Part 1. Overview Information

Key Dates

All applications are due by 5:00 PM local time of applicant organization. 

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

No late applications will be accepted for this Notice of Funding Opportunity (NOFO).

It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide, except where instructed to do otherwise (in this NOFO or in a Notice from NIH Guide for Grants and Contracts).

Conformance to all requirements (both in the Application Guide and the NOFO) 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.

There are several options available to submit your application through Grants.gov to NIH and Department of Health and Human Services partners. You must use one of these submission options to access the application forms for this opportunity.

1. Use the NIH ASSIST system to prepare, submit and track your application online.
2. Use an institutional system-to-system (S2S) solution to prepare and submit your application to Grants.gov and eRA Commons to track your application. Check with your institutional officials regarding availability.
3. Use Grants.gov Workspace to prepare and submit your application and eRA Commons to track your application.

Part 2. Full Text of Announcement

Section I. Notice of Funding Opportunity Description

Background and Program Overview

Over the last decade, rapid advancements in the development of high throughput and cost-effective genome sequencing technologies have made it possible to obtain a precise molecular diagnosis for many individuals with an undiagnosed but likely genetic disease. However, a substantial proportion of individuals with a suspected genetic disease – more than 50% - remain undiagnosed after undergoing clinical genetic testing. In 2021, NHGRI launched the GREGoR (Genomics Research to Elucidate the Genetics of Rare Disease) Consortium, with the goal of developing new approaches to identify causal variants in individuals with rare genetic disease, particularly where whole exome sequencing was not successful. The research centers funded in phase I of GREGoR use approaches such as whole genome sequencing, RNA sequencing, and other methods to solve these more challenging cases. The data generated in GREGoR are shared with the broader research community via NHGRI's Analysis, Visualization, and Informatics Lab-space (AnVIL) through the AnVIL Portal.

Today, whole exome sequencing (WES) is considered to be a first-line approach for identifying the underlying cause of rare genetic disorders. While powerful, whole exome sequencing has a number of critical limitations that may contribute to the high rate of unsolved cases. First, WES cannot readily identify more complex variants such as copy number variants (CNV), repeat expansions, or structural variants (SV) that may contribute to disease. An additional challenge is that WES focuses primarily on protein coding regions of the genome, and is unable to detect potential causal variants in regulatory regions, introns, or other non-coding functional elements in the genome. Due to advances in the development of genomic and other molecular technologies, it is now possible to investigate many aspects of genome organization and function comprehensively and at scale, including RNA, protein and metabolites, genomic interactions, and the epigenome. In order for these technologies to be used to their fullest potential in the clinical genetics setting, more concrete guidance and the development of best practices supporting their use for rare disease diagnosis are needed.

A number of computational and analytical challenges also need to be addressed in order to fully realize the potential of these molecular approaches. For example, the integration of multiple molecular data types (including those generated by large-scale programs such as the Encyclopedia of DNA Elements (ENCODE), the Roadmap Epigenomics Program, or the Impact of Genomic Variation on Function (IGVF) Consortium could inform variant prioritization, however doing so requires specialized domain knowledge or expertise that diagnostic labs may not have access to. Many current analytical approaches have other significant limitations, such as excluding many regions of the genome that may harbor disease-causing mutations, such as centromere, telomeres, repeat regions, and sex chromosomes, or not adequately accounting for more complex modes of inheritance. Finally, new genome representations such as the Human Pangenome Reference have the potential to better enable the identification of disease associated variation in whole genome sequence data, but most currently available tools rely on older, outdated reference genomes.

To close the diagnostic gap for rare diseases, there is a need for continued innovation in how such technologies are used in the clinical genetics setting, and in the computational tools and analytical methods that are used to identify and prioritize candidate genes or variants. In the second phase of GREGoR, GREGoR:innovation (GREGoRi), NHGRI seeks to catalyze a dramatic shift in rare disease diagnosis through the development of highly innovative solutions to some of the current challenges that face this field. In particular, GREGoRi will focus on accelerating the use of new or emerging molecular approaches in clinical genetics, on applying more established molecular technologies in innovative ways to obtain a molecular diagnosis, and on addressing significant computational challenges or analytical blind spots that have the potential to unlock new diagnoses.

To achieve the goals of GREGoRi, NHGRI is issuing an open call for applications through three notices of funding opportunity (NOFOs). These NOFOs are open to any investigator with ideas aligned with the goals of the program, regardless of whether they participated in the initial phase of the GREGoR Research Program. 

The three NOFOs are:

• GREGoRi Technology Integration Center: Accelerating the use of new and emerging genomic and molecular methods in rare disease diagnosis through the generation of a large scale multidimensional dataset, systematic evaluation, and the development of concrete recommendations for their use in this setting RFA-HG-27-012
• GREGoRi Data Coordination and Outreach Center: Providing infrastructure and other support to ensure that the data, resources, computational tools and other products of the GREGoRi Research Program are available and useful to the broader research community, and other stakeholders RFA-HG-27-011
• GREGoRi Innovation Projects (this NOFO): Fostering continued innovation in the tools and technologies for rare disease diagnosis, including proof of concept studies exploring the use of new and emerging molecular technologies in obtaining a molecular diagnosis for individuals with rare genetic diseases, and the development of novel computational tools or analytical methods that facilitate the identification of the gene(s) or variant(s) that contribute to rare genetic diseases RFA-HG-27-013

Scope and Objectives

This NOFO solicits proposals to develop and test highly innovative approaches for identifying the gene(s) and/or variant(s) that contribute to rare genetic diseases. These approaches should have the potential to make transformative improvements to the current state of the art.  Projects should focus on either Technology Innovation or Computational Innovation as described below.

Technology Innovation Projects

GREGoRi Technology Innovation Projects will perform proof-of-concept studies that leverage new and emerging experimental technologies, or make innovative use or greatly extend the capabilities of existing technologies, to advance the stated goals of the GREGoRi program. A major goal for the Technology Innovation Projects is to move beyond the current state-of-the-art approach for diagnosing rare genetic disorders, which is primarily based on DNA sequencing (i.e., WES and WGS) as initial steps in variant or gene identification. These approaches should be applicable to a broad range of rare genetic disorders, although proof-of-concept studies may be carried out in a limited number of exemplar phenotypes.

Examples of work that could be within scope include but are not limited to:

• Testing the potential of new or emerging experimental technologies to accelerate identification of gene(s) or variant(s) that contribute to rare genetic diseases
• Testing novel strategies for using established molecular technologies (such as RNA-seq, DNA methylation assays, metabolomic or proteomic analyses) to accelerate identification of gene(s) or variant(s) that contribute to rare genetic diseases
• Improving or scaling experimental technologies to facilitate their use in rare disease diagnosis, including improvements that democratize technology access
• Developing approaches that employ single-sample collection of multiple molecular data types to inform rare disease diagnosis 
• Developing novel experimental approaches for identifying genetic disease cases caused by complex genetic variation, including combinations of variants

In addition to experimental work, Technology Innovation Projects may propose the development of complementary computational or analytical tools or methods that support or enable the use of experimental approaches.

Technologies that show potential in proof-of-concept studies may be integrated into the activities of the Technology Integration Center in later years.

Computational Innovation Projects

GREGoRi Computational Innovation Projects will develop novel analytical methods and/or user-friendly tools that facilitate the identification of the gene(s) or variant(s) that contribute to rare genetic diseases. Applicants may propose innovative early-stage work such as algorithm or model development and proof-of-concept approaches. Applicants may also propose the development of user-focused end-stage tools. Resulting tools and approaches should be useful for analysis of the GREGoR dataset, or other similar rare disease datasets. Tools or approaches may also leverage other datasets that are or could be made publicly available, including those from programs described below (see: Relationship to Outside Collaborations). Approaches that leverage machine learning, and artificial intelligence are encouraged.

Examples of work that could be in scope include but are not limited to the development of:

• Algorithms, approaches, or tools for integrating genomic data with other molecular, phenotypic, imaging, or environmental data to accelerate identification of gene(s) or variant(s) contributing to rare genetic diseases
• Tools that significantly streamline the analyst experience when prioritizing candidate variants, including innovative data visualization and exploration approaches
• Models or tools that recommend the next data that should be generated to address an unsolved rare genetic disease case
• Algorithms, approaches, or tools that help identify complex modes of inheritance or combinations of variants that contribute to rare genetic diseases
• Tools or approaches that facilitate collection, harmonization, or sharing of genomic and phenotypic data to enable rare genetic disease diagnosis
• Tools to integrate genomic data with large datasets that include longitudinal health data, such as electronic health records, to accelerate the identification of gene(s) or variant(s) contributing to rare genetic diseases
• Platforms or tools enabling streamlined analyst investigation of rare-disease cases through integration of multiple public data sources

Tools or algorithms developed under this NOFO are expected to be made available in AnVIL where they can access the GREGoR, GREGoRi, and other datasets. Computational approaches that show potential in proof-of-concept studies may be integrated into the activities of the Technology Integration Center in later years.

Projects that require concurrent development of computational and experimental approaches should apply as Technology Innovation Projects.

Program formation and governance

The award funded under this NOFO will be a cooperative agreement. The recipient will become a member of the GREGoRi Research Consortium, made up of investigators funded in response to the three related NOFOs. The recipient will be expected to work collaboratively with the other components of the GREGoRi Program and with NIH staff towards meeting consortium goals, in addition to the specific research goals outlined in their application.

Recipient responsibilities will include:

• Working with GREGoRi consortium members to develop standards and metrics for data, metadata, and data quality
• Contributing all data, metadata, protocols, methods, software, and other research products to the GREGoRi Data Coordination Center (DCC) and other appropriate repositories in agreed upon formats
• Sharing best practices and lessons learned within the consortium and the external research community
• Adhering to all consortium policies
• Participating actively in consortium meetings, including the Steering Committee and working groups
• Responding to requests for interim reporting from the GREGoRi DCC or NIH staff

Outside Collaborations

Collaboration with stakeholder research communities outside of the GREGoRi Consortium helps maximize the impact of the Consortium's efforts. Recipients will also be expected to explore collaboration opportunities with other research projects and consortia with related interests or goals, such as the Impact of Genomic Variation on Function (IGVF) Consortium, the Human Pangenome Reference Consortium (HPRC), the Atlas of Variant Effects (AVE) Alliance, the Clinical Genome Resource (ClinGen), Molecular Phenotypes of Null Alleles in Cells (MorPhiC), Multi-Omics for Health and Disease (MOHD), or the Somatic Mosaicism across Human Tissues (SMaHT) Network. This may include participating in cross-consortium activities, such as working group meetings.

Data Sharing and Consents in GREGoRi

A major deliverable of the GREGoRi Research Consortium is the GREGoR Data Resource, which makes all molecular and phenotype data collected under this program available to researchers through controlled access via NHGRI's Genomic Data Science Analysis, Visualization, and Informatics Lab-space (AnVIL). In order to streamline access to this valuable resource, NHGRI expects GREGoRi researchers to use samples that have been consented for the broadest possible data sharing. It is expected that samples will be consented for General Research Use (GRU) or Health/Medical/Biomedical (HMB) without any additional data use limitations, although for proof-of-concept Technology Innovation Projects exceptions will be considered with strong justification. Projects that will enroll participants should aim to enroll them with an informed consent process that meets these guidelines.

For More Information

Prospective applicants are strongly encouraged to contact the email address as the Scientific/Research Contact below to discuss the responsiveness of their planned project, and the alignment of the proposed work with the goals of the GREGoRi initiative.

In addition, NHGRI staff will hold an informational webinar for prospective applicants. At this webinar, staff will present an overview of the GREGoRi NOFOs and answer questions that applicants may have about the NOFOs. The time, date, and links to the webinar will be posted on the NIH website. The webinar is open to all interested applicants, but participation is not required to apply.

Investigators proposing NIH-defined clinical trials may refer to the Research Methods Resources website for information about developing statistical methods and study designs.

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

Section II. Award Information

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

Section III. Eligibility Information

1. Eligible Applicants

Higher Education Institutions - Includes all types

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

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)

Local 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).

Federal Governments

• 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 Organizations)

Foreign Organizations/International Collaborations

Non-domestic (non-U.S.) Entities (Foreign Organizations) 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.

NIH will no longer issue awards (i.e., new, renewal, or non-competing continuation) to domestic or foreign entities that involve foreign subawards/subcontracts. All NIH-funded research involving foreign subawards/subcontracts must be submitted in response to a NOFO that is specifically designated for funded international collaborations. See NIH Grants Policy Statement 16.8 Collaborative International Research Awards.

Applications involving foreign subawards/subcontracts submitted in response to this NOFO will be deemed noncompliant and will not be considered for funding. This policy applies to all monetary international collaborations resulting in foreign subawards/subcontracts, however, it does not preclude unfunded international collaborations or foreign components, funding for foreign consultants, or procurement of unique equipment or supplies from foreign vendors.

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the How to Apply- 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. Failure to complete registrations in advance of a due date is not a valid reason for a late submission, please reference the NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications for additional information.

• 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. Foreign organizations must obtain a NATO Commercial and Government Entity (NCAGE) Code (in lieu of a CAGE code) in order to register in SAM.
  • Unique Entity Identifier (UEI)- A UEI is issued as part of the SAM.gov registration process. The same UEI must be used for all registrations, as well as on the grant application.
• eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their Grants.gov registrations; 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 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.

All PD(s)/PI(s) must be registered with ORCID. The personal profile associated with the PD(s)/PI(s) eRA Commons account must be linked to a valid ORCID ID. For more information on linking an ORCID ID to an eRA Commons personal profile see the ORCID topic in our eRA Commons online help.

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 their organization to develop an application for 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 How to Apply-Application Guide.

2. Cost Sharing

This NOFO does not require cost sharing as defined in the NIH Grants Policy Statement Section 1.2 Definition of Terms.

3. Additional Information on Eligibility

Number of Applications

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, per NIH Grants Policy Statement Section 2.3.7.4 Submission of Resubmission Application. 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 NIH Grants Policy Statement 2.3.9.4 Similar, Essentially Identical, or Identical Applications).

Section IV. Application and Submission Information

1. Requesting an Application Package

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 NOFO. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide except where instructed in this notice of funding opportunity to do otherwise (in this NOFO, in a policy notice, or other notice from NIH Guide for Grants and Contracts). 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.

Page Limitations

All page limitations described in the How to Apply- Application Guide and the Table of Page Limits must be followed.

The following section supplements the instructions found in the How to Apply- Application Guide and should be used for preparing an application to this NOFO.

SF424(R&R) Cover

All instructions in the How to Apply - Application Guide must be followed.

SF424(R&R) Project/Performance Site Locations

All instructions in the How to Apply- Application Guide must be followed.

SF424(R&R) Other Project Information

All instructions in the How to Apply- Application Guide must be followed.

SF424(R&R) Senior/Key Person Profile

All instructions in the How to Apply- Application Guide must be followed.

R&R or Modular Budget

All instructions in the How to Apply- Application Guide must be followed.

• Budgets should include funds for the PD(s)/PI(s) and 1-3 other key personnel from the Center to attend one annual meeting of the full consortium and one additional in-person meeting per year (i.e. a Steering Committee meeting, analysis-focused meetings, etc.)
• Budgets should include any funds required to support sharing of scientific data under this NOFO. This should include funds to prepare data for submission to the GREGoRi Data Coordination and Outreach Center. NIH provides guidance on allowable costs for data management and sharing here. For projects generating genomic data derived from research participants, investigators should consider costs associated with complying with the NIH and NHGRI Genomic Data Sharing (GDS) Policy expectations (e.g., obtaining samples with explicit informed consent for future research use and broad data sharing, implementing processes to seek new consent from study participants, etc.)
• Recipients will be expected to work with other members of the GREGoRi Research Consortium to add new or emerging molecular assays or computational methods with potential to impact rare disease diagnosis into their data production and analysis pipelines 

R&R Subaward Budget

All instructions in the How to Apply - Application Guide must be followed.

PHS 398 Cover Page Supplement

All instructions in the How to Apply - Application Guide must be followed.

PHS 398 Research Plan

All instructions in the How to Apply - Application Guide must be followed, with the following additional instructions:

The Research Plan should describe plans to address the major objectives of the GREGoRi Innovation Projects, described in Section I above. Proposals should be scoped as either a Technology Innovation Project or a Computational Innovation Project. A proposal for technology development can also include complementary computational or analytical tools or methods that support the use of experimental approaches; such a project should still be scoped as Technology Innovation Project. 

Both categories of projects should clearly describe the following: 

• How the proposed work will go beyond incremental improvements and will greatly improve upon the current state of the art capabilities for identifying the gene(s) of variant(s) underlying rare genetic disorders 
• Projects focused on improving or scaling existing technologies or computational tools should clearly describe current limitations and how the improvements will transform the utility of those technologies or computational tools
• How the outcomes will be evaluated to quantify performance relative to the current state of the art  

Technology Innovation Projects should specifically address: 

• What samples will be required and specific timelines for obtaining them 
• If any participants will not be consented in accordance with the expectations for GRU or HMB, a strong justification for including those participants 
• How data generated will be made available on the AnVIL platform and shared with the consortium and the larger research community 
• How the project will support other members of the GREGoRi consortium in incorporating the technologies or computational tools developed  
• How the project will disseminate and monitor adoption of technologies 

Computational Innovation Projects should specifically address: 

• What types of data will be required, how they will be obtained, and how they will be made available to the GREGoRi consortium and the research community 
• How the resulting algorithms, approaches, or tools will be made available to other members of the GREGoRi consortium and the larger research community on AnVIL 
• How the project will disseminate and monitor adoption of the resulting algorithms, approaches, or tools 
• How the project will support other members of the GREGoRi consortium in adopting the algorithms, approaches, or tools developed under the project 

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the How to Apply - Application Guide.

The following instructions also apply:

The Resource Sharing Plan should summarize whether and how resources (e.g., educational materials; methods; models; physical products, materials, and reagents; protocols; research findings and products; and software) will be made available. Applicants should include a description of the format, an indication of who will be responsible for implementation and plans for long-term maintenance, whether there will be opportunities for community input and feedback, platform(s) or mechanism(s) that will be used to make resources publicly accessible, and proposed timeline for implementing the Resource Sharing Plan. Resource Sharing Plans should not duplicate other sections of the main Research Plan but should refer to them when appropriate. After initial review, NHGRI program staff may negotiate revisions of this plan with the prospective awardee. The final negotiated version of this plan will become a term and condition of the award.

 Other Plan(s): 

All instructions in the How to Apply - Application Guide must be followed, with the following additional instructions:

• A Data Management and Sharing Plan (DMS Plan) is required for any NIH-funded or conducted research that will generate scientific data. Applicants must submit the DMS Plan at the time of application using the NIH DMS Plan Format Page. The DMS Plan must address the elements in the structured format. Where the DMS Plan Format Page requires a "Yes or No" response, no additional narrative is allowed.
• Recipients must comply with the NIH Data Management and Sharing Policy and NIH Genomic Data Sharing Policy. See https://grants.nih.gov/policy-and-compliance/policy-topics/sharing-policies. NIH recognizes Tribal sovereignty and the rights associated with Tribal sovereignty around data collection, data management and sharing of data and has published a supplemental Notice regarding the DMS Plan for American Indian/Alaska Native populations, NOT-OD-22-214. NHGRI supports the broadest appropriate data sharing with timely data release through widely accessible data repositories.
• Per NOT-HG-21-022, NHGRI expects applications awarded under this NOFO to share comprehensive metadata and phenotypic, clinical, and environmental exposure data associated with the study; use standardized data collection protocols and survey instruments for capturing data, as appropriate; and use standardized notation for metadata (e.g., controlled vocabularies or ontologies) to enable the harmonization of datasets for secondary research analyses.
• 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 submission of all data to the NHGRI Genomic Data Science Analysis, Visualization, and Informatics Lab-Space (AnVIL), through submission of variant interpretations to ClinVar, and through publication in the scientific literature. Although NHGRI expects project datasets and human variant information from studies selected through this NOFO to be made available through AnVIL and ClinVar, data can be shared in other appropriate resources to enhance dissemination.
• NHGRI strongly encourages studies that propose to derive genomic data from human specimens and cell lines to obtain participant consent either for general research use through controlled access or for unrestricted access. Similarly, consent language should avoid both restrictions on the types of users who may access the data and restrictions that add additional requirements to the access request process. NHGRI acknowledges that this will not always be possible or appropriate. In addition, individual participants who do not consent to future research use or broad sharing of their data (i.e., submission of their data to a publicly accessible data repository) may still participate in the primary study if consistent with study design. Additional guidance on informed consent can be found in the NHGRI Informed Consent Resource.

Appendix: Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the How to Apply - Application Guide.

• No publications or other material, with the exception of blank questionnaires or blank surveys, may be included in the Appendix.

PHS Human Subjects and Clinical Trials Information

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 How to Apply- 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 How to Apply - 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 How to Apply- Application Guide must be followed.

PHS Assignment Request Form

All instructions in the How to Apply- Application Guide must be followed.

Foreign Organizations

Foreign (non-U.S.) organizations must follow policies described in the NIH Grants Policy Statement, and procedures for foreign organizations described throughout the How to Apply- Application Guide.

3. Unique Entity Identifier and System for Award Management (SAM)

See Part 2. 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

4. Submission Dates and Times

Part I. 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 Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications.

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 How to Apply-Application Guide.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Pre-award costs are allowable only as described in the NIH Grants Policy Statement Section 7.9.1 Selected Items of Cost.

Applications must be submitted electronically following the instructions described in the  How to Apply – 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 form. 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 NOFO for information on registration requirements.

The applicant organization must ensure that the unique entity identifier provided on the application is the same identifier used in the organization's profile in the eRA Commons and for the System for Award Management. Additional information may be found in the  How to Apply – 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. 

Recipients or subrecipients must submit any information related to violations of federal criminal law involving fraud, bribery, or gratuity violations potentially affecting the federal award. See Mandatory Disclosures, 2 CFR 200.113 and NIH Grants Policy Statement Section 4.1.35.

Send written disclosures to the NIH Chief Grants Management Officer listed on the Notice of Award for the IC that funded the award and to the HHS Office of Inspector Grant Self Disclosure Program at grantdisclosures@oig.hhs.gov.

Post Submission Materials

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.

Section V. Application Review Information

1. Criteria

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 scored review criteria and additional review criteria (as applicable for the project proposed). An application does not need to be strong in all categories to be judged likely to have a major scientific impact.

Reviewers will consider Factors 1, 2 and 3 in the determination of scientific merit, and in providing an overall impact score. In addition, Factors 1 and 2 will each receive a separate factor score. 

As applicable for the project proposed, reviewers will consider the following additional items while determining scientific and technical merit, but will not give criterion scores for these items, and should consider them in providing an overall impact score.

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.

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by the Center for Scientific Review (CSR), in accordance with NIH peer review policies and practices, 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 will receive a written critique.

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.

Requests for reconsideration of initial peer review will not be accepted for applications submitted in response to this NOFO. 

Applications will be assigned to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this NOFO. 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.
• Synergy with other funded projects and program balance, specifically with regards to the balance between technology-based and computationally-based approaches. 
• Programmatic balance, including a broad range of assays and approaches. 

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 Section 2.5.1. Just-in-Time Procedures. This request is not a Notice of Award nor should it be construed to be an indicator of possible funding.

Prior to making an award, NIH reviews an applicant's federal award history in SAM.gov to ensure sound business practices. An applicant can review and comment on any information in the Responsibility/Qualification records available in SAM.gov. NIH will consider any comments by the applicant in the Responsibility/Qualification records in SAM.gov to ascertain the applicant's integrity, business ethics, and performance record of managing Federal awards per 2 CFR Part 200.206 "Federal awarding agency review of risk posed by applicants." This provision will apply to all NIH grants and cooperative agreements except fellowships.

3. Anticipated Announcement and Award Dates

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 Section 2.4.4 Disposition of Applications.

Section VI. Award Administration Information

1. Award Notices

A Notice of Award (NoA) is the official authorizing document notifying the applicant that an award has been made and that funds may be requested from the designated HHS payment system or office. The NoA is signed by the Grants Management Officer and emailed to the recipient's business official.

In accepting the award, the recipient agrees that any activities under the award are subject to all provisions currently in effect or implemented during the period of the award, other Department regulations and policies in effect at the time of the award, and applicable statutory provisions.

Recipients must comply with any funding restrictions described in Section IV.6. Funding Restrictions. Any pre-award costs incurred before receipt of the NoA are at the applicant's own risk.  For more information on the Notice of Award, please refer to the NIH Grants Policy Statement Section 5. The Notice of Award and NIH Grants & Funding website, see Award Process.

Individual awards are based on the application submitted to, and as approved by, the NIH and are subject to the IC-specific terms and conditions identified in the NoA.

ClinicalTrials.gov: If an award provides for one or more clinical trials. By law (Title VIII, Section 801 of Public Law 110-85), the "responsible party" must register and submit results information for certain "applicable clinical trials" on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov). NIH expects registration and results reporting of all trials whether required under the law or not. For more information, see https://grants.nih.gov/policy/clinical-trials/reporting/index.htm

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

Data and Safety Monitoring Requirements: The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or -supported human biomedical and behavioral intervention studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&R) and PHS 398).

Investigational New Drug or Investigational Device Exemption Requirements: Consistent with federal regulations, clinical research projects involving the use of investigational therapeutics, vaccines, or other medical interventions (including licensed products and devices for a purpose other than that for which they were licensed) in humans under a research protocol must be performed under a Food and Drug Administration (FDA) investigational new drug (IND) or investigational device exemption (IDE).

2. Administrative and National Policy Requirements

The following Federal wide and HHS-specific policy requirements apply to awards funded through NIH:

• The rules listed at 2 CFR Part 200, Uniform Administrative Requirements, Cost Principles, and Audit Requirements for Federal Awards.
• All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the terms and conditions in the Notice of Award (NoA). The NoA includes the requirements of this NOFO. 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, Recipients, and Activities.

All federal statutes and regulations relevant to federal financial assistance, including those highlighted in NIH Grants Policy Statement Section 4 Public Policy Requirements, Objectives and Other Appropriation Mandates.

By applying for or accepting federal funds from HHS, recipients certify compliance with all federal antidiscrimination laws and these requirements and that complying with those laws is a material condition of receiving federal funding streams. Recipients are responsible for ensuring subrecipients, contractors, and partners also comply.

Applicants and recipients are strongly encouraged to refer to the NIH Director's Statement of Priorities, entitled "Advancing NIH's Mission Through a Unified Strategy." 

Recipients are responsible for ensuring that their activities comply with all applicable federal regulations. Pursuant to 2 CFR 200.340, by accepting an NIH award, the recipient agrees that continued funding for the award is contingent upon the availability of appropriated funds, recipient satisfactory performance, compliance with the Terms and Conditions of the award, and may also otherwise be terminated, to the extent authorized by law, if the agency determines that the award no longer effectuates the program goals or agency priorities, in line with 2 CFR 200.340(a)(4).

Pursuant to the Cybersecurity Act of 2015, Div. N, § 405, Pub. Law 114-113, 6 USC § 1533(d), the HHS Secretary has established a common set of voluntary, consensus-based, and industry-led guidelines, best practices, methodologies, procedures, and processes.

Successful recipients under this NOFO agree that:

When recipients, subrecipients, or third-party entities have:

• ongoing and consistent access to HHS owned or operated information or operational technology systems; and
• receive, maintain, transmit, store, access, exchange, process, or utilize personal identifiable information (PII) or personal health information (PHI) obtained from the awarding HHS agency for the purposes of executing the award.

Cybersecurity plans and procedures must at minimum include the following:

• Develop cybersecurity plans and procedures, modeled after the NIST Cybersecurity framework, to protect HHS systems and data:
  • Identify:
    • Develop an inventory of all assets and accounts with access to HHS owned and operated information or operational technology systems or which obtain PII or PHI for the purposes of the award.
  • Protect:
    • Limit access to HHS owned and operated systems to only those in need of access to complete reward activities.
    • Require all staff to complete annual cybersecurity and privacy awareness training. Visit 405(d): Knowledge on Demand (hhs.gov) to obtain free trainings, if needed.
    • Enable multifactor authentication for all employees, subrecipients, and third-party entities to access HHS owned and operated information or operational technology systems.
    • Regularly backup sensitive data and test backups.
  • Detect:
    • Install anti-virus or anti-malware software on all devices, servers, and accounts used to connect to HHS owned and operated systems.
  • Respond:
    • Develop an incident response plan. See Incident-Response-Plan-Basics_508c.pdf (cisa.gov) to learn about developing incident response plans.
    • Have cybersecurity incident reporting procedures that ensure the relevant HHS awarding agencies are notified of a cybersecurity incident within 48 hours of discovery. A cybersecurity incident is defined as an unplanned interruption to a technology service or reduction in the quality of a technology service, or an occurrence that actually or potentially jeopardizes the confidentiality, integrity, or availability of an information system or the information the system processes, stores, or transmits.
  • Recover:
    • Investigate incidents and plug any security gaps identified. 

All activities proposed in your application and budget narrative must align with applicable law, including but not limited to statutes, executive orders, federal regulations and applicable judicial holdings.  Accordingly, discretionary awards shall not be used to fund, promote, encourage, subsidize, or facilitate; racial preferences or other forms of racial discrimination by the recipient, including activities where race or intentional proxies for race will be used as a selection criterion for employment or program participation; denial by the recipient of the sex binary in humans, or the belief that sex is a chosen or mutable characteristic; illegal immigration; or any other initiatives that compromise public safety.  If an application does not align, the application will not receive funding to the extent permitted by law and applicable court orders.

For applications involving substance abuse, the application must not support harm reduction. Please see Updated Funding Guidance for Recipients on Supplies and Services.

For applications involving funding Medication-Assisted Treatment (MAT) or medications for opioid use disorder (MOUD), this funding should be used to provide comprehensive treatment and recovery support services rather than medication-only models for opioid use disorder. Services should include medications, where clinically indicated, in conjunction with psychosocial and other treatment and recovery support services. Funding can also be used to support individualized tapering and discontinuation of medications when clinically indicated. Please see Updated Funding Guidance for Recipients on  MAT/MOUD.

As of October 1, 2025, HHS has adopted 2 CFR Part 200, with some modifications included in 2 CFR Part 300. These regulations replace those in 45 CFR Part 75. However, for NIH, under the Consolidated Appropriations Act for FY 2026, (P.L. 119-75, Division B, Title II, Sec. 224), the provisions relating to indirect costs in 45 CFR 75 continue to apply to NIH awards. Consistent with the statute, NIH will not apply updated thresholds outlined within 2 CFR Part 200, at this time.

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 (HHS) grant administration regulations at 2 CFR Part 200, and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the recipients 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 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 recipients for the project as a whole, although specific tasks and activities may be shared among the recipients and 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
• Ensuring the timely transfer of all data, metadata, protocols, methods, software, and other research products to the GREGoRi Data Coordination Center (DCC) and other appropriate repositories using agreed upon formats and processes
• Assessing and disseminating data, protocols, and methods developed both within and outside the Consortium
• Collaboration with stakeholder research communities outside of the GREGoRi Consortium helps maximize the impact of the Consortium's efforts. Recipients will also be expected to explore collaboration opportunities with other research projects and consortia with related interests or goals, such as the Impact of Genomic Variation on Function (IGVF) Consortium, the Human Pangenome Reference Consortium (HPRC), the Atlas of Variant Effects (AVE) Alliance, the Clinical Genome Resource (ClinGen), Molecular Phenotypes of Null Alleles in Cells (MorPhiC), Multi-Omics for Health and Disease (MOHD), or the Somatic Mosaicism across Human Tissues (SMaHT) Network. This may include participating in cross-consortium activities, such as working group meetings.
• Adhering to consortium policies established by the NIH and the GREGoRi Steering Committee
• Submitting periodic progress reports in a standard format as agreed upon by NIH and the Steering Committee
• Attending and participating in Steering Committee and other working group meetings, and accepting and implementing decisions made by these groups
• Ensuring that appropriate approvals for sharing data with GREGoRi DCC and selected data repositories (such as AnVIL, dbGaP, ClinVar) are in place
• Recipients will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies

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

• Serving as a liaison helping to coordinate activities among and for the recipients, including acting as a liaison to the NHGRI and an information resource for the recipients about genome research activities. The agency program official or IC program director will also coordinate the efforts of the recipient with other groups conducting similar studies
• Negotiating milestones with the recipient as necessary
• Attending all Steering Committee meetings as a voting member and all Working Group meetings, assisting in developing operating guidelines, quality control procedures, and consistent policies for dealing with situations that require coordinated action. NIH staff involved in the Steering Committee will collectively have only one vote.
• Reporting periodically on Consortium progress to the National Advisory Council of Human Genome Research 
• Assisting recipients 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
• Serving on subcommittees of the Steering Committee and working groups as appropriate.
• 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
• In coordination with the Grants Management Official, the Program Official may withhold or reduce support from any recipient that fails to achieve its goals or comply with the Terms and Conditions of Award
• Other NHGRI staff may assist the recipient as designated by the Program Official
• The assigned program director may also serve as an NHGRI Project Scientist

Areas of Joint Responsibility include:

The GREGoRi Innovation Project recipients will be required to interact closely with the other members of the GREGoRi Research Consortium and with NIH staff in order to fully achieve the goals of the GREGoRi initiative.

They will also be expected to work closely with the GREGoRi DCC to establish data formats and standards, report findings, and coordinate the transfer of data, metadata, protocols, methods, software, and other research products to the DCC, who will be responsible for sharing these more broadly.

A Steering Committee will be the main governing body of the GREGoRi Research Consortium. The purpose of the Steering Committee will be to recommend directions for the consortium that are consistent with achieving the goals of the GREGoRi initiative, develop consortium policies that build synergy and improve communication and collaboration among the Consortium researchers, and provide a forum for discussing progress, challenges and opportunities for the consortium. The Steering Committee will be composed of the PD/PI(s) from each of the funded research groups and NIH program staff. Each recipient in the Steering Committee will have one vote. NIH staff involved in the Steering Committee will collectively have only one vote. In addition to the PD(s)/PI(s), key personnel from each research group, including pre- and post-doctoral trainees, will be eligible to attend Steering Committee meetings. The Steering Committee will establish subcommittees or working groups, in order to facilitate collaborative work and standardize approaches, or to achieve other goals of the Consortium.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between recipients and NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual recipient. This special dispute resolution procedure does not alter the recipient's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and HHS regulation 45 CFR Part 16.

A Data Management and Sharing Plan (DMS Plan) is required for any NIH-funded or conducted research that will generate scientific data. Applicants must submit the DMS Plan at the time of application using the NIH DMS Plan Format Page. The DMS Plan must address the elements in the structured format. Where the DMS Plan Format Page requires a "Yes or No" response, no additional narrative is allowed. 

4. Reporting

When multiple years are involved, recipients will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement Section 8.4.1 Reporting. To learn more about post-award monitoring and reporting, see the NIH Grants & Funding website, see Post-Award Monitoring and Reporting.

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 Section 8.6 Closeout. NIH NOFOs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 2 CFR Part 200.301.

Section VII. Agency Contacts

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.

Grants.gov Support Center - Questions regarding Grants.gov registration and services (e.g., Workspace, subscriptions).

NHGRI GREGoR Team
National Human Genome Research Institute (NHGRI)
Email: nhgri-gregor@mail.nih.gov 

Center for Scientific Review (CSR)
Email: NOFOReviewContact@csr.nih.gov

Grants Administration Branch
National Human Genome Research Institute (NHGRI)
Email: nhgrigab@mail.nih.gov

Section VIII. Other Information

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

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 2 CFR Part 200.