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 be interdisciplinary drawing from the natural and social sciences, account for interdependencies across scales of biological, social, and ecological organization, and make extensive use of theory, modeling, and validation with available large-scale datasets.

PAR-25-255: Developing novel theory and methods for understanding the genetic architecture of complex human traits (R01 Clinical Trial Not Allowed)

Posted Date: November 15, 2024 Expiration Date: November 06, 2026

Summary: This funding opportunity announcement (FOA) seeks applications for novel theory and methods development to better understand how genetic and non-genetic factors contribute to complex trait variation. Approaches should be interdisciplinary, account for interdependencies across scales of biological, social, and ecological organization, and utilize theory, modeling, and validation with large-scale datasets.

Part 1. Overview Information

Participating Organization(s): National Institutes of Health (NIH)

Components of Participating Organizations:

• National Human Genome Research Institute (NHGRI)
• National Institute of Mental Health (NIMH)
• National Cancer Institute (NCI)

Funding Opportunity Title: Developing novel theory and methods for understanding the genetic architecture of complex human traits (R01 Clinical Trial Not Allowed)

Activity Code: R01 Research Project Grant

Announcement Type: Reissue of PAR-23-302

Related Notices:

• March 31, 2025: This funding opportunity was updated to align with agency priorities. Carefully reread the full funding opportunity and make any needed adjustments to your application prior to submission.
• April 4, 2024: Overview of Grant Application and Review Changes for Due Dates on or after January 25, 2025. See Notice NOT-OD-24-084.
• 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.

Funding Opportunity Number (FON): PAR-25-255

Companion Funding Opportunity: PAR-25-256, R21 Exploratory/Developmental Grants

Number of Applications: See Part 2, Section III. 3. Additional Information on Eligibility.

Assistance Listing Number(s): 93.172, 93.399, 93.242

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 be interdisciplinary drawing from the natural and social sciences, account for interdependencies across scales of biological, social, and ecological organization, and make extensive use of theory, modeling, and validation with available large-scale datasets.

Funding Opportunity Goal(s): NHGRI supports the development of resources and technologies that will accelerate genome research and its application to human health and genomic medicine.

Key Dates:

• Posted Date: November 15, 2024
• Open Date (Earliest Submission Date): January 05, 2025

Application Due Dates (NIH standard due dates marked with an asterisk):

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: November 06, 2026

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.
  • Use the NIH ASSIST system to prepare, submit and track your application online.
  • 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.
  • Use Grants.gov Workspace to prepare and submit your application and eRA Commons to track your application.

Table of Contents:

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

Part 2. Full Text of Announcement

Section I. 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 disparate 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, special emphasis should be given to 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: 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.
• NIMH: Specifically interested in the genetic architecture of mental illness and related traits.
• NHGRI: 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.
• Do not include a multidisciplinary team of investigators spanning the natural and social sciences.
• 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 financial assistance mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity.

Application Types Allowed:

• New
• Renewal
• Resubmission (The OER Glossary and the How to Apply 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:

• Application budgets are not limited but need to reflect the actual needs of the proposed project.
• For NCI applications, the budget is limited to $350,000 direct costs per year and should reflect the actual needs of the proposed project.

Award Project Period: The scope of the proposed project should determine the project period. The maximum project period is 5 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, Private)
• Nonprofits Other Than Institutions of Higher Education (Nonprofits with 501(c)(3) IRS Status, Nonprofits without 501(c)(3) IRS Status)
• For-Profit Organizations (Small Businesses, Other than Small Businesses)
• Local Governments (State, County, City or Township, Special District)
• Indian/Native American Tribal Governments (Federally Recognized, 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)

Foreign Organizations:

• 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.

Required Registrations:

• Applicant Organizations: Must complete and maintain registrations in:
  • System for Award Management (SAM): Must be active and renewed at least annually. Includes assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations.
  • NATO Commercial and Government Entity (NCAGE) Code: Required for foreign organizations in lieu of a CAGE code for SAM registration.
  • Unique Entity Identifier (UEI): Issued as part of the SAM.gov registration process. Must be used for all registrations and the grant application.
  • eRA Commons: Organizations must register and identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account.
  • Grants.gov: Requires an active SAM registration.
  • Registration can take 6 weeks or more. Failure to complete registrations in advance of a due date is not a valid reason for a late submission.
• 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 create a new account or affiliate an existing account with the applicant organization.
  • If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts.
  • 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.
• For institutions/organizations proposing multiple PDs/PIs, refer to 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 the NIH will not accept:
  • A new (A0) application submitted before the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
  • A resubmission (A1) application submitted before 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 to do otherwise in this NOFO.
• 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.

Instructions for Application Submission: 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.
  • Travel Funds: The budget should include funds for the PD/PI to travel to the Bethesda, MD area every two years 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 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:
  • Research Strategy:
    • Applicants must detail how they have sufficient complimentary expertise across the natural (e.g., genetics, biology, ecology, physics) and social (e.g., demography, psychology, anthropology, sociology, economics) sciences.
    • Applicants must 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.
    • Applicants must justify how their theories, methods, and simulations are being empirically validated and benchmarked using publicly accessible, large-scale datasets.
    • 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 How to Apply- 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):
    • All instructions in the How to Apply-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.
      • 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 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.

7. Other Submission Requirements and Information:

• 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.
• Requests of $500,000 or more for direct costs in any year: Applicants requesting $500,000 or more in direct costs in any year (excluding consortium F&A) must contact a Scientific/Research Contact at least 6 weeks before submitting the application and follow the Policy on the Acceptance for Review of Unsolicited Applications that Request $500,000 or More in Direct Costs as described in the How to Apply-Application Guide.
• Mandatory Disclosure: 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 [email protected]
• 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:

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 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.

Scored Review Criteria: 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.

• Factor 1. Importance of the Research (Significance and Innovation)

  • Significance: Evaluate the importance of the proposed research in the context of current scientific challenges and opportunities, either for advancing knowledge within the field, or more broadly. Assess whether the application addresses an important gap in knowledge in the field, would solve a critical problem, or create a valuable conceptual or technical advance. Evaluate the rationale for undertaking the study, the rigor of the scientific background for the work (e.g., prior literature and/or preliminary data) and whether the scientific background justifies the proposed study.
  • Innovation: Evaluate the extent to which innovation influences the importance of undertaking the proposed research. Note that while technical or conceptual innovation can influence the importance of the proposed research, a project that is not applying novel concepts or approaches may be of critical importance for the field. Evaluate whether the proposed work applies novel concepts, methods or technologies or uses existing concepts, methods, technologies in novel ways, to enhance the overall impact of the project.
  • Specific to this NOFO: Evaluate how the proposed work goes beyond discovering the number, effect sizes, and frequency of trait-associated alleles and includes a more comprehensive characterization of direct and non-direct, additive and non-additive, and/or main and interaction genetic and non-genetic effects.

• Factor 2. Rigor and Feasibility (Approach)

  • Approach: Evaluate the scientific quality of the proposed work. Evaluate the likelihood that compelling, reproducible findings will result (rigor) and assess whether the proposed studies can be done well and within the timeframes proposed (feasibility).
    • Rigor: Evaluate the potential to produce unbiased, reproducible, robust data. Evaluate the rigor of experimental design and whether appropriate controls are in place. Evaluate whether the sample size is sufficient and well-justified. Assess the quality of the plans for analysis, interpretation, and reporting of results. Evaluate whether the investigators presented adequate plans to address relevant biological variables, such as sex or age, in the design, analysis, and reporting.
    • For applications involving human subjects or vertebrate animals, also evaluate:
      • the rigor of the intervention or study manipulation (if applicable to the study design).
      • whether outcome variables are justified.
      • whether the results will be generalizable or, in the case of a rare disease/special group, relevant to the particular subgroup.
      • whether the sample is appropriate and sufficiently diverse to address the proposed question(s).
    • For applications involving human subjects, including clinical trials, assess the adequacy of inclusion plans as appropriate for the scientific goals of the research. Considerations of appropriateness may include disease/condition/behavior incidence, prevalence, or population burden, population representation, and/or current state of the science.
    • Feasibility: Evaluate whether the proposed approach is sound and achievable, including plans to address problems or new challenges that emerge in the work. For proposed studies in which feasibility may be less certain, evaluate whether the uncertainty is balanced by the potential for major advances. For applications involving human subjects, including clinical trials, evaluate the adequacy and feasibility of the plan to recruit and retain a study population that appropriately models the target population. Additionally, evaluate the likelihood of successfully achieving the proposed enrollment based on age, race, ethnicity, and sex. For clinical trial applications, evaluate whether the study timeline and milestones are feasible.
  • Specific to this NOFO:
    • Evaluate whether the proposed methods account for covariances across scales of biological, social, geographic, or other higher-order organizational levels that may confound genetic association.
    • Assess whether the approach develops or makes appropriate use of formalized theory, mechanistic models, and/or simulations.
    • Evaluate the rigor by which the methods or theories are empirically validated using publicly accessible, large-scale datasets.
    • If the methods developed are, or can be, applied to socially sensitive traits or outcomes, evaluate the plan for minimizing misuses or misapplications as well as any plan for communicating the potential harms and benefits of the approach to the broader research community and public.

• Factor 3. Expertise and Resources (Investigator(s) and Environment)

  • Investigator(s): Evaluate whether the investigator(s) have demonstrated background, training, and expertise, as appropriate for their career stage, to conduct the proposed work. For Multiple Principal Investigator (MPI) applications, assess the quality of the leadership plan to facilitate coordination and collaboration.
  • Environment: Evaluate whether the institutional resources are appropriate to ensure the successful execution of the proposed work.
  • Specific to this NOFO: Evaluate how complementary the investigators' expertise are across the natural (e.g., genetics, biology, ecology, physics) and social (e.g., demography, psychology, anthropology, sociology, economics) sciences to achieve the goals of the NOFO.

Additional Review Criteria: 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.

• Protections for Human Subjects: For research that involves human subjects but does not involve one of the categories of research that are exempt under 45 CFR Part 46, 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, 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.
• Vertebrate Animals: When the proposed research includes Vertebrate Animals, evaluate the involvement of live vertebrate animals 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. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animals Section.
• Biohazards: When the proposed research includes Biohazards, evaluate whether specific materials or procedures that will be used are significantly hazardous to research personnel and/or the environment, and whether adequate protection is proposed.
• Resubmissions: As applicable, evaluate the full application as now presented.
• Renewals: As applicable, evaluate the progress made in the last funding period.
• Revisions: As applicable, evaluate the appropriateness of the proposed expansion of the scope of the project.

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.

• Authentication of Key Biological and/or Chemical Resources: For projects involving key biological and/or chemical resources, evaluate the brief plans proposed for identifying and ensuring the validity of those resources.
• Budget and Period of Support: Evaluate 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 {LOCUS OF 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 on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this NOFO.
• 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, consistent with applicable law:
  • 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.
• Please note that reviewers will not consider race, ethnicity, age, or sex of a researcher, award participant, or trainee, even in part, in providing critiques, scores, or funding recommendations. NIH will not consider such factors in making its funding decisions.
• 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.
• 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: 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.
• If a recipient receives an award, the recipient must follow all applicable nondiscrimination laws. The recipient agrees to this when registering in SAM.gov. The recipient must also submit an Assurance of Compliance (HHS-690). To learn more, see the Laws and Regulations Enforced by the HHS Office for Civil Rights website.
• HHS recognizes that NIH 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.
• 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.
• Recipients are responsible for ensuring that their activities comply with all applicable federal regulations. NIH may terminate awards under certain circumstances. See 2 CFR Part 200.340 Termination and NIH Grants Policy Statement Section 8.5.2 Remedies for Noncompliance or Enforcement Actions: Suspension, Termination, and Withholding of Support.
• Successful recipients under this NOFO agree that:
  • Where the award funding involves implementing, acquiring, or upgrading health IT for activities by any funded entity, recipients and subrecipient(s) are required to: Use health IT that meets standards and implementation specifications adopted in 45 CFR part 170, Subpart B, if such standards and implementation specifications can support the activity. Visit https://www.ecfr.gov/current/title-45/subtitle-A/subchapter-D/part-170/subpart-B to learn more.
  • Where the award funding involves implementing, acquiring, or upgrading health IT for activities by eligible clinicians in ambulatory settings, or hospitals, eligible under Sections 4101, 4102, and 4201 of the HITECH Act, use health IT certified under the ONC Health IT Certification Program if certified technology can support the activity. Visit https://www.healthit.gov/topic/certification-ehrs/certification-health-it to learn more.
  • 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.
    • Recipients shall develop plans and procedures, modeled after the NIST Cybersecurity framework, to protect HHS systems and data. Please refer to NIH Post-Award Monitoring and Reporting for additional information.

Cooperative Agreement Terms and Conditions of Award: Not Applicable

3. Data Management and Sharing:

• Consistent with the 2023 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 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.

5. Evaluation:

• Enter text here.

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: [email protected] (preferred method of contact)
  • Telephone: 301-480-7075
• Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
  • Contact Center Telephone: 800-518-4726
  • Email: [email protected]

Scientific/Research Contact(s):

• Alexander Arguello, Ph.D.
  • National Human Genome Research Institute (NHGRI)
  • Telephone: 240-731-3753
  • Email: [email protected]
• Leah Mechanic, PhD, MPH
  • National Cancer Institute (NCI)
  • Phone: (240) 276-6847
  • E-mail: [email protected]
• Jonathan Pevsner, Ph.D.
  • National Institute of Mental Health (NIMH)
  • Telephone: 301-728-5618
  • Email: [email protected]
• Jonathan Pevsner, Ph.D. (Duplicate entry)
  • National Institute of Mental Health (NIMH)
  • Telephone: 301-728-5618
  • Email: [email protected]
• Leah Mechanic, PhD, MPH (Duplicate entry)
  • National Cancer Institute (NCI)
  • Phone: (240) 276-6847
  • E-mail: [email protected]

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):

• Donna Morris
  • National Human Genome Research Institute (NHGRI)
  • Telephone: 301-827-2745
  • Email: [email protected]
• Crystal Wolfrey
  • National Cancer Institute (NCI)
  • Telephone: 240-276-6277
  • Email: [email protected]
• Heather Weiss
  • National Institute of Mental Health (NIMH)
  • Telephone: 301-443-4415
  • Email: [email protected]
• Heather Weiss (Duplicate entry)
  • National Institute of Mental Health (NIMH)
  • Telephone: 301-443-4415
  • Email: [email protected]
• Crystal Wolfrey (Duplicate entry)
  • National Cancer Institute (NCI)
  • Telephone: 240-276-6277
  • Email: [email protected]

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 2 CFR Part 200.

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