Department of Health and Human Services

Participating Organizations
National Institutes of Health (NIH), (http://www.nih.gov)

Components of Participating Organizations
National Human Genome Research Institute (NHGRI), (http://www.genome.gov)

Title: Genome Sequencing Centers (U54)

Announcement Type
New

Update: The following update relating to this announcement has been issued:

• December 14, 2010 - This RFA has been reissued as RFA-HG-10-015.
• March 20, 2006 (NOT-HG-06-010) - This Notice is to inform the scientific community that paragraphs have been inserted following Section IV 6 Plan for Sharing Research Data , and prior to Section IV-6, Sharing Research Resources in RFA-HG-06-001.

• This solicitation seeks renewal of the National Human Genome Research Institute’s large-scale sequencing program. This program has successfully completed the human genome sequence, the genomic sequence of several major biomedical model systems, and is currently emphasizing comparative genomic sequencing to provide a foundation for identifying and understanding conserved functional sequences in the human sequence. More recently, he program has begun to turn its attention to medical sequencing, including the identification of genomic changes implicated in disease. NHGRI intends to renew its large-scale sequencing program, continuing its record of increasing production and decreasing costs over time, and continuing its emphasis contributing to understanding the underlying role that DNA-based changes contribute to biological systems. During the next four years, NHGRI anticipates that the type and number of important large-scale sequencing products will expand, requiring new flexibility form the components of the program.
• Up to $420 million in total costs will be awarded over four years at a level of not more than $130 million per year.
• It is anticipated that 3-5 awards will be made.
• The awards will be made using the NIH Specialized Center-Cooperative Agreement (U54) mechanism.
• Eligible organizations include U.S. for-profit organizations; non-profit organizations; public or private institutions, such as universities, colleges, hospitals, and laboratories; eligible agencies of the Federal government; domestic institutions.
• Eligible principal investigators with the skills, knowledge, and resources necessary to carry out the proposed research are 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.
• Applicants may not submit multiple applications.
• See Section IV.1 for application materials.
• Telecommunications for the hearing impaired is available at: TTY 301-451-5936

Part I Overview Information

Part II Full Text of Announcement

Section I. Funding Opportunity Description
1. Research Objectives

Section II. Award Information
1. Mechanism(s) of Support
2. Funds Available

Section III. Eligibility Information
1. Eligible Applicants
A. Eligible Institutions
B. Eligible Individuals
2.Cost Sharing or Matching
3. Other - Special Eligibility Criteria

Section IV. Application and Submission Information
1. Address to Request Application Information
2. Content and Form of Application Submission
3. Submission Dates and Times
A. Receipt and Review and Anticipated Start Dates
1. Letter of Intent
B. Sending an Application to the NIH
C. Application Processing
4. Intergovernmental Review
5. Funding Restrictions
6. Other Submission Requirements

Section V. Application Review Information
1. Criteria
2. Review and Selection Process
A. Additional Review Criteria
B. Additional Review Considerations
C. Sharing Research Data
D. Sharing Research Resources
3. Anticipated Announcement and Award Dates

Section VI. Award Administration Information
1. Award Notices
2. Administrative and National Policy Requirements
A. Cooperative Agreement Terms and Conditions of Award
1. Principal Investigator Rights and Responsibilities
2. NIH Responsibilities
3. Collaborative Responsibilities
4. Arbitration Process
3. Reporting

Section VII. Agency Contact(s)
1. Scientific/Research Contact(s)
2. Peer Review Contact(s)
3. Financial/ Grants Management Contact(s)

Section VIII. Other Information - Required Federal Citations

1. Research Objectives

This solicitation seeks applications for support of genomic sequencing centers, which will constitute the renewal of the NHGRI large-scale sequencing program. The NHGRI’s large-scale sequencing program has made major contributions to the successful sequencing of the human genome, and those of many major biomedical model systems and other organisms (for an updated list see http://www.genome.gov/10002154). Since the completion of the human genome sequence, much of the NHGRI-supported large-scale sequencing capacity has been directed toward comparative genomic sequencing projects to generate data for annotating the human genome, and informing fundamental questions about genome evolution. Over the next few years, NHGRI expects that these activities will continue while an increasing fraction of the sequencing capacity will be directed to medical sequencing, which is expected to result in the identification of genomic changes implicated in heritable disease and the elucidation of the genetic changes associated with cancer. The program will also increase its attention to the genomic sequencing of eukaryotic pathogens and vectors of human disease.

The current NHGRI large-scale sequencing program is funded as a set of cooperative agreements organized as a Research Network, which has a combined output of approximately 12 billion high quality (Q20) bases per month. One emphasis of the program has been on producing assembled genome sequences (draft or finished) as efficiently as possible. The increases in throughput and efficiency that have been achieved, coupled with cost decreases of approximately half every 22 months, have allowed the NHGRI to decrease the amount of funding for the program in each of the last four years, from a high of over $180 million to its current FY 2006 level of $133 million, while more than tripling output over that time.

For the past two years, the specific sequencing targets addressed by the NHGRI program have been recommended to the NHGRI and the National Advisory Council for Human Genome Research by two working groups composed of members of the research community. Each group periodically makes a set of recommendations about the highest priority sequencing targets in one of two major areas: annotating the human genome and comparative genome evolution. In the summer of 2005, a new working group was organized to provide NHGRI with recommendations about how large-scale sequencing capacity could best be used to elucidate the genetic underpinnings of inherited disease, an area referred to as medical sequencing.

As the end of the current project period for the large-scale sequencing program approached, NHGRI obtained input about the future of large-scale sequencing from variety of sources. The Institute sponsored a workshop in July 2005 ((see http://www.genome.gov/16015129) and has discussed the issue with the National Advisory Council for Genome Research (see http://www.genome.gov/16015016) and a working group of the Council. On the basis of these inputs, NHGRI has concluded that it should continue to support a large-scale sequencing program with both similarities to, and differences from, the current program. The program will continue to consist of a set of large-scale centers supported by cooperative agreements operating as a Research Network. Target selection will continue to depend heavily on recommendations obtained from working groups and approved by the NACHGR. At the same time, there will also be a number of significant modifications in the program that are driven by consideration of the current scientific opportunities (discussed below), of technological changes that appear to be imminent, and of lessons learned from the current program about the added value, beyond the production of large amounts of sequence data, that sequencing centers can bring to the field of genomics.

This RFA seeks applications for research proposals to implement genome sequencing centers that maintain and extend the state of the art for high throughput, low cost genomic sequence data. However, excellence in producing high quality whole genome shotgun sequence data in a highly efficient manner, while a requirement, will not be sufficient for receipt of an award as an NHGRI genome sequencing center in the next project period. Genomic sequencing is becoming a more diversified activity than it has been in recent years. In addition to generating sequence data using Sanger-based sequencing technology for the purpose of assembling whole genome sequences, sequence data produced by other technologies and applied to different purposes are becoming even more important to biomedical research. Therefore, NHGRI intends to support centers that are capable of generating a variety of useful genomic sequence products and have the flexibility to evolve to handle a broad range of projects and to implement new technologies. In the next phase of the NHGRI sequencing program, the Institute is also looking to support centers that will be repositories of knowledge about how to develop and use sequence information and how to disseminate that knowledge, thus serving as intellectual resources in this critical area for the scientific community.

A cardinal accomplishment of the NHGRI large-scale sequencing program over the past several years has been the substantial improvement in the state of the art for large-scale sequencing. In responding to this RFA, the applicant should provide plans for how s/he will continue to drive the state of the art and continue to obtain gains in the efficiency of genomic sequencing. In setting technology improvement as a continuing goal of the program, NHGRI recognizes that the renewal of its genomic sequencing program comes at a time when significant advance(s) in genomic sequencing technology can be anticipated. Several new technologies are currently being or will soon be tested at scale, and it can be expected that one or more of these technologies will be implemented in the sequence production pipeline in the near future. However, it is not clear whether any of the new technologies will fully replace the existing sequencing platform because significant challenges and uncertainties have not yet been resolved. Thus far, the new technologies yield shorter read lengths, paired-end reads are not yet practical for some of the approaches, and there is limited experience is how to use the data in large-scale projects. At the least, it will be some time before data from these technologies will be useful in making a high quality de novo assembly of a complex genome; it is more likely that the new technologies will be first implemented as a complement to the longer reads afforded by existing sequencing platforms.

In renewing the sequencing program, NHGRI intends to provide adequate funding to encourage sequencing centers to explore adoption of the new technologies. Therefore, the applicant should discuss the new sequencing technologies and should describe any plans s/he has for implementation of one or more of them. As part of this discussion, the applicant should address his/her past record of technology development and implementation. Between the continued improvement in the state of the art and the potential effect of disruptive technologies, it is reasonable to expect that sequencing costs could decrease by five-fold or more during the next four years.

If realized, such cost decreases will undoubtedly lead to changes in the scientific opportunities afforded by sequence data. Projects once seen as important but too expensive will become reasonable, and entirely new kinds of highly significant projects will become possible. Such changes will be reflected in the targets addressed by the NHGRI sequencing program, which will increasingly be based on large, compelling scientific questions and less on identifying individual organisms as targets. Given the potential for expanded sequence production over the next four years, there are scientific opportunities in a number of areas. The availability of large-scale genome sequence data in each of these areas has the potential:

• Medical sequencing. The Medical Sequencing Working Group has identified several broad areas of interest and has recommended that the NHGRI’s initial venture into large-scale medical sequencing focus on three of them: (a) finding the sequence variants responsible for rare genetic diseases by sequencing the mapped intervals for up to 100 mendelian disorders; (b) identifying sequence variations that may be associated with up to 130 X-linked diseases by sequencing all of the genes on the X chromosome from affected individuals; and (c) describing the allelic spectrum of common diseases by sequencing genes known to be involved in common diseases in an appropriate set of individuals. By driving technological improvement and contributing to an increase in the understanding of disease, a large-scale medical sequencing program will help to drive the state of the art toward a time that genomic sequencing will become part of the standard of patient care.
• Cancer Genome Sequencing. In collaboration with the National Cancer Institute, NHGRI is planning a program of comprehensive genomic analysis of major tumor types, called The Cancer Genome Atlas (TCGA). The purpose of this program (see http://www.genome.gov/15015123), is to generate a comprehensive description of all genomic variants, including structural variants, that are associated at significant frequency with major tumor types. The NHGRI has committed $16.7 M per year of the funds for the current RFA in Fiscal Years 2007-09 for TCGA. Centers funded through this RFA will have the opportunity to participate in this program. The targets for the cancer genome program will be selected by a process that will involve that program’s panel of scientific consultants, cancer researchers, and the NCI/NHGRI staff on the basis of information from the literature and data that will be generated by Cancer Genome Characterization Centers that will be funded by the NCI as part of TCGA. Management of the cancer genome sequencing effort will include additional aspects separate from the other scientific programs described here, such as coordination with the Cancer Genome Characterization Centers. The NHGRI-supported centers that participate in the TCGA will participate in two research networks; one for the TCGA and the second for the NHGRI sequencing program as a whole (see description of Research Network, below)
• Normal human variation. The HapMap Project has provided an unprecedented level of information about common human genetic variation. To complement this data set, which focused on a description of common variation in the human genome, and to develop a more complete picture of normal human variation as the background for interpreting data on variation in human disease, much deeper knowledge is needed about the occurrence and population distribution of rare variants and structural variation.
• Comparative genome sequencing. Comparative sequencing has been shown to be one of the most efficient and powerful means to delineate important functional features in genomes (especially our own) and to provide insight into major biological innovations. While much has been accomplished, a great deal remains to be learned. For example, it would be very attractive to sequence the primate lineage in more detail, in order to identify primate-specific and human-specific elements and to highlight the genomic differences between ourselves and our closest relatives. In addition, we do not yet have a sufficient amount of comparative data to reliably delineate all of the conserved functional elements in the human genome to the desired resolution, including cis-regulatory sequences, microRNA genes and target sites, splice enhancers/inhibitors, constrained regions of proteins, and others. Comparative genome sequencing can also help inform our understanding of how genomes evolved, including understanding of genome duplication, evolution of gene regulatory pathways, and speciation.
• Parasite and vector genomes. The genomes of fewer than 20 important eukaryotic pathogens of human, and only six vectors of human disease, have been sequenced or are in the process of being sequenced, primarily with support provided by agencies other than NHGRI. NHGRI plans to devote more of its sequencing capacity to the sequencing of additional human pathogens and vectors.
• New model systems. While many of the major model systems have been sequenced, NHGRI is still approached by model organism communities (most recently, those studying Aplysia and the zebrafinch) about sequencing the genomes of the organisms that they are studying.
• Other areas that may arise. It has been NHGRI’s experience that new opportunities for the use of genomic sequence are not always predictable but continue to arise with some regularity. Accordingly, the NHGRI large-scale sequencing program must remain flexible enough to respond to such opportunities. Many factors are involved in this, including the dissemination and growth of the field of genomics which leads to awareness of the utility of sequence data within new communities, advances within the field that lead to insights about new questions and analyses, and changes in technology that make it easier to justify projects that previously seemed too expensive. As one example, there is increasing interest in the area of human metagenomics, or the use of sequencing to characterize our commensal microbial communities. As another, it is becoming clearer that the use of large-insert clone end-sequencing may be a highly productive way to assess structural variation. Finally, the availability of very cheap short reads may lead to a re-invigoration of SAGE-like transcriptome analyses, and the use of sequencing instead of hybridization approaches to look at products of chromatin immunoprecipitation of transcription factors.

The majority of the sequencing targets addressed by NHGRI in the next four years will be chosen by the NACHGR on the basis of recommendations from expert working groups. However, in responding to this RFA, the applicant may propose to use up to 10% of the requested capacity for work on sequencing targets of his/her choice. In introducing the opportunity for centers to choose some targets, NHGRI intends to provide flexibility to pursue exciting opportunities that are not addressed by the working groups, either because they are not within the working groups remits or because they are innovative to the point of demonstrating a new use for sequence information.

In summary, this solicitation seeks applications for genome sequencing centers that will operate at and extend the state of the art of large-scale genomic sequencing with respect to cost, throughput, and quality. The applicant should have a proven track record for producing high quality genome projects. As guidance in preparing an application, NHGRI considers the current state of the art for a genome sequencing centers to encompass most or all of the following:

• An automated production pipeline with a throughput of at least 2.5 million Q20 kilobases and/or 4 million successful sequencing reads per quarter (or most recent three-month period);
• An overall per-read success rate of at least 80% and a high read pairing rate for paired reads
• An ability to efficiently produce the variety of types of data (whole genome shotgun, BAC and fosmid ends) required to produce a whole genome shotgun assembly;
• An overall total cost of production of $1 or less per Q20 kilobase for whole genome shotgun data, including all overhead (indirect) and amortized equipment costs;
• A record of reducing costs and increasing efficiency, and a forward-looking plan to continue to do so;
• The ability to assemble genomic sequence at all scales, including the ability to produce a high quality assembly of whole genome shotgun data;
• The ability to produce finished genomic sequence for less than $20 per kilobase above the cost of a whole genome shotgun data set;
• The ability to use multiple genome sequencing strategies and the ability to adapt and modify approaches as the technology and demands on the center change;
• Integrated bioinformatics capabilities to support production, including systems and database administration, laboratory information management, and data handling and deposition;
• Ability to perform primary annotation of genomic sequence to maximize its utility for the biological community;
• A technology development capability focused on developing and integrating technology improvements (e.g., robotics, chemistries, protocols) that lead to increased efficiency and decreased costs;
• A proven track record in rapidly and efficiently releasing both sequence and trace data to public repositories; and
• A high degree of flexibility and a strong track record of interacting with other publicly funded large-scale sequencing centers, public databases, genome analysis experts, physical mapping groups, and other entities.

In addition to maintaining and defining state-of-the-art capability, this RFA seeks applications for centers that will be flexible enough to be rapidly responsive to the new scientific and technological opportunities discussed above. In other words, a proposed center should have a state-of-the-art ability to produce a widening variety of types of sequence data beyond whole genome shotgun. This would include, for example, directed sequencing reads for medical sequencing projects, EST or SAGE tag sequencing to aid in annotating genome sequences, finished sequence data, improved or refined draft genome sequences. Fundamentally, this solicitation seeks large-scale sequencing centers that can address the most important scientific opportunities, while consistently improving the state-of-the-art in all production areas. NHGRI anticipates that flexibility will be achieved through the program as a whole that is, each center will be expected to have a core expertise in large-scale genomic sequencing, while it is also anticipated that different centers may have different ranges of additional capabilities that would provide the degree of flexibility sought.

Data and Resource Release. NHGRI strongly endorses rapid release of genomic data and materials. Applications submitted in response to this RFA should include a plan for data release. The NHGRI policy on release of sequence data is available at http://www.genome.gov/10506376. The purpose of this RFA is to fund genome sequencing centers that will produce large amounts of DNA sequence data. The utility of the data is largely dependent on how quickly they can be deposited into public databases for use by the scientific community. NHGRI considers its large-scale genomic sequencing program to be a community resource project as discussed in the report Sharing Data From Large-Scale Biological Research Projects - 2003: A System of Tripartite Responsibility available at http://www.genome.gov/10506376. Because some of the medical sequencing information that would be produced through projects as described in this RFA could raise issues about patient confidentiality, it may be appropriate for some medical sequencing information to be released with certain safeguards of confidentiality. For example, patient medical data might be made accessible only on condition of approval by an institutional review board. NHGRI will be developing separate policies for these data and each study design may require separate consideration. Thus applicants proposing to pursue a medical sequencing project must address these issues and propose a plan to protect patient confidentiality.

Applicants should also be familiar with the NIH statements regarding intellectual property of resources developed with Federal funds (http://www.ott.nih.gov/policy/rt_guide_final.html).

Minority Action Plan. NHGRI requires all applicants for this RFA to include separate plans for a program to increase the number of under-represented minorities in genomic sciences. For background and a summary of existing activities, see http://www.genome.gov/14514219.

See SPECIAL GUIDANCE FOR APPLICANTS at the end of this announcement for specific discussion about what should be included in the application.

See Section VIII, Other Information - Required Federal Citations, for policies related to this announcement.

1. Mechanism(s) of Support

This funding opportunity will use the U54 cooperative agreement award mechanism(s).

As an applicant, you will be solely responsible for planning, directing, and executing the proposed project.

The NIH U54 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 VI. 2. Administrative Requirements, "Cooperative Agreement Terms and Conditions of Award". The U54 mechanism requires a non-modular budget. NHGRI intends to re-issue this or a similar funding opportunity at the end of the award period for this RFA.

2. Funds Available

NHGRI intends to commit up to $130 million dollars in FY 2006 and anticipates funding 3-5 new and/or competing continuation grants in response to this RFA. Awards will be made in November, 2006. An applicant may request a project period of up to four years.

Although the financial plans of NHGRI provide support for this program, awards pursuant to this funding opportunity are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. Because of the nature of the large-scale sequencing program and as discussed below, NHGRI may reduce the overall funding for the large-scale sequencing program (and for grants funded through the program) in succeeding years depending on the continued scientific priority of the program, and advances in sequencing technology that may significantly reduce sequencing costs while allowing the program to maintain or even increase overall productivity.

Facilities and administrative costs requested by consortium participants are not included in the direct cost limitation, see NOT-OD-05-004.

1. Eligible Applicants

1.A. Eligible Institutions

You may submit (an) application(s) if your organization has any of the following characteristics:

• For-profit organizations
• Non-profit organizations
• Public or private institutions, such as universities, colleges, hospitals, and laboratories
• Units of State government
• Units of local government
• Eligible agencies of the Federal government
• Domestic Institutions

Foreign institutions may participate as collaborations or subcontracts. Applications for renewal of existing projects are eligible to compete with applications for new awards.

1.B. Eligible Individuals

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.

2. Cost Sharing or Matching

Cost sharing is not required.

The most current Grants Policy Statement can be found at: http://grants.nih.gov/grants/policy/nihgps_2003/nihgps_Part2.htm#matching_or_cost_sharing.

3. Other-Special Eligibility Criteria

Applicants for this RFA must have a proven track record of producing large-scale sequence data at a level similar to that described in the description of the current state of the art. Experience must support the proposed production methods and goals. Documentation of this experience must be included. A template that will assist the applicant in providing this documentation is provided at URL http://www.genome.gov/17515675.

1. Address to Request Application Information

The PHS 398 application instructions are available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. Applicants must use the currently approved version of the PHS 398. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: [email protected].

Telecommunications for the hearing impaired: TTY 301-451-5936.

2. Content and Form of Application Submission

Applications must be prepared using the most current PHS 398 research grant application instructions and forms. Applications must have a D&B Data Universal Numbering System (DUNS) number as the universal identifier when applying for Federal grants or cooperative agreements. The D&B number can be obtained by calling (866) 705-5711 or through the web site at http://www.dnb.com/us/. The D&B number should be entered on line 11 of the face page of the PHS 398 form.

The title and number of this funding opportunity must be typed on line 2 of the face page of the application form and the YES box must be checked.

3. Submission Dates and Times
Applications must be received on or before the receipt date described below (Section IV.3.A). Submission times N/A.

3.A. Receipt, Review and Anticipated Start Dates

Letters of Intent Receipt Date(s): January 11, 2006
Application Receipt Dates(s): April 11, 2006
Peer Review Date(s): June-July 2006
Council Review Date(s): September 12, 2006
Earliest Anticipated Start Date: November 1, 2006

3.A.1. Letter of Intent

Prospective applicants are asked to submit a letter of intent that includes the following information:

• Descriptive title of proposed research
• Name, address, and telephone number of the Principal Investigator
• Names of other key personnel
• Participating institutions
• Number and title of this funding opportunity

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:

Adam L. Felsenfeld, Ph.D.
Division of Extramural Research
National Institute of Human Genome Research
5635 Fishers Lane, Suite 4076 MSC 9305
Bethesda, MD 20892
Telephone: (301) 496-7531
FAX:301-402-2770
Email: [email protected]

3.B. Sending an Application to the NIH

Applications must be prepared using the research grant applications found in the PHS 398 instructions for preparing a research grant application. 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 (U.S. Postal Service Express or regular mail)
Bethesda, MD 20817 (for express/courier service; non-USPS service)

Personal deliveries of applications are no longer permitted (see http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-040.html).

At the time of submission, two additional copies of the application and all copies of the appendix material must be sent to:

Rudy Pozzatti, Ph.D. Office of Scientific Review
National Institute of Human Genome Research
5635 Fishers Lane, Suite 4076 MSC 9305
Bethesda, MD 20892
Telephone: (301) 496-7531
FAX:301-402-2770
Email: [email protected]

Using the RFA Label: The RFA label available in the PHS 398 application instructions 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.

3.C. Application Processing

Applications must be received on or before the application receipt date(s) described above (Section IV.3.A.). If an application is received after that date, it will be returned to the applicant without review. Upon receipt, applications will be evaluated for completeness by the CSR and responsiveness by the NHGRI. Incomplete and non-responsive applications will not be reviewed.

The NIH will not accept any application in response to this funding opportunity 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 a funding opportunity, it is to be prepared as a NEW application. That is, the application for the funding opportunity 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.

Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within eight (8) weeks.

4. Intergovernmental Review
This initiative is not subject to intergovernmental review.

5. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.

Pre-Award Costs are allowable. A grantee may, at its own risk and without NIH prior approval, incur obligations and expenditures to cover costs up to 90 days before the beginning date of the initial budget period of a new or competing continuation award if such costs are necessary to conduct the project, and would be allowable under the grant, if awarded, without NIH prior approval. If specific expenditures would otherwise require prior approval, the grantee must obtain NIH approval before incurring the cost. NIH prior approval is required for any costs to be incurred more than 90 days before the beginning date of the initial budget period of a new or competing continuation award.

The incurrence of pre-award costs in anticipation of a competing or non-competing award imposes no obligation on NIH either to make the award or to increase the amount of the approved budget if an award is made for less than the amount anticipated and is inadequate to cover the pre-award costs incurred. NIH expects the grantee to be fully aware that pre-award costs result in borrowing against future support and that such borrowing must not impair the grantee's ability to accomplish the project objectives in the approved time frame or in any way adversely affect the conduct of the project. See NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part6.htm.

6. Other Submission Requirements

Special Guidance for Applicants

The NHGRI has conducted several competitions for large-scale projects and it has been our experience that there are specific information items and presentation formats that the reviewers have found to be critical for their ability to assess proposals for such efforts effectively. The following guidance summarizes that experience in the form of a format that the applicant may use to provide that information. If there is additional information, not addressed in this Guidance, that the applicant wishes to present, s/he is encouraged to provide it in a concise form, in addition to the information requested here.

Applications should contain a Progress Report not to exceed 15 pages (an introduction and rationale, and also retrospective information about the investigator’s track record in large-scale sequencing) and a Research Proposal (not to exceed 60 pages) containing detailed plans for the future. As one component of both the Progress Report and the Research Proposal, applicants are asked to provide detailed information about throughput, quality, and cost both past performance (Progress Report) and projected performance (Research Proposal).

6.I. Progress Report. The progress report should represent the applicant's past accomplishments, rather than future plans. Brief, concise summaries are encouraged, and the total length of this section must not exceed 15 pages. The Progress Report should address each of the factors discussed in the RESEARCH OBJECTIVES section above and should adequately describe the applicant's past experience in large-scale genomic sequencing. In presenting the information requested in this section, the applicant may choose, but is not required, to use the suggested production throughput and cost reporting format entitled Report of Past Sequencing Activities available at http://www.genome.gov/17515675 to report retrospective cost and production data. This suggested format may be used for the convenience of the applicant; its purpose is to facilitate a uniform summary of the information from applicants to ensure equitable review.

The progress report should include the following:

6.I.1. General introduction and justification. One important aspect of the NHGRI sequencing program has been how it has advanced biomedical knowledge. Therefore, the application should include a brief discussion of how the applicant’s sequencing work has contributed to the advancement of biology and medicine. The track record in outreach to the community using the sequence information generated should be discussed. If the applicant has participated as part of the NHGRI Research Network, or another collaborative research group, efforts to facilitate the success of that larger group should be described.

6.I.2 Genome sequence production. The applicant should include a concise description of past experience in large-scale genome sequencing and describe any relevant sequencing products, including whole genome shotgun data sets, whole genome shotgun assemblies, directed sequencing data sets, refined or finished genome sequence data sets, and so on. The application should also describe experience in relevant related activities such as producing physical maps. Past experience should be related explicitly to the description of the state of the art in large-scale sequencing as discussed in the Research Objectives section.

Each of the following factors should be addressed:

1. Throughput and costs. Items A-E request cost and throughput information for several different sequencing products. Major equipment costs should be amortized over three years. A template is provided at (URL http://www.genome.gov/17515675) that should help the applicant in providing this information in a tabular format, which has proved useful for reviewers of large-scale sequencing applications in the past.

All throughput and cost information should be provided for the most recent three-month period or quarter.

A. Costs and throughput for clone-based or whole genome shotgun sequencing.

i. Throughput and pass rate: provide total number of Q20 bp produced; number of Q20 bases deposited in a public database; pass rate (successful reads/attempted reads) (success is =100 Q20kbp of nonvector sequence). Provide information separately for 1. small insert plasmids; 2. large-insert plasmids; 3. WGS fosmids; 4. BAC-ends

ii. Provide costs broken down into the following categories. Costs in each category should include management, administrative support, personnel, supplies, reagents, informatics support, and indirect costs associated with each category a-j.

a. Base production costs. State as total costs and cost per Q20 kbp, This includes, in addition to the above: management LIMS, informatics support and costs associated with coordination on shared projects, amortized equipment costs (amortized over three years) associated with shotgun sequencing, incremental bioinformatics improvements, incremental technology development, (i.e., improvements to technologies already incorporated into production), routine automated BAC assembly, data submission. Provide information separately for 1. small insert plasmids; 2. large-insert plasmids; 3. WGS fosmids; 4. BAC-ends.

b. Library construction costs.

c. Whole genome assembly costs.

d. Assembly assessment and validation costs. This includes assembly assessment and validation, and assembly quality assessment, map and sequence integration.

e. Heterozygosity testing

f. Manual annotation costs

g. Exploratory bioinformatics development. This includes new and risky development activities, such as building and testing new bioinformatics platforms that have or have not yet been integrated into the production pipeline.

h. Assembly methods development

i. Annotation methods development

j. Exploratory technology development. This includes new and risky development activities, such as building and testing new sequencing platforms or robotics that may or may not be integrated into the production pipeline.

B. Costs and throughput for Finished sequence production: Provide the total number of finished bases produced, and the total costs associated with finishing (over and above those associated with production of the unfinished data)

C. Costs and throughput for PCR-directed sequencing: Provide the total number of bases and the total number of amplicons produced, and the costs associated with small amplicon sequencing (assumes complete coverage with two reads, one on each DNA strand). Please include:

i. Throughput and pass rate: provide the total number of Q20 bases produced; the total number of reads produced; the pass rate (=successful reads/attempted reads). For amplicons greater than 200 bases long, a successful read is defined as a read with 100 bases or more of amplicon sequence in Q20s. For amplicons less than 200 bases long, a successful read is defined as a read with in 50% or more of the amplicon length in Q20s.

ii. Provide total costs, for each of the directed sequencing activities below. Each category should include the pro-rated costs for management, administrative support, personnel, supplies, reagents, informatics support and indirect costs associated with each of category a-f below

a. Base production costs, stated as total cost, cost per Q20 kbp, and per read This includes, in addition to the above: management LIMS, informatics support and coordination associated with coordination on shared projects, amortized equipment costs (amortized over three years) associated with directed sequencing, primer costs including all primers purchased during the quarter, incremental bioinformatics improvements, incremental technology development, (i.e., improvements to technologies already incorporated into production), routine target assembly, data submission.

b. Exploratory bioinformatics development. This includes new and risky development activities, such as building and testing new bioinformatics platforms that may or may not be integrated into the production pipeline.

c. Exploratory technology development. This includes new and risky technology development activities, such as building and testing new sequencing platforms or robotics that may or may not be integrated into the production pipeline.

d. Quality assessment

e. Analysis. Includes funds used for analysis of directed sequencing, e.g., mutation detection

f. Assay design and validation.

D. Costs and throughput for Other directed sequencing. Directed sequencing outside of small amplicons is still in a stage that it is not yet clear what progress information needs to be collected. The applicant is asked to describe the types of projects as well as success and issues with each approach. Please provide total Q20 bp and number of reads produced and total costs associated with producing other types of PCR directed sequencing.

E. Costs and throughput for Additional activities not part of the above. Please list other activities and associated costs. This may include:

i. Mapping all activities associated with generating maps (including bioinformatics and development)

ii. Genome analysis biological analysis of data

iii. Other for example, finding SNPs, EST sequencing, SAGE tag sequencing, publication preparation, outreach, interaction with scientific communities

2. Assessment of quality of various sequencing products. The applicant should describe how the quality of each of the sequencing products that have been produced has been measured or assessed.

3. Prior experience in attaining production milestones. The applicant should discuss his/her track record in attaining production milestones.

6.I.3. Informatics. The applicant should discuss his/her experience with all aspects of informatics related to the production aspects of large-scale sequencing, including basic IT infrastructure, laboratory information management (LIMS), and data handling and deposition. Applicants should also discuss experience with informatics and software development related to analysis of sequence data, including genome assembly, automated annotation, analysis of medical sequencing data, etc.

6.I.4. Technology Development. The applicant should address any experience that s/he has had in developing and improving technology for large-scale sequencing, especially in integrating new sequencing platforms. The discussion should describe, in quantitative terms, the effect that such technology improvements have had in process improvement and decreased production costs.

6.I.5. Outreach and dissemination. The applicant should address past experience in collaborating with individual research communities on specific genome projects. Of particular interest is experience in dissemination of knowledge about how to use the genome sequence , and the scientific outcomes of those collaborative relationships.

6.II. The Research Proposal. This section (a maximum of 60 pages) comprises the applicant's proposed plan for a large-scale genome sequencing center that will meet the objectives of this RFA. The organization suggested below for this section of the application is based on the NHGRI’s staff's current understanding of large-scale sequencing. The applicant is free to use an alternative presentation but, in so doing, must address all of the issues raised below.

6.II.1. Sequence production. The application should describe the sequence production component of the proposed center in the context of the overall sequencing objectives of the center and the NHGRI, the strategy or strategies the center will take to generate various sequencing products, the projected throughput, the expected or needed read characteristics and quality, the assembly strategy and all other pertinent factors.

The applicant should present a clear plan, including concrete milestones, for meeting and exceeding the current state of the art in all areas of production sequencing discussed in this RFA, including whole genome shotgun sequencing, directed sequencing, finishing/refinement, and others. If the applicant proposes a physical mapping capability, that effort should be described and justified in terms of its utility for genome sequencing. All phases of the production process must be addressed, as well as:

A. the overall projected cost and throughput of the proposed center for each year of requested funding, and how those will be attained for each type of sequencing product. Costs, success rates, and throughput must be discussed using the definitions given above in the description of the Progress Report.

B. potential bottlenecks or other problems that can be anticipated, as well as proposed solutions;

C. timelines and quantitative milestones where appropriate, especially for throughput, cost, quality, and adoption of new technologies;

D. how the center will maintain the flexibility needed to produce the variety of sequencing products that have been discussed in this RFA.

6.II.2. Informatics and informatics development. Applicants should discuss the informatics that will be used to support sequence production, including routine IT/systems administration, LIMS, etc.

Applicants should discuss any proposed sequence assembly informatics that will be used in genome assembly. Applicants should discuss informatics that will be used in interpreting medical sequencing data.

Applicants to this RFA may propose appropriate automated annotation and, if so, should provide details in the application about the extent of annotation to be done, justifying choices based on the utility of the annotated sequence to the user community, and defining the point at which primary annotation (of projects, genome assemblies, finished genomes, etc.) will be considered to be complete enough for hand-off to the community. If the applicant proposes to do medical sequencing, s/he should describe any informatics that would be used to interpret such data for example to identify reliable variants in heterozygotes.

Applicants may propose to develop new informatics for any of the areas above. In the application, a distinction should be made between routine or incremental improvements to existing software, and the development of entirely new capabilities (so-called radical informatics development). All development activities should be justified in terms of how they will improve sequencing throughput, efficiency, and/or utility to the community. The costs of radical informatics development activities must be clearly described.

6.II.3. Technology development. The Research Plan should include a separate section describing plans for technology development efforts to improve the efficiency of the production pipeline. Incremental and exploratory (or radical ) technology development should be discussed separately. Any issues involved in integrating new sequencing technology platforms into the production pipeline should be addressed. All technology development must be justified in terms of its utility for increasing efficiency of production or quality of the product. The costs of radical technology development activities must be clearly described.

6.II.4 Outreach and dissemination. The applicant should discuss how s/he would work with the various research communities that are consumers of sequence data, including a description of what the applicants believe is the best product for different research communities, the end-point for particular kinds of projects, and how s/he would propose to increase the ability of those communities to use the sequence data over the short- and long-term. The applicant should discuss how s/he would manage what are likely to be multiple ongoing relationships across many types of project. The applicant is encouraged to demonstrate his/her ability to play this role by proposing collaborations, educational opportunities, and other means to develop a wider community of genomic sequence users. NHGRI has not set a limit on the portion of the budget that can be used for this activity, but the applicant must provide a clear description of plans for these activities and a well-justified budget request. The applicant should explicitly discuss the amount of funds proposed for these activities.

6.II.5 Target selection. This RFA allows the applicant an opportunity to propose the use of up to 10% of the funded capacity for center-initiated sequencing projects. An applicant who wishes to do so should describe the initial projects and their costs. The sequencing targets of these projects should be fully justified in terms of their significance, the unique ability of sequence information to address them, and how the sequence information will be used. The applicant should describe how the projects will be done, including describing collaborations that may be needed. The applicant should also explain how the project(s) will achieve something unique, which is not already being actively pursued by the working group mechanism. The applicant should discuss how s/he will select future self-initiated targets; note that this process must be described even if the applicant does not wish to propose specific targets in the application, but may want to select some in the future . All costs of this component should be stated explicitly.

6.II.6 Training. The applicant must propose a plan to address NHGRI's Minority Action Plan for increasing the number of underrepresented minorities in genome research. For additional background and current application procedures and guidelines, see http://www.genome.gov/10003996. The proposal for the Minority Action Plan should be included in the application as a separate section with its own budget information. An application that is rated highly for its scientific program will not be funded until its proposed Minority Action Plan is deemed to be adequate by peer review. The MAP will be reviewed separately and that its evaluation will not enter into the priority score.

6.II.7 Management Plan. The P.I. of a large-scale project funded under this RFA is expected to devote at least 30% effort to the project. The application should describe the management plan for the proposed center, and how it will support the goals proposed. It should describe the organization of the proposed center and its management structure, including integration of the separate components to form an efficient pipeline, key personnel, section leaders, and reporting relationships. Recruitment and training of personnel should be discussed. The plan should describe how the various components of the proposed center will be integrated, and how collaborations or subcontracts, if proposed, will be managed. The issue of how any other, ongoing large-scale sequencing projects would be integrated with the one to be funded under this RFA should be discussed.

6.III. Budget Request. The budget requested must be described clearly and be well justified. Applicants should submit the Detailed Budget for the Initial Budget Period (page 4 of PHS-398) and the Budget for Entire Proposed Period of Support (page 5 of PHS-398). The budget for the Minority Action Plan must be provided separately.

Additionally, the applicant may use the suggested format cost spreadsheet entitled Year X Projected Sequencing Activities available at http://www.genome.gov/17515675. The spreadsheets are provided for the convenience of the applicant and have been found to be very useful by the review committee to assess the applicant's proposed plans regarding sequencing production and costs. Other formats that provide this information may be used, but sequencing costs and categories must be reported as defined in the Progress Report section above.

Plan for Sharing Research Data

The application for a large-scale sequencing center must include a plan for sharing research data. NHGRI strongly endorses rapid release of genomic data and materials. The specific NHGRI policy on release of sequence data is available at http://www.genome.gov/10506376. Because the purpose of this RFA is to fund large-scale sequencing centers, and the utility of such data is largely dependent on how quickly it can be deposited into public databases, NHGRI considers this RFA to be funding a community resource project as discussed in the report Sharing Data From Large-Scale Biological Research Projects - 2003: A System of Tripartite Responsibility available at http://www.genome.gov/10506376. The general NIH data sharing policy is available at http://grants.nih.gov/grants/policy/data_sharing. All investigators responding to this funding opportunity should include a description of how research data will be shared.

Responses to this RFA should propose a plan for data release, as quality of the data release plan will be a criterion in the review of the application. Appropriate data release plans will be made a condition of the awards made as a result of this RFA. Each of the following items should be discussed separately:

• Release of sequence read and trace data
• Release of assembled projects (large-insert clone assemblies; assembled medical sequencing projects)
• Release of whole genome shotgun assemblies
• Release of annotation performed by the center, including annotation of medical sequencing projects
• Availability of map information

Intellectual property management plan

A primary objective for the " Genome Sequencing Centers is to maximize the public benefit of the data produced. Accordingly, awardees should manage intellectual property (IP) and data in a way that achieves this goal. In the case of the TCGA, as well as many of the medical sequencing projects, awardees are expected to generate a large collection of data that will serve as a foundation for the scientific community to develop future diagnostics, therapeutics and other medical applications. To achieve the objective of producing and broadly sharing the resources generated by both TCGA and the medical sequencing portion of the proposed sequencing capacity, applicants should develop a comprehensive IP and data management strategy that is consistent with the NIH Research Tools Policy (http://ott.od.nih.gov/policy/research_tool.html). Examples which applicants may wish to consider include the recommendations cited in NIH’s Best Practices for the Licensing of Genomic Inventions (http://www.ott.nih.gov/policy/genomic_invention.html).

It is intended that the tools of scientific discovery necessary to rapidly and effectively develop new diagnostics, therapeutics and other medical applications be widely available for research use. Accordingly, awardees will be expected to manage IP in a way that is consistent with the goals of the initiative and in accordance with applicable NIH guidelines and best practices. Applicants should submit an IP Management Plan that assures that data is rapidly released according to approved criteria (see above), that licensing and sharing practices ensure the availability of data and research resources for future use by the scientific community, and that research collaboration or sponsorship agreements are consistent with the requirements of the TCGA and the NHGRI medical sequencing program. IP Management Plans, once approved, will also become Terms and Conditions of award.

Restrictive licensing and sharing practices for TCGA and medical sequencing data could substantially diminish the value and public benefit provided by this community resource project. Management practices that would prevent or block access to, or use of TCGA or medical sequencing data and resources for research use will be considered to be hindering the goals of the NHGRI sequencing program. Applicants are encouraged to clearly demonstrate in their IP Management plan how their strategies will achieve the desired public benefit and programmatic goals through effective sharing of TCGA and medical sequencing data and tools.

Sharing Research Resources

NIH policy requires that grant awardee recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication (NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/index.htm and http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part7.htm#_Toc54600131). Investigators responding to this funding opportunity should include a plan for sharing research resources addressing how unique research resources will be shared or explain why sharing is not possible.

The adequacy of the resources sharing plan and any related data sharing plans will be considered by Program staff of the funding organization when making recommendations about funding applications. The effectiveness of the resource sharing will be evaluated as part of the administrative review of each non-competing Grant Progress Report (PHS 2590, http://grants.nih.gov/grants/funding/2590/2590.htm). See Section VI.3. Reporting.

Applicants should discuss the following:

• Availability of software developed with funds from this award
• Availability of clone resources developed (e.g., 10kb libraries, fosmids)
• Availability of technologies developed with funds from this award

1. Criteria

The following will be considered in making funding decisions:

Scientific merit of the proposed project as determined by peer review;

• Availability of funds;
• Relevance to overall program priorities related to achieving programmatic balance with respect to the flexibility over the program as a whole to respond to scientific opportunities, and related to achieving the overall goals for the program;
• The likelihood that the proposed effort will make a significant contribution to the availability of large-scale genome sequence data to the community;
• The prospect for attaining and improving the state of the art with respect to cost, data quality, and throughput;
• The quality of the plan to share data and materials to make them available to the public and private research community.
• The quality and responsiveness of the Minority Action Plan

This award will entail specific terms and conditions appropriate to the U54 mechanism and the structuring of the large-scale sequencing program as a research network. See Section VI below.

2. Review and Selection Process

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 NHGRI in accordance with the review criteria stated below.

As part of the initial merit review, all applications will:

• Undergo a selection process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed and assigned a priority score.
• Receive a written critique.
• Receive a second level of review by the National Advisory Council on Human Genome Research.

The goals of NIH-supported research are to advance our understanding of biological systems, to improve the control of disease, and to enhance health. In their written critiques, reviewers will be asked to comment on each of the following criteria in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that an 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 this study address an important problem? If the aims of the application are achieved, how will scientific knowledge or clinical practice be advanced? What will be the effect of these studies on the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

• Is there a high likelihood that the proposed center can produce high-quality genomic sequence, based on the applicant’s past experience and the proposed future plans for generating high quality read data, accurate subassemblies and whole genome assemblies, finished sequence, and other kinds of large-scale sequencing products as discussed in this solicitation? Is there a high likelihood that the applicants can accomplish this at and beyond current state-of-the-art levels of throughput, data quality, and cost?

Approach: Are the conceptual or clinical framework, design, methods, and analyses adequately developed, well integrated, well reasoned, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics?

• Does the applicant have adequate plans for increasing throughput while lowering costs? Does the applicant have a successful record in this regard?
• Does the applicant have adequate plans for technology development related to large-sale sequencing,,identifying and solving critical integration problems, and adopting new sequencing platforms to increase efficiency and lower costs? Does the applicant have a successful record in this regard?
• Does the applicant have adequate plans for bioinformatics related to large-scale genomic sequencing, including infrastructure/laboratory information management, assembly, and primary annotation? Does the applicant have a successful record in this regard?
• Is the proposed approach to sequencing adequate,, especially as it may relate to the flexibility to address the variety of potential sequencing targets available? Does the applicant have a successful record in this regard?
• If the applicant proposes plans for choosing center-selected targets, is the plan for doing so adequate? It there a high likelihood that the targets will illuminate significant biomedical problems, will be tractable, and will be novel or otherwise not targets likely to be chosen by other means?
• Are the plans adequate for release of sequence data? Is there evidence that the systems are in place to support rapid data release? Are there adequate plans for release or distribution of other resources, software, or technologies developed under this award? Does the applicant have a successful record in this regard?
• If collaborations are proposed, for example with organism communities, investigators with human sample collections, or with other sequencing centers, are the plans adequate to ensure a productive collaboration? Does the applicant have a successful record of coordinating efforts with other large-scale sequencing centers in the U.S. and abroad? With organism communities?
• Does the applicant have adequate and forward-looking plans to disseminate information about genomes and to collaborate in effective ways with user communities? Does the applicant have a successful record in this regard?

Innovation: Is the project original and innovative? For example: Does the project challenge existing paradigms or clinical practice; address an innovative hypothesis or critical barrier to progress in the field? Does the project develop or employ novel concepts, approaches, methodologies, tools, or technologies for this area?

Investigators: Are the investigators appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers? Does the investigative team bring complementary and integrated expertise to the project (if applicable)?

Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed studies benefit from unique features of the scientific environment, or subject populations, or employ useful collaborative arrangements? Is there evidence of institutional support?

2.A. 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:

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 the Research Plan, Section E on Human Subjects in the PHS Form 398).

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 will be assessed. Plans for the recruitment and retention of subjects will also be evaluated (see the Research Plan, Section E on Human Subjects in the PHS Form 398).

Care and Use of Vertebrate Animals in Research: If vertebrate animals are to be used in the project, the five items described under Section F of the PHS Form 398 research grant application instructions will be assessed.

Biohazards: If materials or procedures are proposed that are potentially hazardous to research personnel and/or the environment, determine if the proposed protection is adequate.

2.B. Additional Review Considerations

Budget: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. The priority score should not be affected by the evaluation of the budget.

2.C. Sharing Research Data

Data Sharing Plan: The reasonableness of the data sharing plan or the rationale for not sharing research data will be assessed by the reviewers. Adequacy of the data release plan will be considered in the review and in making funding decisions, and may be negotiated by program staff prior to making an award. The presence of a data sharing plan will be part of the terms and conditions of the award. The funding organization will be responsible for monitoring the data sharing policy.

2.D. Sharing Research Resources

NIH policy requires that grant awardee recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication (See the NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps/part_ii_5.htm#availofrr and http://www.ott.nih.gov/policy/rt_guide_final.html). Investigators responding to this funding opportunity should include a sharing research resources plan addressing how unique research resources will be shared or explain why sharing is not possible.

Program staff will be responsible for the administrative review of the plan for sharing research resources.

The adequacy of the resources sharing plan will be considered by Program staff of the funding organization when making recommendations about funding applications. Program staff may negotiate modifications of the data and resource sharing plans with the awardee before recommending funding of an application. The final version of the data and resource sharing plans negotiated by both will become a condition of the award of the grant. The effectiveness of the resource sharing will be evaluated as part of the administrative review of each non-competing Grant Progress Report (PHS 2590). See Section VI.3. Reporting.

3. Anticipated Announcement and Award Dates
Not applicable

1. Award Notices

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant. For details, applicants may refer to the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_part4.htm).

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization. The NoA signed by the grants management officer is the authorizing document. Once all administrative and programmatic issues have been resolved, the NoA will be generated via email notification from the awarding component to the grantee business official (designated in item 14 on the Application Face Page). If a grantee is not email-enabled, a hard copy of the NoA will be mailed to the business official.

Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs. See Also Section IV.5. Funding Restrictions.

2. Administrative and National Policy Requirements

Data release and resource sharing plans will be incorporated into the terms and conditions of the award. In general, plans must be consistent with NHGRI policies discussed at http://www.genome.gov/10506376.

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the Notice of Award. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part4.htm) and Part II Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_part9.htm).

The following Terms and Conditions will be incorporated into the award statement and will be provided to the Principal Investigator, as well as to the appropriate institutional official, at the time of award.

2.A. Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement (U54), an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined above.

As indicated above, the activities of the sequencing centers that participate in TCGA will involve additional coordination with the NCI. Therefore, in addition to the terms and conditions relevant to the NHGRI sequencing program, additional terms and conditions will pertain to activities associated with the cancer genome project.

The following terms and conditions apply to all centers participating in the NHGRI Large-scale Sequencing Research Network:

2.A.1. Principal Investigator Rights and Responsibilities

The Principal Investigator will have the primary responsibility for defining the details

for the sequencing production center within the guidelines of this RFA and for performing the scientific activities. The P.I. will agree to accept close coordination, cooperation, and participation of NHGRI staff in those aspects of scientific and technical management of the project as described under "NIH Program Staff Responsibilities."

The P.I. of a genome sequencing production center will:

Determine experimental approaches, design protocols, set project milestones and conduct experiments;

• Provide goals for throughput, quality, and cost to the NHRI as requested (usually at the outset of the award and annually thereafter, but also at other times as requested by NHGRI program staff);
• Ensure that the genomic sequence produced meets the quality standards and costs agreed upon at the time of award or any improved quality standards and costs negotiated during the award period;
• Ensure that the sequence data (reads, assemblies) are deposited in the appropriate public database (e.g., GenBank or other, as specified by NHGRI program staff), that resources developed as part of this project are made publicly available according to NHGRI policies, and that results are published in a timely manner;
• Adhere to the NHGRI policies regarding intellectual property, data release and other policies that might be established during the course of this activity;
• Integrate with the NHGRI’s working group-based process for selecting targets or target genomes, and to make best-faith efforts to sequence those targets as negotiated with program staff.
• Submit data for quality assessment in any manner specified by the Steering Committee or the Scientific Advisory Panel;
• Submit quarterly progress reports in a standard format, as agreed upon by the Steering Committee and the Scientific Advisory Panel;
• Accept and implement any other common guidelines and procedures developed for the NHGRI large-scale sequencing program and approved by the Steering Committee and the Scientific Advisory Panel;
• Accept and participate in the cooperative nature of the Genome Sequencing Research Network;
• Coordinate and collaborate with other U.S. and international groups engaged in large-scale genomic sequencing or other large projects;
• Inform the Program Director of all major interactions of members of the Steering Committee;
• Attend Steering Committee meetings;
• Lead the center's efforts to respond to the NHGRI Minority Action Plan for increasing the representation of under-represented minorities in genome research.

Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies.

2.A.2. NIH Responsibilities

An NIH Project Scientist will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below.

The NHGRI Project Scientist will have substantial scientific/programmatic involvement during the conduct of this activity through technical assistance, advice and coordination. However, the role of NHGRI will be to facilitate and not to direct the activities. It is anticipated that decisions in all activities will be reached by consensus of the Genome Sequencing Research Network and that NHGRI staff will be given the opportunity to offer input to this process.

One NHGRI Project Scientist shall participate as a member of the Steering Committee and will have one vote.

The Project Scientist will:

• Participate (with the other Steering 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 Project Scientist will assist and facilitate the group process and not direct it;
• Negotiate throughput, quality, cost goals, and sequencing target selection with the awardees as necessary;
• Serve as a liaison between the awardees and the Scientific Advisory Panel, the National Advisory Council for Human Genome Research, and the larger scientific community in helping the awardee(s) select targets from the list developed by the working group process;
• Coordinate the efforts of the awardee with others engaged in large-scale sequencing, including other awardees under this RFA and those awardees involved in related NHGRI programs, with other U.S. large-scale sequencing efforts, and with the international sequencing community;
• Attend all Steering 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;
• Periodically report progress to the Director, NHGRI;
• Lend relevant expertise and overall knowledge of NHGRI- sponsored research to facilitate the selection of scientists not affiliated with the awardee institutions who are to serve on the Scientific Advisory Panel and the Steering Committee; serve as liaison between the Steering Committee and the Scientific Advisory Panel;
• Serve on subcommittees of the Steering Committee and the Scientific Advisory Panel, as appropriate;
• Provide advice in the management and technical performance of the investigation;
• Assist in promoting the availability of the genome sequence and related resources developed in the course of this project to the scientific community at large;
• Participate in data analyses, interpretations, and where warranted, co-authorship of the publication of results of studies conducted through the Genome Sequencing Research Network;
• Assist awardees in the development, if needed, of policies for dealing with situations that require coordinated action;
• Retain the option to recommend, with the advice of the Scientific Advisory Panel, the withholding or reduction of support from any cooperative agreement that substantially fails to achieve its goals according to the milestones agreed to at the time of award, fails to maintain state-of-the-art capabilities, or fails to comply with the Terms and Conditions of the award.

2.A.3. Collaborative Responsibilities

A Steering Committee will serve as the main governing board of the Genome Sequencing Research Network. The Steering Committee membership will include the NHGRI Project Scientist(s) and the P.I. of each awarded cooperative agreement. The Steering Committee Chair will not be an NIH staff member. Additional members may be added by action of the Steering Committee. Other government staff may attend the Steering Committee meetings, if their expertise is required for specific discussions. The Steering Committee will:

• Discuss progress in meeting the goals of various sequencing projects;
• Develop recommendations for uniform procedures and policies necessary to meet the goals of the Research Network, for example for data quality measures and assessment, conventions for data deposition, or measuring costs and throughput. Adoption of procedures and policies developed by the Steering Committee will require concurrence by the Scientific Advisory Panel;
• Serve as a venue for coordination on the improvement of genomic sequencing, for example by disseminating best practices and collectively evaluating new procedures, resources, and technologies.
• Schedule the time for, and prepare concise (3 to 4 pages) summaries of, the Steering Committee meetings, which will be delivered to members of the group within 30 days after each meeting.

Each full member will have one vote except NHGRI Project Scientist(s), who will have one collective vote. Awardee members of the Steering Committee will be required to accept and implement policies approved by the Steering Committee.

2.A.4. Scientific Advisory Panel

The Scientific Advisory Panel (SAP) will be responsible for reviewing and evaluating the progress of the members of the Genome Sequencing Research Network toward meeting their individual and collective goals. The SAP will also be responsible for approving final plans for individual sequencing projects undertaken by the centers. The SAP will provide recommendations to the Director, NHGRI, about continued support of the components of the Genome Sequencing Research Network. The Advisory Panel is composed of four to six senior scientists with relevant expertise who are not P.I.s of a cooperative agreement involved in the Genome Sequencing Research Network. The membership of the Scientific Advisory Panel may be enlarged permanently, or on an ad hoc basis, as needed.

The Scientific Advisory Panel will meet at least once a year. During part of this meeting, there will be a joint meeting with the Steering Committee to allow the Scientific Advisory Panel members to interact directly with the awardees. Annually, the Scientific Advisory Panel will make recommendations regarding progress of the Genome Sequencing Research Network and present advice about changes, if any, which may be necessary in the Genome Sequencing Research Network program to the Director, NHGRI.

2.A.5 Arbitration Process

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to arbitration. An Arbitration Panel composed of three members will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. The Arbitration Panel will help resolve both scientific and programmatic issues that develop during the course of work and 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 PHS regulations 42 CFR Part 50, Subpart D and HHS regulations 45 CFR Part 16.

2.A.6 The Cancer Genome Atlas program.

In addition to the rights and responsibilities described above in section 2.A.1, the following will apply to the centers that participate in TCGA:

2.A.6.1 Additional Principal Investigator Rights and Responsibilities with respect to TCGA

The P.I. of a Genome Sequencing Center that participates in TCGA will:

• Provide goals for throughput, quality, and cost specifically for the directed sequencing of cancer genome targets to the NHGRI and NCI as requested (usually at the outset of the award and annually thereafter, but also at other times as requested by NHGRI and NCI program staff);
• Participate in the process for choosing sequencing targets by working closely with cancer researchers, the P.I.s of the NCI-supported Cancer Genome Characterization Centers, the TCGA Panel of Scientific Consultants, and NHGRI and NCI staff , and to make best-faith efforts to sequence those targets, as negotiated with program staff.
• Submit data for quality assessment in any manner specified by the TCGA Research Network Steering Committee and the TCGA Panel of Scientific Consultants;
• Submit quarterly progress reports in a standard format, as agreed upon by the TCGA Panel of Scientific Consultants;
• Accept and implement any other common guidelines and procedures developed for the TCGA Research Network and approved by the TCGA Research Network Steering Committee and the TCGA Panel of Scientific External Steering Committee;
• Accept and participate in the cooperative nature of the TCGA Research Network;
• Coordinate and collaborate with other U.S. and international groups engaged in cancer genome sequencing;
• Inform the Program Director of all major interactions with members of the TCGA Steering Committee;
• Attend TCGA Steering Committee meetings.

2.A.6.2 Additional NIH Responsibilities with respect to the TCGA

In addition to the responsibilities described above in section 2.A.2, an NHGRI Project Scientist will have the following additional responsibilities with respect to the TCGA:

It is anticipated that decisions in all appropriate activities will be reached by consensus of the TCGA Research Network and that NHGRI and NCI staff will be given the opportunity to offer input to this process. One NHGRI Project Scientist and one NCI Project Scientist shall participate as a member of the TCGA Research Network Steering Committee, and each will have one vote.

The Project Scientists will:

• Participate (with the other TCGA Research Network Steering 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 Project Scientists will assist and facilitate the group process and not direct it;
• Negotiate throughput, quality, cost goals, and sequencing target selection with the awardees as necessary;
• Serve as a liaison between the awardees and the TCGA Panel of Scientific Consultants, the National Advisory Council for Human Genome Research, the National Cancer Advisory Board and the larger scientific community ;
• Coordinate the efforts of the awardee with others engaged in cancer genome sequencing, including other awardees under this RFA and those awardees involved in related NHGRI programs, with other U.S. cancer genome sequencing efforts, and with the international cancer sequencing community;
• Attend all TCGA Research Network Steering Committee meetings as voting members and assist in developing operating guidelines, quality control procedures, and consistent policies for dealing with recurrent situations that require coordinated action;
• Periodically report progress to the Director, NHGRI and the Director NCI about the progress of the TCGA Project;
• Serve on subcommittees of the TCGA Research Network Steering Committee , as appropriate;
• Provide advice in the management and technical performance of the investigation;
• Assist in promoting the availability of the genome sequence and related resources developed in the course of the cancer genome project to the scientific community at large;
• Participate in data analyses, interpretations, and where warranted, co-authorship of the publication of results of studies conducted through the TCGA Research Network;
• Assist awardees in the development, if needed, of policies for dealing with situations that require coordinated action;
• Retain the option to recommend, with the advice of the TCGA Panel of Scientific Consultants, the withholding or reduction of support from any cooperative agreement that substantially fails to achieve its goals according to the milestones agreed to at the time of award, fails to maintain state-of-the-art capabilities, or fails to comply with the Terms and Conditions of the award.

Additionally, an agency program official or IC program director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice. The assigned program director may also serve as the NIH Project Scientist.

2.A.6.3 Collaborative Responsibilities

A Steering Committee will serve as the main governing board of the TCGA Research Network. The Steering Committee membership will include the NHGRI and NCI Project Scientist(s) and the P.I. of each of the awarded cooperative agreement for sequencing centers that engage in cancer genome sequencing and the P.I.s of each of the NCI-funded TCGA Characterization Centers. The Steering Committee Chair will not be an NIH staff member. Additional members may be added by action of the Steering Committee. Other government staff may attend the Steering Committee meetings, if their expertise is required for specific discussions. The Steering Committee will:

• Discuss progress in meeting the goals of the various cancer genome analysis projects;
• Develop recommendations for uniform procedures and policies necessary to meet the goals of the Research Network, for example for data quality measures and assessment, conventions for data deposition, or measuring costs and throughput. Adoption of procedures and policies developed by the Steering Committee will require concurrence by the TCGA Panel of Scientific Consultants;
• Serve as a venue for coordination on the improvement of cancer genome analysis, for example by disseminating best practices and collectively evaluating new procedures, resources, and technologies.
• Schedule the time for, and prepare concise (3 to 4 pages) summaries of, the TCGA Research Network Steering Committee meetings, which will be delivered to members of the group within 30 days after each meeting;
• Each full member will have one vote including the NHGRI and NCI Project Scientist(s). Awardee members of the Steering Committee will be required to accept and implement policies approved by the Steering Committee.

2.A.6.4 TCGA Panel of Scientific Consultants

The TCGA Panel of Scientific Consultants (PSC) will be responsible for reviewing and evaluating the progress of the members of the TCGA Research Network toward meeting their individual and collective goals. The PSC will be responsible for approving final plans for targeted sequencing undertaken by the centers. The ESC will provide recommendations to the Director, NHGRI and the Director, NCI about continued support of the components of the TCGA Research Network. The PSC is composed of senior scientists and clinicians with relevant expertise in genomics, cancer and ethics who are not P.I.s of a cooperative agreement involved in the TCGA Research Network. The membership of the PSC may be enlarged permanently, or on an ad hoc basis, as needed.

The PSC will meet at least once a year. During part of this meeting, there will be a joint meeting with the Steering Committee to allow the PSC members to interact directly with the awardees. Annually, the PSC will make recommendations regarding progress of the TCGA Research Network and present advice about changes, if any, which may be necessary in the TCGA Sequencing Research Network program to the Director, NHGRI and/or the Director, NCI.

3. Reporting

Awardees will be required to submit the PHS Non-Competing Grant Progress Report, Form 2590 annually (http://grants.nih.gov/grants/funding/2590/2590.htm) and financial statements as required in the NIH Grants Policy Statement.

Awardees will also be required to submit periodic (quarterly) progress reports in a standard format, as agreed upon by the Steering Committee and the ESC.

Each awardee will be asked to define a set of yearly milestones for caner genome sequencing at the time of the award and to update these milestones annually at the anniversary date. These will be made a condition of the award. In accord with the procedures described above, NHGRI may withhold or reduce funds for a project that substantially fails to meet its milestones or to maintain the state of the art.

We encourage your inquiries concerning this funding opportunity 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:

1. Scientific/Research Contacts:

Adam L. Felsenfeld, Ph.D.; Jane L. Peterson, Ph.D.
Division of Extramural Research
National Human Genome Research Institute
5635 Fishers Lane
Suite 4076 MSC 9305
Bethesda, MD 20892
Telephone: (301) 496-7531
FAX: 301-480-2770
Email: [email protected]; [email protected]

2. Peer Review Contacts:

Rudy Pozzatti, Ph.D.
Office of Scientific Review
National Human Genome Research Institute
5635 Fisher Lane
Suite 4076
Bethesda, MD 20892
Telephone: (301) 496-7531
FAX: (301) 435-1580
Email: [email protected]

3. Financial or Grants Management Contacts:

Cheryl Chick
Grants Management Officer
Grants Administration Branch
5635 Fisher Lane
Suite 4076
Bethesda, MD 20892
Telephone: (301) 496-7531
FAX: (301) 402-1951
Email: [email protected]

Required Federal Citations

Use of Animals in Research:
Recipients of PHS support for activities involving live, vertebrate animals must comply with PHS Policy on Humane Care and Use of Laboratory Animals (http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf) as mandated by the Health Research Extension Act of 1985 (http://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA Animal Welfare Regulations (http://www.nal.usda.gov/awic/legislat/usdaleg1.htm) as applicable.

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).

Data and Safety Monitoring Plan:
Data and safety monitoring is required for all types of clinical trials, including physiologic toxicity and dose-finding studies (phase I); efficacy studies (Phase II); efficacy, effectiveness and comparative trials (Phase III). Monitoring should be commensurate with risk. The establishment of data and safety monitoring boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risks to the participants (NIH Policy for Data and Safety Monitoring, NIH Guide for Grants and Contracts, http://grants.nih.gov/grants/guide/notice-files/not98-084.html).

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 and local IRB rules, as well as local, State and Federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score.

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 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 funding opportunity 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.

Sharing of Model Organisms:
NIH is committed to support efforts that encourage sharing of important research resources including the sharing of model organisms for biomedical research (see http://grants.nih.gov/grants/policy/model_organism/index.htm). At the same time the NIH recognizes the rights of grantees and contractors to elect and retain title to subject inventions developed with Federal funding pursuant to the Bayh Dole Act (see the NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/index.htm). All investigators submitting an NIH application or contract proposal, beginning with the October 1, 2004 receipt date, are expected to include in the application/proposal a description of a specific plan for sharing and distributing unique model organism research resources generated using NIH funding or state why such sharing is restricted or not possible. This will permit other researchers to benefit from the resources developed with public funding. The inclusion of a model organism sharing plan is not subject to a cost threshold in any year and is expected to be included in all applications where the development of model organisms is anticipated.

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 "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines is 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 Clinical Research:
The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all clinical 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 (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 applications for research involving human subjects and individuals designated as key personnel. The policy is available 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://stemcells.nih.gov/index.asp 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 (http://escr.nih.gov). It is the responsibility of the applicant to provide in the project description and elsewhere in the application as appropriate, 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.

NIH Public Access Policy:
NIH-funded investigators are requested to submit to the NIH manuscript submission (NIHMS) system (http://www.nihms.nih.gov) at PubMed Central (PMC) an electronic version of the author's final manuscript upon acceptance for publication, resulting from research supported in whole or in part with direct costs from NIH. The author's final manuscript is defined as the final version accepted for journal publication, and includes all modifications from the publishing peer review process.

NIH is requesting that authors submit manuscripts resulting from 1) currently funded NIH research projects or 2) previously supported NIH research projects if they are accepted for publication on or after May 2, 2005. The NIH Public Access Policy applies to all research grant and career development award mechanisms, cooperative agreements, contracts, Institutional and Individual Ruth L. Kirschstein National Research Service Awards, as well as NIH intramural research studies. The Policy applies to peer-reviewed, original research publications that have been supported in whole or in part with direct costs from NIH, but it does not apply to book chapters, editorials, reviews, or conference proceedings. Publications resulting from non-NIH-supported research projects should not be submitted.

For more information about the Policy or the submission process please visit the NIH Public Access Policy Web site at http://publicaccess.nih.gov/ and view the Policy or other Resources and Tools including the Authors' Manual (http://publicaccess.nih.gov/publicaccess_manual.htm).

Standards for Privacy of Individually Identifiable Health Information:
The Department of Health and Human Services (DHHS) issued final modification to the "Standards for Privacy of Individually Identifiable Health Information", the "Privacy Rule", on August 14, 2002 . The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR).

Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on "Am I a covered entity?" Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

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 PA 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 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.

Loan Repayment Programs:
NIH encourages applications for educational loan repayment from qualified health professionals who have made a commitment to pursue a research career involving clinical, pediatric, contraception, infertility, and health disparities related areas. The LRP is an important component of NIH's efforts to recruit and retain the next generation of researchers by providing the means for developing a research career unfettered by the burden of student loan debt. Note that an NIH grant is not required for eligibility and concurrent career award and LRP applications are encouraged. The periods of career award and LRP award may overlap providing the LRP recipient with the required commitment of time and effort, as LRP awardees must commit at least 50% of their time (at least 20 hours per week based on a 40 hour week) for two years to the research. For further information, please see: http://www.lrp.nih.gov.

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