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Part I Overview Information

Department of Health and Human Services

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

Components of Participating Organizations
This RFA is developed as a Roadmap initiative. All NIH Institutes and Centers participate in Roadmap initiatives. This RFA will be administered by the National Institute of Environmental Health Sciences (NIEHS) on behalf of the NIH http://www.niehs.nih.gov/.

Title: Reference Epigenome Mapping Centers (U01)

Announcement Type
New

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

Request for Applications (RFA) Number: RFA-RM-07-013

Catalog of Federal Domestic Assistance Number(s)
93.310

Key Dates
Release Date: November 15, 2007
Letters of Intent Receipt Date: February 7, 2008
Application Receipt Date: March 7, 2008
Peer Review Date(s): May/June 2008
Council Review Date:August 2008
Earliest Anticipated Start Date: September 30, 2008
Technical Assistance Workshop: December 7, 2007. More information on the workshop can be found at http://nihroadmap.nih.gov/epigenomics
Expiration Date: March 8, 2008

Due Dates for E.O. 12372
Not Applicable

Additional Overview Content

Executive Summary

Table of Contents

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
A.1. Principal Investigator Rights and Responsibilities
A.2. NIH Responsibilities
A.3. Collaborative Responsibilities
A.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

Part II - Full Text of Announcement

Section I. Funding Opportunity Description

1. Research Objectives

Nature of the Research Opportunity

The NIH invites qualified investigators from academic or research institutions to submit an application for a Reference Epigenome Mapping Center (REMC) as part of the NIH Roadmap Epigenomics Program.

The NIH Roadmap is a series of programs designed to foster new ways of doing research, to fill fundamental knowledge gaps, and to encourage risk taking to solve complex problems. The overarching criterion for Roadmap programs is that they are expected to transform the way research is conducted across the spectrum of health research. The programs in their entirety therefore do not address specific diseases, although individual awards within a program may be disease-specific. (For more information on the NIH Roadmap: (http://nihroadmap.nih.gov/)

Epigenomics was selected by the NIH Leadership as a Roadmap Program following a series of discussions with panels of scientific experts and stakeholders and with input from the broad community solicited via a Request for Information in the summer of 2006. The impetus for its selection as a Roadmap program was the growing awareness that the epigenome may have widespread and profound implications for human health and disease, but our current ability to determine the extent to which that is true is limited.

To articulate ways to address this challenge, the NIH convened the Epigenetics of Human Health and Disease Workshop in March 2007 (Bethesda, MD) (http://nihroadmap.nih.gov/epigenomics/) and invited leading experts in the field of epigenetics from the United States, Canada and Europe to identify research opportunities and potential areas for international collaboration. Workshop participants identified the following priorities (1) establish a set of reference epigenomes based on genome-wide characterization of DNA methylation and multiple histone modification marks in multiple human cell types; (2) characterize the epigenetic states associated with major human diseases, response to environmental stressors, and stages of development; (3) seek input from researchers in the international community to define standardized protocols and critical reagents requisite for utilizing cutting edge scientific approaches, and (4) coordinate the informatics/data technology platforms and output formats for publicly accessible data generated by the Roadmap Epigenomics Program.

Critical analysis of the NIH epigenetic research portfolio revealed a limited investment in disease-focused research (except cancer); limited tools to measure epigenetic changes across the genome; and limited approaches to mapping reference epigenomes. Moreover, a consensus reached by participants at multiple epigenetic focused meetings was that the research community would greatly benefit from the development of an organized, integrated, publicly accessible database of signature epigenetic profiles of human stem cells, differentiating cells, differentiated cells, and tissues (http://cancerres.aacrjournals.org/cgi/reprint/65/24/11241; http://www.landesbioscience.com/journals/epigenetics/article/heindelEPI1-1.pdf). The integration of sequence variation data from genomic and HapMap (http://www.genome.gov/10005339) data and other components of DNA that will be cataloged by the NIH ENCODE program (http://www.genome.gov/10005107) with the NIH Roadmap epigenomic data will result in a database developed and maintained by the National Center for Biotechnology Information (NCBI) that will be a resource for researchers working to unravel the components of disease and dysfunction in addition to providing important information about health and normal processes.

There are five components of the Roadmap Epigenomics Program. Four of these are being announced concurrently. The RFA numbers and titles are as follows: RM-07-013, Reference Epigenome Mapping Centers (REMCs); RM-07-014, Epigenomics Data Analysis and Coordination Center (EDACC); RM-07-011 (R01) and RM-07-012 (R21) Technology Development in Epigenetics, and RM-07-015 (R01) and RM-07-016 (R21) Discovery of Novel Epigenetic Marks in Mammalian Cells. A fifth component, addressing the Epigenetics of Human Health and Disease, will be announced in FY2008.

The goals of the Roadmap Epigenomics Program are to establish multiple sets of comprehensive reference epigenomes; develop new reagents and tools for epigenetic research; identify public resources for purified, high quality stem cells, differentiated cells, and tissues; provide publicly accessible data as well as new tools for data integration; and conduct research on novel hypotheses on epigenetic roles in human health and disease.

It is anticipated that research funded by the Roadmap Epigenomics Program will ultimately have significant impact on understanding: 1) human health by assessing cell/tissue variation in epigenetic marks during stem cell differentiation, development, aging, and environmental responsiveness; and 2) human disease in the future by potential identification of biomarkers, therapeutic targets and tissue regeneration strategies.

Purpose

The purpose of this funding announcement is to establish Reference Epigenome Mapping Centers (REMC). There is not one single epigenome, but rather multiple epigenomes or epigenetic profiles; each one defining specific gene expression profiles and therefore the phenotype of a specific cell type, e.g., neuron, T-lymphocyte, type II lung cells, or pancreatic beta cells. For the purposes of this RFA, reference epigenomes are the epigenetic profiles from specific normal cell types that direct gene transcription in a manner that defines the expression profile and therefore phenotype of the normal cell or tissue.

The REMC initiative seeks to develop reference epigenomes of government-approved human embryonic stem cells, differentiating cells, and selected differentiated cell lines and human primary cells that are relevant to complex human disease. In addition the REMC program will generate data and resources that will be integrated/coordinated with existing genomic databases and infrastructure to accelerate application of epigenetics to biology and disease. These reference epigenomes will serve as a resource to be utilized by the community to identify potential therapeutic targets, pursue therapeutic opportunities in stem cell based and tissue regeneration strategies, enhance understanding of disease mechanisms, provide additional insights to genetic susceptibility of disease, provide new information regarding environmental components of disease, and information about normal differentiation, development and aging/senescence.

Background

The organization of DNA into chromatin presents the cell with the opportunity to use powerful regulatory mechanisms broadly defined as epigenetics. Increasing evidence demonstrates epigenetic mechanisms are linked to gene activation, gene silencing and chromosomal instability. Epigenetic processes act in cell specific, temporally regulated manners to direct normal development, organogenesis, tissue formation, differentiation and aging. Epigenetics is an emerging frontier of science that involves the study of changes in the regulation of gene activity and expression that are not dependent on gene sequence. For purposes of this program, epigenetics refers to both heritable changes in gene activity and expression (in the progeny of cells or of individuals) and also stable, long-term alterations in the transcriptional potential of a cell that are not necessarily heritable. While epigenetics refers to the study of single genes or sets of genes, epigenomics refers to more global analyses of epigenetic changes across the entire genome. Epigenetics is an emerging basic field of science as evidenced by the exponential increase in basic epigenetic research literature citations observed between 1990 and 2006. A similar pattern of escalating citations is now being documented with epigenetics and diseases, and multiple disease focused research initiatives and grants that have been awarded by the NIH in recent years.

Epigenetic regulation of gene transcription apparently plays a pivotal role in the governance of normal and disease development through dynamic transcriptional activities from gametogenesis through embryonic and neonatal stages, and continuing throughout adolescence, adulthood and elderly stages/old age. The growth of epigenetic research in human health, aging and disease is rapidly evolving and has reached a critical point where opportunities exist to make significant inroads in understanding how epigenetically regulated transcription directs normal development, differentiation, specialized tissue/organ function, and aging, as well as a number of disease processes. Multiple lines of study focusing on epigenetic mechanisms have begun to yield information about the normal regulation of transcription and human health.

Alterations in normal gene silencing and activation result in inappropriate patterns of gene expression, adversely affecting phenotypic plasticity and resulting in a broad spectrum of tissue dysfunction and disease outcomes, including but not limited to multiple cancers, autoimmune diseases, neurodegenerative disorders, respiratory disorders, and behavioral disorders. The integration of epigenetics with genetics and environmental influences will be necessary to fully understand mechanisms of complex human diseases. Epigenetic mechanisms which are responsible for temporal and tissue specific activation or silencing of gene transcription include: DNA methylation of CpG islands in promoters and other regions of the genome; chromatin remodeling and higher order chromatin structural alterations; post-translational ATP-dependent modifications which include methylation, acetylation, ubiquination, and phosphorylation of histone tail domains; and gene silencing through RNAs thought to escort epigenomic apparatus to specific genomic loci. There are conceivably additional epigenetic mechanisms that have not yet been discovered or elucidated.

Normal development and aging are also directed by epigenetic processes. Programmed transcriptional activation and de-activation directs the phenotypic plasticity of totipotent stem cells into specialized cells and tissues. Human embryonic stem cells are derived from the inner cell mass of the blastocyst and possess an unlimited capacity for self renewal with the potential to give rise to all differentiated cells in the developing embryo. Epigenetic mechanisms are responsible for governing the programmed patterns of gene expression and silencing that direct differentiation of embryonic stem cells into the specialized cells and tissues (e.g., neurons, muscle cells, hepatic cells, etc.) that are the component of the various organs and tissues that constitute the human body. Recent data indicate that developmental nutrition in combination with environmental exposures may alter gene expression via alteration of epigenetic marks. This altered gene expression in many cases is permanent giving rise to increased susceptibility to disease later in life and even across generations.

The discovery and cataloging of epigenetic marks and profiles in normal differentiated tissues/cells and in progenitor stem cells will provide a more comprehensive understanding of differentiation, maintenance of cell-type identity and potentially transform the development of molecular/epigenetic/cell-based strategies for disease intervention. Ultimately the integration of epigenetic and genetic data will further our understanding of health and treatment of disease.

Epigenetic research has enormous potential for significantly improving health outcomes. Other long term potential benefits of the Roadmap Epigenomics program include identification/elucidation of:

Objectives

Each REMC will assemble a team of investigators to develop high resolution reference epigenomes that will serve as a resource and be utilized by the community in future studies to identify potential therapeutic targets, advance knowledge of disease mechanisms, and improve understanding of human development and aging. Each REMC must provide a synergistic research environment that allows robust interactions among research projects within a Center, and among investigators with the other centers. By supporting interrelated projects and collaborative relationships, each REMC is expected to yield results beyond those achievable were each project pursued separately and without formal interaction among the participating investigators. Furthermore, as new knowledge or technologies arise from other components of the Roadmap Epigenomics Program and outside of the program, the REMCs will be encouraged to actively pursue these opportunities. The funded centers will be required to work together collaboratively as a network to provide comprehensive maps of all known epigenetic marks across a set of mutually agreed upon reference cell types. This consortium, with input from advisors, will identify most appropriate cells, determine standardized methods for growing or acquiring the cells so that data can be compared and integrated maps can be generated.

The goals of the network of REMCs are to:

A related RFA [RFA-RM-07-011 (R01) and RFA-RM-07-012(R21)], Technology Development in Epigenetics , is being issued to support R01 and R21 projects developing transforming technologies enabling researchers to discover, monitor, and catalog epigenetic events and alterations relating to development and disease. Another related RFA, RFA-RM-07-015 (R01) and RFA RM-07-016 (R21), Discovery of Novel Epigenetic Marks in Mammalian Cells , will specifically be engaged in the discovery of new epigenetic marks. Through joint annual All Hands meetings of REMC Center Directors, the EDACC Director, and PIs from the other initiatives supported under this program, REMC investigators will be kept abreast of technological and scientific advances and maintain flexibility to utilize such advances or other new information when appropriate. An example of utilizing flexibility to adjust to new technologies or information could be the mapping of previously unknown epigenetic marks. The REMCs will be expected to incorporate knowledge, as appropriate, about new marks into the epigenetic maps that are being developed.

It is anticipated that resources generated by the REMCs will be immediately used by investigators responding to multiple solicitations developed in another component of the Roadmap Epigenomics Program, the Epigenetics of Human Health and Disease.

Research Scope

Each Center will also demonstrate capacity for and expertise in at least one of the following epigenetic marks:

While CpGs motifs and certain histone modifications, e.g., histone H3 lysine (H3K9) trimethylation are known epigenetic marks, others are not as well established, e.g., PIWI RNA and histone ubiquination. The NIH acknowledges that other novel epigenetic marks may exist and mapping of these other marks could significantly advance the epigenetic field. Applicants are encouraged to pursue mapping other epigenetic marks (in addition to at least one of the above listed well established marks) provided sufficient evidence is presented to illustrate that they are relevant epigenetic modifications and rationale is given for how inclusion of these less established epigenetic marks in the mapping effort will contribute to the ultimate goals of this initiative.

Applicants should propose and justify cell lines selected for establishing stable epigenetic marks across the genome and describe how understanding changes in/loss of these marks in these cell lines will contribute to our understanding of development and disease. Given the high value of hESC as a key reference epigenome, applicants should propose the use of at least one hESC cell line in their mapping proposal. Any hESC lines utilized must be selected and approved for research and support by federal funds. All hESC cells proposed for establishment of reference epigenomes should be well characterized, purified homogenous/clonal, pluri-potent cells, with the capacity for multiple rounds of replication without differentiation that have normal karyotypes and no indication of aneuploidy. Applicants should also propose a plan, in principle, for determining the differentiating stem cells, the human non-embryonic stem cell lines and the human cultured cells, and cells from tissue that they propose to map for epigenetic marks. Applicants must demonstrate expertise in growing, maintaining, and characterizing hESC and all other cell types that are proposed to be used as standard quality control procedures. For continuity and completeness of this cooperative large-scale mapping effort, the Steering Committee may alter the final selection of cell types to be mapped after funding and to ensure lack of redundancy, with the exception of studies designed to replicate or reproduce data for quality control purposes.

Genome Scale

If the REMCs are to achieve the programmatic objectives of creating high resolution comprehensive mapping of epigenetic marks the individual projects involved in the effort must attain a high level of production at an affordable cost. As with other genome-scale efforts, it is anticipated that increasing throughput and lowering costs will have concomitant effects on improved data quality through an overall improvement in the technological state of the art. Thus, to be competitive, applicants should address a number of issues related to production in their proposals. They must also demonstrate expertise in using state-of-the-art high throughput technologies. While each center must demonstrate the capacity and expertise to analyze at least one component of the epigenome in a comprehensive manner, centers may propose to analyze more than one.

Quality Control

Adequate process control requires the establishment of quantitative quality metrics at key points in the mapping epigenetic marks process. The quality control description should identify the procedures that will be used to monitor and assess quality at appropriate intermediate points in the process. Applicants should further describe those quality control steps included in the description and should include a background description of how those procedures have been or will be developed. Monitoring the process may be done by sample and reagent tracking, real-time reporting systems, problem detection systems, bar coding, inventory control, or other means. Quantitative metrics, minimum quality standards, and/or the thresholds for moving onto the next step should be clearly defined for individual steps in the process. Applicants should describe the process(es) by which failure rates will be determined and what are acceptable failure rates for individual steps that will still allow the production of a high-quality product. Quality control measures for the overall process should also be addressed and, if possible, evidence of the effectiveness of the proposed quality control programs should be provided. Plans for data verification and validation should be included in this description. For the purposes of this project data verification is defined as assessing the reproducibility of an experiment, while data validation is defined as confirming the biochemical authenticity of the results of an experiment by another, preferably independent, method.

Informatics

One of the critical products that will emerge from this program is an integrated database for epigenetics. Applicants must describe an informatics pipeline for processing the primary data to generate a list of the epigenetic marks found under the experimental conditions. The pipeline should include the informatics and statistical tools necessary to integrate both the primary data and any validation data obtained using different technologies. This informatics pipeline must be well documented and have procedures in place to capture metadata associated with any data transformation that is applied during analysis. An additional informatics component may consider integrative analysis of the data being generated by the different technologies among different centers. These integrative analyses should be limited to those necessary to cross-validate the conclusions from their own project s technology and should be performed in collaboration with the EDACC.

A component of the informatics pipeline should include submission of the primary data and validation data in standardized formats to the EDACC or NCBI as specified by the data release principles (see below). In addition, any metadata such as information about experimental procedures and analysis methods used to generate the data should be submitted to the EDACC. All groups will work with the EDACC to establish the exact types and formats of data and metadata that will be transferred to the EDACC. While any informatics component of the application may include a database as part of a LIMS solution to store and retrieve data, any public interface for the data will be the responsibility of NCBI.

It will be essential for each Center to have expertise in informatics to work closely with EDACC staff and between Centers to provide data generated by the REMCs for integration, analysis and formatting by the EDACC. REMCs will submit data to the consortium database (EDACC) as soon as the data have been determined to be reliable. The EDACC will then provide the data from all mapping centers to NCBI for establishment and maintenance of a publicly accessible database of comprehensive epigenetic marks across the entire genome from the cells/tissues that have been mapped. This data will also be coordinated with data generated from other NIH activities such as ENCODE and HapMap.

An informatics workgroup will be established and will consist of informatics personnel from each center, EDACC personnel and NIH program staff. The group will meet monthly by teleconference or through web-based meeting venues when needed. Each center will have an informatics liaison who will serve as the primary point of contact for the EDACC, and who will be expected to participate in the annual All Hands meeting of the Roadmap Epigenomics Program. This group will be responsible for refining and implementing standards that are established through annual (small) workshops with researchers in the international community in collaboration with EDACC.

Costs

An important factor that needs to be addressed in the REMCs is demonstrating an understanding of costs and how to track them. Without a clear understanding, it will be difficult to approach effectively the goal of lowering costs and achieving economies of scale. Applicants should propose a cost model that accommodates the proposed process. The model should incorporate a standardized cost structure, including a useful unit (e.g., per experiment or per element identified) on which to base costs for the technology or approach proposed, and a description of all of the components used in this cost model. Applicants should consider all aspects (bioinformatics, reagents, personnel, equipment) of the production process and identify large-cost items that dominate the cost model, if appropriate, e.g., microarray, primer or instrument costs. Cost analysis should be structured in such a way that reductions in the cost of applying the technology over the course of the project can be accurately monitored and projected (e.g., reduction in reagent costs, reuse of arrays, or equipment amortization). Using the proposed model, applicants should present a description of costs at the start of the project and then describe anticipated cost reductions. All cost analyses should include an explicit item for F &A Costs, and then present the final costs in terms of Total Costs.

Methodological Improvements

Centers are expected to keep up with state-of-the-art technology improvements. Incremental improvements will play an important role in increasing the efficiency and decreasing the cost of mapping epigenetic marks. The NIH encourages applicants to include plans for such activities in their proposals. Plans for advancing state-of-the-art methodological improvements should be described and the cost of the proposed improvements should be justified in terms of reducing production costs.

Ancillary Studies

Each Center may choose to allocate up to 5 percent of direct costs per year for ancillary studies to develop limited data on functional aspects of epigenetic regulation of gene activity. Functional studies validating the activation/silencing of genes by epigenetic marks using gene expression approaches are examples of what may be proposed.

Additionally, a related Roadmap Epigenomics Program RFA will be released in FY2008 entitled, "Epigenetics of Human Health and Disease" (EHHD). Center grantees will be encouraged to pursue and develop collaborative arrangements with project investigators funded through this RFA, which will focus on the identification of epigenetic marks in selected cell lines and tissues relevant to conditions of human health and disease. Mapping Center investigators will be eligible to receive supplemental funds to support this work. In the event that collaborations of this sort ensue, appropriate budget considerations should be described in EHHD applications.

REMC Components

Each REMC must have an identifiable organizational unit within a university, medical school, non-profit research institute, commercial entity or a consortium of cooperating institutions with a university affiliation. Partnerships may consist of investigators at a single institution or at multiple sites and may include collaborative arrangements as appropriate with organizations, domestic or foreign, public or private (such as universities, colleges, hospitals, laboratories, for-profit and non-profit, units of State and local governments, and eligible agencies of the Federal government), as necessary to conduct portions of the research. Teams that are geographically distributed must be well-justified and steps to minimize the effects of geography should be clearly stated. The REMC Center Director and a majority of the proposed research projects must be based at a domestic institution. Any foreign REMC components are subject to additional considerations and review criteria, as detailed in Section IV.2. Application and Submission Information, Content and Form of Application Submission .

The REMC U01 cooperative agreement mechanism fosters collaborative and integrated basic, clinical and public health research and provides funds to support personnel, equipment, supplies and services for research aims, a management plan, research plan and, if needed, facility cores.

  1. The research aims (as approved by the Steering Committee, see Section VI.2.A.3) provide the intellectual and scientific direction for the program. The application must propose experimental approaches, design protocols, set project milestones, and propose quality control measures both for the cells and the epigenetic marks.
  2. The Director for the REMC is the designated leader and provides the leadership for the administrative, scientific and programmatic direction. It is expected that the director will commit a minimum of 20% effort to the scientific research and administrative management of the Center.
  3. A required Management Plan oversees the organizational, budgeting and reporting aspects of the REMC, provides the environment and infrastructure to promote cross-discipline interactions among all projects and facilitates the use of the REMC. The Management Plan must provide a framework to support participation of the Center Director and Project leaders in regular joint meetings with investigators from other REMCs and in the development of collaborative inter-REMC activities.
  4. Service/Facility Cores are principally designed as a service or resource component to the research projects within the Center. Core facilities may include biostatistics and/or bioinformatics support, and basic molecular/cellular capabilities.

Technical Assistance Workshop

NIH will conduct a Technical Assistance Workshop and videoconference in Research Triangle Park, NC, on December 7, 2007. This will allow potential applicants to discuss and clarify any issues related to this RFA with NIH staff. Detailed information about the workshop (e.g., time, location, videoconference information, etc.) will be available on the Roadmap Epigenomics Program website at http://nihroadmap.nih.gov/epigenomics, and will also be posted to the NIH Guide. Potential applicants will be able to ask questions of program staff involved in managing the program, both in-person and by teleconference during the workshop, but are encouraged to submit their questions or comments in advance of the meeting by sending an email to [email protected].

Evaluation

As part of good program management, NIH assesses the implementation and effectiveness of its programs using evaluation tools and techniques. Grantees may be asked to provide information for program evaluation purposes, both locally and at the national level. Such information may be used in evaluations of the REMCs as well as the Mid-Course review of the entire Roadmap Epigenomics Program. Note that the Roadmap Epigenomics Program Mid-Course evaluation will be directed by the Epigenomics Working Group (EWG). Applicants are advised to review the additional details on evaluation that are provided in Section IV.6. Application and Submission Information, Other Submission Requirements.

Summary of Elements

In summary, applicants for awards under this RFA:

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

Section II. Award Information

1. Mechanism(s) of Support

This funding opportunity will use the U01 Research Project Cooperative Agreement grant mechanism.

In the cooperative agreement mechanism, the Center Director 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 Center Director, as described under the Section VI.2.A Award Administration Information, Administrative and National Policy Requirements, "Cooperative Agreement Terms and Conditions of Award".

The PI will be solely responsible for planning, directing, and executing the proposed project.

This funding opportunity uses the just-in-time budget concepts. It also uses the non-modular budget format described in the PHS 398 application instructions (see http://grants.nih.gov/grants/funding/phs398/phs398.html). A detailed categorical budget for the "Initial Budget Period" and the "Entire Proposed Period of Support" is to be submitted with the application.

2. Funds Available

Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the Institutes and Centers (ICs) 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.

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made in response to this FOA.

Facilities and Administrative (F&A) costs requested by consortium participants are not included in the direct cost limitation. See NOT-OD-05-004.

Section III. Eligibility Information

1. Eligible Applicants

1.A. Eligible Institutions

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

Domestic applicants are encouraged to form multi-institute consortia to accomplish the stated goals. Applications from foreign institutions are not allowed. However, domestic institutions may include a foreign component, provided the majority of the research projects are based at the domestic institution.

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 support.

More than one CD/PI, or multiple CDs/PIs, may be designated on the application for projects that require a team science approach that clearly does not fit the single-CD/PI model. Additional information on the implementation plans and policies and procedures to formally allow more than one CD/PI on individual research projects is available at http://grants.nih.gov/grants/multi_pi. All CDs/PIs must be registered in the NIH eRA Commons prior to the submission of the application (see http://era.nih.gov/ElectronicReceipt/preparing.htm for instructions).

The decision of whether to apply for a single CD/PI or multiple CD/PI grant is the responsibility of the investigators and applicant organizations and should be determined by the scientific goals of the project. Applications for multiple CD/PI grants will require additional information, as outlined in the instructions below. The NIH review criteria for approach, investigators, and environment have been modified to accommodate applications involving either a single CD/PI or multiple CDs/PIs. When considering multiple CDs/PIs, please be aware that the structure and governance of the CD/PI leadership team as well as the knowledge, skills and experience of the individual CD/PIs will be factored into the assessment of the overall scientific merit of the application. Multiple CDs/PIs on a project share the authority and responsibility for leading and directing the project, intellectually and logistically. Each CD/PI is responsible and accountable to the grantee organization, or, as appropriate, to a collaborating organization, for the proper conduct of the project or program, including the submission of required reports. For further information on multiple CDs/PIs, please see http://grants.nih.gov/grants/multi_pi.

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 may submit more than one application, provided they are scientifically distinct.

Milestones

All applications must include a specific section labeled Milestones for each year. The milestones should be well-described, quantitative, and justified and not just simply a restatement of the specific aims. The milestone should offer a timeline and a pathway for the flow, integration, and analysis of data. These milestones will be used to judge the success of the Center. It is expected that the milestones will be adjusted annually at the award anniversary dates to reflect new recommendations of the Steering Committee.

Meetings

The Center Director or Directors in the case of a multiple CD/PI-Center will be expected to attend meetings two times per year and participate in monthly calls to discuss research progress with other members of the Steering Committee. The two meetings per year will be a bi-annual Steering Committee meeting, with an All Hands Roadmap Epigenomics Program meeting co-occurring with every other Steering Committee meeting. Funds to support travel of the key investigators to attend in-person meetings should be included in the application budget.

See Section IV.6. Application and Submission Information, Other Submission Requirements.

Section IV. Application and Submission Information

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.

Guidance for Applicants Submitting a U01 REMC Grant

Applicants should use the following guidance, in addition to the instructions accompanying the PHS 398 form.

Section I. This section includes PHS 398 Form Pages 1-3, PHS 398 Form Page 4 - Detailed Composite Budget for the First 12-month Period Description and Form Page 5 Composite Budget for All Years, all Aims as well as the corresponding budgets for each individual aim and component of the management plan supported by the REMC application. Biographical Sketches should be provided for all KEY investigators using the PHS 398 Biographical Sketch Format Page. List the Center Director(s) first followed by all other key personnel in alphabetical order. Use duplicate copies of the Biographical Sketch Format page for each investigator. Include only one copy of each biosketch in the application. Lastly, Section I should include Institutional Environment and Resources using the PHS 398 Resources Format Page. Include a brief description of the environment where the overall program and other activities will be conducted. If more than one campus or location will be involved, briefly describe each setting. If unique resources are available, briefly describe these and their relevance to the proposed program. Section II.

Section III - V. These sections contain the research plans of the individual research aims and management plan.

General Instructions for all Aims

For the title page of individual aims use the PHS 398 Continuation Page and clearly denote the aim number, the title of the aim, and the aim leader. The title must not exceed 56 characters/spaces. DO NOT provide a face page (i.e., PHS 398 Form Page 1) for individual aims.

The "Description" of the aim should be prepared on a duplicate copy of PHS 398 Form Page 2. All performance sites and key personnel on the aim should be identified.

The name of the Center Director of the REMC grant application is placed in the upper right corner of each page, not the name of the aim leader. Also note: individual aims and cores must not exceed the 25-page limitation for items a - d of the Research Plan. The total number of pages to describe all aims and of the research plan must not exceed 35 pages (follow PHS 398 instructions).

Subsequent pages (following the Description, Performance, and Key Personnel, Form Page 2) should use Continuation Pages and follow PHS 398 Instructions. If collaborative or consortium arrangements are included in the application, follow PHS 398 Instructions. Discussion should be included as to how the collaborative arrangements will be of value in achieving the specific objectives of the aim/core.

The following information should NOT be included in the individual aims. They should be included only in Section I of the application. "Face Page"(Form Page 1); "Research Grants Table of Contents" (Form Page 3); "Detailed Budget for Initial Cost Period" (Form Page 4); "Budget for Entire Proposed Period of Support" (Form Page 5); "Biographical Sketch Format Page"

Include Letters of Commitment and collaborative arrangements/consultants (Research Plan item h ) that are identified in the application.

Include "Resources Format Page" within the individual Aims sections. Include at the end of the Research Plan (a-i).

Applicants should carefully read and adhere to the PHS 398 instructions concerning children, gender and minority inclusion in human study populations.

Section III Individual Research Aims

Research aims should be listed using the following as an example:

Aim 1. Cell culture expertise and capability (including justification of the selection of specific cells and cell lines proposed for mapping)

Aim 2. DNA Methylation (if applicable)

Aim 3. Histone modifications (if applicable)

Aim 4. Informatics (if applicable)

The application should also contain a section describing how the data will be validated and verified. Each application must demonstrate informatics expertise and propose interactions with EDACC (RFA-RM-07-014) for purposes of data sharing.

Follow the instructions in the PHS 398 for the Research Plan (a-i) for describing each research aim. Each aim should clearly state its overall objective and explain its relevance to the central theme of the REMC program. In addition, an explanation should be included describing how the aim relates to and both complements and enhances the other research aims of the program. Specify the overall biomedical significance of the work proposed.

The research plan (a-d; 35 page limit for all projects total, not per project) includes:

Specific Aims List the specific aims of the research project and indicate the priority of each aim in the overall research plan.

Background and Significance Review the most significant previous work and describe the current status of research in this field and document with complete references.

Preliminary Studies Refer to PHS 398 Instructions for Preliminary Studies

Research Design and Methods - Give details of the research plan, including a description of the experiment or other work proposed; present the methods and techniques to be used; note the limitations, if any, of the procedures proposed. Describe the experiments in the sequence in which they would be conducted. (It is important to convey to the reader that the proposed effort would require the time requested for the project period.)

The instructions in the PHS 398 form should be used to complete sections e-i for the individual research projects.

Section IV Management Plan

Follow the instructions in the PHS 398 Research Plan (a-i) as is appropriate for describing the Management Plan.

Within the Management Plan, the specific administrative and organizational structure that is needed to support the research and the synergies enabled by the Center needed to be clearly articulated. Thus a well thought out and carefully described organizational structure will be required.

A narrative description should be provided that includes the planning and coordination of research activities; the oversight of fiscal and resource management; and the maintenance of ongoing communication with the Epigenomics Working Group. Indicate who will be responsible for each of these activities. Describe within the management plan how the center will coordinate internal meetings of their REMC investigators. The applicant should provide travel funds sufficient for attendance of the Center Director(s) and Project and Core leaders at two annual meetings, including a one-day Steering Committee meeting to address business issues of the mapping centers and an All Hands meeting that will bring investigators together from all of the Roadmap Epigenomics Programs. The Management Plan described here should not be confused with the Leadership Plan described at: http://grants.nih.gov/grants/multi_pi, if the application is submitted with multiple PIs. Multiple CD/PI Leadership Plan: For applications designating multiple CD/PIs, a new section of the research plan, entitled Multiple CD/PI Leadership Plan (section 14 of the Research Plan Component in the SF424 R&R or Section I of the Research Plan in the PHS 398), must be included. A rationale for choosing a multiple CD/PI approach should be described. The governance and organizational structure of the leadership team and the research project should be described, including communication plans, process for making decisions on scientific direction, and procedures for resolving conflicts. The roles and administrative, technical, and scientific responsibilities for the project or program should be delineated for the CD/PIs and other collaborators. If budget allocation is planned, the distribution of resources to specific components of the project or the individual CD/PIs must be delineated in the Leadership Plan.

Foreign Organizations

NIH policies concerning grants to foreign (non-U.S.) organizations can be found in the NIH Grants Policy Statement at: http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part12.htm#_Toc54600260.

Applications from foreign organizations must:

Proposed research should provide special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions in other countries that are not readily available in the United States or that augment existing U.S. resources.

Applications From Federal Agencies

The requests from federal agencies, including the NIH intramural program, will not include any salary and related fringe benefits for career, career conditional or other federal employees (civilian or uniformed service) with permanent appointments under existing position ceilings or any costs related to administrative or facilities support (equivalent to Facilities and Administrative costs).

In general, the budget requests will be limited to the incremental costs required for carrying out the proposed work. These costs may include salary for staff to be specifically hired under a temporary appointment for the project, consultant costs, equipment, supplies, travel, and other items typically listed under Other Expenses. While support for extramural collaborators may be requested in a separate grant application, funds can be requested for services by an external investigator or contractor as a subcontract/consortium including the applicable indirect (F&A costs) of the contractor/collaborating institution.

Justification must be provided for all requested support and for the Federal employees who will be committed to the project although no funds are requested in the application.

Applicants should indicate the number of person-months devoted to the project, even if no funds are requested for salary and fringe benefits.

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

Letter of Intent Receipt Date: February 7, 2008
Application Receipt Date: March 7, 2008
Peer Review Date: May/June 2008
Council Review Date: August 2008
Earliest Anticipated Start Date: September 30, 2008

3.A.1. Letter of Intent

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

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:

Frederick L. Tyson, Ph.D.
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
79 TW Alexander Drive
Building 4401, 3rd Floor, Room 3455
Research Triangle Park, NC, 27709
Telephone: (919) 541-0176
FAX: (919) 541-4606
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 five 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).

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 Epigenomics Working Group and incomplete and non-responsive applications will not be reviewed.

If the application is not responsive to the RFA, NIH staff may contact the applicant to determine whether to return the application to the applicant or submit it for review in competition with unsolicited applications at the next appropriate NIH review cycle.

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.

Information on the status of an application should be checked by the Center Director(s) in the eRA Commons at: https://commons.era.nih.gov/commons/.

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

Applicants must budget funds for travel of the Center Director(s) and all Project and Core leaders to attend two yearly meetings. One meeting will be held in Research Triangle Park, NC. The site for the other meeting will be determined jointly as described in the Cooperative Agreement Section.

Milestones and Timeline

Each application must include a timeline as well as PI determined milestones for each proposed year of funding. These milestones should be concrete and quantitative project specific criteria. In all cases, prior to funding the application program staff will negotiate the milestones with the applicant, incorporating recommendations from the review panel. The negotiated milestones will become a condition of the award, including appropriate language to recognize that the project includes research whose outcomes are unpredictable.

Applicants must plan to submit progress reports twice per year-once at the time of the non-competing continuation and once at a time to be determined by program staff. Program staff will use information from reports, site visits, etc. to evaluate each grantees progress and the success of the overall program; this information will be used to determine if funding levels should be increased or decreased for future years, for each grant and for the program. Progress will also be evaluated with the assistance of external advisors at the biannual meeting and at the mid-course review of the entire Roadmap Epigenomics Program (see Management and Evaluation below).

To accelerate progress in the field of epigenomics, grantees will be expected to participate actively and openly in two Steering Committee meetings and one All Hands meeting per year. Substantial information sharing is critical to the program, so how an applicant plans to achieve this would be considered as a term and condition of the award; failure to openly share information will be considered in continued funding consistent with achieving the goals of the program.. It is understood that some information developed under the grants will be proprietary and cannot be shared immediately without damaging the commercialization potential of the technology. Applicants should describe their plans for participating in the grantee meetings and for managing the intellectual property concerns in the context of those meetings and other opportunities for information sharing. Other investigators in the field (i.e., not supported under this program) may be invited to participate in these workshops, but their agreement to share information substantially will be a prerequisite to their participation. Applicants should request travel funds in their budgets for the Center Director and two additional lead investigators to attend the annual meeting, which may be closed to non-roadmap Epigenomics Program investigators.

Management and Evaluation

The project management team will evaluate the grants through annual progress reports and through annual All Hands Roadmap Epigenomics Program meetings starting in year 1 of the award. PIs of funded projects will be required to attend biannual meetings for project evaluation and also All Hands meetings for the Roadmap Epigenomics Program to facilitate technology transfer to the other components of the Roadmap Epigenomics Program. The annual All Hands meetings will include program staff, external advisors, and PIs from all funded awards in the Roadmap Epigenomics Program.

Appendix:

NIH has published new limitations on grant application appendix materials to encourage applications to be as concise as possible while containing the information needed for expert scientific review. See http://grants.nih.gov/grants/guide/notice-files/NOT-OD-07-018.html.

Appendix material is not a part of the application and should not be used to circumvent the page limitations of the Research Plan . See PHS 398 Instructions for list of appropriate Appendix Material. . Appendix materials should be collated by Research Aim, and presented in the same order that they appear in the application. Do not staple or bind Appendix materials. The Appendix material should follow all copies of the application.

Plan for Sharing Research Data

Applicants who are planning to share data may wish to describe briefly the expected schedule for data sharing, the format of the final dataset, the documentation to be provided, whether or not any analytic tools also will be provided, whether or not a data-sharing agreement will be required and, if so, a brief description of such an agreement (including the criteria for deciding who can receive the data and whether or not any conditions will be placed on their use), and the mode of data sharing (e.g., under their own auspices by mailing a disk or posting data on their institutional or personal website, through a data archive or enclave). The precise content of data-sharing plans will vary, depending on the data being collected and how the investigator is planning to share the data. Investigators choosing to share under their own auspices may wish to enter into a data-sharing agreement. References to data sharing may also be appropriate in other sections of the application.

All applicants are expected to include a plan for sharing research data in their application. The 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 final research data will be shared, or explain why data sharing is not possible.

The reasonableness of the data sharing plan or the rationale for not sharing research data will be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or the priority score.

Data Release Structure

One of the goals of the program is to facilitate and enhance further research through the rapid dissemination of data which will ultimately benefit the public health. The Roadmap Epigenomics Program is committed to the principle of rapid data release to the scientific community to achieve this program goal. This principle was initially implemented during the Human Genome Project andhas been applied to other NIH Initiatives since it is recognized as leading to one of the most effective ways of promoting the use of the genome sequence data to advance scientific knowledge. At a meeting in Ft. Lauderdale, FL that was co-sponsored by the Wellcome Trust and NHGRI in January 2003, the concept of rapid data release by genomic sequence data producers was reaffirmed, and the attendees strongly recommended applying the practice to other types of data produced by community resource projects . The attendees recognized, however, that different issues, particularly with respect to data validation, would be involved in the development of appropriate release practices for different types of data. Since they also recognized that sustaining the practice of rapid, prepublication data release by community resources requires that the interests of all involved - including the data producers, data users, and funding agencies - be addressed, they emphasized the need to develop a tripartite system of responsibility. The meeting report from the Ft. Lauderdale meeting can be found on the Wellcome Trust website at http://www.wellcome.ac.uk/assets/wtd003207.pdf.

The NIH has identified the Roadmap Epigenomics Program as a community resource project. It is expected that the consortium governing the project will establish a common data release policy and that all participants will agree to abide by that policy. Based on the Ft. Lauderdale principles, the NIH deems that the following data release policy would be appropriate:

1. Consortium participants would submit data to the EDACC as soon as the data have been determined to be verified (meaning that these are reliable data with high confidence). The timing of data submission may differ for different types of data. The Roadmap Epigenomics Program Steering Committee would establish appropriate data release standards as well as a timeline for each data type.

2. Consortium participants would submit data to the EDACC in the specified format.

3. Upon submission, all data would be made freely available to the entire research community in a form that would allow for redisplay and reanalysis, so that maximal utility of this community resource could be achieved. It is NIH’s expectation that users of these data would respect the legitimate interests of the producers to analyze and publish their results by treating the data as unpublished information, until otherwise indicated. As with any unpublished data, it would be expected that users would provide proper citation of the source of the data. The best interests of all are served when all act responsibly to promote the highest standards of respect for scientific work. In some cases, this might best be done by discussion or coordination with the resource producers at the REMC and EDACC.

4. The individual investigators within the consortium may publish the results of their own work that have been submitted to the EDACC and NCBI database in the course of that work. Neither these individual publications nor any consortium publications should hold up the other's publications.

5. The consortium intends to publish global analyses of the results of the REMC initiative. At the same time, the consortium recognizes that it has the responsibility to do so in a timely manner. While it is not possible, at present, to predict an appropriate time for any such publication(s), the consortium, with guidance from researchers in the international community, will establish a timeframe once the project has been launched and there is a better understanding of the timeframe and scope of the project.

6. Publicly funded consortium participants would fully disclose algorithms, software source code, and experimental methods to the other members of the consortium for purposes of scientific evaluation and will be strongly encouraged to make them available to the broad research community.

Applicants should address data release in their applications either by agreeing to abide by the principles of the proposed Roadmap Epigenomics Program data release policy stated above or by proposing alternative approaches to make the data available for the consortium to consider. Ultimately, the Roadmap Epigenomics Program will develop a common data release policy for all participants.

After completion of the initial review, NIH program staff will be responsible for any additional administrative review of the plan for sharing data. The adequacy of the data sharing plan will be considered by program staff of the funding organization when making recommendations about funding applications. The final accepted data sharing plan will become a term and condition of the award of the cooperative agreement. The effectiveness of the data sharing will be evaluated as part of the administrative review of each non-competing Grant Progress Report (PHS 2590). See Section VI.3. Award Administration Information, Reporting.

Sharing Research Resources

NIH policy expects that grant 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. Award Administration Information, Reporting.

As the Roadmap Epigenomics Program is a community resource program, NIH expects that not only data, but also resources generated during the course of the program should be made rapidly available to the research community and that sharing plans should follow the same principles and spirit as the proposed rapid data release policy. The applicant should provide specific plan for resource sharing and distribution in the application. The reasonableness of any data sharing plans will be assessed by the reviewers. However, reviewers will not factor the proposed resources sharing plan into the determination of scientific merit or the priority score. The adequacy of the resources sharing plan will be considered by the funding organization when making recommendations about funding applications. The presence of a resources sharing plan will be part of the terms and conditions of the award. 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. Award Administration Information, Reporting.

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process.

The following will be considered in making funding decisions:

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 the Center for Scientific Review (CSR) in accordance with the review criteria stated below.

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

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? Does the application address the goals and objectives outlined in the RFA?

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? Do(es) the applicant(s) acknowledge potential problem areas and consider alternative tactics? For applications designating multiple CDs/PIs, is the leadership approach, including the designated roles and responsibilities, governance and organizational structure consistent with and justified by the aims of the project and the expertise of each of the CD/PIs?

Does the data pipeline match the intentions of the RFA?

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? Does the project efficiently use available tools or develop new methods to accomplish the goals of the REMC? Is the proposed analysis plan flexible for innovative approaches?

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 Center Director and other researchers? Does the investigative team bring complementary and integrated expertise to the project (if applicable)? Is there evidence that expertise in the localization of epigenetic marks and capacity to transform the data into formats usable by the EDACC and NCBI for ultimate public use? Do the investigators have appropriate expertise with the cell lines proposed for use?

If multiple CDs/PIs are proposed is there a complete Leadership Plan (Section I) in the application? The quality of the Leadership Plan will be considered by peer reviewers as part of the assessment of scientific and technical merit. Is a governance and organizational structure of the leadership team and the research project described, including communication plans, process for making decisions on scientific direction, and procedures for resolving conflicts? Are the roles and administrative, technical, and scientific responsibilities for the project or program delineated for the CD/PIs and other collaborators? If budget allocation is planned, is the distribution of resources to specific components of the project or the individual CD/PIs delineated in the Leadership Plan? Is the budget allocation appropriate?

Environment: Do(es) the scientific environment(s) 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(s), 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 continue to 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 and Period of Support: The reasonableness of the proposed budget and the appropriateness of the requested period of support in relation to the proposed research may be assessed by the reviewers. 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. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or the priority score. 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. http://grants.nih.gov/grants/policy/data_sharing.

2.D. Sharing Research Resources

NIH policy expects that grant 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. The final version of the data and resource sharing plans will become a term and 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. Award Administration Information, Reporting.

3. Anticipated Announcement and Award Dates

Not applicable.

Section VI. Award Administration Information

1. Award Notices

After the peer review of the application is completed, the Center Director(s) will be able to access their Summary Statement (written critique) via the NIH eRA Commons.

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 12 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 Section IV.5. Application and Submission Information, Funding Restrictions.

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. 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 CD(s)/PI(s) 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 NIH U01, 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 below.

Through various NIH mechanisms, the Roadmap Epigenomics Program is planning to develop 8 distinct activities: (1) An annual workshop with researchers in the international community who are engaged in epigenetics research, (2) Monoclonal Antibodies for Epigenetic Research, (3) NCBI Public Interface for Epigenomic Data, (4) Reference Epigenome Mapping Centers (REMCs), (5) Discovery of Novel Epigenetic Marks in Mammalian Cells (DNEM), (6) Technology Development in Epigenetics (TDE), (7) Epigenomics Data Analysis and Coordination Center (EDACC), and (8) Epigenetics of Human Health and Disease (EHHD).

The Steering Committee (SC) for the REMCs and EDACC will include the: Center Director(s) from each REMC; EDACC PI; an NCBI representative; a Chairperson selected by the Government; and ad hoc representatives from other Roadmap Epigenomics Program initiatives as needed.

The REMC/EDACC SC will convene via monthly conference calls, and twice a year in person. Each individual SC will solicit/accept ad hoc participation during their regular scheduled SC calls/meetings from the other SCs as deemed appropriate. Additional interactions that serve all components of the RMEP will occur at an annual All Hands scientific meeting of the entire body of RMEP investigators and NIH staff. This meeting will be held on the NIH Campus during the odd years (year 1, 3, 5, etc) and at satellite locations in alternate years (year 2, 4, etc). The alternate locations will be chosen by identifying existing larger scientific meetings and determining which represent the best scientific fit. In order for PIs and Center Directors to attend these meetings, PIs and Center Directors need to request appropriate travel budgets in their proposal submissions. The Terms and Conditions described below are specific for this RFA (RM-07-013), but have been coordinated and made consistent with those described in the other FOAs.

2.A.1. Center Director(s)/Principal Investigator(s) Rights and Responsibilities

The Center Director(s) will have the primary responsibility for defining the details for the project within the guidelines of RFA-RM-07-013 and for performing the scientific activities. The Center Director(s) will agree to accept close coordination, cooperation, and participation of NIH staff in those aspects of scientific and technical management of the project as described under "NIH Program Staff Responsibilities".

The Center Director(s) of an REMC will be expected to:

2.A.2. NIH Responsibilities

An NIH Project Scientist from one or more of the participating NIH ICs will be assigned to each REMC and will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below.

The Project Scientists are NIH extramural staff who will have substantial scientific and programmatic involvement during the conduct of this activity through technical assistance, advice, and coordination. However, the role of the Project Scientists 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 Steering Committee and that the NIH Project Scientists will be given the opportunity to offer input to this process. The Project Scientists will have the following substantial involvement:

Additionally, an agency program official or IC Program Director from the lead NIH IC of the initiative will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.

2.A.3. Collaborative Responsibilities

Management and Governance

This initiative is part of the NIH Roadmap and all NIH Institutes and Centers participate in Roadmap initiatives. The Roadmap Epigenomics Program Implementation Working Group of NIH staff is responsible for implementing, monitoring and evaluating the Roadmap Epigenomics Program as a whole. All Roadmap Implementation Working Groups report to the Roadmap Implementation Steering Committee, consisting of NIH Institute and Center Director(s).

All involved investigators of the Roadmap Epigenomics Program will meet two times a year in order to share information and assess progress. The Steering Committee will serve as the main coordinating body of the Consortium. The Steering Committee members will meet annually with researchers in the international community who are engaged in epigenetics research to harmonize NIH-funded epigenomics efforts with private and international efforts and to avoid overlap and maximize synergy. The Steering Committee may add additional members. Other government staff may attend the Steering Committee meetings if their expertise is required for specific discussions.

The Steering Committee will be responsible for coordinating the activities being conducted by the Consortium. To address particular issues, the Steering Committee may establish working groups as needed.

Consortium Steering Committee

The Consortium Steering Committee will consist of Center Director(s), the Center Director of the EDACC and NIH Staff and the chairperson will be selected by the Government and serve one-year terms. The Steering Committee will serve as the main governing board of the Consortium established under this RFA. The committee will meet monthly by teleconference and bi-annually in person (once in conjunction with an All Hands meeting of the Roadmap Epigenomics Program). The Steering Committee will be responsible for making scientific and administrative recommendations to the NIH Epigenomics Project Team for this project as well as the Roadmap Epigenomics Program as a whole.

This committee is expected to meet annually with researchers in the international community who are engaged in epigenetics research. It is anticipated that additional coordination mechanisms will be set up with other U.S. and international groups that may join this effort. Other government staff may attend the Steering Committee meetings, if their expertise is required for specific discussions.

The Steering Committee will be responsible for coordinating the activities being conducted by the Consortium. To address particular issues, the Steering Committee may establish working groups as needed, which may include representatives from the Consortium, the Epigenomics Working Group, and the NIH and possibly other experts. Such groups might include ones to: 1) develop a list of common reagents needed for the pilot project; 2) address data management issues; 3) analyze the project data; 4) develop quality standards and methods to assess data quality; and 5) handle communication issues and develop principles for reporting findings. Each full member will have one vote. Awardee members of the Steering Committee will be required to accept and implement policies approved by the Steering Committee.

External Science Panel

An External Scientific Panel (ESP) will be established by the Epigenomics Working Group (EWG) to evaluate the progress of the Consortium. The ESP will provide feedback to the Epigenomics Working Group about the progress and scientific direction of all components of the program. The ESP will likely be composed of six to eight senior scientists with relevant expertise, although the membership may be altered permanently or on an ad hoc basis as needed. Nominations in the ESP will be solicited from the Steering Committee, REMC Project Team and EWG members. Final membership and leadership (Chair-person) selection will be made by the Epigenomics Working Group.

The ESP will meet approximately twice a year; some meetings may be conducted by telephone conference. At least once a year, there will be a joint meeting with the Epigenomics Working Group to allow the members of the both the ESP and the Steering Committee to interact directly with each other. Twice a year the ESP will make recommendations regarding progress of the Consortium and present advice to the Epigenomics Working Group about changes, if any that may be necessary.

The ESP may be asked to provide informal reviews of the REMCs in years 1, 2, and 4, and more formalized evaluations of the Centers in years 3 and 5. Evaluation questions will address process, output and outcome goals such as, but not limited to, the following:

Process Questions (focused on the operational components of the interactions)

Output Questions (focused on tangible products of the REMCs)

Outcome questions (focused on the long term goals of the REMCs)

2.A.4. 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. 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.

3. Reporting

Periodically, throughout the life of the program, awardees may be required to provide data that can be used to evaluate program progress, such as (but not limited to) the following:

Such information may be used in evaluations of the REMCs as well as the Mid-Course review of the entire Roadmap Epigenomics Program.

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.

Section VII. Agency Contacts

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 Contact(s):

Frederick L. Tyson, Ph.D.
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
79 TW Alexander Drive
Building 4401, 3rd Floor, MD EC-21
Research Triangle Park, NC, 27709
Telephone: (919) 541-0176
FAX: (919) 541-4606
Email: [email protected]

Christine M. Colvis, Ph.D.
Genetics & Molecular Neurobiology Research Branch
National Institute on Drug Abuse
6001 Executive Blvd, Room 4282, MSC 9555
Bethesda, MD 20892-9555
Telephone: (301) 435-1323
FAX: (301) 594-6043
Email: [email protected]

2. Peer Review Contact(s):

Noni Byrnes, Ph.D.
Center for Scientific Review, Room 5130
Division of Molecular and Cellular Mechanisms
6701 Rockledge Dr
Bethesda, MD 20892-7840
Telephone: (301) 435-1023
Email: [email protected]

3. Financial or Grants Management Contact(s):

Michael Loewe, Ph.D.
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
79 TW Alexander Drive
Building 4401, 3rd Floor, MD EC-22
Research Triangle Park, NC 27709
Telephone: (919) 541-7823
FAX: (919) 541-2860
Email: [email protected]

Section VIII. Other Information

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 (45 CFR 46) 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. Beginning October 1, 2004, all investigators submitting an NIH application or contract proposal 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.

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. For publications listed in the appendix and/or Progress report, Internet addresses (URLs) or PubMed Central (PMC) submission identification numbers must be used for publicly accessible on-line journal articles. Publicly accessible on-line journal articles or PMC articles/manuscripts accepted for publication that are directly relevant to the project may be included only as URLs or PMC submission identification numbers accompanying the full reference in either the Bibliography & References Cited section, the Progress Report Publication List section, or the Biographical Sketch section of the NIH grant application. A URL or PMC submission identification number citation may be repeated in each of these sections as appropriate. There is no limit to the number of URLs or PMC submission identification numbers that can be cited.

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 FOA 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 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 Part 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 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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