and develop new 
methods using, as a test bed, a defined 30 Mb of human genome sequence.  
Both computational and experimental approaches will be involved.  A 
prime criterion by which any method or combination of methods will be 
evaluated will be its potential for being efficiently applied at large 
enough scale to characterize the entire human genome.  

The sequence-based functional elements that will be targeted include, 
but are not limited to:

o   Transcribed sequences, including both protein-coding and non-
protein-coding.  A description of the gene structure with 
transcriptional start sites, polyadenylation sites, along with all 
alternative transcripts, is an example.
o   Conserved non-coding sequences that may represent functional 
elements.
o   Cis-acting elements that regulate transcription and/or chromatin 
structure.  These elements include promoters, enhancers, and 
insulators.
o   Sequence features that affect/control chromosome biology.  Examples 
include origins of replication and hot spots for recombination.  
o   Epigenetic changes, such as DNA methylation and chromatin 
modifications.
  
If the ENCODE project is to be successful, it will be critical to 
balance the desire for complete information about genome features with 
the practical ability to obtain a useful amount of information in a 
reasonable and affordable manner.  Therefore, the scope for this RFA 
will be limited to the initial identification and verification of 
sequence-based elements.  This limitation has a number of consequences:

o   Although a minimum amount of functional analysis may be required in 
the process of identification, in-depth study of the biological 
function of genes and gene products, e.g., functional studies in 
vitro or in vivo, is beyond the scope of this RFA.  
o   NHGRI recognizes that the function and activity of sequence elements 
will vary in different cell types.   As this RFA is being issued in 
support of the ENCODE project's pilot phase, proposals should only 
include as many different cells types as necessary to demonstrate 
feasibility of the approaches proposed in the application.  The 
NHGRI will not specify cells or tissues to be used for this project; 
however, proposals must clearly define the cells or tissues to be 
studied along with a justification for their use. 
o   The goal of the pilot project is to test methods for identifying 
functional elements in the human genome.  Experimental work should 
be restricted to human tissues and cells unless a compelling 
argument can be made for the use of model organisms. The functional 
analysis of sequences from other species that are homologous to the 
selected target regions is beyond the scope of this solicitation.

The ENCODE consortium will be open to all academic, government and 
private sector scientists interested in participating in an open 
process to facilitate the comprehensive interpretation of the human 
genome sequence.  It is expected that groups with funding from other 
sources will participate in the ENCODE project and therefore, funding 
through this initiative is not a prerequisite for participation in the 
consortium. 

Participants will be expected to design experiments that apply high 
throughput methods to identify, with high accuracy, functional elements 
in the selected target sequences in the human genome.  In the 
application, the P.I. should describe the functional element to be 
identified, the specific assay(s) to be used, the plans for scaling the 
assay(s) for high-throughput analyses, and the collection and 
processing of data from the experiments.  In addition, applicants 
should describe how the biological authenticity of the identified 
elements could be validated, and plans to validate the technical 
approach should be included.  The large datasets from these experiments 
will be deposited in the ENCODE database(s), and other appropriate 
public databases, as described in the data release policy (see below).  
Through interactions within the ENCODE consortium, the P.I.s may modify 
their experimental approach, either incorporating modified or new 
methods or using new information supplied to the ENCODE consortium, 
such as improved computer predictions of functional elements.

To help plan certain initial aspects of the ENCODE pilot project, NHGRI 
convened an Organizing Committee which identified a set of target 
regions of the genome for study (see below) and recommended a proposed 
set of data release policies.  Once the project has been initiated, it 
will be organized as a Research Network with a Coordinating Committee 
(see Terms and Conditions), which will guide the operations of the 
consortium.  A Scientific Advisory Panel, comprised of scientists not 
directly working on the project, will be convened to provide advice to 
the Director, NHGRI regarding the progress of the project.  

Target Regions.  The 30 Mb target regions to be analyzed in the ENCODE 
pilot project include representative features of the entire genomic 
landscape.  There are forty-four regions altogether, ranging in size 
from 500 Kb to 2 Mb.  Approximately 50% of the 30Mb of sequence was 
chosen manually, based upon two criteria: 1) the existence of an 
extensive amount of comparative sequence data for a region, and 2) 
interesting gene(s) or other sequence features residing in a region.  
The remaining 15Mb were selected randomly using a computer algorithm 
that stratified the human genome based upon two criteria – gene density 
and non-exonic conservation with mouse sequence – and then selected 
regions representative of each stratum.  The list of target regions, as 
well as a more detailed description of the selection process, can be 
found at http://www.genome.gov/page.cfm?pageID=10005107.  Applicants 
must propose to study the entire set of target regions rather than 
focus on only one or a subset of regions.

Comparative sequence analysis of regions homologous to the selected 
target regions will undoubtedly provide valuable information for 
discerning functional sequence elements and it is anticipated that 
these sequences will be determined for a number of species during the 
course of the ENCODE pilot project.  The de novo generation of 
additional sequence information by standard methods will not be 
supported under this RFA, but comparative sequences will be made 
available through the consortium's database. 

Data Release. The ENCODE project aims to function openly by making all 
data available to the scientific community in a timely manner.  The 
ENCODE project is a community resource project. It is expected that the 
consortium will establish a common data release policy and that all 
participants will agree to abide by that policy.  The Organizing 
Committee has recommended to NHGRI a set of practices for data release.  
Taken together with other considerations, the NHGRI deems that the 
following data release policy would be appropriate: 

1.  Participants would submit data to the consortium database(s) as soon 
as the data have been determined to be reliable.  The timing of data 
submission may differ for different types of data.  The consortium's 
Coordinating Committee in conjunction with the Scientific Advisory 
Panel would establish appropriate data release standards for each 
data type.  Approval for participation in the consortium will be 
predicated on agreement to abide by these data release standards.  
Applicants should propose what they consider to be appropriate data 
release practices in the application, and a policy acceptable to the 
investigator, the consortium and NHGRI will be negotiated at the 
time of award.    
2.  Consortium participants would submit data to the consortium 
databases in the specified format.
3.  Upon submission, all data would be made freely available to the 
entire research community in a form that would allow for redisplay 
and reanalysis, so that maximal utility of this community resource 
could be achieved.  It is NHGRI's expectation that users of these 
data would respect the legitimate interests of the producers to 
analyze and publish their results by treating the data as 
unpublished information, until otherwise indicated.  As with any 
unpublished data, it would be expected that users would provide 
proper citation of the source of the data.  The best interests of 
all are served when all act responsibly to promote the highest 
standards of respect for scientific work.  In some cases, this might 
best be done by discussion or coordination with the resource 
producers.
4.  The individual investigators within the consortium may publish the 
results of their own work that have been submitted to the ENCODE 
project's database(s) in the course of that work.  Neither these 
individual publications nor any consortium publications should hold 
up the other's publications.
5.  The consortium intends to publish global analyses of the results of 
the pilot project.  At the same time, the consortium recognizes that 
it has the responsibility to do so in a timely manner.  While it is 
not possible, at present, to predict an appropriate time for any 
such publication(s), the consortium, with guidance from the 
Scientific Advisory Panel, will establish a timeframe once the 
project has been launched and there is a better understanding of the 
timeframe and scope of the project.
6.  Publicly funded consortium participants would fully disclose 
algorithms, software source code, and experimental methods to the 
other members of the consortium for purposes of scientific 
evaluation and will be strongly encouraged to make them available to 
the broad research community.
Applicants should address data release in their applications either by 
agreeing to abide by the proposed ENCODE data release policy stated 
above or by proposing alternative approaches to make the ENCODE data 
available for the consortium to consider.  Ultimately, the ENCODE 
consortium will develop a common data release policy for all 
participants. Funding of any award under this RFA will be contingent on 
negotiation of a data release policy that is acceptable to the 
applicant, to the consortium and to the NHGRI.
Resources for the ENCODE project.  To facilitate the project, the 
storage, display and release of data generated by the consortium will 
be coordinated through a central database.  Ultimately, this database 
will become a knowledgebase that will be a central repository for 
information about the selected genome regions.  This database will not 
be supported by this RFA.

During the course of the ENCODE pilot project, it may be necessary or 
efficient for the NHGRI to provide common sets of reagents and 
resources in support of the consortium's research activities.  It is 
not possible, however, to anticipate what resources may be needed prior 
to the establishment of the consortium and the funding of specific 
projects.  Therefore, each applicant should propose to develop or 
procure the resources needed for the research project and request the 
necessary funds to do so.  The costs for these resources should be 
clearly described in the budget justification section of the 
application.  If common reagents and resources are developed through 
the course of the project, NHGRI will negotiate any appropriate changes 
to the award's budget.  All common reagents developed for the 
consortium, including clones, microarrays, and software, would be made 
available to the entire scientific community.  

Training.  The applicant is strongly encouraged to propose a plan in 
response to NHGRI's Action Plan for increasing the number of 
underrepresented minorities in genome research.  Please see 
http://www.genome.gov/page.cfm?pageID=10003996 for a description of the 
Action Plan.  

In summary, applicants for awards under this RFA:

1.  should provide plans to study the entire set of target regions;
2.  should provide a detailed cost breakout for the development or 
procurement of specialized resources; 
3.  should provide specific plans for data release; 
4.  are strongly encouraged to provide a plan for training 
underrepresented minorities.

MECHANISM OF SUPPORT

This RFA will use the NIH U01 Research Project Cooperative Agreement, 
the U19 Research Program Cooperative Agreement, and the U41 
Biotechnology Resource Cooperative Agreement award mechanisms in which 
the Principal Investigators retain the primary responsibility and 
dominant role for planning, directing, and executing their components 
of the ENCODE pilot 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 30, 2003. 
Applications that are not funded in the competition described in this 
RFA may be resubmitted as NEW investigator-initiated applications using 
the standard receipt dates for NEW applications described in the 
instructions to the PHS 398 application. 

FUNDS AVAILABLE

The NIH intends to commit approximately $10 million total costs in FY 
2003 to fund five to fifteen awards in response to this RFA.  An 
applicant may request a project period of up to three years.  Awards 
pursuant to this RFA are contingent upon the availability of funds and 
the receipt of a sufficient number of meritorious applications.   At 
this time, it is not known if this RFA will be reissued.

ELIGIBLE INSTITUTIONS
 
You may submit (an) application(s) 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

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 their 
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.   

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-03-003 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 
(NHGRI) grant administration policies: 

1.  Cooperative Agreement

The administrative and funding instruments used for this program will 
be the NIH U01 Research Project Cooperative Agreement, the U19 Research 
Program Cooperative Agreement, or the U41 Biotechnology Resource 
Cooperative Agreement award mechanisms.  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-03-003 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 an ENCODE pilot project component will: 

o   Determine experimental approaches, design protocols, set project 
milestones, and conduct experiments.
o   Analyze the entire set of selected regions and not just a subset of 
the target sequences; OR, lead a research group composed of several 
individuals with a shared experimental approach with each individual 
examining a part of the target sequences, provided that the group as 
a whole will gather data on the entire set of target regions and 
that the P.I. will take responsibility for this.
o   Share results according to the data sharing policy developed for and 
by this project. 
o   Participate in group activities, including attending periodic 
workshops to discuss the project's progress and coordinating the 
publication of research results. 
o   Fully disclose all algorithms, software source code, and 
experimental methods to the other members of the consortium for 
purposes of scientific evaluation. 
o   Not disclose confidential information obtained from other members of 
the consortium.
o   Adhere to 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 Scientific Advisory Panel.
o   Accept and implement the common guidelines and procedures approved 
by the Coordinating Committee, Scientific Advisory Panel and NHGRI. 

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 ENCODE Research Network 
Coordinating Committee and that NIH staff will be given the opportunity 
to offer input to this process.  One NHGRI 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 as an 
information resource about extramural genome research activities.  
The Program Director will also coordinate the efforts of the 
Research Network with groups participating in the ENCODE consortium.
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 ENCODE pilot project to 
the Director, NHGRI.
o   Provide relevant expertise and overall knowledge of NIH-sponsored 
research to facilitate the selection of scientists not affiliated 
with the awardee institutions to serve on the Scientific Advisory 
Panel.
o   Serve as a liaison between the Coordinating Committee and the 
Scientific Advisory Panel, attending Scientific 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 ENCODE and related 
resources developed in the course of this project to the scientific 
community at large.
o   Participate in data analyses, interpretations, and, where warranted, 
co-authorship of the publication of results of studies conducted 
through the ENCODE Research Network. 

4.  Collaborative Responsibilities

The Coordinating Committee will serve as the main governing board of 
the ENCODE Research 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 the 
activities being conducted by the ENCODE Research Network.  To address 
particular issues, the Coordinating Committee may establish working 
groups as needed, which will include representatives from the Research 
Network and the NHGRI and possibly other experts.  Such groups might 
include ones to: 1) develop a list of common reagents needed for the 
pilot project; 2) address data management issues; 3) analyze the pilot 
project data; 4) develop quality standards and methods to assess data 
quality; and 5) handle communication issues and develop principles for 
reporting findings.  

5.  Scientific Advisory Panel

A Scientific Advisory Panel will be established by the NHGRI to 
evaluate the progress of the ENCODE Research Network. The Scientific 
Advisory Panel will provide recommendations to the Director, NHGRI 
about the progress and scientific direction of all components of the 
program.  The Scientific Advisory Panel will be composed of six to 
eight 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 conducted by telephone conference.  At least once a 
year, there will be a joint meeting with the Coordinating Committee to 
allow the members of the both the Scientific Advisory Panel and the 
Coordinating Committees to interact directly with each other.  Twice a 
year the Scientific Advisory Panel will make recommendations regarding 
progress of the ENCODE Research Network and present advice to the 
Director of NHGRI about changes, if any, that may be necessary in the 
ENCODE Research Network program.   

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. 

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 Direct your questions about scientific/research issues to:

Elise Feingold, PhD or Peter Good, PhD
Program Directors
Division of Extramural Research
NHGRI
Building 31, Room B2B07
Bethesda, MD  20892-2033
Telephone:  (301) 496-7531
FAX:  (301) 480-2770
Email: Elise_Feingold@nih.gov or GoodP@mail.nih.gov

o Direct your questions about peer review issues to:

Rudy Pozzatti, PhD
Scientific Review Administrator
Division of Extramural Research
NHGRI
Building 31, Room B2B37
Bethesda, MD  20892-2032
Telephone:  (301) 402-0838 
FAX:  (301) 435-1580
Email: pozzattr@mail.nih.gov

o Direct your questions about financial or grants management matters 
to:

Jean Cahill
Chief, Grants Administration Branch
Division of Extramural Research
NHGRI 
Building 31, Room B2B34 
Bethesda, MD  20892-2031
Telephone:  (301)435-7858
FAX: (301) 402-1951
Email: cahillj@mail.nih.gov

7.  Prospective applicant meeting.  There will be a combined meeting at 
the Natcher Conference Center on the NIH campus from 9:00 a.m. to 
approximately 2:00 p.m. on March 7, 2003 to launch the ENCODE project 
and to answer questions about the RFA from prospective applicants.  
Attendance at this meeting is not a prerequisite for responding to the 
RFA or for participation in the ENCODE consortium.  For more 
information about this meeting, see 
http://www.genome.gov/Pages/Research/ENCODE/ or email: encode@mail.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, 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 the date listed at the beginning 
of this document.  The letter of intent should be sent to:

Elise Feingold, PhD
Program Director, Genome Analysis Program
Division of Extramural Research
NHGRI
Building 31, Room B2B07
Bethesda, MD  20892-2033
Telephone:  (301) 496-7531
FAX:  (301) 480-2770
Email: Elise_Feingold@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, 
Telephone (301) 435-0714, Email: GrantsInfo@nih.gov.

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, typewritten 
original of the application, including the Checklist, and three signed, 
photocopies, in one package to:
 
Center For Scientific Review
National Institutes Of Health
6701 Rockledge Drive, 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 
must be sent to: 

Rudy Pozzatti, PhD
Scientific Review Administrator
Division of Extramural Research
NHGRI
Building 31, Room B2B37
Bethesda, MD  20892-2032
Telephone:  (301) 402-0838 
FAX:  (301) 435-1580
Email: pozzattr@mail.nih.gov

APPLICATION PROCESSING: Applications must be received on or before the 
application receipt date listed in the heading of this RFA.  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.  While the investigator may 
still benefit from the previous review, the RFA application is not to 
state explicitly how.
 
PEER REVIEW PROCESS  
 
Upon receipt, applications will be reviewed for completeness by the CSR 
and responsiveness by the NHGRI.  

Incomplete 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 in accordance with the review 
criteria stated below.  As part of the initial merit review, all 
applications will:

o Receive a written critique
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 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?  Does the 
applicant propose to study the entire set of target regions? Does the 
technical approach have the potential to be applied efficiently and 
cost-effectively at large scale?  Will the experiments proposed 
demonstrate that potential?  

(3) INNOVATION:  Does the project employ novel concepts, approaches, or 
methods for identifying and verifying sequenced-based functional 
elements?  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?  

(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, the 
following items will be considered in the determination of scientific 
merit and the priority score:

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 RELEASE:  The adequacy of the proposed plan to release data in 
concert with the guidelines stated in this RFA.

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 13, 2003
Application Receipt Date:           May 13, 2003
Peer Review Date:                   July 2003
Council Review:                     September 2003
Earliest Anticipated Start Date:    September 30, 2003

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 scientific approaches
o Efficiency of scientific approach
o Availability of funds
o Programmatic priorities

REQUIRED FEDERAL CITATIONS 

INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the 
policy of the NIH that women and members of minority groups and their 
sub-populations must be included in all NIH-supported clinical research 
projects unless a clear and compelling justification is provided 
indicating that inclusion is inappropriate with respect to the health 
of the subjects or the purpose of the research. This policy results 
from the NIH Revitalization Act of 1993 (Section 492B of Public Law 
103-43).

All investigators proposing clinical research should read the AMENDMENT 
"NIH Guidelines for Inclusion of Women and Minorities as Subjects in 
Clinical Research - Amended, October, 2001," published in the NIH Guide 
for Grant0s and Contracts on October 9, 2001 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html);
a complete copy of the updated Guidelines are available at http://
grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm.
The amended policy incorporates: the use of an NIH definition of
clinical research; updated racial and ethnic categories 
in compliance with the new OMB standards; clarification of language 
governing NIH-defined Phase III clinical trials consistent with the new 
PHS Form 398; and updated roles and responsibilities of NIH staff and 
the extramural community.  The policy continues to require for all NIH-
defined Phase III clinical trials that: a) all applications or 
proposals and/or protocols must provide a description of plans to 
conduct analyses, as appropriate, to address differences by sex/gender 
and/or racial/ethnic groups, including subgroups if applicable; and b) 
investigators must report annual accrual and progress in conducting 
analyses, as appropriate, by sex/gender and/or racial/ethnic group 
differences.

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. This policy applies to all initial 
(Type 1) applications submitted for receipt dates after October 1, 1998.

All investigators proposing research involving human subjects should 
read the "NIH Policy and Guidelines" on the inclusion of children as 
participants in research involving human subjects that 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.

HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of 
research on hESCs can be found at 
http://grants.nih.gov/grants/stem_cells.htm and at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html.  
Only research using hESC lines that are registered in the NIH Human 
Embryonic Stem Cell Registry will be eligible for Federal funding (see 
http://escr.nih.gov).   It is the responsibility of the applicant to 
provide the official NIH identifier(s)for the hESC line(s)to be used in 
the proposed research.  Applications that do not provide this 
information will be returned without review. 

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. 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.health.gov/healthypeople.

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 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.  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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