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

One of the central problems in biology is understanding how genomic variation affects genome function to influence phenotypes. NHGRI considered this problem in part through a workshop entitled From Genome to Phenotype: Genomic Variation Identification, Association, and Function in Human Health and Disease as part of its strategic planning efforts. Functional genomics was a priority topic across several workshop discussions (workshop report can be found at: https://www.genome.gov/sites/default/files/media/files/2019-05/Genome_to_Phenotype_Workshop_Report.pdf). Workshop recommendations highlighted the need for utilizing and developing improved approaches to methodically evaluate the function and phenotypic outcomes of genomic variation. This includes: use of multi-omic and single cell technologies to catalog association between DNA sequence, variation, and function across cell types; high-content, high-resolution functional genomic data following large-scale perturbations in pooled cells; gene regulatory or multi-scale models from multi-layered data across biological systems; as well as improved data interpretation and visualization tools. Ultimately, it was clear that a multi-pronged approach would be needed to better understand genomic function and the role of genetic variation in disease.

Breakthroughs in our understanding of genomic variation and the role it plays in human health and disease have come from a broad community of biomedical researchers and have been supported by research efforts such as NHGRI’s Genome Sequencing Program, the 1000 Genomes Project, numerous Genome-Wide Association Studies, and NHGRI’s Genome Technology Program. Genomic analyses of populations or individuals to identify disease-associated genomic variants are becoming routine. However, establishing causal relationships between variants and disease risk is hampered by a lack of mechanistic understanding. Similarly, understanding the clinical relevance of variants is stymied by the overwhelming and ever-growing number of variants of unknown significance (VUSs). Key challenges and opportunities lie in defining the role of genomic variants in influencing phenotypes, including human health and disease.

Research efforts have systematically identified candidate functional elements, genes and regulatory regions in the human genome, and have begun establishing what those elements do. For example, the NHGRI’s Encyclopedia of DNA Elements (ENCODE) and the NIH Common Fund’s Roadmap Epigenomics Mapping Consortium (REMC) use biochemical signatures of gene regulation to identify candidate elements. The goal of the NHGRI Genomics of Gene Regulation (GGR) project was to develop better methods to construct gene-regulatory network models, while the goal of the NHGRI Non-Coding Variants (NoVa) program was to develop methods to predict which disease-associated variants were most likely causal. Importantly, functional elements are known to have distinct effects based on cell type, and significant work remains to build on these other efforts and link the activity of specific candidate functional elements (if any) and genomic variants to specific cell types and phenotypes.

Based on the workshop recommendations and building on prior work, NHGRI is initiating a new program the Impact of Genomic Variation on Function (IGVF) Consortium that will develop a framework for systematically understanding the effects of genomic variation on genome function and how these effects shape phenotypes. This program will examine how genomes function, how genome function shapes phenotypes, and how these processes are influenced by genomic variation. The IGVF program will consist of five interrelated components that will utilize emerging experimental and computational approaches to build a catalog of the impact of genomic variants on genome function and phenotypes. The goals of the program are: (1) systematic perturbation of the genome to assess the impact of genomic variation on genome function and phenotype, (2) high-resolution identification of where and when genes and regulatory elements function, (3) advancement of network-level understanding of the influence of genetic variation and genome function on phenotype, (4) development and testing of innovative predictive models of the impact of genomic variation on genome function, (5) generation of a resource centered on a catalog of variant impacts and including data, tools, and models that will be shared with the broader research community, and (6) enabling others to perform related studies using these approaches.

To achieve these goals the following FOAs are issued:

• RFA-HG-20-043; Systematic Characterization of Genomic Variation on Genome Function and Phenotype (UM1 Clinical Trial Not Allowed). These are referred to as Functional Characterization Centers .
• RFA-HG-20-044; Defining Genomic Influence on Gene Network Regulation (U01 Clinical Trial Not Allowed). These are referred to as Regulatory Network Projects .
• RFA-HG-20-045; Single-cell Profiling of Regulatory Element and Gene Activity in Relationship to Genome Function (UM1 Clinical Trial Not Allowed). These are referred to as Mapping Centers .
• RFA-HG-20-046; Genomic Variation and Function Data and Administrative Coordinating Center (U24 Clinical Trial Not Allowed). This is referred to as the "DACC".
• RFA-HG-20-047; Developing Predictive Models of the Impact of Genomic Variation on Function (U01 Clinical Trial Not Allowed). These are referred to as Predictive Modeling Projects .

The IGVF program will be organized as a research consortium that brings investigators together in a highly collaborative effort. Synergies among the different components will be identified and pursued to generate a better understanding of how genomic variation impacts genome function, and to develop a community resource of data, models, analyses, and tools that will be both accessible to researchers and useful for advanced machine learning approaches. This resource will be durable such that the content can be extended and re-used by the community allowing for its expanded utility over time. Applicants must be willing to work collaboratively to achieve the consortium goals. If applicable, awardees are expected to comply with the NIH Genomic Data Sharing (GDS) Policy. NHGRI supports the broadest appropriate genomic data sharing with timely data release through widely accessible data repositories. More information on this expectation can be found on NHGRI s Genomic Data Sharing Policy FAQs webpage and described below in the Research Scope and Objectives and Resource Sharing Plan sections.

Improved methods to accurately predict the impact of untested genomic variants (individually or in combination) on genome function and phenotype (including disease phenotypes), are needed because it is not feasible to experimentally probe all genomic variants of interest in all contexts. Recent advances in high-throughput functional genomic methods, including those that will be employed by other components of this consortium, offer increasing amounts of multidimensional data that can serve as input for models predicting relationships between variation, function, and phenotype. Concurrent advances in machine learning and other artificial intelligence approaches offer increasingly powerful means to utilize genomic data to model gene-regulatory networks and predict the impact of untested genomic variants on genome function and phenotype.

Projects supported through this FOA will develop interpretable models predicting the impact of genomic variation on genome function and phenotype (molecular, cellular, and/or organismal), leveraging advances in machine learning and related approaches and using genetic and functional genomic data (including data generated by IGVF) as inputs. Importantly, predictive modeling projects will play a key role in designing the overall IGVF data collection and analysis strategies so that experimental data generation is informed by the parameter needs of model developers and collected data are useful for formulating testable hypotheses.

Objectives

The objectives for projects from this FOA are:

• Develop or refine computational approaches to model and predict relationships among variation, functional elements, genome function, and phenotype
• Collaborate to define the IGVF consortium data collection and analysis strategies
• Generate a variant/element/phenotype catalog for the community
• Contribute analytical expertise to the consortium

The scope of this FOA also includes the following:

• Enable others to perform related studies using these approaches
• Create tools to enable inferences about genome function (optional)

Develop and/or refine computational approaches to model and predict relationships among variation, function, and phenotype: Predictive modeling projects will develop and/or refine computational models predicting the impact of genomic variation on genome function and/or phenotype. Projects will develop models predicting at least one of:

• The impact of changes in DNA sequence (coding or non-coding, single variants or multiple variants simultaneously) on genome function and molecular, cellular, or organismal phenotype, including disease phenotypes, in specific cellular or physiological contexts
• Causal variants among the many variants associated with a complex disease or trait
• Variant pathogenicity based on genome function data
• The impact of biochemical modifications of individual functional genomic elements or changes in higher-order chromatin structure on genome function and phenotype

Projects may additionally propose development of models predicting:

• The impact of structural or biochemical modifications of classes of functional genomic elements on genome function and phenotype
• The location of regulatory elements in the genome and/or their function in specific cell and spatial contexts
• Genetic interactions (in cis or in trans) of genomic variants in protein-coding and non-coding functional elements and their effects on genome function and phenotype

Projects will generate models that predict consequences of changes in genomic sequence or structure on genome function and/or phenotype and generate hypotheses that can be tested experimentally. Models should be tested against benchmarks. Emphasis should be placed on interpretable models that allow for a clear understanding of contributions of model parameters and model biases and that enable a greater understanding of biological mechanisms. Projects will pursue modeling approaches that are generalizable to systems beyond those they are studying.

Predictive modeling projects are expected to help define the consortium data generation strategy (see below) and to use consortium generated data in the development and refinement of predictive models. Applicants are encouraged to review companion FOAs (RFA-HG-20-043, RFA-HG-20-044, RFA-HG-20-045, RFA-HG-20-046) and communicate with program staff to understand the range of data types that may be generated as part of IGVF. Because the full range of data types will not be known at the time of application, projects should demonstrate flexibility to accommodate new and emerging data. Because the first year of the program will focus on establishing the Consortium’s scientific direction, predictive modeling projects should not be dependent on generation of new data in the first 1-2 years but will initially utilize pre-existing data (e.g., publicly available data or other data generated outside the IGVF consortium). Predictive modeling projects are also encouraged to make use of existing publicly available datasets that adhere to FAIR principles (see below).

Predictive modeling projects will be expected to form collaborations with IGVF experimental data generation components, in particular functional characterization centers, to facilitate use of consortium-generated data for model development, testing, and refinement. Applicants may also propose limited experimental (wet-lab) work to iteratively test predictions and refine models.

Predictive models may be developed in the context of specific diseases and/or biological systems. However, any proposed disease/system-specific work must be generalizable to applications beyond the study of a particular disease or small number of diseases/systems.

A key goal of the consortium is development of a community resource of data, models, and tools, useful for both machine-learning and human-guided data exploration, that other researchers can reuse and extend. Predictive modeling projects are therefore expected to share models, predictions, and software in robust and reproducible open-source formats enabling such use, and to make use of publicly available computational frameworks for building and refining computational models and making them available to the community.

Collaborate to define the consortium data collection and analysis strategies: In its first year the IGVF consortium will focus on development of strategies for data collection and analysis in order to identify the highest priority samples, approaches, and experiments for the consortium to study in order to maximize the consortium’s overall impact. Predictive modeling projects are expected to play a critical role in this planning process and provide leadership and recommendations to the consortium on topics including:

• Selection of experimental systems and samples for consortium focus (e.g., identifying the most informative tissues or cell types for consortium study)
• Identification of genomic regions or sets of genetic variants to prioritize for perturbation or functional characterization experiments
• Experimental and analytical design parameters that will help achieve IGVF consortium goals (e.g., statistical considerations, replicate structure, sample size, metadata elements)
• Experimental and analytical design parameters that ensure the data will be useful as a community resource that extends beyond the IGVF consortium
• Identification or selection of benchmarking and/or ground truth data sets
• Development of a data resource useful for both machine-learning and human-guided data exploration

Projects will devote a substantial fraction of their year 1 effort to consortium planning efforts and work in close collaboration with other funded groups from all consortium components. Applicants must set aside 20% of the direct costs from years 2-5 of the award to support shared work with other Predictive Modeling projects and other consortium components in consultation with NHGRI staff. Projects must agree to collaborate effectively with each other and NHGRI staff and abide by consortium-wide policies. This collaborative work is anticipated to further both the needs of the individual funded projects, and the IGVF consortium as a whole.

Generate a variant/element/phenotype catalog for the community: A primary goal of the predictive modeling projects is to collaboratively produce a variant/phenotype catalog for use by the community. For all variants that were tested by the consortium, this catalog will report the perturbation and phenotype assay(s), the biological system(s), results and interpretation, along with predicted effects of untested variants. Comparisons across assays and predictive models and with data from other projects will be used to assess the accuracy and biological relevance of the findings. The predictive modeling projects and characterization centers will co-lead this collaborative effort, which will also include mapping centers, the data coordinating center, and NHGRI staff. Other groups may participate in the collaboration as appropriate.

Contribute analytical expertise to the consortium: In addition to helping to develop the consortium experimental and analytical strategy, predictive modeling projects are expected to serve as a source of analytical and computational expertise over the entire project period, and may be expected to:

• Provide leadership in development/adoption/benchmarking of data analysis and processing tools and methods across the consortium
• Provide ongoing input on data production goals, including feedback on data production strategy based on early results
• Provide input on data formats, quality metrics, uniform data processing and analysis pipelines, and other consortium analytical work
• Lead working groups dedicated to specific analysis topics of importance to the consortium
• Interact with groups outside the IGVF consortium working in related areas, including integrating or adopting outside data sources, methods, and analytical tools complementary to IGVF efforts
• Lead other consortium analytical efforts as needed

Create tools to enable inferences about genome function and phenotype (optional): Predictive modeling projects may develop tools enabling research efforts to understand genomic variation, function, and phenotype relationships, including:

• Tools enabling human-guided data exploration, including exploration of functional annotations and variant impacts
• Genomic data visualization tools
• Tools that facilitate integration of IGVF data with data from outside sources
• Tools that facilitate use of IGVF data for studies of the genetic basis of disease or clinical applications of genomics

Enabling others to perform related studies using these approaches: Predictive modeling projects will fully share data, analyses, algorithms, software, protocols, models and technologies. Awardees will assess approaches used by all predictive modeling projects. This may include the specificity, sensitivity, accuracy and generalizability of approaches. It may also include determining the systematic limitations and biases as well as strengths of the approaches. Awardees may identify what is needed to improve future assessments of the role of genetic variation in genome function.

Considered non-responsive: Projects with the following properties will be considered non-responsive, and will not be reviewed:

• Projects that propose extensive wet-lab data generation. Applicants may propose limited (<10% annual direct costs) wet-lab work to inform modeling efforts
• Projects that propose developing predictive models that are not comprehensive in scope (e.g., applicable to only one or a small set of genomic loci/sequences/elements)
• Projects that propose developing predictive models that are not generalizable (e.g., applicable to one or a small number of diseases or biological systems)
• Projects that do not propose plans to help design experimental strategies generating data useful for predictive modeling
• Projects that do not propose to contribute analytical expertise to consortium
• Proposed work that does not indicate plans to participate in the ramp-up year and to collaborate with and contribute to consortium-wide, collaborative activities and analyses throughout the course of the project.

This FOA uses the Cooperative Agreement mechanism. Successful applicants will become members of the IGVF Consortium composed of investigators who have been funded in response to at least one of the five related FOAs. Awardees are expected to work collaboratively with all members of the consortium towards meeting consortium goals, in addition to the research goals outlined in their individual applications. Awardee responsibilities will include:

• Contributing to the development of a catalog of the impact of genomic variants on genome function and phenotypes.
• Planning experiments, implementing studies, and analyzing results from within component and consortium-wide projects, typically through working groups.
• Developing standards and metrics for data, metadata, data quality, and analyses.
• Contributing all data, metadata, protocols, methodologies, analyses, software, and other products to the DACC and appropriate repositories in specified formats.
• Sharing best practices and lessons learned within the consortium and with the external community.
• Following consortium policies on data sharing and publication.
• Taking part in consortium-wide, Steering Committee, and working group meetings.
• Contributing to outreach efforts.
• Collaborating with other consortia and projects.

All investigators will be required to attend a kickoff meeting for the consortium that will take place soon after awards are made. This meeting will be the start of the program’s first year activities. A major focus of the first year will be establishing the consortium’s scientific direction and interactions within and between components. During this time, a Steering Committee composed of the funded PDs/PIs and NHGRI staff will be established to guide the overall scientific direction of the consortium. The Steering Committee will meet regularly and be complemented by a set of working groups. NHGRI staff will also recruit outside experts (non-awardees) as an External Consultants Panel to provide advice directly to NHGRI. The first year will be used to plan within component and consortium-wide strategies for data collection and analyses for a ramp-up of activities in years 2-5. Awardees will also work together in year 1 to characterize the strengths, synergies, and weaknesses of their proposed approaches. Specific roles for each program component during this ramp-up year are described in the Research Scope and Objectives and Research Plan sections. To allow for flexibility, NHGRI will reserve 10% of the approved funding level in years 2-5 of the consortium and may shift funding from one group to another as dictated by new opportunities.

NHGRI strongly encourages all investigators with innovative ideas aligned with the goals of this FOA to submit applications. NHGRI especially encourages applicants who are new investigators, experienced investigators who are new to genomic science, investigators that have not previously participated in a NHGRI-consortium or program, and investigators from demographic groups or institutions that are generally underrepresented in genomic science. Applicants to this FOA can also apply to one or more of the related FOAs. However, when making funding decisions, NHGRI intends to consider whether an applicant will be funded as a PD/PI through the other FOAs and may choose to limit awards from multiple FOAs to encourage participation from a broad representation of the research community.

All applicants are strongly encouraged to contact NHGRI Staff to discuss the responsiveness and alignment of their proposed work with the goals of this program. An informational webinar will be held for potential applicants. NIH staff will be available to answer questions related to this FOA. Time, date, and dial in information will be announced in an NIH Guide Notice and will be posted on the NHGRI website: http://www.genome.gov/. During the webinar, NHGRI staff will present overviews of the FOAs and answer FOA-related questions from prospective applicants. The informational webinar is open to all prospective applicants, but participation is not a prerequisite for submission of an application.

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:

o Hispanic-serving Institutions

o Historically Black Colleges and Universities (HBCUs)

o Tribally Controlled Colleges and Universities (TCCUs)

o Alaska Native and Native Hawaiian Serving Institutions

o 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.
• o 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:

Daniel Gilchrist, Ph.D.
Telephone: 301-402-0911
Email: [email protected]

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed. The Research Strategy is limited to 12 pages, exclusive of the specific aims page. The following subsections are recommended:

• Overview
• Developing computational approaches to model and predict relationships among variation, functional elements, genome function, and phenotype
• Collaborating to define the IGVF consortium data collection and analysis strategies
• Generating a variant/phenotype catalog for the community
• Contributing analytical expertise to the consortium
• Creating tools to enable inferences about genome function (optional)

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.

• For single PD/PI applications, the PD/PI is expected to devote at least 3 person months, based on a 12-month calendar. If multi-PDs/PIs are proposed, then at least one PD/PI is expected to commit at least 3 calendar months annually and the other(s) should devote sufficient time to serve his/her proposed role. The appropriateness of the effort of key personnel must be justified in the budget justification.
• Budgets should include funds for the PD(s)/PI(s) and key personnel to attend the initial consortium kickoff meeting, and for the PD(s)/PI(s) and 2-4 members of the center to attend annual consortium meetings thereafter that start in year 1. Budgets should also include funds in years 1 and 2 for the PD(s)/PI(s) to attend mid-year, in-person Steering Committee meetings.
• 20% of the direct costs from years 2-5 of the award must be allocated to support shared work with other Predictive Modeling projects and other components in consultation with NHGRI staff. This work is anticipated to further both the needs of the funded centers and the IGVF Consortium.
• Budgets should include any funds required to support sharing of genomic data under this FOA (e.g., to obtain samples with explicit informed consent for future research use and broad data sharing, or to prepare the data for submission to appropriate repositories).

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:

Overview

Applicants must provide a high-level view of the proposed project, including:

• The goals of the proposed project.
• Expected outcomes relative to the overall consortium goal as well as the objectives for projects from this FOA defined in the Background section.
• An overview of the significance, innovation and approach. Details should be provided in the following sections.

Development and/or refinement of computational approaches to model and predict relationships among variation, function, and phenotype

Applicants must propose a plan to develop or refine computational approaches to model and predict variation/function/phenotype relationships. Applicants should:

• Describe plans to develop and/or refine computational approaches predicting the impact of genomic variation on genome function and/or phenotype, including what proposed models will predict, model inputs and outputs, and plans for testing and validation. This should include potential problems, alternative strategies, and benchmarks for success.
• Explain the rationale for the selection of proposed computational, analytical, and modeling approaches.
• Describe how developed models will emphasize interpretability and enable understanding of biological findings, contributions of model parameters, and biases.
• Detail the innovative aspects of their application, justifying how the proposed work goes beyond incremental improvements to existing methods and explaining how the applicants propose to balance development of novel methods, models, and analyses with the ability to deliver useful predictions to the community.
• Explain plans to incorporate data types likely to be produced by other IGVF consortium components into model development and testing. As the strategy will be decided by the consortium during the first year, applicants should indicate how they would revise their plan to take into account the consortium strategy.
• Explain the rationale for the selection of any pre-existing data used in model development and testing.
• Explain the rationale for selection of any specific biological or disease systems for focus, including justification of how the approach and system can generalize to other outcomes, systems, or diseases.
• Explain the rationale for any proposed experimental (wet-lab) work. If applicable, describe how high-quality samples with consents appropriate to project will be obtained. NHGRI expects that all human data generated by this NHGRI-funded research project will be derived from specimens or cell lines for which explicit consent for future research use and broad data sharing can be documented (NOT-HG-20-011). Sources with participant consent for unrestricted access are strongly encouraged. Sources consented for broad General Research Use (GRU) or Health, Medical, and Biomedical (HMB) through a controlled-access environment may also be considered, but need to be well justified. As appropriate, studies should involve samples that are diverse with respect to ancestry and involve both sexes.
• Describe plans for providing models, software, and other outcomes in robust and reproducible formats as part of a community resource.
• Applicants should indicate willingness to abide by software and data sharing policies developed and agreed upon by the Consortium.

Collaborate to define the consortium data collection and analysis strategies

Applicants must propose their ideas for a plan to work collaboratively to define a data collection strategy for functional characterization centers (RFA-HG-20-043), mapping centers (RFA-HG-20-045) and predictive modeling projects. This plan should describe how predictive modeling projects, characterization centers, mapping centers, and NHGRI staff might work collaboratively. The implemented plan will be developed and selected by the consortium during the first year, and thus may not match the plan proposed by any applicant. The plan should:

• Describe the data and experimental and analytical design parameters that are needed to support predictive modeling efforts, and how to achieve them.
• Present and explain a rationale for data collection that balances breadth and depth in terms of sample selection and variants tested.
• Describe how to determine the required extent of overlap to compare assays and phenotypic endpoints.
• Describe how benchmarking and/or ground truth data sets will be identified or generated.
• Describe plans for working with other groups to outline alternative approaches and achieve consensus when needed.

Generation of a variant/element/phenotype catalog for the community

Applicants must present a proposal to develop a catalog relating variants/elements to phenotypes. This proposed plan must indicate how the catalog would allow the community to interpret the results obtained. This plan must be compatible with the predictive models of the proposed project. Ultimately the consortium will generate a single catalog. This catalog will be hosted by the DACC. The implemented plan will be selected by the consortium during the first year, and thus may not match the plan proposed by any applicant.

This plan should:

• Describe the information to be reported in the catalog.
• Describe the approach to integrating results from different models, assays, biological systems and phenotypic endpoints.
• Describe how concordant and discordant data will be presented and interpreted, as well as sparse data.
• Describe the use cases for the external community that would be supported by the catalog.
• Applicants should describe plans for employing best practices and state of the art technology, including where appropriate, emphasis on data interoperability and scalability of tools, software, and approaches.
• Applicants should indicate willingness to abide by software and analysis release policies developed and agreed upon by the Consortium.
• Applicants should indicate how they would work with the consortium to achieve consensus for a single catalog, and how they will revise their plan to take into account the consortium strategy.

Contribute analytical expertise to the consortium

Applicants must propose their ideas for a plan to contribute analytical expertise to the consortium. The implemented plan will be developed by the consortium during the first year, and thus may not match the plan proposed by any applicant. This plan should:

• Describe the areas of overall consortium activities and goals where the proposed project is best suited to contribute analytical expertise, including citing relevant experience.
• Describe how the proposed project will provide input on data production, data formats, quality metrics, uniform data processing and analysis pipelines.
• Describe potential challenges to consortium wide analysis and planning, and alternative approaches.
• Describe how the propose project will lead interactions with groups outside the consortium working in related areas, including identifying and adopting outside data sources, methods, and analytical tools complementary consortium efforts.

Create tools to enable inferences about genome function (optional)

Applicants may propose plans to create tools to enable inference about genome function. This plan should:

• Describe any plans to develop tools for genomic data visualization, human-guided data exploration, data integration, or use of IGVF data for studies of the genetic basis of disease or clinical applications of genomics, and explain how these would enable work by the consortium and/or larger community.
• Describe how tools will be integrated with other consortium activities.
• Describe plans for making tools broadly available to the research community in useful and robust formats as part of a community resource.

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.
• Resource Sharing Plans are expected for this FOA.
• In the Resource Sharing Plan, applicants should indicate their willingness to abide by all data deposition, data quality metrics, standards and metrics for data, metadata requirements, and data/software release policies developed by the IGVF Consortium's Steering Committee and approved by NHGRI staff. Awardees are expected to develop such policies as members of the consortium's Steering Committee in collaboration with NHGRI and should indicate their willingness to participate in the development of such policies and to accept them. These policies will remain consistent with NIH and NHGRI policies on data and resource sharing.

Plan for Data Sharing: A key goal of the IGVF Consortium is to build a durable community resource of data, models, and tools designed and built to enable future data exploration and use by humans and computers. Applicants should propose a data sharing plan consistent with this goal that addresses rapid data sharing with the community and describes plans to adhere to the FAIR Guiding principles (Findable, Accessible, Interoperable, Reusable), including:

• Data and metadata assigned unique and persistent identifiers.
• Data and metadata retrievable using standardized protocols/APIs.
• Data pass strict quality metrics.
• Data have clear provenance.
• Rich metadata are collected with all data.
• Wherever possible, community-standard formats, vocabularies, ontologies, quality metrics are used.
• Plans for sharing protocols and methodologies should be included.

Applicants should discuss the use of human biological samples obtained with consents allowing for future use and broad genomic data sharing. Specifically, applicants should describe previous experience with obtaining samples using consents allowing for unrestricted data sharing or controlled-access data sharing broadly consented, as well as the feasibility of obtaining such consent for biological samples proposed in the research plan. Applicants should indicate their agreement to obtain and use these appropriately consented samples in the proposed studies.

Selection of Biological Samples, Genomic Data and Genomic Data Sharing: In order to maximize the utility of the IGVF Consortium data, all human biological samples to be studied that are derived from specimen or cell line sources are expected to have been obtained using a documented informed consent process that explicitly allows for future research use and broad data sharing (NOT-HG-20-011). Sources with participant consent for unrestricted access is strongly encouraged. Sources consented for sharing through a controlled-access environment, such as General Research Use (GRU) or Health, Medical, and Biomedical (HMB) without additional restrictions, will also be considered and should be well justified. As outlined above, the consent process for human biological samples should be described in the Plan for Data Sharing.

Studies should include samples that are derived from individuals of diverse ancestry and allow for consideration of sex as a biological variable. Applicants should propose study of samples and disease models with consideration of diseases disproportionately affecting disadvantaged or under-represented populations.

Plan for Software and Data Analysis Sharing: NHGRI is also committed to the timely release of open source software and well-documented data analyses including models and tools developed from proposed studies. Applicants should include detailed plans for open dissemination of methods, software, and tools to the community such that they are readily usable and extensible, where applicable. These should be made freely available to biomedical researchers and educators. There is no prescribed license for software produced by applications responding to this announcement, but any software license selected by applicants should allow for unrestricted redistribution and modification of software.

• Methods, tools, and software should be well-documented and where applicable made available via version-controlled public repositories.
• Where applicable, applicants should describe solutions for portable implementations.
• Solutions that enhance reproducibility when used by the community and ability of the community to integrate into automated pipelines should be emphasized.

Plan for Resource Sharing: As the IGVF Consortium is creating a community resource, NHGRI intends that, in addition to data, software, and analyses, any physical resources, such as DNA clones and cell lines, generated by awardees should be made rapidly available to the research community and that resource sharing plans should follow the same principles and spirit as data, software, and analysis release plans. The applicant should provide specific plans for resource sharing and distribution in the application.

After initial review, NHGRI program staff will conduct an additional administrative review of the plans for sharing data, software, data analysis, and resources and may negotiate modifications of these plans with the prospective awardee. The final negotiated version of these plans will become a term and condition of the award of the cooperative agreement.

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.

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?

Specific to this FOA:

• Will the proposed project contribute to the consortium goals of assessing the impact of genomic variation on genome function and phenotype?
• Will the proposed project generate data and analyses that will be of high utility to the research community?
• Will the proposed strategies enable the study of the impact of genomic variation on genome function and phenotypes relevant to human health and disease?

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?

Specific to this FOA:

• Has the team demonstrated a track record in team science?
• Has adequate leadership for the day-to-day project management activities (e.g., a project manager or sufficient PD(s)/PI(s) effort) been described?
• Does the applicant indicate a willingness to work with other centers and participate in Consortium activities?
• Does the project team have a track record of disseminating novel software, tools, and techniques broadly?

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?

Specific to this FOA:

• Are the proposed approaches well justified, including their relevance to human health and disease?
• Are the proposed modeling approaches state-of-the-art, and capable of producing useful and interpretable models?
• Do the proposed models appropriately balance comprehensiveness, accuracy, and usefulness?
• Are the proposed approaches appropriate for the data types likely to be produced by other IGVF consortium components?
• Are the milestones, timelines and goals proposed for the research project reasonable and appropriate?
• Are the plans for validation reasonable and adequate?

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?

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).

Examples of resources to share could include, but are not limited to: protocols and methodologies; tools; model organisms; metadata; and human specimens and cell lines.

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 (NACHGR). 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.

• Programmatic balance, including a diversity of approaches
• Potential to work effectively in large collaborative efforts or research consortia, which may be based on previous experience with NIH-funded research consortia, if applicable
• Adequacy of data sharing, software and analysis sharing and resource sharing plans
• Synergy with other funded projects and program balance
• Expansion of the community of genomic science to include new investigators, experienced investigators who are new to this field, and investigators from demographic groups or institutions that are generally underrepresented in genomic science
• Inclusion of new investigators and experienced investigators that are new to NHGRI consortia
• Whether an applicant will be funded as a PD/PI through the other FOAs in the IGVF Consortium to encourage participation from a broader representation of the research community

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.

After the initial NIH peer review of a grant application, NHGRI program staff will conduct an additional administrative review of the Resource Sharing Plan, including the Plan for Sharing Data and Genomic Data and may negotiate modifications with the prospective awardee to ensure it is consistent with the principles stated above. The final negotiated version of the Resource Sharing Plan will become a term and condition of the award of this FOA per the NIH GDS Policy.

The PD/PI grantees will have the primary responsibility for sharing research results according to the NIH Genomic Data Sharing Policy, NHGRI-specific data sharing expectations (if applicable) and any other data sharing policy or plan agreed to between the NIH and the applicant.

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/browse.aspx?lvl=2&lvlid=53.
• 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 following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Part 75, and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this award will be managed as a 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 awardee. Specific tasks and activities may be shared among the awardees within the consortium and the NHGRI staff as defined below.

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

• Determining research approaches, designing protocols, setting project milestones and timelines, providing milestone revisions as requested to NHGRI, and conducting research.
• Ensuring that the genomic data, and other types of data, software, resources, materials, etc. produced as part of this project are released appropriately according to the final negotiated version of the Resource Sharing Plan, IGVF Consortium policies, and NIH policies.
• Serving as a member of the IGVF Consortium Steering Committee.
• Adhering to policies regarding standardized formats; timely publication of abstracts, presentations and publications; and intellectual property established by the NIH, NHGRI, and the Steering Committee (SC).
• Not disclosing confidential information.
• Interacting with other relevant NHGRI and NIH activities, as needed, to promote synergy and consistency among similar or related projects.
• Adopting a perspective prioritizing diversity in human genomics, emphasizing the use of samples that are derived from individuals of diverse ancestry, allow for consideration of sex as a biological variable, and allow for the consideration of applications to diseases disproportionately affecting disadvantaged or under-represented populations.
• The PD/PI and his/her staff will be required to fully participate in a cooperative, interactive, and collaborative manner with NIH staff, IGVF Consortium investigators, and one another.
• Collaborating with the Data and Administrative Coordinating Center (DACC). Awardees that are part of a consortium will work collaboratively with a DACC that is tasked with a variety of roles, such as: ensuring that the products are the highest quality; developing standards; disseminating information; providing logistics, outreach and training, etc. In order for the collaboration to be effective, PDs/PIs are responsible for:
• Ensuring that the awardee receives the appropriate approvals for sharing data between the DACC and data repositories approved by the consortium and NHGRI. Examples could be AnVIL, dbGaP, GEO, and ClinVar and other appropriate public databases.
• Transferring, in a timely manner, of detailed (sequence, variant, other genomic, functional, phenotypic, , etc.) and related data and metadata, as appropriate, to the DACC, using agreed-upon formats and processes, to facilitate dissemination of data more broadly through databases such as AnVIL, dbGaP, GEO or ClinVar, and other appropriate databases.
• Collaborating with the DACC to establish data formats and standards, to track and document collaborations and incoming samples, report findings, etc.
• Fully disclosing data, analyses, algorithms, software source code, and experimental methods to the other members of the consortium for the purpose of scientific evaluation and use by other consortium members.
• Submitting periodic progress reports in a standard format, including metrics of the use and impact on the community, agreed on with the NHGRI Project Scientist/Scientific Officer (PS/SO).
• Providing reports, summary statistics, and data, as appropriate, in a timely fashion as agreed upon by the PS/SO.
• Assessing and disseminating data, protocols, consent materials, methods, analyses, research resources, software, and tools developed for or derived from the DACC within and outside the consortium, as appropriate and according to the release policies developed for and by this project.
• Abiding by common definitions, protocols, and procedures.
• Attending and participating in SC and other working group meetings and accepting and implementing decisions made by the SC.

Consistent with 45 C.F.R. 75.322, the awardee will own the data and software developed under this award and be able to continue to use these data and software upon expiration or termination of the award. NIH will have unrestricted access to and use of the data and software, including the right to transfer them to other resource projects for their use, distribution, and integration with other data. NIH expects that the awardee will grant other resources the ability to use and redistribute the data, including integrating the data with other datasets, without restriction, unless otherwise limited by consent requirements.

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

The Project Scientist/Scientific Officer (PS/SO) at NHGRI is a dual role held by a NHGRI Program Director. In the Project Scientist role, the Program Director will have substantial scientific and programmatic involvement during the conduct of this activity through technical assistance, advice, and coordination. In the Scientific Officer role, the Program Director will be responsible for the normal scientific and programmatic stewardship of the award and manages concerns about bias as it affects the project. The role of NHGRI PS/SO will be to facilitate and not to direct the activities. The PS/SO will be named in the Notice of Award.

The PS/SO will have the following substantial involvement:

• Serving as a liaison, helping to coordinate activities among and for the awardees, including acting as a liaison to the NHGRI and as an information resource for the awardees about genome research activities. The PS/SO will also coordinate the efforts of the awardee(s) with other groups conducting similar studies.
• Negotiate milestones, e.g., throughput, quality, and biological samples with the awardees, as necessary.
• Participate in data analyses, interpretations, and, where warranted, co-authorship of the publication of results of studies conducted through the IGVF Consortium.
• Participate with the other SC 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.
• Reporting periodically on the progress of the awardees to the NHGRI Director and to the National Advisory Council for Human Genome Research.
• Assisting awardee(s) in the development, if needed, of policies for dealing with situations that require coordinated action.
• Providing advice on the management and technical performance of the award.
• Assisting in promoting the availability of the data and related resources developed in the course of the award to the scientific community.
• Being responsible for the normal scientific and programmatic stewardship of the award, including assessments of how well the awardee has met any milestones required for each year of funding.
• Curtailing, withholding or reducing support for any awardee that fails to make sufficient progress toward the work scope that NHGRI approved, has ethical or conflict of interest issues, or fails to comply with the Terms and Conditions of Award.
• Involving NIH or NHGRI staff who may assist the awardee(s) as designated by the PS/SO.

External Scientific Panel (ESP): The NHGRI PS/SO may engage external scientists with relevant scientific and consortium experience, who are not funded as part of the project and who agree to a confidentiality policy, to provide input and advice to the NHGRI PS/SO about the project. The PS/PO will appoint scientists to the ESP and will determine the durations of service. Activities of the ESP could include:

• Participating, as appropriate, in consortium meetings, Steering Committees calls, and the annual awardees meetings; a subset of ESP members may also meet remotely at other times during the project period, as needed.
• Reviewing and evaluating the progress of awardees (individually or as a group) in achieving the goals of the project.
• Recommending changes in priorities based on scientific advances within and outside the consortium;
• Providing individual recommendations regarding any changes in the project or grant(s) as necessary.

The PS/SO will use recommendations from the ESP to make project changes, as appropriate.

Areas of Joint Responsibility:

Close interaction between the participating awardee(s) and the PS/SO will be required, to manage, assess, and implement activities towards the common goals of the consortium. This is accomplished by:

• Meeting monthly for conference calls to share information on data resources, methodologies, analytical tools, data analyses, preliminary results, etc.
• Establishing best practices for data integration and collaborative analyses as appropriate.
• Setting research priorities, deciding optimal research approaches and protocol designs, and contributing to the adjustment of research protocols or approaches as warranted.
• Generating responses to ESP recommendations.

The PS/SO will assist and facilitate the group process and not direct it.

• Steering Committee (SC): The SC will be the main governing body of the consortium. The purpose of the SC will be to recommend directions for a consortium consistent with achieving the project goals, develop consortium policies to build synergy and improve communication and collaboration between the projects, and to provide a forum for discussing progress, challenges and opportunities for the consortium.
• The SC will convene for monthly conference calls and twice per year in-person meetings in the first two years, and monthly conference calls and one time per year in-person meetings in years 3-5 to share information on data resources, methodologies, analytical tools, data analyses, preliminary results, etc. As needed, additional meetings of the SC, working groups and consortium members will be determined by the SC.
• The SC will be composed of one representative from each of the grants awarded in the consortium. Each PD/PI will decide who will be its representative. Multi-PI grants will have one representative. Each representative will have one vote; The PS/SO will be a voting member. Other designated NIH staff, External Program Consultants, or other designated participants may attend the SC meetings on a regular or ad-hoc basis, but will be ex officio (non-voting) members.
• The SC will develop its own operating procedures.
• The SC may establish working groups to oversee the development and implementation of consortium policies including data and software releases, publications and standards, etc. Working groups may be either permanent or time limited, may include additional experts, depending on the needs of the research.
• The PD(s)/PI(s) will be expected to play an active role in these working groups, as appropriate.
• It is expected that most of the decisions on the activities of the SC will be reached by consensus.
• NIH staff will review and approve policies developed by the SC.
• Awardees will be required to accept and implement policies approved by the SC.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NHGRI may be addressed by convening a Dispute Resolution Panel. It will be composed of 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 disagreement for one award, the first member may be chosen by that 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]

Daniel Gilchrist, Ph.D.
National Human Genome Research Institute (NHGRI)
Telephone: 301-402-0911
Email: [email protected]

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

Lisa Oken
National Human Genome Research Institute (NHGRI)
Telephone: 301-402-0911
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.