Department of Health and Human Services

Part 1. Overview Information
Participating Organization(s)

National Institutes of Health (NIH)

Components of Participating Organizations

National Human Genome Research Institute (NHGRI)

Funding Opportunity Title

Population Architecture Using Genomics and Epidemiology (PAGE), Phase II – Study Investigators (U01)

Activity Code

U01 Research Project – Cooperative Agreements

Announcement Type

New

Related Notices

None

Funding Opportunity Announcement (FOA) Number

RFA-HG-12-010

Companion Funding Opportunity

RFA-HG-12-015, U01, Population Architecture Using Genomics and Epidemiology (PAGE), Phase II – Coordinating Center

Number of Applications

See Section III. 3. Additional Information on Eligibility.

Catalog of Federal Domestic Assistance (CFDA) Number(s)

93.172 

Funding Opportunity Purpose

The purpose of this funding opportunity is to provide support for investigators to sample and assess genomic variation from well-phenotyped individuals of non-European (EA) ancestry and disseminate the resulting data to form a population resource that will expand understanding of ancestral differences in genomic disease associations. This four-year program will extend the initial experience of PAGE I to add large-scale, dense assays of common and rare coding and/or potentially functional genomic variation in a large number of non-EA ancestry participants with existing and extensive phenotype information.

Key Dates
Posted Date

June 20, 2012

Open Date (Earliest Submission Date)

September 18, 2012

Letter of Intent Due Date

September 18, 2012

Application Due Date(s)

October 18, 2012, by 5:00 PM local time of applicant organization.

AIDS Application Due Date(s)

Not Applicable.

Scientific Merit Review

February/March, 2013

Advisory Council Review

May, 2013

Earliest Start Date(s)

June, 2013

Expiration Date

October 19, 2012

Due Dates for E.O. 12372

Not Applicable.

Required Application Instructions

It is critical that applicants follow the instructions in the SF 424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

Table of Contents

Part 1. Overview Information
Part 2. Full Text of the Announcement
Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

Nature of the Research Opportunity

The purpose of this funding opportunity is to provide support for investigators who are affiliated with existing population studies to sample and assess genomic variation from well-phenotyped individuals of diverse ancestry, particularly those of non-European ancestry (EA), and disseminate the resulting data to expand understanding of ancestral differences in SNP-disease associations observed in PAGE Phase I and similar studies. This four-year program will extend the initial experience of PAGE I to add large-scale, dense assays of common and rare coding and/or potentially functional genomic variation in a large number of diverse ancestry participants, particularly groups with disproportionate disease burdens, and with existing and extensive phenotype information. For the purposes of this FOA, “affiliated with” means ongoing or future access to data and samples from an existing population study in a highly-effective collaborative relationship with the investigators responsible for establishment, maintenance, and data coordination of the population study. ”Assess genomic variation” means using the most comprehensive and cost-effective technology to capture the majority of inter-individual variation; currently the “exome chip” but likely to evolve over the four-year course of this FOA.  Collections of “well-phenotyped individuals” may be cross-sectional, if extensive, or, preferably, prospective and longitudinal.  “Non-EA” and “ancestrally diverse” populations refer to individuals whose ancestral (e.g., grandparents’) continent of origin lies outside Europe.  “Potentially functional variation” means coding or non-coding variants that influence genomic function and are related, or suspected of being related, to human diseases.

The goals of this program are to collaboratively utilize existing population-based cohorts to:  1) identify disease-associated genomic regions where between-population differences may be attributable to differences in allele frequency or LD structure; 2) build a population resource of non-EA individuals whose comprehensive genotype and phenotype data would serve as a reference population for the scientific community; and 3) explore the associations of DNA sequence variation with a broad range of phenotypes, including conditions with disproportionate disease burdens in persons of non-EA ancestry.  

This funding opportunity will provide support for genotyping using large-scale and dense genotyping arrays; statistical analysis of the prevalence and associations of genetic variants on a population basis; provision of individual-level genotype and phenotype data to a central database; cataloguing and disseminating the characteristics of participating population studies to be used for such investigations; and inviting collaborations with outside investigators for further functional or translational research. 

To ensure that the maximal scientific benefit is derived from this significant public investment, this funding opportunity aims to support widespread sharing of the resulting data with the broad scientific community for research use, through community resource databases such as dbGaP (http://www.ncbi.nlm.nih.gov/gap) or other databases to be developed within or outside this project. 

Background

PAGE Phase I is an ongoing, five-year cooperative agreement funded to utilize existing population-based cohort studies and clinical trials to: 1) determine the population-based profile, or “epidemiologic architecture,” of potentially causal variants, including prevalence in racial and ethnic subgroups of relevance to the U.S. population and magnitude of disease risk and associations with other health characteristics; 2) identify modifiers of gene-trait associations, particularly lifestyle factors or medication use; and 3) identify potential clues to the biological basis of an association by studying the relationship of the robustly associated variants to phenotypic characteristics such as laboratory measures or imaging findings.  In July, 2008, NHGRI funded 4 grants in response to RFA-HG-07-014, “Epidemiologic Investigation of Putative Causal Genetic Variants” (http://grants.nih.gov/grants/guide/rfa-files/RFA-HG-07-014.html) and 1 grant in response to RFA-HG-07-015, “Epidemiologic Investigation of Putative Causal Genetic Variants – Coordinating Center”.  Collectively, PAGE analyses have included more than 100,000 participants, representing individuals of European ancestry as well as individuals of African American, Hispanic/Latino, Asian, Native Hawaiian, and American Indian ancestry.  Among the approximately 70,000 non-EA PAGE participants analyzed during the later project years, 49% are African American, 31% Hispanic/Latino, 18% Asian, and 2% Native Hawaiian. PAGE I analyses leveraged the considerable breadth and depth of phenotypes from these cohorts to compare cross-population allele frequencies, relative risks, and distribution of phenotypes associated with particular variants and their environmental modifiers among populations of European and non-EA descent. This work was accomplished through the formation of many Working Groups, convened to harmonize phenotypes, conduct consortium-wide meta-analyses and write manuscripts, and provide consistent guidance across the consortium with regards to statistical analyses, ethnicity/ancestry analysis, publications, and implications for data display and dissemination. Key findings from PAGE I include characterization across multiple ancestral groups of lipid and metabolic traits, stroke, coronary heart disease, endometrial cancer, and type 2 diabetes.  In addition to conducting carefully harmonized and a priori analyses of specific traits, PAGE I is analyzing and depositing association data across nearly all phenotypes, yielding data suitable for preliminary, highly exploratory phenome-wide association studies (PheWAS). 

As the limitations of characterizing a genome-wide association study (GWAS) locus in diverse ancestry populations using a single variant became evident, PAGE undertook a pilot study in 2009 to test the feasibility and value of expanding genotying to denser fine mapping around many GWAS loci.  This pilot study, made possible by the American Recovery and Reinvestment Act (ARRA), genotyped approximately 5,000 African Americans using the Metabochip, a dense genotyping array of ~200K SNPs, including ancestry-specific fine mapping variants, for a range of metabolic and cardiovascular traits. The resulting pilot data demonstrated a number of GWAS associations that do not generalize to African American populations, demonstrating the importance of dissecting GWAS signals in an ethnic-specific way. Taking advantage of increased cost-efficiencies in genotyping arrays and the need for dense genotyping data from diverse ancestry groups, in the latter years of the project period PAGE is generating and analyzing Metabochip data on approximately 70,000 participants of African American, Hispanic/Latino, Asian, and Native Hawaiian descent. Summaries of the PAGE Steering Committee (SC) and External Scientific Panel (ESP) discussions which led to this shift in genotyping are available at https://pagestudy.org/index.php/public-documents

PAGE II seeks to expand understanding gained during PAGE I and similar studies of how ancestry-specific differences in allele frequencies and LD may explain differences in risks of common traits and conditions. Recent studies have identified rare genetic variants that are likely to contribute to common diseases and traits and observed that rare variants likely to be functional, such as those in coding and regulatory regions, tend to be population-specific.  PAGE II is expected to start with the most comprehensive and cost-effective technologies currently available, such as the next generation of high density genotyping arrays (e.g., exome chip) to continue its emphasis on characterizing population-level disease risks in non-EA individuals.  As sequencing technologies advance in efficiency and decline in cost, PAGE II may adopt more advanced approaches as was done in PAGE I.

Scientific Knowledge to be Achieved

This funding opportunity and the related RFA-HG-12-015, “Population Architecture Using Genomics and Epidemiology (PAGE), Phase II – Coordinating Center”, will provide detailed, population-based information on genomic variants robustly associated with or strongly suspected of influencing complex diseases and traits.  It will do so in a rapid and cost-effective manner by assaying these variants in representative population samples already well-characterized for a number of phenotypic traits and exposure variables. The individual-level genotype and phenotype data and resulting descriptive data will be provided to an NIH-designated data repository for dissemination to the scientific community. 

Objectives of this Research Program

This FOA will support multiple investigative groups with population-based epidemiologic and analytic expertise, and affiliated with existing population studies, to investigate and disseminate information on ancestral differences in genomic variation associated with human disease.  Investigative groups will be responsible for study design, genetic assays, analysis and data submission of their individual studies to the CC and to dbGaP.  The CC will be responsible for providing support and assistance to accomplish the goals of the program.  Together with the PAGE II CC, investigative groups will work to coordinate genotyping and analysis of disease-associated genomic regions where between-population differences may be attributable to differences in allele frequency and/or LD structure.  To maximize the numbers of diverse and well-phenotyped participants in PAGE II (at least ~10,000 participants per site over the project period), cost-effective high-density SNP arrays will be the primary source of genotyping technology. Whereas PAGE I focused on characterizing findings from GWAS, PAGE II will focus on extending regions of interest to findings from sequencing studies, particularly those in exonic or potentially functional regions of the genome.  Depending on the prevailing content of exonic-focused genotyping arrays at the time PAGE II genotyping is underway, efforts to augment this content with genetic variation representative of diverse ancestry populations using additional genomic assays may be a key focus of PAGE II. The final choice of genotyping array(s) or technology will be discussed and agreed upon by the PAGE SC in conjunction with the NHGRI, and may evolve over the project period. As in PAGE I, genotyping will likely revolve around approximately yearly batches to facilitate cross-study analyses throughout the project period.   Investigators should describe the expertise that makes them well qualified to address the challenges and opportunities inherent to assessing and implementing rapidly changing technology to accomplish the goals of PAGE II. These discussions will provide valuable guidance to the studies participating in this program and to population studies in general. 

Once approaches for genetic investigations are generally agreed upon, subsequent investigation within the consortium supported by this program might include: 1) prioritizing appropriate participants within studies to be assayed and the relevant phenotypic and exposure data to be used in analyses; 2) conducting genotypic and other evolving genomic assays as needed to characterize novel and reported associations; 3) contributing scientific expertise to PAGE-wide phenotype harmonization efforts; 4) contributing individual-level genotype and phenotype data to one or more PAGE-wide datasets for centralized (i.e., consortium-wide) analyses;  5) analyzing the resulting data in detail, in relation to all or nearly all the relevant phenotypic, covariate/exposure, and population ancestry data available; and 6) inviting collaborations with outside investigators for further functional or translational research.  The most rapid possible timeframe for these steps should be proposed, and should continue to accelerate over the course of the program as efficiencies and best practices evolve. 

A key step in this process will be fully utilizing the available data beyond a given genotype-phenotype association (that is, the condition for which a variant has been identified as robustly associated) in ways that maximize information on population impact and potential gene function, while minimizing spurious findings and difficulty sifting through the resulting analyses.  Applicants will propose methodological approaches to leverage the considerable phenotype data available to PAGE II. These efforts may include expansion on the PheWAS design, development of new methods to simultaneously incorporate high dimensionality genotype and phenotype data, and/or dissemination of association data in a user-friendly manner. Pooling of analyses and harmonization of phenotypes across investigative groups are expected to be major components of this program.  A key aim of PAGE II will be to take advantage of the large, ancestrally diverse population samples collectively available throughout the consortium.  Accordingly, applicants will propose a set of cross-study analyses that their group would be well suited to lead within PAGE II, recognizing that cross-study analyses, prioritized by the SC, will be done where possible. Investigator expertise and interest in facilitating centralized analysis, including expertise related to phenotype harmonization, should be described.   Additionally, applicants should describe the full set of study participants available for genotyping or sequencing and subsequent analysis, and their associated phenotypes and informed consent status, should additional funding or genotyping/sequencing capacity be made available during the project period. Sharing of expertise and experience  across investigative groups will be a major goal of this collaborative program, with the intent of better understanding the characteristics and implications of genetic variants that generalize across multiple ancestry groups, and making the resulting findings available and understandable to investigators from a wide range of disciplines.

Each application should propose a method for rapid investigation and dissemination of genetic association findings in a cohort study or clinical trial, or consortium of cohorts or trials.  These should involve large numbers (10,000 or more as a rough estimate) of well-characterized participants in whom extensive phenotype, covariate, and exposure data are available and high-quality DNA is isolated and accessible.  The status of informed consent with regard to participation in genomic- or sequencing-related research and broad dissemination of deidentified individual- or association-level data should be described.  Studies should be of sufficient size and breadth to permit examination of a wide range of variants and traits, and to identify ancestry-specific associations and interactions with sufficient power.  Applications should describe the experience of the investigators with regard to genotyping of the participant samples using large-scale genotyping arrays and subsequent analysis.

Applicants may propose to work within a single population study, suitably diverse in demographics and diseases and characteristics measured, or in multiple population studies, to cover a wide range of relevant genetic variation, population subgroups, and participant characterization likely to be investigated in the four-year course of this program.  An applicant might propose, for example, to include a prospective cancer cohort and a diabetes clinical trial and a pediatric cohort if such a combination would permit investigation of a broad range of variants, characteristics, and participants.  Each application should clearly define the source population, eligibility criteria, informed consent and consultation process, recruitment methods, and numbers and demographics of participants currently in the population study or proposed for inclusion.  Applications should clearly document ongoing or future access to data and samples in a highly-effective collaborative relationship with the investigators responsible for establishment and maintenance of the population study, and the applicant’s ability to commit the study’s data and samples, in consultation with appropriate decision-makers, to participate in this program.  The organization, governance structure, funding, and history of the population studies proposed for inclusion, including expectations of, and commitments (explicit or implicit) made to and by investigators responsible for the establishment and maintenance of the population study, should also be clearly described.  Investigators should describe any procedures that will be implemented to simplify consortium-wide data access, as well as any requirements for approval of consortium-wide use of the data, a clear timeline and process for data delivery to the consortium, and plans for expediting the process should delays be encountered. Adequacy of current informed consent and IRB approvals for genotyping and other assays proposed for inclusion, and for investigation and dissemination of study data, should be clearly described along with any restrictions on research use or sharing of the data. 

Type, quality, and amount of biospecimens available on participants to be studied under this FOA should be explicitly described, including source (tissue, blood, urine, etc); methods for collection (surgical excision, fine needle aspiration, phlebotomy, etc), aliquoting and tracking; storage conditions; DNA extraction methods; methods for whole genome amplification or cell transformation as applicable, as well as DNA quantity and quality (and methods used to assess them).  Prior experience in using the biospecimens for genetic research should be described, along with any prior or planned genotyping and sequencing that could contribute to or overlap with the goals of this FOA, and proposed plans for integrating these data.

Each applicant should describe current and/or proposed methods for genotyping and other assays proposed for inclusion. The primary focus of this FOA will be on large-scale genotyping arrays that assay common and rare variation, with an emphasis on exonic and regulatory regions likely to harbor functional variants (e.g., “exome chip”).  Existing large-scale genotyping or sequencing data available for analysis and/or data dissemination from each cohort, as well as the anticipated scientific value that the genotyping proposed for this FOA would add to existing data, should be described.  Additionally, applicants should describe how they will adapt to changing technology (e.g., novel content on high density SNP arrays) as well as increasing cost-efficiencies of different but relevant technologies (e.g., sequencing).  Each applicant should propose genotyping costs for these activities, clearly identified and separable from other cost components, including personnel, supplies, indirect costs, etc.  Given the importance of minimizing costs and maximizing efficiency, shortly after review NHGRI will compare prevailing costs and timeframes for genotyping proposed at each investigative site to centralized genotyping at large-scale, high throughput facilities. Should NHGRI decide to centralize genotyping, the PAGE CC would solicit a subcontractor to perform PAGE-wide genotyping. Study Investigator awards would be reduced accordingly. Study Investigator applicants should propose the most cost-effective possible approach at the time of application, as well as their approach for ensuring minimal costs and maximal efficiency throughout the course of the project.  Applicants should describe their willingness to send samples to a centralized genotyping facility and prior experience in collaborating with such facilities.  Applicants should also note that costs for genomic arrays are subject to NIH policy; for example, NOT-OD-10-097, Budgeting for Genomic Arrays for NIH Grants, Cooperative Agreements and Contracts (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-10-097.html).

Neither recruitment of participants nor collection of phenotype, covariate or exposure data will be supported by this initiative.  Applicants are encouraged to include in each study a broad range of non-EA participants relevant to the diversity of the U.S. population on race/ethnicity and other factors such as age, sex, socioeconomic status, U.S. geographic region, and urban/rural residence.  Studies involving racial or ethnic minorities, particularly those experiencing disproportionate burdens of disease, are an emphasis of PAGE II and would particularly be sought.  Applicants should describe the characteristics of the proposed population that make it suitable for studies of non-European ancestry persons. Foreign components of applications should describe the racial and ethnic makeup of study participants and their relevance to the non-EA U.S. population. 

A detailed analytic plan should address issues related to the large amount of data to be generated such as multiple testing and assessing complex interactions. The potential impact of population ancestry/history and population stratification on association analyses should be discussed regardless of the populations under study, and means for minimizing the effects of population stratification proposed. Methodologic development and collaborative activities such as harmonizing phenotypes, refining analytic strategies and assessing data quality and potential biases will also be supported. 

Program Organization

The awards funded under this FOA will be cooperative agreements (see Section VI.2.A. Cooperative Agreement Terms and Conditions of Award).  The solicitation “RFA-HG-12-015, Population Architecture Using Genomics and Epidemiology (PAGE), Phase II – Coordinating Center,” will support the coordination and many of the collaborative activities of the program.  Close interaction among awardees and the NIH will be expected to develop appropriate strategies and tools to carry out this program.  The awardees will meet as a Steering Committee (SC), which will include the PD(s)/PI(s) from each investigative group, the Coordinating Center (CC), and the NIH Project Scientist, to first examine the phenotypic, covariate, and exposure data available in each participating population study, including the variables collected, methods used, and documentation available.  Sample sizes specific for phenotypes of high program-wide priority and for major ancestral groups will be assessed and documented by each awardee across all participating studies.  Information on study design, characteristics, available data and quality and quantity of DNA available for PAGE analyses will be compiled by each investigative group and provided to the CC for public dissemination in a user-friendly manner. 

Options for genomic investigations will be discussed by the SC. Once a consensus regarding genotyping platform(s) is reached, the SC will prioritize the highest priority genomic regions and their associated phenotypes, in the context of the overall racial/ethnic distribution, for characterization in the various ancestral groups.  Although the primary focus of PAGE II will be to further characterize disease-associated regions, opportunities to use the data to facilitate discovery of novel genomic variants across the allelic frequency spectrum will also be explored.  The SC will also identify strengths and weaknesses of the various participating studies in terms of traits and covariates available for investigation, and suggest best uses for specific studies, such as examining the impact of a particular risk factor on a given genotype-phenotype association, or the risk of a specific trait associated with a given variant. 

An important product of PAGE II will be a collective dataset comprehensive of genotype and phenotype information, for use by the scientific community as a reference for population-based estimates of allele frequencies and association sizes across a broad range of phenotypes. To this end, PAGE II Study Investigators will be actively engaged with the CC. The CC will have primary responsibility for:

Approaches to genotyping quality control, phenotype harmonization, statistical analysis and data synthesis will be shared and reviewed in SC meetings.  The SC will propose and agree upon approaches to establish an efficient cross-study analysis pipeline, with procedures and results to be standardized as much as feasible across participating studies and provided as rapidly as possible.  These results will be compiled by the CC and provided to the scientific community through databases such as dbGaP or others to be developed through this program.  Appropriate embargoes on submission of publications from these findings, consistent with NHGRI and NIH guidelines, will be applied.  Sharing of genotype and phenotype data on individual study participants in databases such as the controlled access portion of dbGaP is required to participate in the program, in keeping with NHGRI and NIH policies.

The SC will meet in person 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.  PAGE II will continue to have Working Groups in areas of interest to the awardees and the funding institute(s).  Currently PAGE I has several such groups focused on phenotype harmonization and phenotype-specific analyses, along with committees focused on ethnicity/ancestry, data display and dissemination, statistical analysis, SNP selection and quality control, and implementation of the Metabochip pilot and subsequent scale-up. The tasks of the Working Groups will include, among other responsibilities: identifying common scientific areas and adjusting projects to accommodate shared interests, identifying novel projects that may result from synergy among the awarded groups, apprising the SC on progress, and identifying ways to interact with external ongoing networks and initiatives.  Working Groups may propose new research collaborations with non-network investigators and organizations, as long as most or all PAGE sites have the opportunity to participate, according to criteria established by the PAGE SC. Key co-investigators and pre- and postdoctoral trainees, in addition to the PD(s)/PI(s), will be eligible to attend SC meetings. PD(s)/PI(s) are encouraged to include investigators and trainees who are members of under-represented minority groups and those from different but related disciplines such as bioinformatics, public health, social sciences, 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.  

Data from this FOA are expected to be handled so as to increase the value of the significant public investment in genotyping and analysis in the participating population studies.  NHGRI intends that descriptive study materials and data generated through genotyping efforts supported in this FOA will be widely shared with the scientific community for research uses through NIH-supported databases such as dbGaP.  Although NHGRI expects these materials and data to be available through a database such as dbGaP, the NHGRI does not intend dbGaP, or any single database, to become the exclusive source of this program’s data; other databases, public web sites, and/or publication in the scientific literature may be suitable additional venues for data dissemination. 

Applicants should indicate their willingness to share individual-level genotype data as soon as they are generated and undergo quality control (QC) with PAGE II investigators and through dbGaP and other databases.  Additionally, PAGE II sites are expected to contribute individual-level phenotype data to be used within PAGE and for dissemination to dbGaP and other databases.  The PAGE II CC will be tasked with generating one or more PAGE-wide datasets for use in centralized analyses, including data cleaning and QC.  Complexities that would impact timely and efficient sharing of data for shared analysis among PAGE II Investigators and/or broad dissemination through databases, such as study-specific policies or expectations, should be noted, and plans for overcoming such challenges should be proposed. Applicants should indicate their willingness to cooperate with other awardees in the development and design of research and analysis methods, procedures, policies and strategies to be applied in this program. Applicants should also describe prior experience in working as part of a research consortium or other collaborative activities to meet individual study and collaborative goals.

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

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

Section II. Award Information
Funding Instrument

Cooperative Agreement

Application Types Allowed

New

The OER Glossary and the SF 424 (R&R) Application Guide provide details on these application types.

Funds Available and Anticipated Number of Awards

The number of awards is contingent upon NIH appropriations, and the submission of a sufficient number of meritorious applications.

NIH intends to fund an estimate of 3-5 awards, corresponding to a total of $4.2M, for fiscal year 2013. Future year amounts will depend on annual appropriations.

Award Budget

Individual application budgets should not exceed $1,100,000 total costs per year and must reflect actual needs of the proposed project.

Award Project Period

The total award period requested for this FOA may not exceed four years.

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

Section III. Eligibility Information

1. Eligible Applicants

Eligible Organizations

Higher Education Institutions

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

Nonprofits Other Than Institutions of Higher Education

For-Profit Organizations

Governments

Other

Foreign Institutions

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Required Registrations

Applicant organizations must complete the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. Applicants must have a valid Dun and Bradstreet Universal Numbering System (DUNS) number in order to begin each of the following registrations.

All Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) must also work with their institutional officials to register with the eRA Commons or ensure their existing eRA Commons account is affiliated with the eRA Commons account of the applicant organization.

All registrations must be completed by the application due date. Applicant organizations are strongly encouraged to start the registration process at least 4-6 weeks prior to the application due date.

Eligible Individuals (Program Director(s)/Principal Investigator(s))

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization 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.

For institutions/organizations proposing multiple PD(s)/PI(s), visit the Multiple Program Director(s)/Principal Investigator(s) Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF 424 (R&R) Application Guide.   

2. Cost Sharing

This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.

3. Additional Information on Eligibility

Number of Applications

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

NIH will not accept any application in response to this FOA that is essentially the same as one currently pending initial peer review unless the applicant withdraws the pending application. NIH will not accept any application that is essentially the same as one already reviewed.

Section IV. Application and Submission Information

1. Requesting an Application Package

Applicants must download the SF424 (R&R) application package associated with this funding opportunity using the “Apply for Grant Electronically” button in this FOA or following the directions provided at Grants.gov.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

For information on Application Submission and Receipt, visit Frequently Asked Questions – Application Guide, Electronic Submission of Grant Applications.

Letter of Intent

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.

By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

The letter of intent should be sent to:

Lucia Hindorff, Ph.D., M.P.H.
National Human Genome Research Institute
National Institutes of Health
5635 Fishers Lane, Suite 3058, MSC 9307
Bethesda, MD 20892-9307
Rockville, MD 20852 (courier/FedEx/UPS)
Telephone: 301-496-7531
Email: hindorffl@mail.nih.gov

Required and Optional Components

The forms package associated with this FOA includes all applicable components, mandatory and optional.  Please note that some components marked optional in the application package are required for submission of applications for this FOA. Follow all instructions in the SF424 (R&R) Application Guide to ensure you complete all appropriate “optional” components.

Page Limitations

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.

PHS 398 Research Plan Component

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:  

Resource Sharing Plan

Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) as provided in the SF424 (R&R) Application Guide, with the following modification:

Appendix

Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

3. Submission Dates and Times

Part I. Overview Information contains information about Key Dates. Applicants are encouraged to submit in advance of the deadline to ensure they have time to make any application corrections that might be necessary for successful submission.

Organizations must submit applications via Grants.gov, the online portal to find and apply for grants across all Federal agencies. Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration.

Applicants are responsible for viewing their application in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

4. Intergovernmental Review (E.O. 12372)

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.

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.   

6. Other Submission Requirements and Information

Applications must be submitted electronically following the instructions described in the SF 424 (R&R) Application Guide.  Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically.

Important reminders:
All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF 424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the Central Contractor Registration (CCR). Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete and/or nonresponsive will not be reviewed.  

In order to expedite review, applicants are requested to notify the NHGRI Referral Office by email at nakamurk@mail.nih.gov when the application has been submitted. Please include the FOA number and title, PD/PI name, and title of the application.

Post Submission Materials

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-10-115.

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

Overall Impact

Reviewers will provide an overall impact/priority score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

Scored Review Criteria

Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Significance

Does the project address an important problem or a critical barrier to progress in the field? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

How relevant are the proposed non-EA population(s) to minority populations residing in the U.S.? 

Investigator(s)    

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD(s)/PI(s), do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project? 

Have the investigators adequately described the accessibility of cohort data to the PAGE II consortium, including proposed steps to simplify access, any cohort-specific requirements for consortium-wide use of the data, a proposed timeframe for data delivery, and steps to be taken in the event of delays? 

Innovation

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?   

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? 

If the project involves clinical research, are the plans for 1) protection of human subjects from research risks, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, justified in terms of the scientific goals and research strategy proposed?

Have the sources and representativeness of the study population(s) been clearly described?  Have any potential biases in study participants and phenotypic/exposure ascertainment been identified, and are the applicants’ approaches for minimizing these biases appropriate?  Are the phenotype and exposure measures of sufficient quality and completeness to provide maximal scientific value from the addition of large-scale genotyping, or do they have the potential to be such within the project period?   Are current informed consent and IRB approvals sufficient to permit the proposed project to proceed?  Are the proposed plans to share data in a timely manner likely to provide maximal scientific value for expanding understanding of ancestral differences in SNP-disease associations?

Are the plans for site-specific genotyping well described and likely to meet the goals of the program?  Do the investigators describe effective plans for shifting to centralized genotyping should that be deemed advantageous by NHGRI?   

Environment

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements? 

Additional Review Criteria

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact/priority score, but will not give separate scores for these items.

Protections for Human Subjects

For research that involves human subjects but does not involve one of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Human Subjects Protection and Inclusion Guidelines.

Inclusion of Women, Minorities, and Children 

When the proposed project involves clinical research, the committee will evaluate the proposed plans for inclusion of minorities and members of both genders, as well as the inclusion of children. For additional information on review of the Inclusion section, please refer to the Human Subjects Protection and Inclusion Guidelines.

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Biohazards

Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

Resubmissions

Not Applicable.

Renewals

Not Applicable.

Revisions

Not Applicable.

Additional Review Considerations

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact/priority score.

Applications from Foreign Organizations

Not Applicable.

Select Agent Research

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Resource Sharing Plans

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: 1) Data Sharing Plan; 2) Sharing Model Organisms; and 3) Genome Wide Association Studies (GWAS).

Budget and Period of Support

Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by the NHGRI, in accordance with NIH peer review policy and procedures, using the stated review criteria. Review assignments will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

Appeals of initial peer review will not be accepted for applications submitted in response to this FOA.

Applications will be assigned to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the National Advisory Council on Human Genome Research. The following will be considered in making funding decisions:

3. Anticipated Announcement and Award Dates

After the peer review of the application is completed, the PD(s)/PI(s) will be able to access his or her Summary Statement (written critique) via the eRA Commons

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

Section VI. Award Administration Information

1. Award Notices

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. 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.      

Any application awarded in response to this FOA will be subject to the DUNS, CCR Registration, and Transparency Act requirements as noted on the Award Conditions and Information for NIH Grants website.

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General  and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) 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, 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.

The PD(s)/PI(s) will have the primary responsibility for:

NIH staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

The Project Scientist is a scientist of the NHGRI staff who will have substantial scientific and programmatic involvement during the conduct of this activity through technical assistance, advice, and coordination.  However, the role of NIH staff will be to facilitate and not to direct the activities.  It is anticipated that decisions in all activities will be reached by consensus of the program and that NIH staff will be given the opportunity to offer input to this process.  The Project Scientist will participate as a member of the SC and will have one vote.  The Project Scientist will have the following substantial involvement:

Collaborative Responsibilities:

Close interaction among the participating investigators will be required, as well as significant involvement from the NIH, to develop appropriate strategies and tools to design, perform,and analyze studies of ancestral differences in genomic variation associated with human diseases. The awardees and the Project Scientist will meet as the program SC 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 PD(s)/PI(s), are eligible to attend these meetings.

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

Each full member (PD/PI or NHGRI Project Scientist) will have one vote. Awardee members of the SC will be required to accept and implement policies approved by the SC.

As described above, PAGE II will convene working groups to plan and implement cross-study activities.  The PAGE II SC will have the overall responsibility of assessing and prioritizing the progress of the various working groups. Awardees agree to work collaboratively to:

External Scientific Panel:

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

The ESP is currently composed of five senior scientists with relevant expertise, although in PAGE II the ESP may be augmented permanently or on an ad hoc basis as needed.  The ESP will continue to meet at least twice a year; some meetings may be conducted by telephone conference. Occasionally, the ESP may be asked to advise PAGE Investigators and the NHGRI on timely issues during the interim period between meetings.  At least once a year, there will be a joint meeting with the SC to allow the members of the both the ESP and the SC to interact directly.  Twice a year the ESP will make recommendations regarding progress of the program to the National Advisory Council for Human Genome Research about changes, if any, which may be necessary in the program.

Dispute Resolution:

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 Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee of the SC 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 dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

3. Reporting

When multiple years are involved, awardees will be required to submit the Non-Competing Continuation Grant Progress Report (PHS 2590) annually and financial statements as required in the NIH Grants Policy Statement.

A final progress report, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later.  All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000.  See the NIH Grants Policy Statement for additional information on this reporting requirement. 

Section VII. Agency Contacts

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

Application Submission Contacts

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading or navigating forms)
Contact Center Phone: 800-518-4726
Email: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone 301-435-0714
TTY 301-451-5936
Email: GrantsInfo@nih.gov

eRA Commons Help Desk (Questions regarding eRA Commons registration, tracking application status, post submission issues)
Phone: 301-402-7469 or 866-504-9552 (Toll Free)
TTY: 301-451-5939
Email: commons@od.nih.gov

Scientific/Research Contact(s)

Lucia A. Hindorff, Ph.D., M.P.H.
National Human Genome Research Institute
Telephone: 301-496-7531
Email: hindorffl@mail.nih.gov

Peer Review Contact(s)

Ken D. Nakamura, Ph.D.
National Human Genome Research Institute
Telephone: 301-402-8823
Email: nakamurk@mail.nih.gov

Financial/Grants Management Contact(s)

Cheryl Chick
National Human Genome Research Institute
Telephone:  301-435-7858
E-mail: chickc@mail.nih.gov

Section VIII. Other Information

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Authority and Regulations

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92.


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