PAR-25-256: Developing novel theory and methods for understanding the genetic architecture of complex human traits (R21 Clinical Trial Not Allowed)

PAR-25-256: Developing novel theory and methods for understanding the genetic architecture of complex human traits (R21 Clinical Trial Not Allowed) is sponsored by National Institutes of Health (NIH). Supports exploratory research to develop novel theories and methods for understanding the genetic architecture of complex human traits.

PAR-25-256: Developing novel theory and methods for understanding the genetic architecture of complex human traits (R21 Clinical Trial Not Allowed) 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. Department of Health and Human Services Part 1.

Overview Information Participating Organization(s) National Institutes of Health ( NIH ) Components of Participating Organizations National Human Genome Research Institute ( NHGRI ) National Cancer Institute ( NCI ) Funding Opportunity Title Developing novel theory and methods for understanding the genetic architecture of complex human traits (R21 Clinical Trial Not Allowed) R21 Exploratory/Developmental Research Grant 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) Companion Funding Opportunity See Section III. 3.

Additional Information on Eligibility. Assistance Listing Number(s) 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.

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. Open Date (Earliest Submission Date) The following table includes NIH standard due dates marked with an asterisk.

Renewal / Resubmission / Revision (as allowed) AIDS - New/Renewal/Resubmission/Revision, as allowed 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.

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. Workspace to prepare and submit your application and eRA Commons to track your application. 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 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.

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 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 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 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. Not Allowed: Only accepting applications that do not propose clinical trials. Need help determining whether you are doing a clinical trial?

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. 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 .

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 Higher Education Institutions Public/State Controlled Institutions of Higher Education Private Institutions of Higher Education Nonprofits Other Than Institutions of Higher Education Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education) Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education) For-Profit Organizations (Other than Small Businesses) City or Township Governments Special District Governments Indian/Native American Tribal Governments (Federally Recognized) Indian/Native American Tribal Governments (Other than Federally Recognized).

Eligible Agencies of the Federal Government U.S. Territory or Possession 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 Non-domestic (non-U.S.) Entities (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. Applicant organizations must complete and maintain the following registrations as described in the How to Apply- Application Guide to be eligible to apply for or receive an award.

All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. Failure to complete registrations in advance of a due date is not a valid reason for a late submission, please reference the NIH Grants Policy Statement Section 2.

3. 9. 2 Electronically Submitted Applications for additional information.

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

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.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the How to Apply-Application Guide. 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 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. 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.

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. 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 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.). 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.

All instructions in the How to Apply- 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 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 .

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; 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 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.

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 (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. 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. All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile form .

Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this NOFO for information on registration requirements.

The applicant organization must ensure that the unique entity identifier provided on the application is the same identifier used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the How to Apply Application Guide. See more tips for avoiding common errors.

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

Recipients or subrecipients must submit any information related to violations of federal criminal law involving fraud, bribery, or gratuity violations potentially affecting the federal award. See Mandatory Disclosures, 2 CFR 200. 113 and NIH Grants Policy Statement Section 4.

1. 35 . Send written disclosures to the NIH Chief Grants Management Officer listed on the Notice of Award for the IC that funded the award and to the HHS Office of Inspector Grant Self Disclosure Program at [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 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: Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following scored review criteria and additional review criteria (as applicable for the project proposed).

An application does not need to be strong in all categories to be judged likely to have a major scientific impact. Reviewers will consider Factors 1, 2 and 3 in the determination of scientific merit, and in providing an overall impact score. In addition, Factors 1 and 2 will each receive a separate factor score.

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

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) 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). 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).