Department of Health and Human Services

Part 1. Overview Information

Participating Organization(s)

National Institutes of Health (NIH)

Components of Participating Organizations

National Cancer Institute (NCI)

National Human Genome Research Institute (NHGRI)

Funding Opportunity Title
Developing novel theory and methods for understanding the genetic architecture of complex human traits (R21 Clinical Trial Not Allowed)
Activity Code

R21 Exploratory/Developmental Research Grant

Announcement Type
New
Related Notices
  • December 6, 2023 - Notice of NCI's participation in PAR-23-301, Developing novel theory and methods for understanding the genetic architecture of complex human traits (R21 Clinical Trial Not Allowed). See Notice NOT-CA-24-018
  • August 31, 2022- Implementation Changes for Genomic Data Sharing Plans Included with Applications Due on or after January 25, 2023. See Notice NOT-OD-22-198.
  • August 5, 2022- Implementation Details for the NIH Data Management and Sharing Policy. See Notice NOT-OD-22-189.
Notice of Funding Opportunity (NOFO) Number
PAR-23-301
Companion Funding Opportunity
PAR-23-302 , R01 Research Project
Number of Applications

See Section III. 3. Additional Information on Eligibility.

Assistance Listing Number(s)
93.399, 93.172
Funding Opportunity Purpose

The goal of this NOFO is to support applications for novel theory and methods development that enable better understanding of how genetic and non-genetic factors contribute to complex trait variation across individuals, families, and populations. Approaches should account for interdependencies across scales of biological, social, and ecological organization, make extensive use of theory, modeling, and validation with available large-scale datasets, and may be interdisciplinary drawing from the natural and social sciences.

Key Dates

Posted Date
September 26, 2023
Open Date (Earliest Submission Date)
January 16, 2024
Letter of Intent Due Date(s)

Not Applicable

The following table includes NIH standard due dates marked with an asterisk.
Application Due Dates Review and Award Cycles
New Renewal / Resubmission / Revision (as allowed) AIDS - New/Renewal/Resubmission/Revision, as allowed Scientific Merit Review Advisory Council Review Earliest Start Date
February 16, 2024 * March 16, 2024 * Not Applicable July 2024 October 2024 December 2024
June 16, 2024 * July 16, 2024 * Not Applicable November 2024 January 2025 April 2025
October 16, 2024 * November 16, 2024 * Not Applicable March 2025 May 2025 July 2025
February 16, 2025 * March 16, 2025 * Not Applicable July 2025 October 2025 December 2025
June 16, 2025 * July 16, 2025 * Not Applicable November 2025 January 2026 April 2026
October 16, 2025 * November 16, 2025 * Not Applicable March 2026 May 2026 July 2026
February 16, 2026 * March 16, 2026 * Not Applicable July 2026 October 2026 December 2026
June 16, 2026 * July 16, 2026 * Not Applicable November 2026 January 2027 April 2027
October 16, 2026 * November 16, 2026 * Not Applicable March 2027 May 2027 July 2027

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.

Expiration Date
January 08, 2027
Due Dates for E.O. 12372

Not Applicable

Required Application Instructions

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.


  4. Table of Contents

Part 2. Full Text of Announcement

Section I. Notice of Funding Opportunity Description

Background

The genetic architecture of complex traits herein, the number, frequency, impact, and interaction of alleles influencing a trait is shaped by evolutionary forces including mutation, migration, and selection. Complex traits are also shaped by the active and passive interactions of the individual with their physical and social environments. Such interactions themselves may be heritable resulting in seemingly inextricable and recursive sources of trait variation. Yet while current approaches for describing the genetic basis of human traits have advanced our understanding of disease, they largely represent reductive frameworks focused on the molecular biology of the cell and the physiology of the individual. Thus, as noted in NHGRI’s 2020 Strategic Vision, new approaches are needed to tease apart associations among genetic as well as non-genetic factors and to account for the myriad complexities influencing human traits.

Partitioning components of trait variation has been a goal of quantitative genetics since its inception over a century ago. Subsequent theoretical advances in evolutionary biology and ecology from inclusive fitness to multi-level selection to niche construction have underscored how organisms and conspecifics in their biotic and abiotic environments interact and how these interactions shape the genetic architecture of traits over evolutionary time. In areas amenable to experimentation like agriculture, approaches for teasing apart sources of phenotypic variation have been developed and successfully applied to traits such as animal products and crop yield. The application of variance decomposition approaches to complex traits in people, however, although having a long history, requires strong simplifying assumptions and is fraught with confounding and bias for all but the simplest of traits.

The increasing availability of population-scale genetic cohorts with deep phenotypic, lifestyle, and environmental data, coupled with advances in computation, present an opportunity to advance new approaches that address the complexity of human traits related to health and disease. It is now possible to begin characterizing the contribution, at genome-scale, of genetic and non-genetic factors to phenotypic variation across individuals, families, and populations. The richness of data also affords the possibility to develop new theories and mathematical or statistical models delineating the processes generating trait variation. The complexity of the dynamic space representing the sources of human phenotypic variation, however, is vast. Thus, formalized theory and mechanistic models derived from both the natural and social sciences are needed to narrow the search space, fortify causal inferences, and identify effective levels of intervention.

Research objectives

We seek novel approaches for characterizing the genetic architecture of complex human traits that go beyond methods focused on the number, impact, and frequency of trait-associated alleles. These approaches should include a more comprehensive characterization of direct and non-direct, additive and non-additive, and main and interaction genetic and non-genetic effects. Approaches should also account for interdependencies across scales of biological, social, and ecological organization that may confound genetic association studies. Proposed frameworks should make extensive use of formal theory, mechanistic models, robust simulations, and empirical validation with publicly accessible, large-scale datasets from populations with diverse environmental exposures, life experiences, demographics, or geographic histories. If comparing populations, applicants should heed the recommendations of the National Academies report Using Population Descriptors in Genetics and Genomics Research: A New Framework for an Evolving Field. Finally, we encourage assembling interdisciplinary teams at the intersection of statistical, quantitative, and population genetics, evolutionary biology, behavioral ecology, epidemiology, sociology, econometrics, and the science of complex systems. The end result will be more comprehensive and holistic methods for understanding how and why people vary in their propensity for and presentation of diseases and traits.

Genetic and Phenotypic Data

Applicants should justify their choice of datasets and how the genetic data, traits, environmental measures, and/or populations are appropriate for the proposed approaches and research questions. The focus of this NOFO is on new theory, models, and methods development. Any existing data sources used should be publicly available. When new data generation is proposed for validation, it is not to exceed 20% of direct costs. Methods and data (whether derived or new) should be made available to ensure analyses and findings are reproducible.

In some cases, certain traits and outcomes may be socially sensitive especially when there are disparities among marginalized or minoritized groups. Applicants should indicate how they will minimize misapplications and misconceptions about their approaches and findings as well as how they will communicate the potential harms and benefits of the research to the scientific community and lay public. Special care and consideration should be given to ensure the proposed work is both scientifically rigorous and socially responsible.

Specific areas of interest

NCI is interested in applications that use systems epidemiology modeling or analysis approaches to advance the understanding of multilevel and dynamic factors that affect cancer risk and related outcomes, including factors that contribute to cancer disparities. For applications to be considered responsive to NCI interest, they will need to include all three of the following components: i) integrate germline genetic and environmental data, ii) utilize data across multiple scales (e.g., biological, social, or ecological organization), and iii) consider dynamism or multiple time points in the analysis.

NHGRI is interested in approaches that are generalizable across a range of genetic architectures and complex traits in humans. This includes, but is not limited to, development of theory, models, and methods for:

  • Robust and efficient approaches for simulating multivariate traits of varying genetic architectures with realistic model parameters (e.g., linkage disequilibrium, pleiotropy, non-random mating, gene-environment covariances, environmental factors), and their response to changing selective forces.
  • Constructing hierarchical or nested genotype-phenotype maps of genetic architecture spanning levels of biological organization from molecules to cells to tissues to individuals to populations.
  • Determining optimal study designs for mapping the contribution of direct and non-direct genetic effects across the allelic frequency spectrum for traits with different genetic architectures.
  • Scalable and computationally efficient whole-genome x whole-phenome methods to identify non-linear effects of genetic and non-genetic factors on heritable trait variation.
  • Delineating the evolutionary and/or sociocultural forces that have shaped heritable trait variation and its genetic architecture, as well as the extent that inter- and intra-population trait differences are related to genetic and non-genetic factors.
  • Agent-based models of mating, migration, and other behaviors that influence the genetic and non-genetic transmission of traits across generations and geography and how this agency shapes genetic architecture across varying time scales.

Non-responsive applications

Applications with the following properties will be considered non-responsive and will not be reviewed:

  • Do not focus on human traits.
  • Approach is only applicable to or focuses solely on specific diseases/traits, genes, or variants.
  • Methods are not generalizable or applicable across human health and disease relevant traits.
  • Make use of or generate data that is not publicly accessible.
  • Focused on data generation (>20% of direct costs) rather than methods development.
  • Focused solely on approaches for the prediction of traits without addressing the underlying mechanisms, however abstracted, that shape genetic architecture.
  • Focused exclusively on human microbial genomics or the microbiome.

Applicants are strongly encouraged to reach out to the NOFO scientific/research contact prior to submission to discuss whether their application is responsive.

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

Section II. Award Information

Funding Instrument

Grant: A support mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity.

Application Types Allowed
New
Resubmission
Revision

The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types. Only those application types listed here are allowed for this NOFO.

Clinical Trial?

Not Allowed: Only accepting applications that do not propose clinical trials.

Funds Available and Anticipated Number of Awards

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

Award Budget

The combined budget for direct costs for the two-year project period may not exceed $275,000. No more than $200,000 may be requested in any single year.

Award Project Period

The scope of the proposed project should determine the project period. The maximum project period is 2 years.

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

Eligible Organizations

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

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 Institutions)
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.

Required Registrations

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 Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

  • System for Award Management (SAM) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
    • NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
    • 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.

Eligible Individuals (Program Director/Principal Investigator)

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. Individuals from diverse backgrounds, including underrepresented racial and ethnic groups, individuals with disabilities, and women are always encouraged to apply for NIH support. See, Reminder: Notice of NIH's Encouragement of Applications Supporting Individuals from Underrepresented Ethnic and Racial Groups as well as Individuals with Disabilities, NOT-OD-22-019.

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.

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

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

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. 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 SF424 Application Guide and the Table of Page Limits must be followed.

Instructions for Application Submission

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

SF424(R&R) Cover

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

SF424(R&R) Project/Performance Site Locations

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

SF424(R&R) Other Project Information

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

SF424(R&R) Senior/Key Person Profile

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

R&R or Modular Budget

All instructions in the SF424 (R&R) Application Guide must be followed. The additional instructions apply:

Travel Funds: The budget should include funds for the PD/PI to travel to the Bethesda, MD, area each year to participate in a research symposium.

Scientific data sharing: Budgets should include any funds required to support sharing of scientific data under this NOFO. 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 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.).

R&R Subaward Budget

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

PHS 398 Cover Page Supplement

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

PHS 398 Research Plan

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

Research Strategy: Applicants should explain how their approaches go beyond discovering the number, effect sizes, and frequency of trait-associated alleles and include a more comprehensive characterization of direct and non-direct, additive and non-additive, and/or main and interaction genetic and non-genetic effects.

  • Applicants must demonstrate how the proposed methods account for covariances across scales of biological, social, geographic, or other higher-order organizational levels that may confound genetic association studies.
  • Approaches must specify how they are making appropriate use of formalized theory, mechanistic models, and/or simulations.
  • The use of existing or new data, including genetic, phenotypic, and environmental measures, must be justified for the proposed approaches and research question.
  • If the methods developed are, or can be, applied to socially sensitive traits or outcomes, there must be a plan for minimizing misuses or misapplications as well as a plan for communicating the potential harms and benefits of the approach to the broader research community and public.

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.

For the Resource Sharing Plan, applicants should discuss how any research tools (including informatics analysis or data processing tools) and new methods developed under this award will be made available. For this NOFO, tools, methods, and software should be well-documented and, where applicable, should be made available via version-controlled public repositories. See list of frequently asked questions about Best Practices for Sharing Research Software.

Other Plan(s): Note: Effective for due dates on or after January 25, 2023, the Data Management and Sharing Plan will be attached in the Other Plan(s) attachment in FORMS-H application forms packages.

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

  • All applicants planning research (funded or conducted in whole or in part by NIH) that results in the generation of scientific data are required to comply with the instructions for the Data Management and Sharing Plan. All applications, regardless of the amount of direct costs requested for any one year, must address a Data Management and Sharing Plan.
  • Please follow the NIH guidance on writing a Data Management and Sharing (DMS) Plan here, and ensure the Plan is in alignment with NHGRI’s data sharing expectations, which are summarized at genome.gov/data-sharing.
  • 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. All resulting scientific data should be submitted to an established repository as described in the Data Management and Sharing Policy guidance and NHGRI’s guidance on where to submit scientific data.
  • Where human biological samples will be studied, they are expected to have been obtained using a documented informed consent process that allows for future research use and broad data sharing (NOT-HG-20-011).
  • If new human biospecimens will be collected, the consent process should be described at a high level in the Research Plan and detailed in the Human Subjects Section.

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

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 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.

PHS Assignment Request Form

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

Foreign Institutions

Foreign (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide.

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

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

4. Submission Dates and Times

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 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 SF424 (R&R) 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.

7. Other Submission Requirements and Information

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 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 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.

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.

For this particular announcement, note the following:

The R21 exploratory/developmental grant supports investigation of novel scientific ideas or new model systems, tools, or technologies that have the potential for significant impact on biomedical or biobehavioral research. An R21 grant application need not have extensive background material or preliminary information. Accordingly, reviewers will emphasize the conceptual framework, the level of innovation, and the potential to significantly advance our knowledge or understanding. Appropriate justification for the proposed work can be provided through literature citations, data from other sources, or, when available, from investigator-generated data. Preliminary data are not required for R21 applications; however, they may be included if available.

Overall Impact

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).

Scored Review Criteria

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


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


Are the 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?


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?

Specific to this NOFO:

How adequately d o the proposed approaches go beyond discovering the number, effect sizes, and frequency of trait-associated alleles and include a more comprehensive characterization of direct and non-direct, additive and non-additive, and/or main and interaction genetic and non-genetic effects?


Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?

Specific to this NOFO:

  • How sufficiently do the methods proposed sufficiently account for covariances across scales of biological, social, geographic, or other higher-order organizational levels that may confound genetic association studies?
  • How extensively do the approaches proposed develop or make appropriate use of formalized theory, mechanistic models, and/or simulations?
  • If the methods developed are, or can be, applied to socially sensitive traits or outcomes, how adequate is the plan for minimizing misuses or misapplications as well as a plan for communicating the potential harms and benefits of the approach to the broader research community and public?

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

Additional Review Criteria

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact 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 Animals 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.


For Resubmissions, the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.


For Renewals, the committee will consider the progress made in the last funding period.


For Revisions, the committee will consider the appropriateness of the proposed expansion of the scope of the project. If the Revision application relates to a specific line of investigation presented in the original application that was not recommended for approval by the committee, then the committee will consider whether the responses to comments from the previous scientific review group are adequate and whether substantial changes are clearly evident.

Additional Review Considerations

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact 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 Resource Sharing Plan(s) (e.g., Sharing Model Organisms) or the rationale for not sharing the resources, is reasonable.


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.

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 , 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.

Applications will be assigned to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications. Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. 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.

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

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 recipient's business official.

Recipients must comply with any funding restrictions described in Section IV.6. 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 NOFO will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.

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

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Recipients, and Activities, including of note, but not limited to:

If a recipient is successful and receives a Notice of Award, 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.

Should the applicant organization successfully compete for an award, recipients of federal financial assistance (FFA) from HHS will be required to complete an HHS Assurance of Compliance form (HHS 690) in which the recipient agrees, as a term and condition of receiving the grant, to administer their programs in compliance with federal civil rights laws that prohibit discrimination on the basis of race, color, national origin, age, sex and disability, and agreeing to comply with federal conscience laws, where applicable. This includes ensuring that entities take meaningful steps to provide meaningful access to persons with limited English proficiency; and ensuring effective communication with persons with disabilities. Where applicable, Title XI and Section 1557 prohibit discrimination on the basis of sexual orientation, and gender identity. 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 https://www.hhs.gov/civil-rights/for-individuals/nondiscrimination/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 NOFO.

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 and 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.

Cooperative Agreement Terms and Conditions of Award

Not Applicable

3. Data Management and Sharing

Note: The NIH Policy for Data Management and Sharing is effective for due dates on or after January 25, 2023.

Consistent with the NIH Policy for Data Management and Sharing, when data management and sharing is applicable to the award, recipients will be required to adhere to the Data Management and Sharing requirements as outlined in the NIH Grants Policy Statement. Upon the approval of a Data Management and Sharing Plan, it is required for recipients to implement the plan as described.

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.

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. 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 45 CFR Part 75.301 and 2 CFR Part 200.301.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for recipients of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All recipients 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 the threshold. 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 2 CFR Part 200.113 and Appendix XII to 45 CFR Part 75 and 2 CFR Part 200, 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 and 2 CFR Part 200 Award Term and Condition for Recipient Integrity and Performance Matters.

Section VII. Agency Contacts

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

Application Submission Contacts

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: https://www.era.nih.gov/need-help (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: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-637-3015

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: support@grants.gov

Scientific/Research Contact(s)

Alexander Arguello, Ph.D.
National Human Genome Research Institute (NHGRI)
Telephone: 240-731-3753
Email: alexander.arguello@nih.gov

Leah Mechanic, PhD, MPH
National Cancer Institute (NCI)
Phone: (240) 276-6847
E-mail: mechanil@mail.nih.gov

Peer Review Contact(s)

Examine your eRA Commons account for review assignment and contact information (information appears two weeks after the submission due date).

Financial/Grants Management Contact(s)

Lisa Oken
National Human Genome Research Institute (NHGRI)
Telephone: 301-594-5250
Email: Lisa.Oken@nh.gov

Crystal Wolfrey
National Cancer Institute (NCI)
Telephone: 240-276-6277
Email: crystal.wolfrey@mail.nih.gov

Section VIII. Other Information

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

Authority and Regulations

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75 and 2 CFR Part 200.

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