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

Title: Genome-Wide Studies in Biorepositories with Electronic Medical Record Data (U01)

Announcement Type
New

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


Request For Applications (RFA) Number: RFA-HG-07-005

Catalog of Federal Domestic Assistance Number(s)
93.172

Key Dates
Release Date: March 23, 2007
Letters of Intent Receipt Date(s): April 17, 2007
Application Receipt Date(s): May 17, 2007
Peer Review Date(s): July/August 2007
Council Review Date(s): August 2007
Earliest Anticipated Start Date(s): September 30, 2007
Additional Information To Be Available Date (Url Activation Date): N/A
Expiration Date: May 18, 2007

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
1. Principal Investigator Rights and Responsibilities
2. NIH Responsibilities
3. Collaborative Responsibilities
4. Arbitration Process
3. Reporting

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

Section VIII. Other Information - Required Federal Citations

Part II - Full Text of Announcement

Section I. Funding Opportunity Description

1. Research Objectives

Nature of the Research Opportunity

The purpose of this funding opportunity is to provide support for investigative groups affiliated with existing biorepositories to develop necessary methods and procedures for, and then to perform, if feasible, genome-wide studies in participants with phenotypes and environmental exposures derived from electronic medical records (EMR). It includes support for sharing previously collected DNA samples with NHGRI-designated laboratories for performance of state-of-the-art genomic technologies such as genome-wide association (GWA) genotyping subject to any applicable approvals and assurances. To ensure that the maximal scientific benefit is derived from this significant public investment and is consistent with the goals of proposed NIH policy on data sharing in genome-wide association studies (GWAS) (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-06-094.html), this funding opportunity aims to support rapid sharing of the resulting data with the broad scientific community for research use, through community resource databases such as dbGaP (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gap). Investigative groups funded by this RFA may also request support to analyze their Project Datasets for associations with genotyping data provided by NHGRI-designated genomic laboratories. No funding should be requested for genotyping or other genomic technologies, as the costs for these assays, if awarded, will be borne separately by NHGRI.

For the purposes of this RFA, a biorepository is defined as a resource that collects and stores biospecimens from which DNA sufficient for genome-wide studies can be isolated on individuals, and which are (or can be) linked to electronic personal health information on these individuals. The biospecimens may have been collected in the course of clinical care or as part of a research resource. Electronic medical records are defined as computerized data obtained in the course of clinical care that can be electronically accessed, manipulated, shared, and analyzed, with appropriate consent and participant protections, for research purposes. Affiliation with a biorepository means documented ongoing or future access to data and samples in a highly-effective collaborative relationship, and ability to commit the biorepository data and samples, in consultation with appropriate decision-makers, to participate in this RFA. Project Datasets are individual-level phenotype and exposure data proposed for analyzing associations with genome-wide data.

The goal of this funding opportunity is to develop and apply approaches for using U.S. biorepositories with EMR systems for large-scale, high-throughput genomic research. Specifically, the aims are to determine, for each participating biorepository: 1) completeness, validity, and reliability of available phenotypic and exposure data for use in genome-wide studies; 2) adequacy of existing consent for high-throughput genome-wide technologies such as GWA genotyping or sequencing, and for sharing data; 3) needs for additional consent and/or consultation with biorepository participants, investigators, and other relevant groups; 4) best practices for IRB interactions, participant consent, and results reporting, and for collecting, formatting, documenting, and sharing data; 5) representativeness and diversity of individuals participating in the biorepository in relation to the source population from which they are drawn; and 6) associations of genome-wide data with specific EMR-derived phenotype(s).

Background

Biorepositories or biobanks, in which biospecimens linked to personal health information are collected and stored on large numbers of persons, are increasingly being established for genomic research. Many US biorepositories are being developed in hospitals and clinics with existing EMR systems, such as the Children’s Hospital of Philadelphia, Kaiser Permanente Northern California, Marshfield Medical Clinic, Northwestern University, Vanderbilt University, and the Veterans Health Administration. Extensive international experience with biorepositories has demonstrated the power and efficiency of linking genetic data to diagnoses derived from existing record systems, but the reliability and completeness of EMR in these settings have been questioned. Reliability and completeness of EMR in the US are largely unknown.

Population-based studies of genetic and environmental contributions to disease have contributed valuable information on disease etiology but are often limited in scope or population diversity. Study designs that can address these limitations are currently under development in the US, both within and outside existing biorepositories. Large-scale US prospective cohort studies, for instance, could be greatly facilitated by availability of complete, standardized, and unbiased data from EMR systems. To the extent that EMR data may be used for systematic ascertainment of incident disease and, to a lesser extent, for exposure assessment, information is needed on the validity and reliability of these data before embarking on such studies. Potential biases in diagnoses, and limitations in exposure assessment and comparability, need to be defined and approaches developed for addressing them. Completeness of coverage of clinical care of any given health care system and its EMR must be assessed, as multiple potential sources of care may be available to a given patient and captured with varying degrees of completeness in the EMR.

In addition to issues of EMR validity, the suitability of clinical data for research use by investigators outside a given EMR system has not been examined. Information is needed on the extent or complexity of data extraction needed to obtain clinical information necessary for genome-wide research, and on the compatibility of existing EMR formats with each other, with various Unified Medical Language Systems (http://www.nlm.nih.gov/research/umls/), and with standardized databases such as the National Center for Biotechnology Information’s dbGaP. Information is also needed about procedures for preparing and depositing research-ready data into such databases, and adequacy of documentation and user-friendliness of available data to outside users.

Concerns related to widespread data sharing for research use outside a given health care or EMR system have not been assessed. Information is needed on acceptability of such research to biorepository participants, their physicians and other care providers, biorepository investigators, and biorepository IRBs; completeness of participants understanding of the consent process, including benefits and risks of participation, and of the potential of the biorepository for research use; and participants concerns regarding data sharing, evolving technologies, and return of individual results of genetic studies. Concerns of clinicians and investigators, and of biorepository IRBs, technology transfer offices, and other institutional officials regarding data sharing, results reporting, and rights to publications and intellectual property must also be addressed if this research is to be successful. The impact on the biorepositories themselves of adding evolving genomic technologies and widespread data-sharing is largely unknown, particularly in terms of participation rates, participants restrictions on use or sharing of data or samples, and willingness of investigators and institutions to contribute to resources destined for widespread sharing.

Adequacy of participant consent for research use of stored biospecimens and data, including for existing and prior research, or collected in the course of clinical care, has not been systematically evaluated. Existing consent stipulations can rapidly become outdated as technology advances, and may be insufficient for newer genomic technologies. Genome-wide studies that were barely conceivable just a few years ago, due to technical obstacles or cost, are now in progress. Approaching participants for reconsent, which in some studies has been required several times in a single year, has the potential to be overwhelming or counter-productive. To the degree that technologic evolution can be foreseen, or that consent processes can focus on the intent of the proposed research rather than on rapidly changing technical specifications, approaches are needed for making consent processes as dynamic and flexible as possible so participants have sufficient information to make consent for use of their data and samples truly informed and meaningful.

At present, the best technology for relating variation across the genome to diseases and traits in unrelated persons is GWA genotyping, in which hundreds of thousands of single-nucleotide polymorphism (SNP) markers are assayed, but that may well change during the course of the studies contemplated for in this RFA. The predominant initial focus of this RFA will be on genome-wide association genotyping, but other genome-wide technologies (including but not limited to extensive sequencing, assessment of structural variation, DNA methylation, proteomics, etc) should be anticipated and, where appropriate, may be proposed and justified. Applicants should not request funding for genotyping or other genome-wide technologies, as the costs for these assays will be borne separately by NHGRI. Note that for the purposes of this RFA, genome-wide refers to comprehensive measurement of all or nearly all variation in all human chromosomes, rather than, for example, studies of candidate genes or isolated chromosomal regions.

The focus in this RFA on biorepositories with EMR systems should not be interpreted as an endorsement of this particular design, nor of the particular biorepositories ultimately selected for award, as optimal models. Biorepositories represent a potentially important research innovation, however, and many are being developed expressly for large-scale genomic research. Evaluating the strengths and weaknesses of this model and developing best practices for conducting genome-wide studies in these settings, while encouraging the use and sharing of these resources for genomic research, will facilitate both the application of genomic technologies to population studies and the development of research resources for identifying genes related to complex diseases; these are the core goals of NHGRI’s population genomics efforts.

Scientific Knowledge to be Achieved

The potential for leveraging existing health care systems for genomic research is vast, particularly in regard to speed, efficiency, cost-effectiveness, and potential for rapid translation to clinical care. The challenges posed by such research, however, must be carefully examined and addressed if risks are to be minimized and the full value of such repositories realized. This funding opportunity will define important potential sources of bias and error in phenotypic and exposure data derived from EMR, identify approaches for improving data collection and standardization for genomic research, and examine the feasibility of such enhancements in consultation with EMR experts. It will also identify sources of concern among biorepository participants and other relevant groups regarding current consent and consultation processes for application of genome-wide technologies, and for sharing of data; define needs for additional consent and/or consultation; and recommend approaches for improving consent and consultation processes in biorepository-based research. It will define optimal approaches for conducting genome-wide research in biorepositories so as to maximize the scientific value of the biorepository for identifying genes related to complex diseases. For proposed genome-wide studies likely to provide maximal scientific value for such research, it will investigate genetic variants associated with specific complex diseases and traits derived from EMR data. It is expected that the resulting data will be made rapidly and widely available for research use. By working collaboratively to share experience and expertise across participating biorepositories, guidelines will be developed for dissemination to other biorepositories on consultation and consent for such research, and on collecting, formatting, depositing, and documenting phenotype and exposure data to databases such as dbGaP.

Objectives of this Research Program

This RFA will support investigative groups affiliated with existing biorepositories to develop necessary methods and procedures for, and as appropriate, to perform, large-scale, high-throughput genomic technologies in participants with stored biospecimens and with phenotypes and environmental exposures derived from existing EMR systems. The potential barriers to conducting such research, and approaches for addressing those barriers, will be investigated both in terms of: 1) technical challenges in extracting and combining valid phenotypic and exposure information from EMR systems and in obtaining adequate biospecimens for genomic studies, and 2) sociocultural challenges in ensuring adequate human subject protections and addressing participant concerns regarding such research. These two complementary aspects of genomic research will be pursued together in a closely integrated research program in which their interdependence is recognized, fostered, and fully taken advantage of to provide the most comprehensive and effective approaches to establishing and utilizing biorepositories as research resources.

Current and planned biorepositories may not currently have all the necessary information, consultations, procedures, and policies in place to permit application of genome-wide technologies and sharing of resulting individual-level data with the broad scientific community. Some biorepositories may have particular expertise in one area, such as standardization or extraction of EMR data, and be in need of expertise in another, such as community consultation or IRB interactions. Sharing of this expertise across biorepositories will be a key goal of this collaborative program, with the intent of raising the standards for such research across all biorepositories, while recognizing that outside of this RFA biorepositories may at times be competing with one another. Early in the project period, investigative groups supported by this RFA will work together to define optimal approaches for conducting genome-wide research in biorepositories, including but not limited to: extracting complete and unbiased phenotype/exposure data from EMR; obtaining suitable consent for genome-wide studies and broad data sharing; interacting with participants, communities, and IRBs; and ensuring a diverse and representative patient population.

NHGRI will develop specific criteria for the selection of samples from the participating biorepositories for genome-wide studies to be conducted at NHGRI-designated laboratories. Each investigative group desiring to submit samples for genome-wide studies will be expected to address these criteria, or to demonstrate why such criteria are not relevant to their biorepository before proposed genome-wide studies are selected for inclusion within this RFA. These criteria may include, but may not be limited to: validity, reliability, and comprehensiveness of EMR data; documentation and ease of deposition and use of EMR data by others unfamiliar with the EMR or health care system from which they are derived; adequacy of available biospecimens; reduction of biases in participant recruitment or exposure/outcome ascertainment; consistency of consent for genome-wide technologies and data sharing; appropriateness of plans for reporting results; appropriateness of consultation with participants, communities, IRBs, institutions, and other relevant groups and potential scientific value as a research resource for identifying genes associated with complex diseases. Once these criteria are addressed, the quality of the data set has been checked by NCBI, and the quality of the DNA has been assured by an NHGRI-specified genomic facility, genomic studies on specimens provided by the biorepository may be approved by NHGRI to proceed.

Genomic studies should be designed to identify genetic variants and their environmental modifiers associated with diseases and traits of substantial public health impact. The choice of study designs, with appropriate scientific justification, is at the discretion of the applicant and may include (but is not limited to) case-control, population, cohort, clinical, or family studies or clinical trials.

Investigators are expected to have access to data and sources of DNA from an existing biorepository with a study population(s) of sufficient size to test a hypothesized genetic effect through genome-wide studies within one year of the anticipated date of award (that is, by September 2008). Funding will be provided to support methodologic development and collaborative activities such as harmonizing phenotypes, developing data capture methods and analytic strategies, assessing data quality and potential biases, and evaluating or improving consent or data protection processes. If a genomic study is approved for support under this RFA, funding will also be provided for sharing phenotype and exposure data with a database such as dbGaP, and DNA samples (or biospecimens for DNA extraction) with a central genomic laboratory facility, and for data analysis. Investigative groups will be encouraged and supported to continue to participate in other collaborative activities of the program, as appropriate, even if insurmountable obstacles preclude submission of their samples to NHGRI-designated laboratories for genomic studies. No participant recruitment or direct data collection for use in genome-wide studies (such as questionnaires, examinations, or laboratory measures), or sample acquisition will be supported by this RFA. If awarded, NHGRI will support the genotyping activities of the program separately; no funding should be requested for genotyping or other genomic technologies.

Each application should propose a GWA study of 1,000-1,500 cases and suitable controls (or 3,000 cohort members) sufficient to identify genetic variants associated with complex diseases or traits. Investigators could propose to select cases for a single trait, so that a single investigator could conduct a valid, stand-alone GWA study, or cases for three to five traits (~300-500 patients each) and suitable controls that could be combined with cases and controls from other investigators participating in the RFA. The latter design, though more complicated and dependent on the availability of comparable cases and controls from other investigators receiving awards, would be more effective in evaluating the challenges in pooling information across biorepositories. Applicants are encouraged to discuss possible collaborations with other potential applicants during the application process, if desired, and to propose groups with whom they might collaborate and possible traits for joint study. Applications may also propose and justify use of other genome-wide technologies in addition to GWA genotyping, but all applications should include a GWA genotyping component. Studies will be selected to provide the program as a whole a broad range of participants approximating the diversity of the US population on major demographic factors such as age, race/ethnicity, socioeconomic status, US geographic region, and urban/rural residence. Participating biorepositories should also have comprehensive EMR systems, ideally capturing all or nearly all inpatient and outpatient visits and medications for the past several years. Phenotypes and environmental exposures for inclusion in the proposed GWA study should be derived entirely or nearly entirely from existing EMR systems.

Each application should clearly define the source population, eligibility criteria, consent and consultation process, participant recruitment methods, percent participation, losses to follow-up, and numbers and demographics of participants currently in the biorepository and expected to be available one year after the anticipated award date (that is, in September 2008). Numbers (and methods of ascertainment) of confirmed or possible cases of a variety of complex diseases of public health importance available at the time of submission and expected to be available one year after award should also be described. Each application should also define the subgroup of biorepository participants proposed for genome-wide study under this RFA, whether in case-control, cohort, family, or other design, including inclusion and exclusion criteria, definition of primary and secondary phenotypes and exposures or covariates from EMR, and any potential biases in subject selection or phenotypic/exposure assessment.

The organization, governance structure, funding, and history of the biorepository, including expectations of, and commitments (explicit or implicit) made to and by biorepository participants, clinicians, and investigators, should also be clearly described. Adequacy of current informed consent for GWA studies and for application of other genome-wide technologies, and for controlled but widespread data access, should be clearly described along with any restrictions on research use of the data. Processes and outcomes of consultation with participants, their families, communities, and physicians or other care providers, and with biorepository investigators, IRBs, and institutions, at the initiation of the biorepository and as it evolves, should be described, including plans for or outcomes of such consultation specifically related to participation in this RFA. Obtaining additional consent, if necessary, will be an allowable cost under the awards to be made, to the extent that resources permit.

The biorepository’s current EMR system should be described in detail, including data standards (such as SNOMED, HL-7, LOINC, or other Unified Medical Language Systems) used for recording, formatting, and retrieving this information from the EMR, as well as attempts at mapping existing EMR to such standard formats. The precise phenotypic and exposure variables available or derivable from existing EMR for use in the proposed genome-wide study and the completeness and validity of these measures (if known) should be described. Availability of additional data outside of the EMR on participants proposed for genome-wide study, particularly to the degree such data can be used for validating data derived from EMR, and approaches for using these data in genotype-phenotype association analyses and other genomic research, should be described. Data security measures should be described in detail, including precautions taken to ensure removal of individual identifiers and to prevent inadvertent release of data or identification of participating individuals or groups. Funding will be provided to enhance data formatting and documentation as needed, to the extent that resources permit.

Type, quality, and amount of biospecimens available on participants to be studied under this RFA should be explicitly described, including source (tissue, blood, urine, etc); methods for collection (surgical excision, fine needle aspiration, phlebotomy, etc), aliquoting and tracking; storage conditions; DNA extraction methods; and DNA quantity and quality (and methods used to assess them). Prior experience in using the biospecimens for research should be described. Applicants may provide suggestions on choice of genotyping platform, but genome-wide technologies and platforms will be selected by the NHGRI.

A detailed analytic plan should address issues related to the large amount of genome-wide data to be generated such as multiple testing and assessing complex interactions. The potential impact of population ancestry/history and stratification on genome-wide analyses should be discussed regardless of the population chosen for study, and means for minimizing the effects of population stratification proposed. The analytic plan should detail methods to address false positive genome-wide results and adjust for multiple testing.

Program Organization

The awards funded under this RFA will be cooperative agreements (see Section VI.2.A. Cooperative Agreement Terms and Conditions of Award). Close interaction among awardees and the NIH will be required to develop appropriate strategies and tools to carry out this program. The awardees will meet as a Steering Committee, which will include the Principal Investigators from each investigative group and the NIH Project Scientist, to identify optimal approaches for conducting genome-wide research in biorepositories so as to maximize the scientific value of the biorepository for identifying genes related to complex diseases. Administrative Coordinating Center functions will be performed by one of the awardees in order to organize and monitor study committees, including an Expert Scientific Panel (ESP) to evaluate the progress of the program, as described below.

Responsibilities of the Steering Committee will include evaluating existing phenotypic and exposure data, as summarized and presented by each investigative group, for completeness, potential biases, standardization, reproducibility, and comparability across sites. The Steering Committee will also evaluate data available in the biorepositories existing EMR systems for completeness, compatibility across sites and with databases such as dbGaP, extent of documentation, and ease of use by naive users, as well as potential biases in clinical diagnoses, secondary phenotypes, and environmental exposures. Approaches for improving data collection and standardization, where possible, will be identified and the feasibility of such enhancements examined by the Steering Committee in consultation with EMR experts and clinical information technology (IT) specialists affiliated with the biorepositories. Processes for obtaining informed consent, community input, and IRB approval will be reviewed for suitability of the biorepository samples for GWA genotyping or other genomic technologies, data sharing, and results reporting, and potential needs for additional consent identified. Potential biases in participation will be assessed by comparing participants to non-participants on relevant factors such as demographic and clinical characteristics; if available, reasons for participation or refusal will be evaluated.

The Steering Committee will also jointly develop and implement approaches for evaluating concerns among biorepository participants and their families, clinicians, investigators, IRBs, institutional officials, and other relevant groups regarding addition of genomic technologies to the biorepository and widespread sharing of resulting data.

The Steering Committee will meet three times per year and monthly on conference calls as needed to share information on data resources, methodologies, analytical tools, as well as data and preliminary results. Subcommittees and working groups may be established, such as a Consent group or an EMR group. Key co-investigators, and pre- and postdoctoral trainees, in addition to the PIs, will be eligible to attend Steering Committee meetings. PIs are encouraged to include investigators and trainees who are members of under-represented minority groups and those from different but related disciplines such as bioinformatics, computational biology, public health, social sciences, systems medicine, and translational research where appropriate. The cost of 3-4 persons to attend these meetings, as well as the costs associated with monthly conference calls, should be included in the proposed research budge.

NIH has issued a proposed policy on data sharing in GWAS (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-06-094.html) and NHGRI expects awardees to follow this policy, or any successor, once finalized. In the interim, data from this RFA are expected to be handled so as to increase the value of the significant public investment in conducting genome-wide studies on samples from the participating biorepositories. NHGRI intends that Project Datasets and associated genotyping data from the participating biorepositories be widely shared with the scientific community for research uses through NIH-supported databases such as dbGaP, which contains both an open and controlled access section. Although NHGRI expects all Project Datasets and genetic data from genome-wide studies selected as part of this RFA to be available through a database such as dbGaP, the NHGRI does not intend dbGaP, or any single database, to become the exclusive source of this program’s data. Summary data and other information such as study protocols, descriptions, and publications are expected to be made available through an open access section of a database such as dbGaP, other public web sites, and/or publication in the scientific literature.

The genomic data generated for each sample, plus coded phenotype and exposure data, are expected to be deposited as soon as both the Project Datasets submitted by Investigators and the genomic data have passed appropriate data quality assessments, conducted in collaboration with NCBI and NHGRI. Simple, unadjusted genomic- or genotype-phenotype associations ( pre-computes ) may be calculated and made available through these resources.

Applicants should indicate their willingness to cooperate with other awardees in the development and design of research and consultation methods, procedures, policies and strategies to be applied in this program before genome-wide studies are undertaken. Applicants should also describe prior experience in working as part of a research consortium or other collaborative activities to meet individual study and collaborative goals

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

This initiative will not support additional recruiting of human subjects for genome-wide studies, collecting human samples, or for collecting medical or phenotype data to develop or broaden the biorepository. It will not support studies using animal models. Applications that include recruiting human subjects for genome-wide studies, collecting human samples, collecting medical or phenotype data to develop or broaden the repository, and applications using animal models will be considered non-responsive and returned to the applicant.

Proof of appropriate informed consent and/or IRB approval for using the EMR and previously collected data and biospecimens for genomic research, or a plan for reconsent, should be provided at the time of application submission. Only applications describing protection of participants privacy and confidentiality will be considered.

Section II. Award Information

1. Mechanism(s) of Support

This funding opportunity will use the U01 award mechanism(s).

As an applicant, you 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.

The NIH (U01) is a cooperative agreement award mechanism. In the cooperative agreement mechanism, the Principal Investigator retains the primary responsibility and dominant role for planning, directing, and executing the proposed project, with NIH staff being substantially involved as a partner with the Principal Investigator, as described under the Section VI. 2. Administrative Requirements, "Cooperative Agreement Terms and Conditions of Award".

There are no plans at present to reissue this RFA.

2. Funds Available

NHGRI intends to commit approximately 4,200,000 dollars in FY07 to fund 3-5 new and/or competing continuation grants in response to this RFA. An applicant may request a project period of up to 4 years and a budget for direct costs up to $590,000 in FY07, $630,000 in FY08, $660,000 in FY09, and $520,000 in FY10. Applicants proposing to serve as the Administrative Coordinating Center may request an additional $500,000 direct costs per year.

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 IC(s) 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.

Facilities and administrative 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:

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.

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

N/A

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.

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: April 17, 2007
Application Receipt Date(s): May 17, 2007
Peer Review Date: July/August 2007
Council Review Date: August 2007
Earliest Anticipated Start Date: September 30, 2007

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:

Jeffery P. Struewing, MD, MS
National Human Genome Research Institute
5635 Fishers Lane
Suite 4076, MSC 9305
Bethesda, MD 20892-9305 (U.S. Postal Service Express or regular mail
Rockville, MD 20852 (express/courier service; non-USPS service)
Telephone: 301-594-3757
FAX: 301-480-2770
Email: [email protected]

3.B. Sending an Application to the NIH

Applications must be prepared using the research grant applications found in the PHS 398 instructions for preparing a research grant application. Submit a signed, typewritten original of the application, including the checklist, and three signed photocopies in one package to:

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD 20892-7710 (U.S. Postal Service Express or regular mail)
Bethesda, MD 20817 (for express/courier service; non-USPS service)

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

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

Rudy Pozzatti, PhD
National Human Genome Research Institute
5635 Fishers Lane
Suite 4076, MSC 9305
Bethesda, MD 20892-9305 (U.S. Postal Service Express or regular mail)
Rockville, MD 20852 (express/courier service; non-USPS service)
Telephone: 301-496-7531
FAX: 301-435-1580
Email: [email protected]

Using the RFA Label: The RFA label available in the PHS 398 application instructions must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/labels.pdf.

3.C. Application Processing

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

The NIH will not accept any application in response to this funding opportunity that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to a funding opportunity, it is to be prepared as a NEW application. That is, the application for the funding opportunity must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes from the previous unfunded version of the application.

Information on the status of an application should be checked by the Principal Investigator 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

Special Application Requirements

Applicants must address the following when preparing applications in response to this RFA. Items A D in the application (Specific Aims, Background and Significance, Preliminary Studies, and Research Design and Methods) should not exceed 25 pages.

Access to and Sharing Data and Specimens

Applicants are expected to document access to DNA specimens and phenotypic and exposure data derived from electronic medical records from an existing biorepository. DNA samples should be available for sharing with the program’s genome-wide technology facilities within one year of award. For the proposed genome-wide study, applicants should describe all relevant phenotypic and environmental exposure measures proposed for use in the study, and justify the choice of population and sampling design.

Administrative Coordinating Center

The Administrative Coordinating Center functions will be performed by one of the awardees. The Administrative Coordinating Center will coordinate activities across the three to five studies funded in this RFA and assist in the organization and monitoring of committees and issues that have broad applicability across all funded studies, such as recruitment, informed consent, analysis methodology and data sharing. The Administrative Coordinating Center will also be responsible for monitoring membership of Program-wide committees, tracking and scheduling of committee meetings and conference calls, preparing concise minutes or summaries of Steering Committee meetings for distribution within 30 days, and planning the Expert Scientific Panel meetings.

Applicants who are interested in fulfilling the role of the Administrative Coordinating Center for this RFA should include a separate section of 3-5 pages (not counted toward the 25-page limit) describing their anticipated activities as the Administrative Coordinating Center and a separate budget for these activities. Applicants interested in fulfilling this role should include costs of monthly Steering Committee conference calls and travel funds for four to eight Expert Scientific Panel members to attend meetings in Bethesda twice a year. Total direct costs requested for support of the Administrative Coordinating Center should not exceed $500,000 per year for each of the four years of the project. These costs are in addition to costs requested for other activities described in the RFA.

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

The applicant must address human subjects issues, including potential barriers to sharing phenotypic/exposure and genetic data from individual participants with the broad scientific community.

Applicants are expected to demonstrate that the proposed uses under this RFA are acceptable to biorepository participants, associated communities, supporting institutions, and other relevant groups. Documentation of any required approvals by the local IRB, (if, for example, one or more participating investigators retain the ability to identify subjects), should also be provided. If additional consent or approval is needed, a plan should be proposed for obtaining reconsent including IRB approval, or an IRB waiver of reconsent for data sharing, and a specific budget for reconsent (if needed) should be provided. Restrictions on data use (such as limitations to a specific disease or condition or to non-commercial investigators) should be clearly described. Investigators are strongly encouraged to provide Project Datasets with the widest possible application and greatest potential value for identifying genes related to complex diseases. Copies of the applicable informed consent forms and IRB approvals (if needed) should be included in the grant application.

If proposed genome-wide studies are selected to proceed, applicants will be expected to send coded individual-level phenotype and/or exposure data to NCBI within two weeks of receiving notice that their proposed genome-wide study is being considered for approval. Approval is contingent on technical evaluation of the dataset by NCBI including assessment of: extent of human curation needed to integrate the documentation with the phenotype/exposure data; certainty with which NCBI can interpret the meaning of the variables provided, with or without reference to supplemental documentation; frequency and distribution of trait measures that have been recoded and quality of documentation to define those values; extent of missing and out-of-range values; and clarity of case and control definitions, if relevant. Applicants are responsible for removing any potentially identifying information prior to submission of the information.

Applicants being considered for approval for a proposed genome-wide study will also be expected to submit a randomly-selected sample of about 100 DNA specimens, or specimens from which DNA will be extracted, for assessment of DNA quantity and quality, within two weeks of receiving notice that their proposed genome-wide study is being considered for approval. Approval is contingent on acceptable DNA quantity and quality as judged by the assigned genomic facility. If approval is not given, individual-level data will be treated as confidential; they will not become part of any database and will not be shared.

Applicants being considered for approval for a proposed genome-wide study are expected to have obtained appropriate Institutional Review Board (IRB) and any other required approvals for sharing individual-level data with NIH and submitting DNA specimens, or specimens from which DNA will be extracted, with an NIH-designated central genotyping facility. Applicants will also be expected to document IRB approval for submitting individual-level phenotype and exposure data and genotyping results to a shared data resource as described under Plans for Sharing Research Data, or IRB approval for a reconsent process.

Plan for Sharing Research Data

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.

The applicant is expected to provide specific plans for data sharing and data release in the application and indicate whether they are willing to abide by the proposed NIH data sharing policy for GWAS. See Request for Information: Proposed Policy for Sharing of Data obtained in NIH supported or conducted Genome-Wide Association Studies (GWAS); http://grants.nih.gov/grants/guide/notice-files/NOT-OD-06-094.html. It is expected that NIH will finalize a common policy for data release, publication, and intellectual property for GWA studies and NHGRI will expect applicants to abide by that policy.

The NIH is committed to the principle of rapid data release to the scientific community. This principle was initially implemented during the Human Genome Project and has been 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 report from the Ft. Lauderdale meeting can be found on the Wellcome Trust website at: http://www.wellcome.ac.uk/doc_wtd003208.html.

The NIH has identified this program as a community resource project. As such, the program aims to function openly by making all data available to the scientific community in a timely manner prior to publication, with suitable restrictions for protection of human research subjects. The NIH is committed to creating a resource founded on the principle of no-cost, rapid, and complete release of genotype-phenotype datasets for use by investigators throughout the global scientific community who, along with their institutions, certify their agreement with NHGRI and NIH policies ( Approved Users ). All participants in the program are expected to promote NHGRI and NIH policies on data access, publication, and intellectual property summarized below, and describe their methods for doing so in the application. NHGRI will establish mechanisms to monitor data use in agreement with these policies.

The NHGRI will make all final decisions concerning program policies. All program policies are subject to change by the NHGRI as deemed necessary to sustain program principles and priorities, or to ensure the highest standards for responsible research conduct within program operating procedures.

Publication Policy: Consistent with the proposed policy on data sharing in GWAS, the NIH expects that beginning on the date that a Project Dataset is released for distribution through a database such as dbGaP, there will be a period of twelve months during which Investigators retain the exclusive right to submit publications developed with the data and samples they contributed. During this twelve-month period of publication exclusivity, Approved Users will have access to data, but will agree not to submit for publication any results or analyses derived from the use of any Project Dataset within that period without consent of the Investigator. Submission of publications using genotype data only that may be available through databases such as dbSNP is permissible during this period. Investigators will be encouraged to shorten the period of exclusivity at their own discretion. NHGRI may request a shorter period of exclusivity. The NIH expects that, in all resulting oral or written publications, disclosures, or publications, all investigators who access these datasets will acknowledge the Investigator(s) who conducted the original study and the funding organization(s) that supported the work.

Intellectual Property Policy: The NIH expects that data generated under the support of this RFA and conclusions derived directly therefrom will remain freely available, without any licensing requirements, for uses such as, but not necessarily limited to, markers for developing assays and guides for identifying new potential targets for drugs, therapeutics, and diagnostics. The intent is to discourage the use of patents that would prevent use of or block access to any genotype-phenotype data developed with support of this RFA. The NIH encourages broad use of these Project Datasets that is consistent with a responsible approach to management of intellectual property derived from downstream discoveries as outlined in NIH’s Best Practices for the Licensing of Genomic Inventions and the NIH Research Tools Policy (http://grants.nih.gov/grants/intell-property_64FR72090.pdf).

The filing of patent applications and/or the enforcement of resultant patents in a manner that might restrict use of these Project Datasets and dbGaP could substantially diminish the utilization of information and the potential public benefit they could provide. Approved Users and Investigators supported under this RFA, and their institutions, should acknowledge the program’s IP Policy, the goal of which is to ensure the greatest possible public benefit from the Project Datasets generated under this RFA.

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. Reporting.

As this program is a community resource project, NIH expects that not only data, but also resources generated during the course of the program, such as guidelines, best practices, analytic methods, and data standards, will be made rapidly available to the research community and that sharing plans should follow the same principles and spirit as the rapid data release policy. The applicant should provide specific plans for resource sharing and distribution in the application.

Section V. Application Review Information

1. Criteria

The following will be considered in making funding decisions:

Additional criteria for award will include:

The awardee must agree to the Cooperative Agreement Terms and Conditions of Award in Section VI.2.A. Award Administration Information.

2. Review and Selection Process

Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by NHGRI in accordance with the review criteria stated below.

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

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?

Approach: Are the conceptual or clinical framework, design, methods, and analyses adequately developed, well integrated, well reasoned, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? Have the sources and representativeness of the biorepository’s study population(s) been clearly described, have any potential biases in biorepository participants and phenotypic/exposure ascertainment been identified, and are the applicants approaches for minimizing these biases appropriate? Are the phenotype and exposure measures derived from EMR of sufficient quality and completeness to provide maximal scientific value from the addition of genomic technologies, or do they have the potential to be such within the project period? Are the proposed plans to share data in a timely manner likely to provide maximal scientific value for identifying genes related to complex diseases?

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? What advantages does the project offer for investigation of issues and concerns of biorepository participants, investigators, IRBs, and other relevant groups? What is the richness of the biorepository and linked EMR system for future studies that may be based on other phenotypes or benefit from information on environment exposures?

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

Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed studies benefit from unique features of the scientific environment, or subject populations, or employ useful collaborative arrangements? Is there evidence of institutional support? Is the bioinformatics infrastructure sufficient to accomplish the goals of the project? Have the investigators documented their ongoing or future access to data and samples from the biorepository in a highly-effective collaborative relationship, and their ability to commit the biorepository data and samples, in consultation with appropriate decision-makers, to participate in this RFA?

Administrative Coordinating Center: (For applicants proposing to fulfill this role) Are the proposed plans for providing operational coordination of the program as a whole and of committees and issues that have broad applicability across all funded studies, such as informed consent and data sharing, adequate? Are the proposed plans for providing logistical support, such as monitoring committee membership, tracking and scheduling of committee meetings and conference calls, and planning Expert Scientific Panel meetings adequate? Is the applicant experienced in providing operational coordination and logistical support for multi-center studies? Is the institutional infrastructure adequate to provide operational and logistical support for the program?

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).

2.B. Additional Review Considerations

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

2.C. Sharing Research Data

Data Sharing Plan: The reasonableness of the data sharing plan or the rationale for not sharing research data will be assessed by the reviewers. 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.

The NIH has identified this program as a community resource project. As such, the program aims to function openly by making all data available to the scientific community in a timely manner prior to publication, with suitable restrictions for protection of human research subjects. The applicant is encouraged to provide specific plans for data release in the application. It is expected that NIH will soon establish a common data release policy for GWA studies and all participants will be encouraged to abide by that policy; see Request for Information (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-06-094.html).

Program staff will be responsible for the 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. Program staff may negotiate modifications of the data sharing plan with the awardee before recommending funding of an application. The final negotiated version of the data sharing plan will become a 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. Reporting.

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 are expected to include a sharing research resources plan addressing how unique research resources will be shared or explain why sharing is not possible.

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

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

3. Anticipated Announcement and Award Dates

It is anticipated that awards will be made by September 30, 2007.

Section VI. Award Administration Information

1. Award Notices

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the 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 Also Section IV.5. Funding Restrictions.

2. Administrative and National Policy Requirements

The NIH has identified this program as a community resource project. As such, the program aims to function openly by making all data available to the scientific community in a timely manner prior to publication, with suitable restrictions for protection of human research subjects. It is expected that NIH will establish a common data release policy for GWA studies prior to the anticipated award date for the program, and all awardees will be expected to agree to the policy; see Request for Information (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-06-094.html).

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 Principal Investigator as well as to the appropriate institutional official, at the time of award.

2.A. Cooperative Agreement Terms and Conditions of Award

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

The administrative and funding instrument used for this program will be the cooperative agreement (the NIH U01 Research Project Cooperative Agreement award mechanism), 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.

2.A.1. Principal Investigator Rights and Responsibilities

The Principal Investigator will have the primary responsibility for defining the details for meeting the project requirements of RFA HG-07-005 and for:

Administrative Coordinating Center

The Principal Investigator will have the primary responsibility for defining the details of the Administrative Coordinating Center within the guidelines of RFA HG-07-005 and for performing these activities. The Principal Investigator will agree to accept close coordination, cooperation, and management of the project as described under NIH Responsibilities. Specifically, the Principal Investigator will:

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

2.A.2. NIH Responsibilities

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

The Project Scientist is a scientist of the NHGRI 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 NIH staff will be to facilitate and not to direct the activities. It is anticipated that decisions in all activities will be reached by consensus of the program and that NIH staff will be given the opportunity to offer input to this process. The Project Scientist will participate as a member of the Steering Committee and will have one vote. The Project Scientist will have the following substantial involvement:

Additionally, an NHGRI Program Official will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice. The assigned Program Official may also serve as the Project Scientist.

Other NHGRI staff may assist the awardees as designated by the Program Official.

The NCBI is substantially involved. Prior to proposed genome-wide studies being approved for genotyping or application of other genome-wide technologies, they will provide technical evaluation of the meta-data and, when appropriate, individual-level data that are proposed to be shared by investigative groups and their affiliated biorepositories. NCBI manages and maintains data security for dbGaP. They will work with the genomic facilities, the Administrative Coordinating Center, and Investigators, as appropriate, to ensure data integrity and clarify data definitions.

2.A.3. Collaborative Responsibilities

Close interaction among the participating investigators will be required, as well as significant involvement from the NIH, to develop appropriate strategies and tools to design, perform, and analyze genome-wide studies. The awardees and the Project Scientist will meet as the program Steering Committee three times per year and monthly on conference calls as needed to share information on data resources, methodologies, analytical tools, as well as data and preliminary results. Key co-investigators and pre- and postdoctoral trainees, especially those who are members of under-represented minority groups or those from different but related disciplines, in addition to the PIs, are eligible to attend these meetings.

The Steering Committee will serve as the main scientific body of the program. The Steering Committee will be responsible for coordinating the activities being conducted by the program. The Steering Committee membership will include one NHGRI Project Scientist and the P.I. from each awarded cooperative agreement. The Steering Committee may add additional members, and other government staff may attend the Steering Committee meetings as desired. It is anticipated that additional coordination mechanisms may be set up with other U.S. and international groups that may collaborate with the program. 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.

To address particular issues, the Steering Committee may establish working groups as needed, which will include representatives from the program and the NIH and possibly other experts. Awardees agree to work collaboratively to:

Expert Scientific Panel

An Expert Scientific Panel (ESP) will evaluate the progress of the program. The ESP will provide recommendations to the National Advisory Council for Human Genome Research about the progress and scientific direction of all components of the program.

The ESP will be composed of four to eight senior scientists with relevant expertise, although the membership may be enlarged permanently or on an ad hoc basis as needed. The ESP will meet at least twice a year; some meetings may be conducted by telephone conference. At least once a year, there will be a joint meeting with the Steering Committee to allow the members of the both the ESP and the Steering Committee to interact directly. Twice a year the ESP will make recommendations regarding progress of the program to the National Advisory Council for Human Genome Research about changes, if any, which may be necessary in the program.

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

Awardees will be required to submit electronically quarterly reports that describe the status and progress for all aspects of the study. The quarterly report will be used as a management tool for the NIH and the program’s Steering Committee. Reporting on cost will also be required.

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 Contacts:

Jeffery P. Struewing, MD, MS
National Human Genome Research Institute
5635 Fishers Lane
Suite 4076, MSC 9305
Bethesda, MD 20892-9305 (U.S. Postal Service Express or regular mail)
Rockville, MD 20852 (express/courier service; non-USPS service)
Telephone: 301-594-3757
FAX: 301-480-2770
Email: [email protected]

2. Peer Review Contacts:

Rudy Pozzatti, PhD
National Human Genome Research Institute
5635 Fishers Lane
Suite 4076, MSC 9305
Bethesda, MD 20892-9305 (U.S. Postal Service Express or regular mail)
Rockville, MD 20852 (express/courier service; non-USPS service)
Telephone: 301-496-7531
FAX: 301-435-1580
Email: [email protected]

3. Financial or Grants Management Contacts:

Ms. Cheryl Chick
National Human Genome Research Institute
5635 Fishers Lane
Suite 4076, MSC 9306
Bethesda, MD 20892-9306 (U.S. Postal Service Express or regular mail)
Rockville, MD 20852 (express/courier service; non-USPS service)
Telephone: 301-435-7858
FAX: 301-402-1951
Email: [email protected]

Section VIII. Other Information

Required Federal Citations

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

Sharing Research Data:
Investigators submitting an NIH application seeking $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible (http://grants.nih.gov/grants/policy/data_sharing).

Investigators should seek guidance from their institutions, on issues related to institutional policies 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.

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.

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

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

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

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

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

URLs in NIH Grant Applications or Appendices:
All applications and proposals for NIH funding must be self-contained within specified page limitations. For publications listed in the appendix and/or Progress report, internet addresses (URLs) must be used for publicly accessible on-line journal articles. Unless otherwise specified in this solicitation, Internet addresses (URLs) should not be used to provide any other information necessary for the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site.

Healthy People 2010:
The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This RFA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople.

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

The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

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

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