It is critical that applicants follow the Research (R) Instructions in the SF424 (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.

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

This Funding Opportunity Announcement (FOA), RFA-HG-20-001, invites applications to participate as Polygenic Risk Score Study Sites (PRS SSs), in collaboration with one Coordinating Center (CC, RFA-HG-20-002), to develop methods and collaboratively generate and refine PRS for populations of diverse ancestry by integrating existing datasets with genomic and phenotype data for a range of complex diseases and traits. The grantees funded under these two FOAs will form a PRS Diversity Consortium with the primary objectives of: 1) leveraging genetic diversity to develop methods to predict health and disease risk and improve the applicability of PRS across diverse populations, and for a broad range of health and disease measures; and 2) optimizing the integration of large-scale, harmonized genomic and phenotype data to facilitate collaborative analysis, dissemination of PRS-related data, and development of related methods and resources.

Definitions. For the purposes of this FOA, the following definitions are used:

• Affiliate member refers to a representative of a cohort that is not directly funded through this cooperative agreement but has agreed to share cohort data and contribute to PRS-based analyses of health and disease within the Consortium. Affiliate members may be provided with limited travel and analysis support as described in the Coordinating Center FOA (RFA HG-20-002).
• Clinical Information (also phenotype or trait ) refers to a participant's non-genetic medical information such as personal medical history, family history, physical and laboratory measurements, lifestyle habits, and environmental exposures/social history.
• Consortium refers to PRS Diversity Consortium comprising the grants to be funded under this FOA and RFA-HG-20-002, unless otherwise indicated.
• Cohort(s) refers to one or more studies with extant genomic (genotype or sequencing) and phenotype data and for which individual-level data are available for PRS analyses. Cohort is used in a general sense and can apply to heterogeneous study designs such as case-control, biobank, or other studies.
• "Diversity" and diverse populations address the concept of ancestral diversity and refer to the inclusion of persons who represent populations that are not well-represented in genetic research; for example, racial or ethnic minority populations.
• Diversity first refers to the principle that PRS methods development and refinement for the purposes of this RFA will emphasize the use of non-EA data (see next bullet) until maximum value has been extracted from them before exploring data from EA participants, even if the EA datasets are much larger and more frequently utilized. Clear description of the proposed scientific purpose and potential pitfalls of using data from potentially larger numbers of EA participants should be provided, with strong justification and proposals for addressing any resulting biases, rather than simple convenience or expediency.
• European ancestry (EA) refers to a person of European descent without significant admixture from the indigenous Americas (the latter typically including persons considered to be of American Indian, Alaska Native, Hispanic or Latino ancestry).
• Genomic risk assessment is a process to quantitatively assess an individual’s probability of developing a particular disorder using mathematical or statistical models and incorporating such factors as allele frequencies of known genomic risk variants, personal health history, family medical history, physical characteristics, and laboratory measurements.
• Minority (also non-European ancestry, non-EA ) refers to persons who come from the following minority racial/ethnic populations: African American or Black, Asian, American Indian or Alaska Native, Native Hawaiian or other Pacific Islander (e.g., Guam, Tonga), or Latino or Hispanic. (https://www.nimhd.nih.gov/docs/2009-2013nih_health_disparities_strategic_plan_and_budget.pdf).
• Polygenic risk score (PRS) is a numeric estimate based on the presence of multiple genomic risk variants and their associated risk estimates (odds ratios, relative risks, etc.) to predict an individual’s risk of developing a disease. PRS as used here comprises only allelic data and no other non-genetic indicators of risk.

Background and Objectives

PRS developed using large-scale genomic data from epidemiological studies are rapidly becoming linked to clinical implications, such as identifying individuals who would particularly benefit from modification of coronary heart disease risk factors. In May, 2019, NHGRI convened leaders in genomic medicine, healthcare, and research to discuss the role of genomics in risk prediction (https://www.genome.gov/event-calendar/genomic-medicine-xii-genomics-and-risk-prediction). Several gaps in PRS development and validation were noted in the recommendations from this meeting (https://www.genome.gov/sites/default/files/media/files/2019-07/GMXII_Executive_Summary.pdf) First, there was a need to determine whether ancestry-specific PRS are needed for every ethnic group or every condition or whether different weightings or pan-ethnic scores may be possible for some conditions. Next, development of PRS for specific disease subtypes may be needed; a one size fits all approach does not always work when predicting disease risk, especially in non-EA populations. Also, the need to increase transparency and standardize methods of risk score characterization, development, and validation to facilitate comparison was noted. Meeting participants also recommended prioritizing investigation of diseases with existing data, longitudinal cohorts, and availability of well-defined clinical endpoints.

This FOA follows up on these recommendations to specifically address the gap between the generation and use of PRS in EA and non-EA individuals by generating and refining PRS that are more applicable to diverse populations. Currently available scores show poorer risk prediction in non-European populations due to vast under-representation of non-European ancestry (EA) populations in the underlying GWAS data. Incomplete modeling of risk may be due to several factors, including differences in linkage disequilibrium among populations or omission of ancestry information, functional information on genetic variants, or multidimensional phenotype information. Methodological approaches cannot reliably eliminate the biases due to underrepresenting non-EA data, underscoring the importance of increasing the genetic diversity of the data on which PRS-based prediction is based. The focus of the Consortium will be on developing methods for integrating and analyzing extant GWAS datasets from genetically diverse populations to develop PRS that are more predictive of health and disease than PRS currently available in published scientific literature. Although the work funded by this FOA may impact the clinical utility and applicability of PRS in non-EA populations, this FOA is not intended to address the clinical implementation of PRS scores, nor will PRS scores be returned to study participants as part of this Program. Clinical implementation of PRS as part of genomic risk assessment will be part of a separate FOA for the Electronic Medical Records and Genomics (eMERGE) Genomic Risk Assessment and Management Network (https://grants.nih.gov/grants/guide/rfa-files/rfa-hg-19-013.html).

Several characteristics of this research area are particularly amenable to collaboration. The rapid translation of PRS-related findings to the clinical setting is likely to incentivize data sharing to improve PRS prediction more broadly. Additionally, synergy is likely to be gained in studying multiple phenotypes with a similar approach. Summary statistics may also facilitate integration of data that may not be feasible to share at the individual level. This initiative depends on the ability to efficiently integrate data from heterogeneous sources and will provide an opportunity to address the data science of integrating and analyzing large-scale datasets. The data science will be driven by the need to develop and implement efficient approaches to data harmonization, integration and analysis that adhere to findable, accessible, interoperable and reusable (FAIR) principles (https://www.nature.com/articles/sdata201618).

The primary objectives of this Consortium will be to: 1) leverage genetic diversity to develop methods and improve the applicability of PRS to predict health and disease risk across diverse populations, and for a broad range of health and disease measures; and 2) optimize the integration of large-scale, harmonized genomic and phenotype data to facilitate collaborative analysis, dissemination of PRS-related data, and development of related methods and resources.

Research Approach

During the five-year project period, the Consortium will support 3-5 PRS SSs and one CC. To address the primary objectives above, the Consortium will identify and address scientific challenges and opportunities related to several areas:

1. Identifying relevant cohorts.

Much of the first two years will focus on establishing expectations for data sharing, inventorying and integrating extant phenotype and genotype data, convening working groups to harmonize phenotypes among participating cohorts, and developing and assessing PRS methods applicable to diverse populations.

PRS SS applicants should describe the study population and associated genomic and phenotype data that are being proposed for PRS analysis.

2. Standardizing genomic and phenotype data, and mapping to existing ontologies.

Each applicant will propose approaches to harmonizing genomic (genotype or sequencing information) and phenotype data across the Consortium, recognizing that the Consortium will work together to implement common approaches to standardization of genomic and phenotypic data. Existing ontologies and standards, particularly for phenotypic data, will be a cross-Consortium focus.

3. Developing and applying methods to generate PRS for diverse populations and refining PRS to improve prediction of health and disease risk.

Each PRS SS applicant will propose site-specific approaches to developing methods, generating and refining PRS, and coming to consensus on PRS approaches to be applied to ancestrally diverse populations for the phenotypes proposed for analysis. The Consortium will work together to revise site-specific approaches and develop a consensus approach to developing and applying PRS. Methods development may include, but is not limited to, statistical, epidemiological, population genetics, computational, or functional approaches to improving prediction of health and disease (see Research Examples below for additional topics).

Methods development and refinement in this area will adopt a diversity first principle, avoiding the tendency to rely on the largest EA datasets for convenience and expediency, at the expense of non-EA data.

Depending on the trait, there may also be research opportunities to assess the value added by PRS to prediction of health and disease beyond traditional clinical information, similar to the genomic risk assessment approach described in RFA HG-19-013. For these traits, applicants should propose an analytic approach to performing genomic risk assessment using Consortium datasets and describe the scientific benefit and clinical implications of this genomic risk assessment. Note that this FOA does not support participant recruitment, return of results to study participants, nor clinical implementation research.

4. Establishing external collaborations for PRS validation and implementation research.

No participant recruitment, disclosure of PRS results to participants, nor clinical implementation efforts will be supported by this FOA. Members of the PRS Diversity Consortium will be expected to work with the Electronic Medical Records and Genomics (eMERGE) Genomic Risk Assessment and Management Network, funded under RFA-HG-19-013, RFA-HG-19-014, and RFA-HG-19-015 to develop and assess application of PRS to diverse populations. Much of the first year of eMERGE will focus on utilizing existing genotype and e-phenotype data to validate a genomics-based risk assessment approach for roughly 20 common, complex diseases using publicly available data. This initial effort will focus on widely validated (and preferably peer-reviewed) PRS and will assess the predictive value of these scores for e-phenotypes in both EA and non-EA populations.

In its first year, the PRS Diversity Consortium will interact with eMERGE investigators to assess how work done by eMERGE on methods development, validation and prediction of existing PRS for non-EA populations could be adapted for use in the PRS Diversity Consortium. The PRS Diversity Consortium is also expected to interact with the Clinical Genome Resource’s Complex Disease Working Group and Polygenic Score Catalog as they are working toward standards for describing PRS in publication. These consortia will work together to minimize duplication of effort with respect to curating the PRS literature, PRS methods development, and establishment of standards for generating and applying PRS in diverse populations.

Information on the performance of the PRS developed and refined by the Consortium, as well as the scores themselves, are likely to provide useful information about the degree to which PRS might generalize across diverse populations or add additional information to prediction of health and disease beyond clinical data. Although clinical implementation of PRS scores is beyond the scope of this FOA, the work done in years 3-5 to generate, refine and assess performance of PRS scores would be useful for clinical implementation efforts that are not directly funded by this initiative. Regular outreach is planned throughout the project period to efforts such as eMERGE and All of Us to ensure that the work of this initiative has a high likelihood of adoption by clinical implementation studies.

5. Identifying secondary uses of the data related to health and disease research and making data available for such uses, consistent with participants consent.

Though not the primary goal of this program, the approaches to data integration, phenotype harmonization and collaborative analyses developed in this Consortium may serve as an example for related studies of complex disease genomics. Applicants should describe the significance of the PRS analyses and data integration efforts to be done in this Consortium to other studies of genetic variation and disease, or large scale -omics research in diverse populations.

Data sharing in this Initiative

To ensure that maximal scientific benefit is derived from this significant public investment, this funding opportunity aims to advance and accelerate research by supporting rapid sharing of the resulting data with the broad scientific community for research use, through community resource databases such as the NHGRI Genomic Data Science Analysis, Visualization, and Informatics Lab-Space (AnVIL), Database of Genotypes and Phenotypes (dbGaP), ClinVar, and the Polygenic Score Catalog. The AnVIL is a scalable and interoperable platform established by NHGRI to reduce barriers for collaboration by leveraging a cloud-based infrastructure for democratizing genomic data access and sharing, and for securely computing across large genomic related datasets.

NIH recognizes that data sharing is essential to advance genomic research and will expect awardees to address and adhere to NIH, NHGRI, and NCI data sharing policies. Whenever possible, NHGRI strongly encourages studies involving human data to use data generated from sources that can document explicit consent for future research use and broad data sharing. Similarly, consent language should avoid restrictions on the types of users who may access the data. NHGRI acknowledges that this will not always be possible or appropriate. In addition, data from individual participants who do not consent to future use or broad data sharing may still be used in analysis, if consistent with study design. More information on this expectation regarding explicit consent and on requesting exceptions can be found in the NIH Guide (NOT-HG-20-011) and the NHGRI s Genomic Data Sharing Policy FAQs. NCI expects awardees to propose and implement a robust data sharing plan that details how external investigators gain access to data.

General data sharing principles

Information such as study protocols, software code and algorithms, descriptions, and publications are expected to be made available through databases such as AnVIL, dbGaP, and ClinVar; other public web sites; and/or publication in the scientific literature. All metadata and descriptive information (e.g., protocols or methodologies used) needed to support future use of the data should be submitted.

As much de-identified phenotype data as is practicable should be submitted. At a minimum, data pertinent to the interpretation of genomic data, including the minimal phenotype information needed to reproduce the primary analysis such as associated phenotype data (e.g., clinical information), exposure or environmental data, demographic variables, relevant metadata, and descriptive information (e.g., protocols or methodologies used) are expected to be shared, consistent with achieving the goals of the program. Data vocabularies, ontologies, models, and dictionaries relevant to the phenotype data are also expected to be shared, consistent with achieving the goals of the program. Note that this initiative is expected to generate data subject to the NIH Genomic Data Sharing policy and to the NHGRI Implementation of this policy (e.g., limited genotyping and Consortium-wide imputation efforts to be carried out by the Coordinating Center).

To maximize synergy with ongoing efforts, the Consortium will adopt and adapt existing standards for data sharing, genomic and phenotype harmonization, and other data standards as feasible, working with organizations such as the Global Alliance for Genomics and Health (GA4GH), with phenotype standardization efforts such as the Human Phenotype Ontology and Monarch, and with data models such as the Observational Medical Outcomes Partnership. To assist in improving data sustainability and utility, applicants are encouraged to align the development of their data sets using the FAIR Guiding Principles. Policies and standards related to data sharing and data integration to be implemented in this Consortium, including those relevant to ethical, legal and social implications (ELSI), will be shared with the broader community.

Data security encompasses confidentiality, data integrity, and availability. Confidentiality includes managing data access to maintain data security and making data accessible to authorized users only for authorized purposes. Data security protection and proper stewardship of human genomic, phenotypic, clinical, and other sensitive information stored and distributed is of the utmost importance. The Notice for Use of Cloud Computing Services for Storage and Analysis of Controlled-Access Data Subject to the NIH Genomic Data Sharing (GDS) Policy allows investigators to perform genomic analyses on a cloud platform. The NIH security best practices and provisions should be implemented to protect the privacy and confidentiality of research participants and prevent unauthorized access to data. Investigators are expected to develop policies and procedures for notifying NHGRI, and managing, and mediating any loss of data or compromise of data confidentiality.

After the initial peer review, NIH staff will conduct an additional administrative review of the plan for sharing data and may negotiate modifications of the data sharing plan with the prospective awardee. The final negotiated version of the data sharing plan will become a term and condition of the award of the cooperative agreement.

Data sharing within the Consortium

Consortium-wide analyses will rely primarily on extant datasets made available to the Consortium through data sharing agreements. To facilitate the establishment of Consortium-wide data sharing agreements, applicants should describe to what extent the proposed dataset(s) are already accessible through one or more of the following avenues:

• NIH-supported databases, such as AnVIL or dbGaP
• Publicly-available non-NIH databases, such as the European Genome-phenome Archive (EGA)
• Databases not currently publicly available

NHGRI intends for Consortium-wide collaborative analyses to be conducted on, but not limited to, the AnVIL platform (https://grants.nih.gov/grants/guide/notice-files/NOT-HG-19-024.html), though NHGRI intends to provide funding support only for analyses conducted on AnVIL. PRS SSs and the CC will need to budget for compute and egress charges on AnVIL based on Google Cloud Platform pricing. NHGRI will continually assess the utilization of AnVIL and determine whether additional limited support for site-specific analyses on AnVIL is needed.

Data sharing beyond the Consortium

Project datasets. NHGRI intends that Project Datasets from each funded PRS SS, including genomic, clinical, phenotypic, and other relevant data from each contributing cohort are expected to be widely shared with the scientific community for research uses. As stated in the NHGRI Genomic Data Sharing Policy, whenever possible, NHGRI strongly encourages studies involving human data to use data generated from sources with participant consent for unrestricted access or for General Research Uses through controlled access. Similarly, consent language should avoid restrictions on the types of users who may access the data. NHGRI acknowledges that this will not always be possible or appropriate. In addition, individual participants who do not consent to future use or broad data sharing may still participate in the primary study, if consistent with study design. It is not the intent of this initiative to duplicate efforts to disseminate datasets already available publicly or through controlled access, such as those available through, but not limited to, dbGaP or EGA. These datasets would be made available to external researchers in accordance with the policies of the respective sources.

PRS summary data, methods, and meta-data. In addition to Project Datasets available from each funded PRS SS, NHGRI expects that PRS summary data, methods and meta-data derived from Consortium-wide analyses will be made available to the broad scientific community via AnVIL or another NIH-designated data repository. At a minimum, the following aggregate data will be shared: the genetic variants contributing to the PRS; other covariates used to derive the PRS; sample size and ancestry information; a description of the statistical and/or computational methods used to calculate the PRS, and other information needed to apply the Consortium-derived PRS to an external dataset.

Although NIH expects all datasets from genomic studies selected as part of this FOA to be available through public databases such as AnVIL, dbGaP, and ClinVar, NIH does not intend for any single database to become the exclusive source of this program’s data.

Estimated timeline

In years 1-2, funded PRS SSs will work together and with the CC, AnVIL, NHGRI, and other resources to integrate genomic and phenotype data for collaborative analyses. Investigators will maximize the sample size and genetic diversity of available data and address challenges presented by potential differences across cohorts in availability of clinical data, data use limitations, informed consent, and availability of summary statistics vs. individual level data. The Consortium will develop and refine methods and agree upon a set of health and disease measures to further validate and analyze; convene Working Groups to harmonize health and disease measures, harmonize genomic information, including imputation as needed; develop and select common metrics for refining and improving PRS-based prediction, and develop ways to integrate ancestry measures into the analysis. In years 2-4 investigators will analyze genomic and phenotype data across the Consortium to generate and refine PRS models related to multiple health and disease measures and update these PRS models with new data. In years 4-5, investigators will continue to disseminate results and refine PRS models based on community input.

Research Examples

NIH intends to support multiple PRS Study Sites and a Coordinating Center to integrate large-scale, harmonized data and develop, perform and disseminate PRS analyses across a broad range of phenotypes and across large and diverse participant populations. In developing an approach to accomplishing the objectives of this research project, applicants should describe the research topics addressed by their approach, and describe their reasons for choosing this approach.

Examples of topics include, but are not limited to, the following:

• Statistics or epidemiology
• Integrating multidimensional phenotype information into PRS
• Integrating clinical information into PRS
• Evaluating differences in PRS models of risk prediction across subgroups, such as those defined by genetic diversity, disease subtypes, or sex, with an emphasis on non-EA populations
• Integrating PRS with existing risk stratification models to identify individuals at particularly high or low risk of disease, or at the extremes of health status
• Evaluating the performance of different PRS models on the ability to predict polygenic influence on health and disease
• Population genetics
• Incorporating diverse genetic ancestry or admixture in models of polygenic risk
• Using population genetics to study why PRS differ across populations and how to account for these differences
• Computational or functional genomics
• Incorporating functional information about genetic variants into models of polygenic risk
• Developing network or pathway approaches to integrating information on genotype, phenotype and other -omics to predict polygenic risk
• Developing methods to deconvolute the black box of PRS scores to improve understanding of variant function
• Efficient approaches to harmonizing phenotypes derived from different sources, including, but not limited to, electronic health records, health or disease repositories, medical chart review, or self-report.
• Data science: applicants are encouraged to develop research topics around the data science of integrating and analyzing large-scale datasets, including the application of FAIR Guiding Principles.
• Use of PRS developed for this Consortium to research other topics related to genomics in relation to health and disease, including, but not limited to:
• Genetic architecture of health and disease
• Phenome-wide association studies (PheWAS)
• Added value of variant functional information, multidimensional phenotype information, or clinical information to prediction of health and disease

NCI is interested in PRS SS focused on cancer. Applicants are not limited to addressing the list of topics described above and are strongly encouraged to contact NIH (program contacts listed below) to discuss their proposed topic(s) for relevance to the objectives of this FOA.

Program Formation and Governance

PRS SSs

Under this FOA, each funded application will comprise a PRS SS responsible for convening one or more cohorts to accomplish the research objectives described above. Applicants are encouraged to leverage existing collaborations and consortia where feasible, to build on prior experience with data harmonization and collaborative analyses.

In collaboration with the CC and NIH, PRS SSs will be responsible for developing and implementing an approach to integrating extant genotype and phenotype data for the purpose of conducting and disseminating Consortium-wide PRS analyses. This approach will include genotype and phenotype harmonization; methods development and application to incorporate genetic, ancestry and phenotype information into prediction of health and disease; analyzing and interpreting research results; and collaborating to validate PRS in clinical settings by working with ongoing genomic medicine efforts. Each PRS SS will participate in a cooperative and interactive manner with all other PRS SSs and the CC in all aspects of the network, including developing network procedures and working groups; finalizing protocols and costs. The PRS SSs will also work collaboratively with each other and the CC for timely and efficient transmission, in as automated a fashion as possible, of data needed for cross-Consortium analyses and for the CC to monitor and disseminate study results across the entire Consortium. It is encouraged that the investigators participating in the Consortium come from diverse backgrounds, such as racial and ethnic minority populations, to ensure a diversity of experience and perspectives.

Consistent with the emphasis of this FOA on diversity, PRS SS applicants will be asked to describe the ability of proposed cohorts to meeting the following criteria:

Strongly encouraged. Within each PRS SS, across all proposed cohorts:

• At least 1 non-European ancestry group with 10,000 or more participants, OR
• At least 20K participants, at least 50% of whom must belong to one or more non-EA ancestry groups

Additional high priority. In addition to the criteria above, within each PRS SS, across all proposed cohorts:

• At least 50,000 participants
• Large numbers (10,000 or more) of non-EA participants belonging to a single non-EA ancestry group
• Broad phenotype information (availability of multiple phenotype measures per participant; availability of phenotypes spanning multiple organ systems)
• Commitment to data sharing

Coordinating Center

The CC is responsible for overall logistical coordination and will play a major research role in leading the data science component of the Consortium. The data science will be driven by the need to develop and implement efficient approaches to data harmonization, integration and analysis that adhere to FAIR principles. The CC will also work with the AnVIL resource to facilitate data sharing and analysis within the Consortium. ELSI considerations are inherent to integrating heterogeneous datasets and generating PRS data which may differentially impact individuals of diverse ancestry. The CC will also provide and convene ELSI expertise to address these and other ELSI issues that arise during the conduct of this research. Recognizing that the funded PRS SSs may not capture all available diverse cohorts, the CC will also identify and invite researchers representing high priority cohorts to participate as affiliate members and provide limited genotyping and analysis support for them if needed. The CC, working with the PRS SSs, will also collect data on Consortium progress and report progress to the Steering Committee (SC), External Scientific Panel (ESP), and NIH. The CC will also be responsible for ensuring data generated by the Consortium are deposited into a publicly accessible data repository such as AnVIL, dbGaP, or ClinVar.

PRS SS applicants should refer to RFA-HG-20-002 for more details on the responsibilities of the CC.

NIH

NIH is responsible for organizing and providing overall support and management for the Consortium. In addition to regular grant stewardship, the NIH Project Scientist(s) will be involved substantially with the awardees, consistent with the Cooperative Agreement mechanism. The NIH Project Scientist(s) will, together, comprise a voting member of the SC.

Steering Committee

A SC comprising Program Director(s)/Principal Investigator(s) [PD(s)/PI(s)] of the PRS SSs and the CC, and the NIH Project Scientist(s), will constitute the main governing body of the Consortium. Major scientific decisions will be determined by consensus and, as needed, majority vote of the SC. It is anticipated that the SC will meet at least twice per month by conference call and three times per year in person the first year as needed, and then monthly by conference call and three times per year in person in years 2-5. The SC will have primary responsibility for the general organization of the Consortium, approving a consensus process for PRS data integration and analyses, facilitating the conduct and monitoring of progress, identifying and resolving bottlenecks, reporting results in a timely manner, and working with NIH to disseminate the findings. The SC will be responsible for creating a plan for clinical and genomic data sharing consistent with NIH policies during the first year of the program. Working groups of the SC will be established to address specific activities, such as methods development, phenotype harmonization, and cross-site analysis. Awardees will be expected to accept and implement policies approved by the SC.

External Input to the Network

The PRS Diversity Consortium will have an External Scientific Panel (ESP). The ESP will advise NHGRI and the Consortium on performance and overall progress. The ESP will consist of experts in epidemiology, biostatistics, data science, population genetics, and other areas as needed. An NHGRI scientist will serve as the Executive Secretary to the ESP. The ESP will be appointed by NHGRI and will meet semi-annually (one conference call and one in-person meeting per year). Following each meeting, the ESP will submit recommendations to NHGRI, from which NHGRI will prepare a report for PD(s)/PI(s). The Consortium SC members will receive and consider the ESP’s comments and will provide a written response to the recommendations through NHGRI.

See Section VIII. Other Information for award authorities and regulations.

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

Higher Education Institutions

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

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

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

• Small Businesses
• For-Profit Organizations (Other than Small Businesses)

Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)
• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations
• Non-domestic (non-U.S.) Entities (Foreign Institutions)

Non-domestic (non-U.S.) Entities (Foreign Institutions) are 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.

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
• NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
• eRA Commons - Applicants must have an active DUNS number to register in eRA Commons. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration, but all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

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 PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

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

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

The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101).

The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

It is critical that applicants follow the Research (R) 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.

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:

• Descriptive title of proposed activity
• Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
• Names of other key personnel
• Participating institution(s)
• Number and title of this funding opportunity

The letter of intent should be sent to:

Lucia A. Hindorff, Ph.D., M.P.H.
Telephone: 240-271-1509
Email: [email protected]

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

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

SS budgets should include the costs required for active Consortium participation, including regular teleconferences and meetings of the SC and its working groups. For budgeting purposes, applicants should budget for attendance of 4-5 investigators from each CS at 3 SC meetings (2 days, 1-2 nights) per year. SS budgets should include personnel costs for twice monthly Steering Committee conference calls in the first year, and monthly conference calls in years 2-5.

Costs of Consortium-wide data storage and computation will be borne by the CC. SS budgets should not include costs for local storage of Consortium data. Both SSs and the CC are expected to conduct both site-specific and large-scale collaborative analyses on the AnVIL platform. SSs will need to budget for compute and egress charges on AnVIL based on Google Cloud Platform pricing. NHGRI will continually assess the utilization of AnVIL and determine whether limited support for site-specific analyses on platforms external to AnVIL is needed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

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

Research Strategy: Describe the overall strategy, methodology, and analyses to be used to accomplish the specific aims of the project as well as the following aspects.

Selection of cohorts and phenotypes

Applicants should describe and justify the proposed cohort(s) and phenotype(s) that they plan to study, recognizing that the phenotypes to be analyzed across the Consortium will be decided upon by consensus of the Steering Committee after award. A collaborative approach to selecting and prioritizing health and disease phenotypes to maximize sample sizes and genetic diversity available for cross-Consortium analysis should be proposed.

Applicants should describe the ability of the proposed cohort(s) to meet the following criteria:

Strongly encouraged. Within each PRS SS, across all proposed cohorts:

• At least 1 non-European ancestry group with 10,000 or more participants, OR
• At least 20K participants, at least 50% of whom must belong to one or more non-EA ancestry groups

Additional high priority. In addition to the criteria above, within each PRS SS, across all proposed cohorts:

• At least 50,000 participants
• Large numbers (10,000 or more) of non-EA participants belonging to a single non-EA ancestry group
• Broad phenotype information (availability of multiple phenotype measures per participant; availability of phenotypes spanning multiple organ systems)
• Commitment to data sharing

Methods development and refinement in this area will adopt a diversity first principle. Applicants proposing datasets for which, in aggregate, the number of EA participants exceeds the number of non-EA participants, should first emphasize the use of non-EA data until maximum value has been extracted from them before exploring the inclusion of data from EA participants, even if the EA datasets are much larger and more frequently utilized. A clear description of the value of analyses to be performed using data that meet the strongly encouraged and additional high priority criteria should be provided. Separately from this, the additional value, i.e., the proposed scientific purpose and potential pitfalls, of using data from potentially larger numbers of additional EA participants should be provided, with strong justification and proposals for addressing any resulting biases, rather than simple convenience or expediency.

Each application should clearly define the source population, eligibility criteria, informed consent, phenotyping methods (whether based on clinical or non-clinical data), and numbers and demographics of participants from the proposed studies. As part of an appendix, applicants must submit a summary table that describes each phenotype proposed for analysis, the corresponding number of subjects with the phenotype, and if known, the distribution of the phenotype in the proposed population (e.g., mean SD for continuous variables; frequency in % of exposure or most common variable; see https://www.cidr.jhmi.edu/access/GWAS_Summary_Table.pdf for an example).

Commitment to data sharing

Whenever possible, NHGRI strongly encourages studies involving human data to use data generated from sources that can document explicit consent for future research use and broad data sharing. Similarly, consent language should avoid restrictions on the types of users who may access the data. NHGRI acknowledges that this will not always be possible or appropriate. In addition, data from individual participants who do not consent to future use or broad data sharing may still be used in analysis, if consistent with study design. More information on these expectations can be found in the NIH Guide (NOT-HG-20-011) and the NHGRI s Genomic Data Sharing Policy FAQs.

NCI expects awardees to propose and implement a robust data sharing plan that details how external investigators gain access to data. All NCI applications, regardless of the amount of direct costs requested for any one year are expected to include a Data Sharing Plan that is compliant with NIH data sharing policies, including the NIH 2003 Data Sharing Policy (NOT-OD-03-032) and the NIH Genomic Data Sharing Policy (NOT-OD-14-124). Examples of projects that fall within the scope of the GDS Policy are available on the NCI Genomic Data Sharing webpage (https://gds.nih.gov/03policy2.html). The data sharing plan should include, at a minimum: 1) a statement of all NIH resource sharing policies relevant to the proposed grant application, 2) the extent and type of data that will be shared, 3) the data repository to which the data will be submitted (Repository must be publicly accessible/controlled access, but is not limited to NIH repositories, See www.nlm.nih.gov/NIHbmic/nih_data_sharing_repositories.html for a full listing of NIH repositories), and 4) the timeline for the data to be shared.

Applications should clearly document ongoing or future access to data in a highly-effective collaborative relationship with the investigators responsible for establishment and availability of the datasets, and the applicant’s ability to commit the study’s data, 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 analysis and dissemination of study data, should be clearly described along with any restrictions on research use or sharing of the data. Note that this initiative is expected to generate data subject to the NIH Genomic Data Sharing policy and to the NHGRI Implementation of this policy (e.g., limited genotyping and Consortium-wide imputation efforts to be carried out by the Coordinating Center). To facilitate Consortium-wide data sharing, PRS SS applicants should describe any limitations of the proposed datasets for imputing genomic data and disseminating data from imputed datasets generated by the Coordinating Center. These limitations may include, but are not limited to, the explicit informed consent for future research use of the data, and for broad data sharing.

Neither recruitment of participants nor collection of phenotype, covariate or exposure data will be supported by this initiative.

Genomic information, PRS approach and analysis

For the proposed cohort(s), applicants should describe the genotype and/or sequence information available for PRS analysis, including the DNA source, details of the assay/sequencing, and, if applicable, availability of imputed data (and the reference sequences on which the imputed data are based). To plan for collaborative PRS analyses, applicants should describe needs and recommendations for harmonizing genomic info for diverse populations, recognizing that the CC will be responsible for imputation.

Each applicant should propose one or more approaches to developing methods for, refining, and applying one or more PRS models predictive of health and disease in diverse populations. The incorporation of ancestry information, including for ancestry groups not represented in the application but relevant to the U.S. population at large, should be described. A description of the statistical PRS model and the data upon which the model is based, including ancestry, should be provided. If different approaches are needed for different phenotypes, an explanation should be provided. Proposed approaches may use novel or existing PRS methods. Methods to be developed as part of this application should address aspects of statistics, epidemiology, population genetics, or computational or functional genomics relevant to large-scale PRS analysis. Applicants should also propose approaches for reaching consensus across the Consortium to identify and implement a common set of PRS analyses, recognizing that not all site-specific approaches may be able to be implemented.

Applicants should describe how ancestry will be taken into account in the proposed PRS analyses. Proposed approaches may use novel or existing PRS methods. The generalizability of the approaches to cohorts other than the one(s) proposed in the application, which may have different genotyping and ancestry information, should be described. As described in the section titled, Program Formation and Governance (PRS SSs), awardees will be asked to prioritize non-EA samples for data integration and PRS analysis.

Metrics for evaluating and comparing the performance of PRS in predicting health and disease across diverse populations should be proposed. The choice of PRS model and alternatives considered, including additional plans for methods development and validation proposed in this application, should be described. Investigators seeking additional opportunities for methods development should consider applying to NOT-HG-20-010. Recognizing that Consortium-wide analyses will be decided upon by consensus of the Steering Committee after award, applicants should address the need to prioritize PRS models, and propose an approach that is collaborative and transparent. Investigator expertise and interest in facilitating centralized analysis, including expertise related to genotype and phenotype harmonization, should be described.

Applicants should describe their experience in working in and across consortia to accomplish common goals. Applicants should describe their willingness and experience in leading Working Groups, which will be the focal point for PRS analysis related to a specific trait (or closely-related traits). These Working Groups will leverage domain expertise and analysis effort from each contributing cohort.

General data sharing

Applicants should describe their experience in working with and analyzing data under existing standards for data sharing, genomic and phenotype harmonization, and other data standards as feasible, working with organizations such as the Global Alliance for Genomics and Health (GA4GH), with phenotype standardization efforts such as the Human Phenotype Ontology (HPO) and Monarch, and with data models such as the Observational Medical Outcomes Partnership (OMOP). To assist in improving data sustainability and utility, applicants are encouraged to align the development of their data sets using the FAIR Guiding Principles. PRS SS applicants should describe their experience in integrating and sharing data, both within and external to the relevant collaborations. Potential bottlenecks in adopting FAIR approaches and proposed methods for overcoming them should be described. Applicants proposing datasets including European participants or derived from European sources should address the extent to which the General Data Protection Regulation (GDPR) will impact data sharing and collaborative analyses proposed in this FOA.

Data sharing within the Consortium

Applicants should describe whether data proposed in the application are derived from individual-level data or summary statistics; the nature of the access (e.g., unrestricted vs. controlled access); any data use limitations, and relevant experience with establishing multi-institutional data sharing agreements involving the proposed dataset(s). If the proposed dataset(s) are not available through NIH-supported databases, publicly-available non-NIH databases, or databases not currently publicly available, applicants should describe a plan for making the dataset(s) available through one of the above avenues within six months of award, or an alternate plan for making data available to the Consortium.

Data sharing beyond the Consortium

Project datasets. In addressing the points from the section Data sharing within the Consortium, applicants should note any exceptions to the availability of proposed dataset(s) to researchers external to the Consortium. If the proposed dataset(s) are not available to researchers external to the Consortium, applicants should provide a justification for why the dataset(s) cannot be made available.

External collaborations for PRS validation and implementation research

No participant recruitment, disclosure of PRS results to participants, or clinical implementation efforts will be supported by this FOA. However, regular outreach is planned throughout the project period to efforts such as eMERGE and All of Us to ensure that the work of this initiative has a high likelihood of adoption by clinical implementation studies. Applicants should describe their experience and interest in collaborating with external groups on genomic risk assessment, clinical utility or clinical implementation of PRS.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.
• A plan for sharing project datasets (phenotypic, environmental, covariate, process data, outcome measures, etc.) and associated genomic data should be provided. Awardees are expected to comply with the NIH Genomic Data Sharing Policy (https://gds.nih.gov/) and the NHGRI implementation of this policy. The plan should also describe how informed consent will be designed and obtained to allow broad data sharing of project datasets for unrestricted access or for General Research Use under controlled access, as defined by NIH at https://osp.od.nih.gov/wp-content/uploads/standard_data_use_limitations.pdf. Broad data sharing for general research use is strongly encouraged for Consortium datasets. A plan to share computerized resources such as study protocols, informed consent form templates, results report templates, and bioinformatic tools should also be provided.

Appendix:

Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

When involving human subjects research, clinical research, and/or NIH-defined clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered Yes to the question Are Human Subjects Involved? on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the SF424 (R&R) Application Guide must be followed.

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

Foreign (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions.

See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

Organizations must submit applications to 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. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.

Applicants are responsible for viewing their application before the due date 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.

This initiative is not subject to intergovernmental review.

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.

Applications must be submitted electronically following the instructions described in the SF424 (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 How to Apply Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.

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 SF424(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. See Section III of this FOA for information on registration requirements.

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 System for Award Management. 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 and compliance with application instructions by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

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

Applicants are required to follow the instructions for post-submission materials, as described in the policy. Any instructions provided here are in addition to the instructions in the policy.

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

Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

Reviewers will provide an overall impact 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).

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.

Does the project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? 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?

Are the scientific rationale and need for PRS analyses of the proposed phenotypes and populations well supported by preliminary data, methodological advances, or information in the scientific literature? Will the proposed approaches contribute to evaluating differences in PRS-based prediction of health and disease in diverse populations?

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those 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/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

Do the investigators have appropriate experience working in multi-site research networks or consortia, developing methods, harmonizing phenotypes, integrating disparate datasets, and analyzing large-scale data to ensure the results are high quality and are produced in a timely way?

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?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? 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? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address

1) the protection of human subjects from research risks, and

2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?

Have the sources and diversity of the study population(s) been clearly described? Have the applicants clearly described a diversity first approach to methods development, selection of datasets, harmonization and analytic approach? Has the applicant clearly described the scientific value of the non-EA data, under the strongly encouraged and additional high priority criteria? Are the genotype, sequencing and phenotype measures of sufficient quality and completeness to provide maximal scientific value to large-scale collaborative PRS analyses, or do they have the potential to be such within the project period? Are current informed consent and data use limitations sufficient to permit the proposed project to proceed? Have the investigators adequately described the accessibility of cohort data to the 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? Are the proposed plans to share data in a timely manner likely to provide maximal scientific value for expanding understanding of ancestral differences in PRS-based prediction? Could the proposed harmonization and analytic approaches be applied to similar cohorts that are not part of the Consortium?

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?

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 score, but will not give separate scores for these items.

For research that involves human subjects but does not involve one of the 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 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 Guidelines for the Review of Human Subjects.

When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of individuals of all ages (including children and older adults) to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

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.

Not applicable.

Not applicable.

Not applicable.

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 score.

Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.

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).

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) Genomic Data Sharing Plan (GDS).

For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

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

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

As part of the scientific peer review, all applications:

• May undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.
• Will receive a written critique.

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

Applications will be assigned on the basis of established PHS referral guidelines 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 for Human Genome Research. The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.
• Cohorts comprising at least 50,000 participants, of whom at least 50% must belong to one or more non-EA ancestry groups
• Large numbers (10,000 or more) of non-EA participants belonging to a single non-EA ancestry group
• Broad phenotype information (availability of multiple phenotype measures per participant; availability of phenotypes spanning multiple organ systems)
• Commitment to data sharing

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. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

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

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 terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.

Institutional Review Board or Independent Ethics Committee Approval: Grantee institutions must ensure that protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the awardee must provide NIH copies of documents related to all major changes in the status of ongoing protocols.

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.

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights laws that prohibit discrimination on the basis of race, color, national origin, disability, age and, in some circumstances, religion, conscience, and sex. This includes ensuring programs are accessible to persons with limited English proficiency. The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-providers/provider-obligations/index.html and http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html.

HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research. For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA.

• Recipients of FFA must ensure that their programs are accessible to persons with limited English proficiency. HHS provides guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/fact-sheet-guidance/index.html and https://www.lep.gov. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at https://minorityhealth.hhs.gov/omh/content.aspx?ID=88.
• Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html.
• HHS funded health and education programs must be administered in an environment free of sexual harassment. Please see https://www.hhs.gov/civil-rights/for-individuals/sex-discrimination/index.html; https://www2.ed.gov/about/offices/list/ocr/docs/shguide.html; and https://www.eeoc.gov/eeoc/publications/upload/fs-sex.pdf. For information about NIH's commitment to supporting a safe and respectful work environment, who to contact with questions or concerns, and what NIH's expectations are for institutions and the individuals supported on NIH-funded awards, please see https://grants.nih.gov/grants/policy/harassment.htm.
• Recipients of FFA must also administer their programs in compliance with applicable federal religious nondiscrimination laws and applicable federal conscience protection and associated anti-discrimination laws. Collectively, these laws prohibit exclusion, adverse treatment, coercion, or other discrimination against persons or entities on the basis of their consciences, religious beliefs, or moral convictions. Please see https://www.hhs.gov/conscience/conscience-protections/index.html and https://www.hhs.gov/conscience/religious-freedom/index.html.

Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 Federal awarding agency review of risk posed by applicants. This provision will apply to all NIH grants and cooperative agreements except fellowships.

Cooperative Agreement Terms and Conditions of Award

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:

• Determining research approaches, designing protocols, setting project milestones, and conducting research.
• Participating in group activities, including a study-wide Steering Committee to share design and analysis techniques and promote comparability across studies wherever possible.
• Implementing Steering Committee recommendations for integrating data, harmonizing phenotypes, analyzing PRS data, evaluating PRS results, and dissemination of PRS findings.
• Collaborating with all Consortium sites in making Consortium findings and procedures as widely available and applicable as possible.
• Sharing results according to the NIH data sharing policy.
• Adhering to policies regarding data access, publication, and intellectual property established by NIH and the Steering Committee for this program.
• Adhering to NIH policies regarding genomic data sharing and other policies that might be established during the course of this activity, as appropriate.
• Cooperating with other awardees in the development and design of research methods, protocols, tools, and strategies.
• Working productively with program staff from other NIH institutes who may be providing co-funding for projects.
• Working cooperatively with investigators who may be collaborating with other components of the Consortium, including with affiliate members, data repositories, or community data portals.
• Abiding by common definitions, protocols, procedures, etc. as chosen by majority vote of the Steering Committee.
• Accepting and complying with study policies established by NIH, and with additional non-conflicting policies approved by the Steering Committee.
• Cooperating with other awardees in the publication and dissemination of program results and the eventual release to the scientific community of methods, tools, and results, and other resources.
• Not disclosing confidential information obtained from other members of the program.
• Submitting periodic progress reports in a standard format, as agreed upon by the Steering Committee and External Scientific Panel.
• Attending and participating in Steering Committee meetings and accepting and implementing the guidelines and procedures of the External Scientific Panel and NIH, as appropriate.
• Submitting datasets generated from the Consortium to public data repositories such as AnVIL, dbGaP, and ClinVar.
• Adopting a diversity first perspective, emphasizing the use of non-EA data until maximum value has been extracted from them before exploring data from EA participants, even if the EA datasets are much larger and more frequently utilized.
• 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 DHHS, PHS, and NIH policies.

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 Steering Committee and will have one vote. The Project Scientist will have the following substantial involvement:

• Participating with the other 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 Project Scientist will assist and facilitate the group process and not direct it.
• Serving 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 Project Scientist will also coordinate the efforts of the program with other groups conducting similar studies.
• Attending all Steering Committee meetings as a voting member and assisting in developing operating guidelines, quality control procedures, and consistent policies for dealing with situations that require coordinated action. The Project Scientist will be responsible for working with the Coordinating Center as needed to manage the logistic aspects of the program.
• Reporting periodically on the progress of the program to the Director, NHGRI, and to the National Advisory Council for Human Genome Research.
• Serving as a liaison between the Steering Committee and the External Scientific Panel, attending External Scientific Panel meetings in a non-voting liaison member role, and arranging for timely preparation and distribution of meeting minutes.
• Serving as a liaison between the Steering Committee and other federal agencies such as the Food and Drug Administration (FDA) or the Centers for Medicaid and Medicare Services (CMS).
• Serving on working groups of the Steering Committee and the External Scientific Panel, as appropriate.
• Assisting awardees in the development, if needed, of policies for dealing with situations that require coordinated action.
• Providing advice in the management and technical performance of the award.
• Assisting in promoting the availability of the data and related resources developed in the course of this program to the scientific community at large.
• Participating in data analyses, interpretations, and, where warranted, co-authorship of the publication of results of studies conducted through the program.
• An agency program official or IC program director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice. The NHGRI assigned program director may also serve as an NHGRI Project Scientist.
• The Program Official may withhold or reduce support from any awardee that 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 Program Official.

Areas of Joint Responsibility include

Close interaction among the participating investigators will be required, as well as significant involvement from the NIH, to develop appropriate strategies and tools for genomic medicine discovery and implementation research. The awardees and the Project Scientist will meet as the program Steering Committee three times per year and twice monthly on conference calls in the first year, and three times per year and monthly on conference calls in years 2-5, to share information on data resources, methodologies, analytical tools, as well as data analyses and preliminary results. In addition to the PIs, 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, are eligible to attend these meetings.

The Steering Committee will serve as the main scientific body of the program. The Steering Committee will be responsible for coordinating the activities being conducted by the program. The Steering Committee membership will include one NHGRI Project Scientist and the PI from each awarded cooperative agreement. Cooperative agreements with multi-PI arrangements will have a single vote to be decided as desired within the multi-PI award. The Steering Committee may add additional members, and other government staff may attend the Steering Committee meetings as desired. It is anticipated that additional coordination mechanisms may be set up with other U.S. and international groups that may collaborate with the program.

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

• Share experience and expertise across participating PRS SSs and the CC and develop consensus approaches to integrating, harmonizing, analyzing and disseminating data for dissemination to other Consortium members, the broader scientific community, and NIH-designated databases.
• Establish best practices for data integration and collaborative analyses as appropriate.
• Inventory, harmonize and analyze Consortium data.
• Develop and refine approaches to PRS-based prediction of health and disease, and evaluating comparability of different approaches.
• Define optimal approaches for PRS-based prediction of health and disease, and work with external collaborators to validate PRS results and where relevant, inform clinical implementation research.
• Prioritize the design and implementation of PRS analyses to address gaps in data based on measures of ancestral diversity.
• Analyze resulting data to understand and address differences in PRS-based prediction of health and disease in diverse populations.

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.

When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

A final RPPR, 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.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 Award Term and Conditions for Recipient Integrity and Performance Matters.

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

eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten submission by the due date, and post-submission issues)

Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-945-7573

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: [email protected]

Lucia A. Hindorff, Ph.D, M.P.H.
National Human Genome Research Institute (NHGRI)
Telephone: 240-271-1509
Email: [email protected]

Damali N. Martin, Ph.D., M.P.H.
National Cancer Institute (NCI)
Telephone: (240) 276-6746
Email: [email protected]

Rudy Pozzatti, Ph.D.
National Human Genome Research Institute (NHGRI)
Telephone: 301-402-8739
Email: [email protected]

Zephaun Harvey
National Human Genome Research Institute (NHGRI)
Telephone: 301-435-7859
Email: [email protected]

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.

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 Part 75.