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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 part of the NIH-wide Genes, Environment, and Health Initiative. All NIH Institutes and Centers participate in NIH-wide initiatives. This RFA will be administered by NHGRI (http://www.genome.gov) on behalf of the NIH (http://www.nih.gov).

Title: Genome-wide Association Studies in the Genes, Environment, and Health Initiative - Study Investigators (U01)

Announcement Type
This is a reissue of RFA-HG-06-033, which was previously released September 7, 2006.

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

Request For Applications (RFA) Number: RFA-HG-07-012

Catalog of Federal Domestic Assistance Number(s)
93.172

Key Dates
Release Date: August 9, 2007
Letters of Intent Receipt Date(s): September 18, 2007
Application Receipt Date(s): October 18, 2007
Peer Review Date(s): March, 2008
Council Review Date(s): May 2008
Earliest Anticipated Start Date(s): July 1, 2008
Additional Information To Be Available Date (Url Activation Date): N/A
Expiration Date: October 19, 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 ( Study Investigators ) to conduct genome-wide association (GWA) genotyping and/or replication studies, using data and specimens from human subjects on whom information is available for conditions/traits of public health importance and relevant environmental exposures. It includes support for sharing the specimens and data and analyzing the resulting data as part of the NIH-wide Genes, Environment, and Health Initiative (http://www.genome.gov/19518663). Although the focus of this RFA is on initial genome-wide scanning and replication studies, follow-up genotyping studies may be proposed.

The Genes, Environment, and Health Initiative (GEI) is a four-year, NIH-wide program designed to identify major genetic susceptibility factors for diseases of substantial public health impact and to develop technologies for reliable and reproducible measurement of potentially causative environmental exposures. It is being implemented by an NIH-wide GEI Coordinating Committee, administratively led by the National Human Genome Research Institute (NHGRI) and the National Institute of Environmental Health Sciences (NIEHS).

GEI is a multi-component program involving several related solicitations. A major component (GEI-GWA) supports genome-wide association studies (GWAS), either in an initial discovery phase (assaying single nucleotide polymorphisms, or SNPs, to capture at least 80% of human genomic variation), or in a replication phase (such as assaying a subset of the most strongly associated SNPs or other genetic variants in one or more additional groups of subjects). Other GEI genetics components currently funded or included in current or future solicitations include developing data analytic methods, further replication and follow-up genotyping studies, sequencing, functional studies, database development, and clinical translation. As these latter activities depend on availability of robust findings from high-throughput GWA genotyping, the production and analysis of those data are the focus of this component of GEI.

Recognizing that chronic diseases are likely due to environmental and behavioral factors interacting with genetic predisposition, GEI also includes a substantial environmental component devoted to developing and field testing new technologies for assessing such exposures. The potential for applying these technologies (particularly those suitable for use on stored biospecimens) in population samples selected through GEI for GWA studies will also be examined. Other GEI exposure biology components include developing environmental sensors for measuring toxins, dietary intake, and physical activity; biologic markers of response, including oxidative stress, epigenetics, and DNA damage; and psychosocial stressors.

The value of the existing epidemiologic data in population samples for investigating gene-environment interactions will be increased substantially by the addition of GWA genotyping. To ensure that the maximal scientific benefit is derived from this significant public investment, this funding opportunity aims to support rapid and widespread sharing of the resulting genotype data, combined with phenotype and exposure data provided by the Study Investigators according to their data sharing plans, through community resources such as dbGaP (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gap), consistent with the goals of NIH policies on data sharing in GWAS (http://grants.nih.gov/grants/gwas/).

Background

Genome-wide association studies have emerged as a powerful new tool for identifying genetic variants related to common, complex diseases such as age-related macular degeneration and diabetes. Diseases such as hypertension, osteoporosis, and stroke, which have generally not yielded genetic variants of large population impact in family linkage studies, may be amenable to study through interrogation of common genetic variation as defined by the International HapMap Project and related programs. Identification of disease-related genes can now be accelerated by systematically genotyping large collections of specimens from human subjects who have already been carefully characterized for a wide variety of common diseases and traits. Many large population studies have been supported by NIH to collect DNA specimens and perform extensive and often repeated measurements of physical characteristics, disease risk factors and outcomes, and environmental exposures. These specimens are now well suited for application of HapMap-based, genome-wide association technology, either as initial discovery studies interrogating the entire genome, or as replication studies to confirm initial results with additional population samples.

Genotyping platforms are continuing to evolve, with ever-larger numbers of SNPs available for typing at progressively lower costs. Technologies are also under development for assaying genetic markers other than SNPs, such as small insertions/deletions and copy number variants; these may be incorporated into genotyping platforms in the four-year course of GEI. Technologic developments are anticipated to continue for the duration of GEI, and will require the program to remain flexible in adapting to evolving technology. Indeed, GEI-supported research can be expected to contribute positively to this developmental process.

Although traditional methods to assess exposure can accurately determine the concentration of a variety of toxins in the environment or in human biospecimens, these methods fall short of accurately determining the biological response to exposures. Evidence suggests that the biological response to the exposure, rather than simply the exposure, is more tightly related to the ultimate impact on human health. For the purposes of GEI, environmental exposure refers to chemical toxicants such as metals and solvents, and biological agents such as toxins released from mold and bacteria, that are contaminants of the natural environment of air, water, and soil. It also encompasses lifestyle factors such as diet and physical activity which contribute to and modulate the biological response to these environmental agents, as well as family, social and cultural influences. It is fully expected that the technological achievements supported by GEI will result in assays providing biological fingerprints of prior exposure to environmental agents and lifestyle choices (http://grants.nih.gov/grants/guide/rfa-files/RFA-ES-07-001.html, http://grants.nih.gov/grants/guide/rfa-files/RFA-CA-07-032.html, http://grants.nih.gov/grants/guide/rfa-files/RFA-DA-07-005.html, http://grants.nih.gov/grants/guide/rfa-files/RFA-ES-06-011.html, http://grants.nih.gov/grants/guide/rfa-files/RFA-ES-06-012.html, http://grants.nih.gov/grants/guide/rfa-files/RFA-ES-06-013.html). These improved exposure measures can be linked to GWA data to determine their relationships to genomic variants, as well as their potential for modifying the associations of these variants with disease.

Scientific Knowledge to be Achieved

The NIH-wide Genes, Environment, and Health Initiative (GEI) has the long-range goal of determining the etiology of common diseases by focusing on genetic and environmental factors that increase the risk of these diseases, and the interaction among these factors. GEI will provide valuable scientific contributions to minority health and health disparities research by collecting and analyzing genotype, phenotype, and exposure data, while simultaneously measuring other factors within disease subgroups (e.g., race, ethnicity, behaviors, geography, genetic backgrounds, exposures and social environments) that may lead to differential health outcomes.

The GWA component of GEI (GEI-GWA) will identify genetic variants associated with complex diseases and traits in initial genome-wide discovery studies and, as feasible and appropriate, will reduce false positive associations through suitable replication and follow-up strategies. It will also identify variations in gene-trait associations related to environmental exposures, to distinguish population subgroups potentially susceptible to these exposures. The GWA component will address potential pathways to disparities in health outcomes, including but not limited to environmental exposures, genetic variations and/or other underlying biological, race/ethnic, social, and familial factors, to the extent feasible with the data available in existing studies.

Objectives of this Research Program

This RFA will support Study Investigators to add genome-wide association studies to existing studies of diseases and traits of substantial public health impact. Although the focus of this RFA is on initial genome-wide scanning and replication studies, follow-up genotyping studies may be proposed. Study designs may include case-control, population, cohort, clinical, or family studies or clinical trials. Study Investigators may seek to identify associations of genetic variants with the presence of a particular disease or discrete trait (such as colorectal cancer or anxiety disorder), or with levels of a quantitative trait (such as cognitive function or visual acuity) and may examine interactions among genetic and environmental factors, susceptibility to multiple conditions, or associations of genes with disease risk factors, disease incidence, or therapeutic responsiveness. Studies focusing on a diverse set of conditions and traits will be supported through the GEI-GWA program; the scientific and programmatic priority of the proposed condition(s) or trait(s) will be evaluated using the criteria included in Section V. of this RFA.

A diversity of participant populations regarding age, sex, race/ethnicity, and environmental exposures will be supported under this RFA. Inclusion of environmental exposures is not required; availability of exposure data will be considered as part of the scientific merit in the context of the trait or condition being studied, and in programmatic review. The degree to which the application addresses gaps in knowledge about minority health and health disparities issues relevant to the U.S. population will also be considered as part of the scientific merit in the context of the trait or condition being studied and in programmatic review.

Investigators are expected to have access to data and sources of DNA from an existing study population(s) of sufficient size at the time that the application is submitted to adequately address the specific aims. Funding will be provided to support sharing phenotype and exposure data with a central database, and DNA specimens (or biospecimens for DNA extraction) with a central genotyping facility, as well as for collaborative activities (standardizing or harmonizing phenotypes where possible, assessing data quality, developing analytic strategies, etc.) and data analysis. No recruitment or specimen acquisition will be supported by this RFA. Awardees from two earlier solicitations: HG-06-014, Genome-wide Association Studies in the Genes and Environment Initiative Genotyping Facilities, and HG-06-032, Genome-wide Association Studies in the Genes and Environment Initiative Coordinating Center, support the genotyping and coordination activities of the program. Overall, NIH anticipates funding about 10 studies: 6 studies in FY07 under HG-06-033, 2-4 studies in FY08 under this RFA, and possibly 1-2 studies under a solicitation planned for release in FY09.

Each application should clearly define: the public health significance and genetic complexity of the trait(s) proposed for study; the need for a genome-wide association study (initial discovery phase or replication phase), as proposed in the application; the strength of the evidence for a genetic component for the trait; the anticipated size of a detectable genetic effect; and the power of the proposed sample to detect it. Choice of population and study design should be dictated and justified by the scientific questions addressed in the application, such as the epidemiology and biology of the disease or trait. Adequacy of informed consent for GWA studies and for controlled but widespread data access (described below) should be clearly described, along with any restrictions on research use of the data. Each application should also clearly describe the types, quality and completeness of the available phenotype and environmental exposure data, the strength of evidence for an environmental component for the trait, the anticipated size of the environmental effect, and the power to detect it.

This RFA may support a variety of study designs derived from existing population, family and clinical studies including, but not limited to, case-control, cohort, case-cohort, family-based studies, and clinical trials. Sources of, inclusion and exclusion criteria for, and generalizability of the population sample (whether cohort, case-control, etc) should be clearly described. Any potential biases in subject selection (including, if applicable, controls as well as cases) and approaches for minimizing these biases should be described.

Genome-wide genotyping will be performed by one of the GEI-GWA Genotyping Facilities, and should not be included in budget in responding to this RFA. We expect that Affymetrix and Illumina platforms will be available. It is anticipated that a minimum of 2.5 micrograms of DNA will be needed for the genome-wide genotyping. DNA extraction and whole genome amplification may be included in the budget, or may be performed at one of the GEI-GWA Genotyping Facilities. Applicants may provide suggestions on choice of genotyping platform, number of genetic markers and method of choosing genetic markers with respect to the proposed study population, design, analytic plan and biology and epidemiology of the disease or phenotype. Final decisions on genotyping platform and marker selection will be made by the GEI-GWA Project Scientist, in collaboration with the GEI-GWA Steering Committee.

Applicants should describe any previous genotyping carried out on the specimens to be submitted, particularly whether any genome-wide linkage or association studies have been carried out and how those data will be incorporated into the analyses proposed in this application. A strong justification should be provided for additional genotyping beyond what has already been performed, and a clear indication given of whether results of prior genotyping efforts will be included in the dataset submitted to National Center for Biotechnology Information (NCBI, see below). Applicants should also describe any known GWA studies by other investigators of the same disease or trait as proposed in their application, and explain how genotyping the proposed specimens will complement these efforts.

Phenotypes selected for GWA analysis should be unambiguously defined using standardized and validated methods where possible. Standardized and validated methods should also be described for any environmental exposures and other covariates proposed for inclusion in analyses. Completeness and validity of data on important covariates and environmental exposures, and the approach for using these data in genotype-phenotype association analyses, should be described.

Exposure data to be included in GWA analysis should be clearly described and may include: questionnaire- or interview-based information about environmental exposure to chemicals and biological toxins, diet, and physical activity; environmental monitoring data derived from analysis of air (particulates, gases), water, soil, sediment, or food samples collected in the personal, home, school or general environment; or previously collected body burden estimates. It is highly desirable to have available biospecimens (such as whole blood or serum, urine, hair, or RNA) for future analysis when new methods and technology for exposure assessment become available. Such testing will be done under a separate GEI solicitation. Applicants should describe the types of stored biospecimens from participants proposed for GWA or follow-up analysis, and the availability of these specimens for future use.

A detailed analytic plan should address issues related to the large amount of genomic data to be generated such as multiple testing and assessing complex interactions (e.g., gene by gene, gene by environment including gene by drug, pleiotropy, epistasis). The potential impact of population ancestry/history and stratification on 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 positives and adjust for multiple testing.

If proposing an initial genome-wide genotyping scan, applicants should describe their plans for replication and follow-up genotyping studies if an association is found, including current availability of a suitable replication sample. Applicants may propose a study for initial GWA (discovery) genotyping, for replication testing of a subset of associated markers from a prior GWA discovery study, or a combination of approaches. Plans for replication of GEI-GWA findings should be described in detail, whether proposed for support within GEI-GWA or not. Such plans should include strategies to minimize false negative as well as false positive associations, and should specify and justify the size and number of the replication phases and the criteria for retaining candidate markers from one stage to the next. Such criteria may include, for example, the anticipation of a few relatively strong genetic determinants vs. many relatively weak ones, and should be supported by available data or literature. Applicants should describe the similarity (or differences, if appropriate) between replication phases in terms of disease definition, populations, covariates, environmental exposures, study designs, and recommended genotyping technology, and the approach for dealing with multiple subphenotypes or extreme phenotypes, if applicable. Although the focus of this RFA is on initial genome-wide scanning and replication studies, follow-up genotyping studies may be proposed.

Study Investigators will receive the genotyping data from NCBI through the data access process described in Section 6. under Plan for Sharing Research Data. The data will include genotyping assays, genotype calls, quality scores, and .cel files (or their equivalent). NCBI will work with the Genotyping Facilities and Study Investigators to resolve any issues with the genotyping data prior to making the genotyping available for analysis. Study Investigators will have primary responsibility for analyzing genotype and phenotype data from their own studies, but may receive advice or assistance from the GEI-GWA Coordinating Center as funding permits. In contrast, the Coordinating Center will be responsible for cross-study functions, such as harmonizing data across studies and leading any cross-study analyses.

At some point in this overall analytic process, candidate markers of great interest (as defined by consistency of findings, magnitude of effect, biologic credibility, etc) will emerge and should be followed up by efforts to genotype with greater density in the areas surrounding the particular marker. Applicants should describe plans for such follow-up genotyping studies, if appropriate, in their replication strategies, as an option to be considered once the scope of follow-up genotyping is better defined. Such plans should include criteria for when to begin follow-up genotyping efforts, how to select candidates for these efforts and/or functional analysis of candidate variants, and when to move from follow-up genotyping with existing markers to direct resequencing efforts. These plans will likely be the subject of much discussion within the GEI-GWA collaborative group, which will work together to develop a consensus strategy for such studies. Note that, although future plans may describe sequencing and functional studies, only genotyping is currently anticipated for inclusion in this program; support for future sequencing or functional studies may be available through GEI using other mechanisms.

Applicants should describe their plans for ensuring the security and integrity of GEI-GWA data and for maintaining the privacy of study participants.

Program Organization

The GEI-GWA program is part of the larger GEI program, which includes additional initiatives in genetics and exposure biology. The GEI-GWA program includes FY07 awards for Study Investigators (HG-06-033), a Coordinating Center (HG-06-032), and Genotyping Facilities (HG-06-014), and this re-release of the Study Investigators RFA (HG-07-012). The awards funded under all GEI-GWA RFAs are cooperative agreements (see Section VI.2.A. Cooperative Agreement Terms and Conditions of Award).

Close interaction with the other components of the GEI-GWA program, including the NIH, will be required to develop appropriate strategies and tools to design, perform, and analyze genome-wide association studies. The awardees will meet as a GEI-GWA Steering Committee, which will include representatives from the Coordinating Center, Genotyping Facilities, Study Investigators, and NIH, 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 Genotyping group or an Analysis group. Key co-investigators, and pre- and postdoctoral trainees, in addition to the PIs, are eligible to attend these 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 computational biology, social sciences, public health, 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 budget. All unidentified, individual-level phenotypic, environmental exposure, and genotypic data proposed for GEI-GWA analysis will be made available to the scientific community through a controlled access process managed by NIH. Summary data and other non-identifying information such as study protocols, descriptions, and publications will be made openly available through a public web site and publication in the scientific literature.

This initiative will not support recruitment of human subjects, collection of human specimens, collection of medical or phenotype data, or studies using animal models. Applications that include recruitment of human subjects, collection of human specimens, collection of medical or phenotype data, or studies using animal models will be considered non-responsive and returned to the applicant.

Proof of appropriate informed consent for the previously collected data, 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.

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 NIH U01 Cooperative Agreement award mechanisms.

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".

NIH may reissue this RFA in FY09 to fund roughly 1-2 additional GWA studies as funding permits.

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 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 applications if your organization has any of the following characteristics:

Investigators from the NIH Intramural Research Program (IRP) will also be eligible to participate in the NIH-wide Genes, Environment, and Health Initiative (GEI). This will serve to expand the resources available to GEI, by encouraging significant participation of intramural investigators and staff whose salaries are already supported by the NIH. NIH is seeking a broad range of studies for inclusion in GEI, and recognizes that potentially eligible and meritorious studies may be ongoing within the IRP. Expanding this program to include IRP investigators will help GEI meet its goals of including the most highly scientifically meritorious projects, accessing diverse population samples, and ensuring programmatic balance across disease areas. It will also assist in meeting goals for enhancing intramural-extramural collaborations as outlined in the 2003 Institute of Medicine Report, Enhancing the Vitality of the National Institutes of Health. IRP investigators will not be directly competing for the R01 awards. They will be submitting requests to compete for the provision of IRP funds, which have been allocated for GEI. Requests for the participation of the NIH IRP will be competitively reviewed.

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.

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.

NIH Intramural Research Program (IRP)

The requests from NIH intramural scientists will be submitted using the format of PHS 398 application kit (http://grants.nih.gov/grants/funding/phs398/phs398.html). The NIH intramural scientist requests will be reviewed separately by the same peer review group.

3. Submission Dates and Times

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

3.A. Receipt, Review and Anticipated Start Dates
Letters of Intent Receipt Date: September 18, 2007
Application Receipt Date: October 18, 2007
Peer Review Date: March 2008
Council Review Date: May 2008
Earliest Anticipated Start Date: July 1, 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:

Emily L. Harris, Ph.D.
National Human Genome Research Institute
5635 Fishers Lane
Suite 4076, MSC 9305
Bethesda, MD 20892-9305
For overnight courier service use Rockville, MD 20852
Telephone: (301) 594-6524
FAX: (301) 402-1950
Email: [email protected]

3.B. Sending an Application to the NIH

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

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

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

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

Rudy Pozzatti, Ph.D.
Scientific Review Branch
National Human Genome Research Institute
5635 Fishers Lane
Suite 4076, MSC 9305
Bethesda, MD 20892-9305
For overnight courier service use Rockville, MD 20852
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 NIH. 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 GUIDANCE FOR STUDY INVESTIGATORS

Applicants should 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.

Applicants are expected to document access to existing DNA specimens and phenotypic data from an existing human population-, clinic-, or family-based study. Consistent with the data sharing plan, specimens should be available for sharing with GEI-GWA Genotyping Facilities within one month of award. Applicants should describe all relevant phenotypic and environmental exposure measures from the study. Applicants should provide strong justification for the choice of population and sampling design.

The applicant is expected to include summary phenotypic, exposure, and covariate data on subjects proposed for genotyping as part of the Research Plan in her/his application, including the distribution and the degree of missing data for each variable. Taken together, the text of the application and appendices should include sufficient information to evaluate the study design and measures that will be included in the study and GEI databases. Appendix information may include the study protocol or procedures manual and data collection instruments. As described below under Human Subjects, copies of the applicable existing informed consent forms should also be included as Appendices to the grant application. Study material included as Appendices should be submitted electronically (i.e., on CD) with the application (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-07-018.html).

Applicants who are being considered for an award under this RFA will be expected to send individual-level data to the National Center for Biotechnology Information (NCBI) within two weeks of receiving notice that they are being considered for an award. Award is contingent on consistency of the dataset with the summary data provided as part of the application, as assessed by NIH staff. Such applicants 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 they are being considered. Award is contingent on acceptable DNA quantity and quality as judged by the assigned Genotyping Facility. If an award is not made, individual-level data will be treated as confidential, in the same manner and under retention policies as all other information in a grant application; they will not become part of the GEI-GWA database and will not be shared. If an award is made, the individual-level data will become part of the GEI-GWA database and will be made available as described under Plans for Sharing Research Data. No funding will be available to the applicant to support these pre-award evaluations.

Applicants should describe prior experience in working as part of a research consortium or other collaborative activities to meet individual study and collaborative goals.

If selected, NIH intramural scientists will participate in GEI programs as Principal Investigators in accord with the Terms and Conditions of Award provided in this FOA.

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

The applicant should address human subjects issues, including sharing phenotypic and genetic data from individual participants with the broad scientific community.

Applicants are expected to demonstrate that the informed consent for the existing study population(s) allows for the genetic study proposed and sharing phenotypic and genetic data with the broad scientific community. If this is not the case, 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 should be provided. Plans for reconsent, including consent forms, must be approved by the NHGRI Program Director prior to implementation. Any restrictions on data use (such as limitations to a specific disease or condition or to non-commercial investigators) should be clearly described. Restrictions on data use will be considered in the selection process. Copies of the applicable existing informed consent forms should be included in the grant application. NIH staff will review existing consent forms to assess adequacy of language for sharing data or specimens with other researchers for future genetic research, and limitations on data use.

Applications that include recruiting human subjects, collecting human specimens, and/or collecting phenotypic or medical data will be considered non-responsive and returned to the applicant.

Applicants being considered for an award are expected to have in place appropriate Institutional Review Board (IRB) and any other required approvals when sharing individual-level data with NIH and submitting DNA specimens, or specimens from which DNA will be extracted, to an NIH-designated central genotyping facility. Applicants being considered for an award will also be required to document IRB approval when 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 reasonableness of the data sharing plan 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 expected to indicate whether they are willing to abide by the current NIH data release policy, as modified by the public input process described below. 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 soon establish a common policy for data release, publication, and intellectual property for GWA studies, and it is expected that all participants will 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 the GWA component of GEI 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 GEI-GWA Project Datasets for use by investigators throughout the global scientific community who, along with their institutions, certify their agreement with GEI policies ( Approved Users ). All participants in GEI-GWA (Study Investigators, Coordinating Center, Genotyping Facilities, NIH, and Approved Users) are expected to promote the GEI-GWA policies on data access, publication, and intellectual property summarized below, and describe their methods for doing so in the application. NIH, in collaboration with the GEI-GWA Steering Committee, will establish mechanisms to monitor data use in agreement with GEI policies.

The NIH, in consultation with the GEI-GWA Steering Committee, will make all final decisions concerning GEI-GWA policies. All GEI-GWA policies are subject to change by the NIH as deemed necessary to sustain program principles and priorities, or to ensure the highest standards for responsible research conduct within GEI operating procedures. Access to the GEI-GWA Database, managed by NCBI, will be overseen by the NIH in accordance with U.S. Government rules and policies.

Data Access: The GEI-GWA Database will comprise two sections: open access and controlled access. Information describing the phenotype data, such as the variables measured and protocols used to collect the data and specimens, but not the phenotype dataset itself, will be made available in the open access part of the GEI-GWA Database. GEI-GWA Project Datasets (genotype data as well as genotype-phenotype datasets along with pre-computed analyses of them) will be available through the controlled access section of the GEI-GWA Database. Although all GEI-GWA Project Datasets from funded applications will be made available through the controlled access section of the GEI-GWA Database, the NIH does not intend the GEI-GWA Database to become the exclusive source of GEI-GWA Project Datasets.

The genotype data generated for each specimen, plus unidentified phenotype and exposure data, are expected to be deposited in a controlled access section of the GEI-GWA Database as soon as both the phenotype and exposure data submitted by Study Investigators and the GEI-GWA genotype data have passed appropriate data quality assessments; quality standards will be developed by the GEI-GWA Steering Committee in collaboration with NCBI and NHGRI. Simple, unadjusted genotype-phenotype associations ( pre-computes ) will be calculated and posted in the GEI-GWA Database, along with a listing of all variants known to be in strong linkage disequilibrium with variants showing significant association with a phenotype or trait. Other analyses, such as annotated information on genes and genomic features in identified regions of interest, may be provided as well.

Access to GEI-GWA Project Datasets through the GEI-GWA Database will be provided for research purposes through a Data Access Committee (DAC). To become an Approved User, investigators seeking data from the controlled access section of the GEI-GWA Database should submit a Data Use Certification that is co-signed by the designated Institutional Official, for approval by the GEI-GWA DAC. The Data Use Certification will include a brief description of the proposed research use of the requested GEI-GWA Project Dataset(s). As part of the Data Use Certification, investigators will stipulate that they will: use the data only for the approved research use; protect data confidentiality; follow all applicable laws and any local institutional policies and procedures for handling GEI-GWA Project data; not attempt to identify individual participants from whom data within a dataset were obtained; not sell or share any of the data elements from datasets obtained from the GEI-GWA Database with third parties, other than sharing with their own research staff who have agreed to GEI policies; and provide annual progress reports on research. Access to a GEI-GWA Project Dataset through the GEI-GWA Database will be approved by the DAC following: completion of the Data Use Certification; and confirmation that the proposed research use is consistent with any constraints identified by the Study Investigators who submitted the data to the GEI-GWA Database.

The terms and conditions governing data access for research use of GEI-GWA Project Datasets for GEI-supported investigators and NIH will be identical to those for any other member of the scientific community seeking to become an Approved User, except that a Study Investigator may be able to identify individual participants in her or his own study and may share her or his own data with third parties at her or his discretion. All Submitted specimens provided to GEI-GWA Genotyping Facilities by Study Investigators for GEI-GWA use will be returned or destroyed following the completion of the specified genotyping services according to the procedures set by the contributing study site.

Publication Policy: Beginning on the date that a GEI-GWA Project Dataset is released for distribution through the GEI-GWA Database, there will be a period of nine months during which Study Investigators are expected to retain the exclusive right to submit publications developed with the data and specimens they contributed. During such nine-month period of exclusivity, Approved Users will have access to data in the GEI-GWA Database, but would be expected to agree not to submit for publication any results or analyses derived from the use of any GEI-GWA Project Dataset within that period without consent of the Study Investigator. Submission of publications using GEI-GWA genotype data only that may be available through dbSNP is permissible during this period. Study 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 GEI-GWA Project Datasets will acknowledge the Study Investigator(s) who conducted the original study and the funding organization(s) that supported the work.

Intellectual Property Policy: The NIH expects that GEI-supported data, and conclusions derived directly from the data therefrom ,will remain freely available, without any licensing requirements, for uses, such as 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 in a manner that would prevent use of or block access to any genotype-phenotype data developed with GEI support. The NIH encourages broad use of GEI-GWA 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 the GEI-GWA Project Datasets and the GEI-GWA Database could substantially diminish the utilization of information and the potential public benefit they could provide. Approved Users and GEI-supported investigators, and their institutions, should acknowledge the GEI-GWA IP Policy, the goal of which is to ensure the greatest possible public benefit from GEI-GWA Project Datasets.

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 the GWA component of GEI is a community resource project, NIH expects that not only data, but also resources generated during the course of the program, such as 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? Does the application address a significant and genetically complex trait and demonstrate the need for a genome-wide association study for this trait? When scientifically appropriate to the trait or disease being studied, does the application address minority health and health disparities relevant to the U.S. population?

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? Are the study design and population chosen appropriate for the aims proposed? Are the proposed plans to share data in a timely manner adequate? Have the sources and generalizability of study subjects, particularly the controls (if applicable) been clearly described, have any potential biases in subject selection been identified, and are the applicants approaches for minimizing these biases appropriate? When scientifically appropriate to the trait or disease being studied, are important exposures or covariates available for analysis and inclusion in the GEI datasets? Are the phenotype and exposure measures to be included in the GEI datasets of sufficient quality and completeness to provide maximal scientific value from the addition of GWA genotyping?

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 this data set offer over others in terms of strategies for data management and data analysis? What advantages does it offer for replication studies and follow-up studies to identify causative genetic variants and develop diagnostic, preventive, or therapeutic strategies? What is the richness of the dataset for future studies that may be based on other phenotypes or benefit from information on environment exposures? What advantages does it offer for the investigation of new measures of environmental exposures developed by the GEI exposure biology component?

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?

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

The NIH has identified the GWA component of GEI 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 should 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 that all participants are expected to agree to abide by that policy; see Request for Information (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-06-094.html).

Data Sharing Plan: The reasonableness of the data sharing plan may 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. Any accepted 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.

Program staff will be responsible for the administrative review of any plan submitted for sharing data. The adequacy of such 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 such data sharing plan with the awardee before recommending funding of an application. The final negotiated version of any data sharing plan will become a condition of the award of the cooperative agreement. The effectiveness of such 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 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 any plan submitted for sharing research resources.

The adequacy of such 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 such data and resource sharing plans with the awardee before recommending funding of an application. The final version of any data and resource sharing plans negotiated by both will become a condition of the award of the grant. The effectiveness of such 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 July 1, 2008.

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 the GWA component of GEI 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 this RFA, and that all awardees will agree to abide by that 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 Notice of Award. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part4.htm) and Part II Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_part9.htm).

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

2.A. Cooperative Agreement Terms and Conditions of Award

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

The administrative and funding instrument used for this program will be the cooperative agreement (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 the project within the guidelines of RFA HG-07-012 and for performing the scientific 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 NIH Project Scientist will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below.

The GEI-GWA Project Scientist is a scientist of the NIH 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 GEI-GWA program and that NIH staff will be given the opportunity to offer input to this process. The GEI-GWA Project Scientist will participate as a member of the GEI-GWA Steering Committee and will have one vote. The GEI-GWA Project Scientist will have the following substantial involvement:

An NHGRI Program Director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice. The NHGRI Program Director may also serve as the GEI-GWA Project Scientist.

Other NIH staff may assist the awardees as designated by the Project Scientist and Program Director.

An NIH-wide GEI Coordinating Committee, administratively led by the National Human Genome Research Institute (NHGRI) and the National Institute of Environmental Health Sciences (NIEHS) will participate in the selection of awardees, oversee the complex set of GEI programs, including the GEI-GWA program, and ensure coordination of GEI throughout the NIH.

The NCBI is substantially involved. Prior to making awards, they will provide technical evaluation of the individual-level data that are shared by applicants for Study Investigators (RFA-HG-07-012). NCBI will manage and maintain security for the GEI-GWA database. They will work with the Genotyping Facilities, the Coordinating Center, and Study Investigators, as appropriate, to ensure data integrity and clarify data definitions.

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

2.A.3. Collaborative Responsibilities

The Genes, Environment, and Health Initiative (GEI) is a four-year, NIH-wide program. GEI is a multi-component program involving several related solicitations. A major component will support genome-wide association studies (GWAS), either in an initial discovery phase (assaying single nucleotide polymorphisms, or SNPs, to capture at least 80% of human genomic variation), or in a replication phase (assaying a subset of the most strongly associated SNPs or other genetic variants in one or more additional groups of subjects), or both. Other GEI genetics components under consideration for future solicitations include development of data analytic methods, further replication and follow-up genotyping studies, sequencing, functional studies, database development, and clinical translation. RFA-HG-06-033 for Study Investigators and this reissue of that RFA, in concert with RFA-HG-06-032 for a Coordinating Center and RFA-HG-06-014 for Genotyping Facilities, comprise the GWA component of GEI (GEI-GWA).

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 association studies. The awardees from all GEI-GWA RFAs and the GEI-GWA Project Scientist will meet as the GEI-GWA 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 GEI-GWA Steering Committee will serve as the main governing board of the GEI-GWA program. The GEI-GWA Steering Committee will be responsible for coordinating the activities being conducted by the GEI-GWA program. The GEI-GWA Steering Committee membership will include one GEI-GWA Project Scientist and the PI from each awarded cooperative agreement. The awardees funded through RFA-HG-06-033, Genome-wide Association Studies in the Genes and Environment Initiative Study Investigators, RFA-HG-06-032, Genome-wide Association Studies in the Genes and Environment Initiative Coordinating Center, which supports the coordination and analytic needs of this program, and RFA-HG-06-014, Genome-wide Association Studies in the Genes and Environment Initiative Genotyping Facilities, which supports the genotyping needs of this program, will also participate in the program and be members of the GEI-GWA Steering Committee. The GEI-GWA Steering Committee may add additional members, and other government staff may attend the GEI-GWA Steering Committee meetings as desired. It is anticipated that additional coordination mechanisms will be set up with other U.S. and international groups that may collaborate with the GEI-GWA program.

To address particular issues, the GEI-GWA Steering Committee may establish working groups as needed, which will include representatives from the program and the NIH and possibly other experts. These might include groups to: 1) assess and enhance standardization and comparability of phenotypic and exposure variables across studies undergoing GEI-GWA genotyping; 2) address data management issues; 3) propose and evaluate strategies for follow-up of GEI-GWA discovery and replication findings; 4) develop quality standards and methods to assess data quality; and 5) handle communication issues and develop principles for reporting findings.

A goal of this program is for all unidentified phenotypic, environmental exposure, and genotypic data proposed for GEI-GWA analysis in individual research subjects to be made available to the scientific community through a controlled access process managed by NIH. Summary data and other non-identifying information such as study protocols, descriptions, and publications are also expected to be made openly available through a public web site and publication in the scientific literature.

Awardees are expected to agree to:

A Scientific Advisory Panel (SAP) will be established by the NIH to evaluate the progress of the GEI-GWA program. The SAP will provide recommendations to the Director of NHGRI, the National Advisory Council for Human Genome Research, and the NIH GEI Coordinating Committee about the progress and scientific direction of all components of the GEI-GWA program. The SAP will be composed of six to eight senior scientists with relevant expertise, although the membership may be enlarged permanently or on an ad hoc basis as needed.

The SAP 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 GEI-GWA Steering Committee to allow the members of the both the SAP and the GEI-GWA Steering Committee to interact directly. Twice a year the SAP will make recommendations regarding progress of the GEI-GWA program and present advice to the Director of NHGRI, the National Advisory Council for Human Genome Research, and the NIH GEI Coordinating Committee about changes, if any, which may be necessary in the GEI-GWA 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 data and specimens that have been shared with the designated Genotyping Facility and NCBI database(s), respectively. The quarterly report will be used as a management tool for the NIH and the GEI-GWA Steering Committee to determine the most efficient approaches to conducting studies and to identify early any correctable problems. 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:

Emily L. Harris, Ph.D.
National Human Genome Research Institute
5635 Fishers Lane
Suite 4076, MSC 9305
Bethesda, MD 20892-9305
For overnight courier service use Rockville, MD 20852
Telephone: (301) 594-6524
FAX: (301) 402-1950
Email: [email protected]

2. Peer Review Contacts:

Rudy Pozzatti, Ph.D.
Scientific Review Branch
National Human Genome Research Institute
5635 Fishers Lane
Suite 4076, MSC 9305
Bethesda, MD 20892-9305
For overnight courier service use Rockville, MD 20852
Telephone: (301) 496-7531
FAX: (301) 435-1580
Email: [email protected]

3. Financial or Grants Management Contacts:

Ms. Cheryl Chick
Grants Administration Branch
National Human Genome Research Institute
5635 Fishers Lane
Suite 4076, MSC 9306
Bethesda, MD 20892-9306
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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