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 and Environment 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 and Environment Initiative Coordinating Center (U01)

Announcement Type
New

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

• October 27, 2006 - See Notice NOT-HG-07-001 Availability of Additional Information.
• October 13, 2006 - See Notice NOT-OD-07-006, This notice is to inform potential applicants that investigators from the NIH Intramural Research Program (IRP) will be eligible to participate in the NIH-wide Genes and Environment Initiative (GEI)..

• The purpose of this funding opportunity is to provide support for a Coordinating Center (CC) to serve as a centralized resource to facilitate and support genome-wide association studies and other research activities of the four-year NIH-wide Genes and Environment Initiative (GEI).
• $1.2 million in FY 2007 funds have been committed to fund applications received in response to this RFA.
• It is anticipated that one award will be made under this RFA. Awards are contingent on the availability of funds and the submission of a sufficient number of meritorious applications.
• The total project period for an application submitted in response to this RFA may not exceed four years.
• This RFA will use the U01 Cooperative Agreement award mechanism.
• Eligible organizations include: For-profit organizations; non-profit organizations; public or private institutions, such as universities, colleges, hospitals, and laboratories; units of State and local governments; eligible agencies of the Federal government; and domestic institutions.
• Eligible principal investigators include individuals with the skills, knowledge, and resources necessary to carry out the proposed research. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.
• See Section IV.1 for application materials.
• Telecommunications for the hearing impaired is available at: TTY 301-451-5936.

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 a Coordinating Center (CC) to serve as a centralized resource to facilitate and support genome-wide association studies and other research activities of the four-year NIH-wide Genes and Environment Initiative (GEI) (http://www.genome.gov/17516707).

The Genes and Environment Initiative (GEI) is a four-year, NIH-wide program proposed in the President’s FY2007 budget and currently awaiting Congressional approval. If approved, the program will support efforts 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 developed and 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 intended to be a multi-component program involving several related solicitations. A major component (GEI-GWA) 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 fine mapping 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 will be the focus of this first 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 under consideration include development of environmental sensors for measurement of 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 these population samples for investigation of 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, genotype data produced by GEI-GWA will be combined with phenotype and exposure data shared by the Study Investigators, according to their data sharing plans, and will be made rapidly and widely available for research use, consistent with evolving NIH policies on data sharing in GWAS (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-06-094.html).

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 cancer, 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 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 samples and perform extensive and often repeated measurements of physical characteristics, disease risk factors and outcomes, and environmental exposures. These samples are now well suited for application of HapMap-based, genome-wide association technology, either as initial discovery studies interrogating the entire genome, or as follow-up replication studies to confirm initial results with additional population samples.

Interrogation of the genome with hundreds of thousands of genotype assays remains costly and has the potential for producing many false positive associations, even at the most stringent levels of type I error correction. This may best be dealt with by using a multi-stage design, in which very large numbers of markers are typed in a subset of a given population sample, and those most strongly associated with the trait of interest are subsequently typed in the remainder of the sample. Various strategies have been proposed for analyzing the resulting data, such as separate, independent analyses or a joint analytic scheme. Replication of findings in an independent study sample, collected under different conditions or by different investigators, has been suggested as a requirement for publication of GWAS findings. Strategies for reducing false discoveries and identifying true positives in a rapid and cost-effective way are currently the subject of intense research. Other analytic issues, such as identification of gene-gene and gene-environment interactions, interpretation of resequencing data, and adjustment for population structure, are also subjects of active investigation, which will be further stimulated by the wide availability of GWA data.

Genotyping platforms are also continuing to evolve, with ever-larger numbers of SNPs available for typing at progressively lower costs. A variety of approaches has been proposed for selecting a set of tag SNPs to capture the majority of inter-individual genomic variation for use in GWA discovery scans, and for determining which subsets of associated markers should be followed up in replication studies. SNP selection can also be limited by genotyping platforms, and generally becomes less flexible as the number of SNPs to be assayed increases. Patterns of linkage disequilibrium (LD) and founder effects also influence the selection of markers, with larger numbers needed for populations with lower levels of LD, such as those of recent African ancestry, and potentially different markers needed for those with strong founder or selection effects. 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. Family, social and cultural influences that may modify the pathophysiologic responses to environmental exposures will be considered to the extent that they can be measured in biological assays. 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. 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 and Environment 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 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 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 a Coordinating Center (CC) to facilitate and support the activities of the GEI genome-wide association program and, as needed, for GEI-supported replication and fine mapping activities, sequencing, functional studies, etc. Two accompanying solicitations: HG-06-014, Genome-wide Association Studies in the Genes and Environment Initiative Genotyping Facilities, and HG-06-033, Genome-wide Association Studies in the Genes and Environment Initiative Study Investigators, will support the genotyping and data/sample sharing and analysis activities of the GEI-GWA project. Overall, NIH anticipates funding 12-15 studies: 8-10 studies under HG-06-033, and roughly six studies under solicitations planned for release in FY08 and FY09.

Genotyping data produced through GEI-GWA funding will be combined with phenotype and exposure data shared by the Study Investigators with a restricted-access database under development by the National Center for Biotechnology Information (NCBI). Access to genotype, phenotype, and exposure data from individual participants and monitoring of the research use of these data will be managed administratively by NIH. NCBI will have primary responsibility for development of the genotype-phenotype database and distribution of data and associated materials (protocols, data dictionaries, etc), including initial genotype-phenotype associations. NCBI will also have primary responsibility for clarifying genotyping quality issues with individual genotyping centers and data definitions with each individual study’s investigators and/or existing coordinating center.

In most cases, NCBI will work directly with Study Investigators and their specific study’s Coordinating Center to verify and format the phenotype and exposure data shared and provide appropriate documentation of data collection protocols. But, in some instances, Study Investigators may no longer have a Coordinating Center or investigators funded for this purpose. The GEI-GWA CC should be prepared to assist in this process, providing appropriate expertise for interpreting available phenotypic and environmental exposure data, evaluating its quality, and obtaining suitable documentation for submission to NCBI in collaboration with the Study Investigators.

Although GEI-GWA will seek to include a wide variety of diseases and traits for its GWA studies, it is anticipated that many studies will include similar or identical traits (body mass index, serum creatinine, cognitive function) suitable for cross-study analyses. Many studies are also likely to include similar measures of environmental factors such as interview- or questionnaire-based information on exposure to chemicals or biologic toxins, or cigarette smoke, dietary intake, or physical activity, or environmental monitoring data. The GEI-GWA CC will play a major role in assessing the standardization, reproducibility, and comparability of these common variables in collaboration with the Study Investigators and NIH. It will work within this collaboration to provide bioinformatic and statistical support for cross-study analyses, including construction of harmonized variables and common data elements, preparation of analytic data sets, development of analytic methods and software, and calculation of associations and other analyses as needed where methods, phenotypes, and/or exposures are similar across genotyped studies. These variables, datasets and tools will be provided to NIH as appropriate for posting on public websites or dissemination through controlled access processes.

GEI-GWA anticipates supporting multiple genotyping facilities, potentially using multiple genotyping technologies, to encourage continued improvements in methodologies and cost-efficiencies within the program and to provide the ability to compensate for possible poor performance by one facility or take advantage of an improved platform. Quality control standards for these technologies will to some extent be technology-specific, but comparability across technologies must be assessed and cross-platform standards established. The GEI-GWA CC will play a major role in defining these standards, particularly in providing analytic support for determining the best and most streamlined set of standards that will produce high-quality, complete, and comparable data across GEI-GWA Genotyping Facilities. The GEI-GWA CC will apply these standards to data produced by the Genotyping Facilities to assess comparability and suitability of data for cross-study or cross-phase (discovery, replication, fine-mapping, etc) analyses and for comparable data arising from other studies (Genetic Association Information Network or GAIN, Wellcome Trust case-control consortium, etc) proposing to collaborate with GEI-GWA. The GEI-GWA CC will also work with NCBI and the Genotyping Facilities to provide analytic support for genotyping quality control assessments within individual genotyping facilities as needed, including evaluation of data on blind replicates, quality of amplification, trend analysis , etc.

Development of strategies for replication and follow-up studies, including subject selection, sample sizes, joint vs. individual analyses, etc., are subjects of active research that is likely to continue for the duration of GEI-GWA, as described above. The GEI-GWA CC will contribute to the development of these strategies by providing statistical support for modeling and selecting options for replication and follow-up studies, and, as appropriate, for selecting targets for sequencing and functional studies. It will also provide statistical support for further development of analytic methods in collaboration with the other components of the GEI-GWA project. The GEI-GWA CC will provide support and back-up as needed to Study Investigators for data analysis (especially multi-study analyses), to NCBI for assessing genotype data quality (especially comparability across platforms and over time), and to the GEI Program Office for program management.

The Coordinating Center funded by this RFA will manage the logistics of the GEI-GWA program in collaboration with the NIH Program Office, including organizing meetings and teleconferences, distributing materials, recording draft minutes for Program Office review, etc. The CC will also be responsible for obtaining reports and other information from the Study Investigators, Genotyping Facilities, and other investigator participants in the GEI-GWA and preparing reports for review by NIH program staff, outside advisors, etc.

Funding will be provided for data analysis, coordination, monitoring, supporting, and logistical activities. No recruitment, data collection, or sample acquisition will be supported by this RFA.

Study Investigators will be responsible for study design and analysis of their individual studies. The Genotyping Facilities will be responsible for producing high-quality genotyping data. The Coordinating Center will be responsible for providing support and assistance to accomplish the goals of GEI-GWA, including providing support and assistance to the Study Investigators and Genotyping Facilities to accomplish their goals, and conducting any cross-study analyses. Applicants should describe their experience in working as part of a research consortium or other collaborative activities that included both laboratory and clinical/epidemiologic partners.

Applicants for the Coordinating Center should address design and biostatistical issues related to GWA discovery and replication studies and follow-up studies. Points to consider include selection of genetic markers and platforms, proportion of genomic variation to be assayed and variations in proportion captured across platforms and study populations, definition and standardization of phenotypes and environmental exposures, sample size requirements, and corrections for multiple comparisons. The Coordinating Center will work collaboratively with NCBI, which will receive data directly from the Genotyping Facilities and Study Investigators and provide data directly to the Coordinating Center for assessment of data quality, standardization, and cross-study comparability as described above. Coordinating Center applicants should discuss the mechanics of interacting with NCBI, Genotyping Facilities, and Study Investigators and provide a variety of models under which this can be achieved depending on the capabilities of the other participants and the complexity of the data involved.

The GEI-GWA program 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. Applicants should describe analytic challenges related to these various designs and challenges in combining the resulting data, as well as approaches to minimizing any associated biases. Applicants may provide suggestions on choice of genotyping platform, number of genetic markers and method of choosing them 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 in collaboration with the GEI-GWA Steering Committee and the GEI-GWA Project Scientist.

Applicants should describe their plans for facilitating and supporting the activities of the GEI-GWA program in collaboration with the Study Investigators, Genotyping Facilities, and NIH. Such activities include:

• Approaches for selecting phenotypes for GWA analysis, including assessment of standardization, comparability, and validity of phenotype definitions should be described. Approaches for assessing completeness and validity of data on important covariates and environmental exposures, and for selecting and using these data in genotype-phenotype association analyses and assessment of gene-environment interaction, should be described.
• A detailed analytic plan should address issues related to the large amount of GWA 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 GWA 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.
• Applicants should describe strategies for designing replication and follow-up studies if an association is found, including criteria for selecting a particular strategy and for evaluating its superiority over other strategies. Such plans should describe approaches 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 impact and desirability of similarities (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.
• 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 strategies for designing such fine mapping studies, including approaches to developing criteria for when to begin fine-mapping efforts, how to select candidates for these efforts, and when to move from fine mapping with existing markers to direct resequencing efforts and/or functional analysis of candidate variants. 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.

The exact boundaries of the activities of the GEI-GWA Coordinating Center, Study Investigators, and NCBI are not possible to predict at this time, and will depend in large degree on the capacities and experience of the Study Investigators selected. These responsibilities will need to be negotiated once the project is funded and underway, and may change as new Study Investigators are added with the anticipated re-issuance of the Study Investigators RFA in FY08 and FY09. Applicants should describe their willingness to be flexible in assuming or relinquishing responsibilities as program needs arise.

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 will include additional initiatives in genetics and exposure biology. The GEI-GWA program includes awards for a Coordinating Center (this RFA), Genotyping Facilities (HG-06-014), and Study Investigators (HG-06-033). The awards funded under all three GEI-GWA RFAs will be 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.

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

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

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".

2. Funds Available

• The expected amount for the award is approximately $4,800,000 (total costs) over the full project period.
• The NIH anticipates funding one new award in response to this announcement.
• An applicant should request a project period of four years.
• The expected amount for the award is approximately $3,200,000 direct costs over the full project period, approximately $800,000 direct costs each year.
• The anticipated start date is July 1, 2007 and the period of performance is July 1, 2007 to June 30, 2011.

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 if your organization has any of the following characteristics:

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

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

An applicant may submit one application in response to this RFA.

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
Letters of Intent Receipt Date(s): November 1, 2006
Application Receipt Date(s): November 29, 2006
Peer Review Date(s): March, 2007
Council Review Date(s): May, 2007
Earliest Anticipated Start Date(s): July 1, 2007

3.A.1. Letter of Intent

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

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

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

The letter of intent is to be sent by the date listed at the beginning of this document.

The letter of intent should be sent to:

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

The awardee must have demonstrated experience in evaluation and analysis of phenotypic and environmental exposure data relevant to a variety of disease conditions and traits.

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.

Plan for Sharing Research Data

All applicants must 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 should provide specific plans for data sharing and data release in the application and indicate his/her willingness 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, after public input, NIH will establish a common policy for data release, publication, and intellectual property for GWA studies and that all participants will agree 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 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. The NIH, in collaboration with the GEI-GWA Steering Committee, will establish mechanisms to monitor data use in agreement with GEI-GWA 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-GWA operating procedures. Access to the GEI-GWA Database, managed by the 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 samples, 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 sample, plus unidentified phenotype and exposure data, will 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-GWA 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 Samples 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 retain the exclusive right to submit publications developed with the data and samples they contributed. During this nine-month period of exclusivity, Approved Users will have access to data in the GEI-GWA Database, but will 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 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 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 requires that grant awardee recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication (NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/index.htm and http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part7.htm#_Toc54600131). Investigators responding to this funding opportunity should include a plan for sharing research resources addressing how unique research resources will be shared or explain why sharing is not possible.

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

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:

• Scientific merit of the proposed project as determined by peer review
• Availability of funds (requires approval of GEI funding in the President s FY2007 budget)
• Relevance of program priorities
• Synergy with other funded projects

Additional criteria for award will include:

• Willingness of PI and major co-investigators to collaborate with the NIH and with Study Investigators and Genotyping Facilities participating in the GEI-GWA program

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:

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

The goals of NIH supported research are to advance our understanding of biological systems, to improve the control of disease, and to enhance health. In their written critiques, reviewers will be asked to comment on each of the following criteria in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that an application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward.

Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge or clinical practice be advanced? What will be the effect of these studies on the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field? Does the application address the problem outlined in this RFA?

Approach: Are the conceptual or clinical framework, design, methods, and analyses adequately developed, well integrated, well reasoned, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? Are the proposed plans for providing operational and analytic coordination and support likely to promote productive collaborations and provide maximal scientific value? Are the proposals for promoting cross-study analyses, constructing harmonized variables, and preparing analytic data sets adequate? Are the plans for ensuring comparability across Genotyping Facilities, assisting with quality control, providing logistical support and fulfilling Coordinating Center functions likely to increase the synergy and productivity of the program? Are the plans to share data in a timely manner adequate?

Innovation: Is the project original and innovative? For example: Does the project challenge existing paradigms or clinical practice; address an innovative hypothesis or critical barrier to progress in the field? Does the project develop or employ novel concepts, approaches, methodologies, tools, or technologies for this area? Does the application propose novel approaches or methods for promoting cross-study collaboration and analysis? Valid statistical and computational methods for doing this may represent sufficient innovation for this RFA.

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.

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 will 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. The presence of a data sharing plan will be part of the terms and conditions of the award. The funding organization will be responsible for monitoring the data sharing policy. http://grants.nih.gov/grants/policy/data_sharing.

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 requires that grant awardee recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication (See the NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps/part_ii_5.htm#availofrr and

http://www.ott.nih.gov/policy/rt_guide_final.html). Investigators responding to this funding opportunity should include a sharing research resources plan addressing how unique research resources will be shared or explain why sharing is not possible.

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

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

3. Anticipated Announcement and Award Dates

It is anticipated that awards will be made by July 1, 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 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 the GEI-GWA Program, 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-06-032 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:

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

Interact with all of the participants of the GEI-GWA program to determine data standards and approaches for joint analyses.

Provide integrative and supporting function for entire GEI genome-wide association program and, as needed, for GEI-GWA replication and fine mapping activities, sequencing, functional studies, etc.

Provide support and back-up as needed to Study Investigators for data analysis (especially multi-study analyses), to NCBI for assessing genotype data quality (especially comparability across platforms and over time), and to GEI-GWA Program Office for program management.

Provide high-quality documentation as needed, particularly of variables defined for cross-study analysis, including study protocols, manuals, coding, and other information that will be sufficient for outside users to understand and use the data with minimal assistance.

Share results according to the data sharing policy developed for and by this program.

Ensure that the data and analytic tools produced by the CC are made publicly available and can be retrieved from the CC through multiple methods of querying, including simple web interfaces for common standard queries and tools and more complex methods as appropriate.

Fully disclose all database schema, algorithms, software source code, and methods to the other members of the program for purposes of scientific evaluation and application.

Participate in group activities, including a study-wide, GEI-GWA Steering Committee to share design and analysis techniques and promote comparability across genotyped studies wherever possible.

Not disclose confidential information obtained from other members of the program.

Adhere to policies regarding data access, publication, and intellectual property established by NIH and the GEI-GWA Steering Committee for this program.

Adhere to NIH policies regarding genome-wide association studies and other policies that might be established during the course of this activity.

Submit periodic progress reports in a standard format, as agreed upon by the GEI-GWA Steering Committee and Scientific Advisory Panel.

Attend GEI-GWA Steering Committee meetings and accept and implement the common guidelines and procedures approved by the GEI-GWA Steering Committee, Scientific Advisory Panel, and NIH.

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 GWA-GEI Project Scientist will have the following substantial involvement:

• Participate with the other GEI-GWA Steering Committee members in the group process of setting research priorities, deciding optimal research approaches and protocol designs, and contributing to the adjustment of research protocols or approaches as warranted. The GEI-GWA Project Scientist will assist and facilitate the group process and not direct it.
• Make the assignment of genotyping projects to the Genotyping Facilities.
• Serve as a liaison, helping to coordinate activities among and for the awardees, including acting as a liaison to the NIH, and as an information resource for the awardees about genome research activities. The GEI-GWA Project Scientist will also coordinate the efforts of the GEI-GWA program with other groups conducting similar GWA studies.
• Attend all GEI-GWA Steering Committee meetings as a voting member and assist in developing operating guidelines, quality control procedures, and consistent policies for dealing with recurrent situations that require coordinated action. The GEI-GWA Project Scientist should be informed of all major interactions of members of the GEI-GWA Steering Committee. The GEI-GWA Project Scientist will be responsible for working with the GEI-GWA Coordinating Center to schedule the time and prepare concise minutes or summaries of the GEI-GWA Steering Committee meetings, which will be delivered to members of the group within 30 days after each meeting.
• Report periodically on the progress of the GEI-GWA Program to the Director, NHGRI and to the National Advisory Council for Human Genome Research.
• Retain the option to recommend the withholding or reduction of support from any project that fails to achieve its goals or comply with the Terms and Conditions of award.
• Provide relevant expertise and overall knowledge of NIH-sponsored research to facilitate the selection of scientists not affiliated with the awardee institutions to serve on the Scientific Advisory Panel.
• Serve as a liaison between the GEI-GWA Steering Committee and the Scientific Advisory Panel, attending Scientific Advisory Panel meetings in a non-voting liaison member role.
• Serve on subcommittees of the GEI-GWA Steering Committee and the Scientific Advisory Panel, as appropriate.
• Assist awardees in the development, if needed, of policies for dealing with situations that require coordinated action.
• Provide advice in the management and technical performance of the award.
• Assist in promoting the availability of the GEI-GWA data and related resources developed in the course of this program to the scientific community at large.
• Participate in data analyses, interpretations, and, where warranted, co-authorship of the publication of results of studies conducted through the GEI-GWA program.
• 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.
• The Program Director may withhold or reduce support from the Coordinating Center if it fails to achieve its goals or comply with the Terms and Conditions of Award.

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 meta-data and, when appropriate, individual-level data that are shared by applicants for Study Investigators (RFA-HG-06-033). 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.

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 three 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 the GEI-GWA Project Scientist and the P.I. from each awarded cooperative agreement. The awardees funded through the concurrent RFAs, HG-06-014, Genome-wide Association Studies in the Genes and Environment Initiative Genotyping Facilities, which will support the genotyping needs of this program, and HG-06-033, Genome-wide Association Studies in the Genes and Environment Initiative Study Investigators, which will support the data/sample sharing and analytic 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.

All unidentified phenotypic, environmental exposure, and genotypic data proposed for GEI-GWA analysis in individual research subjects 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.

Awardees agree to:

• Participate in GEI-GWA Steering Committee meetings (expected to occur three times per year in the Bethesda, MD area) and regular telephone conference calls.
• Cooperate with other awardees in the development and design of research methods, protocols, tools, and strategies.
• Abide by common definitions, protocols, procedures, etc. as chosen by majority vote of the GEI-GWA Steering Committee.
• Actively seek to exchange analytical methods and potentially data sets with other awardees in the Program.
• Accept and comply with study policies established by NIH, and with additional non-conflicting policies approved by the GEI-GWA Steering Committee.
• Cooperate with other awardees in the publication and dissemination of GEI-GWA Program results and the eventual release to the scientific community of methods, tools, and results, and other resources.

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

The awardee will be required to submit electronically quarterly reports that describe the Coordinating Center support and facilitation activities. 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 supporting and facilitating the GEI-GWA program 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]

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 PA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople.

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

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

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

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