NHLBI TOPMed: Omics Phenotypes of Heart, Lung, and Blood Disorders (X01)

NHLBI TOPMed: Omics Phenotypes of Heart, Lung, and Blood Disorders (X01) is sponsored by National Heart, Lung, and Blood Institute (NHLBI), NIH. Provides access to TOPMed data and resources for omics studies on heart, lung, blood disorders including sickle cell disease phenotypes.

PAR-25-447: NHLBI TOPMed: Omics Phenotypes of Heart, Lung, and Blood Disorders (X01 - Clinical Trial Not Allowed) Department of Health and Human Services Part 1.

Overview Information Participating Organization(s) National Institutes of Health ( NIH ) Components of Participating Organizations National Heart, Lung, and Blood Institute ( NHLBI ) Funding Opportunity Title NHLBI TOPMed: Omics Phenotypes of Heart, Lung, and Blood Disorders (X01 - Clinical Trial Not Allowed) X01 Resource Access Award 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) 93.

839, 93. 838, 93. 233, 93.

837, 93. 840 Funding Opportunity Purpose This Notice of Funding Opportunity (NOFO) invites applications to use NHLBI-funded TransOmics for Precision Medicine (TOPMed) program to access TOPMed capacity to generate a large volume of integrated genetic and multi-omics data to facilitate discovery of the molecular mechanisms of Heart, Lung, Blood, and Sleep (HLBS) disorders. No funding will be provided under this NOFO.

The genomic data and related phenotypic data will be deposited in a public NIH-designated controlled-access database such as the database for Genotypes and Phenotypes (dbGaP) and NHLBI’s BioData Catalyst (BDC). The overall goal is to move from simply cataloging genetic associations to understanding how genetic factors contribute to HLBS diseases at the molecular and cellular levels.

This transformation will help move TOPMed from genetic Map to Mechanism with potential applications of AI and ML tool sets where possible, enabling functional genomics research that will accelerate mechanistic personalized medicine.

Funding Opportunity Goal(s) The National Heart, Lung, and Blood Institute (NHLBI) provides global leadership for a research, training, and education program to promote the prevention and treatment of heart, lung, and blood diseases and enhance the health of all individuals so that they can live longer and more fulfilling lives.

Open Date (Earliest Submission Date) 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 How to Apply - Application Guide and the NOFO) is required and strictly enforced.

Applicants must read and follow all application instructions in the How to Apply - Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the How to Apply - 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 National Heart, Lung, and Blood Institute (NHLBI) provides global leadership in research, training, and education to promote the prevention and treatment of heart, lung, blood and sleep disorders.

NHLBI's mission covers many common diseases, such as heart disease and chronic respiratory diseases, some of the leading causes of death in the US and worldwide. NHLBI also supports research on many rare and complex diseases and conditions, such as sickle cell disease, bone marrow failure syndromes, dilated cardiomyopathy, and interstitial lung disease.

While there are established treatments for many of these, they often target symptoms rather than underlying causes, or the treatments are effective for only a fraction of patients. A better understanding of the molecular mechanisms underlying pathobiological causes of diseases could lead to more effective prevention and treatment approaches.

Advances in high throughput technologies in the areas of genomics, epigenomics, metabolomics, and proteomics provide an opportunity to accelerate the discovery of the molecular causes of complex HLBS disorders. NHLBI's TransOmics for Precision Medicine ( TOPMed ) program was established in 2014 to generate large scale genomics data for the research community to enable the study of the molecular basis underlying HLBS disorders. TOPMed2.

0 will continue to support the production of substantial quantities of omics data utilizing standardized protocols, and to release the resulting datasets for public access in a uniform data format in accordance with the NIH Genomic Data Sharing Policy . No funding will be provided under this NOFO.

The omics and related phenotypic data will be deposited in a public NIH-designated controlled-access database such as the d ata b ase for G enotypes a nd P henotypes ( dbGaP ) and NHLBI’s BioData Catalyst (BDC) . Potential applicants are encouraged to discuss data sharing concerns with the NHLBI contacts listed in this NOFO.

Nature of the Research Opportunity The overarching goal of TOPMed is to generate information integrated from many existing studies to create a resource with greater scientific value than data from individual studies in isolation while continuing to benefit the research of individual studies.

Applicants will be expected to agree to participate in TOPMed data-sharing and integration, and will need to have existing, high quality biospecimens collected from well-phenotyped human subjects from studies designed to inform the molecular pathobiology of HLBS disorders. Information on the omics centers and assays will be updated on the NHLBI TOPMed webpage for frequently asked questions ( FAQ ).

The focus may be genetics and/or functional genetics seeking multi-omics data at tissue and single-cell levels to support studies with systems and precision medicine approaches and to produce the knowledge needed to inform our understanding of the underlying biology. Information on the omics centers and assays will be updated in the webpage for frequently asked questions ( FAQ ).

Types of Research Projects This NOFO will continue to enable generation of whole genome sequencing (WGS) data. Applicants are encouraged to explain the unique/additional contributions to current TOPMed data of 200,000 WGS in more than 100 well-phenotyped epidemiology cohorts and disease studies. ( https://topmed.

nhlbi. nih. gov/group/project-studies ).

The focus of this round will support studies for understanding how genetic factors contribute to HLBS disorders at the molecular and cellular levels to empower the analysis of genetic Map to Mechanism (M2M) with potential applications of artificial intelligence (AI) and machine learning (ML) tool sets where possible. Applications may seek to obtain one or more than one kind of omics data at tissue and single-cell levels ( FAQ ).

Applicants should provide justification of the request for each type of omics approach and assess the unique/additional contributions to the current multi-omics data in TOPMed.

Applications will be expected to target specific knowledge gaps relevant to HLBS disorders, including common diseases and with strong interest in rare diseases (e.g. Sickle Cell and bone marrow failure diseases, sarcoidosis, peripartum cardiomyopathy and rare inherited cardiomyopathies) and explain why the existing TOPMed data are not sufficient to address the challenge.

Phenotypically well-characterized cohorts with sample collections will be desired if they enrich the scientific value of current TOPMed datasets.

As a condition of access, all omics and related phenotypic data must be shared with the broader research community through a public NIH-designated database such as dbGaP and BDC, in a manner consistent with the expectations of the NIH Genomic Data Sharing Policy, consistent with achieving the goals of the program.

Also, applicants must ensure that all human subjects used in their applications are appropriately consented for data-sharing, in a manner consistent with the expectations of NIH data sharing policies. Successful applicants are expected to join NHLBI's TOPMed consortium, participate in its advisory and collaborative discussions , and contribute their data to build tools like TOPMed Imputation server and variant-Browser BRAVO .

Applicants are encouraged to contact NHLBI staff prior to preparing an application to discuss the purpose, scope, and scale of their applications and to obtain updates regarding the technical requirements and analytical capabilities of the program.

In general, TOPMed will provide capacity-generating data for WGS, bulk RNA-seq, methylome, metabolome, proteome, and single-cell or single-nucleus omics (e.g., sc/snRNA-seq, sc/snATAC-seq) and spatial omics, though not all may be available every year. Applicants are encouraged to consult with the NHLBI contacts listed in this NOFO and check updates on the frequently asked questions ( FAQ ) page for the most current information.

An NHLBI-designated informatics center will perform basic data processing. For WGS, the center will provide quality control and data harmonization for all data from all studies through joint variant-calling, and if needed, produce other variants realizable via WGS (e.g., SVs, mt-DNA variants, telomere length, CHIP, and so on).

For other omics data, the center will perform quality control of all studies according to TOPMed’s standards and create cross-study molecular QTL (molQTL) for all studies. Individual studies may also conduct their own molQTL analyses separately.

In addition to publishing individual level data in dbGaP and BDC, TOPMed also provides aggregated data directly to the research community, such as TOPMed Imputation Server and variant server, BRAVO . Concerns about data-sharing methods should be discussed with the NHLBI TOPMed contacts. For details, please visit the TOPMed website and the frequently asked questions ( FAQ ) page.

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

Award Information Other: A financial assistance mechanism that is not a grant or cooperative agreement. Examples include access to research resources or pre-applications. 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 projects granted access to omics assay resources is contingent upon the number of meritorious applications and the capacity of the omics centers. NHLBI intends to approve up to 10 projects. Not applicable.

Funds are not awarded via this X01 resource access award. The maximum project period is 3 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 - Includes all types Public/State Controlled Institutions of Higher Education Private Institutions of Higher Education Nonprofits Other Than Institutions of Higher Education Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education) Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education) For-Profit Organizations (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) Foreign Organizations/ International Collaborations NIH will no longer issue awards (new, renewal, or non-competing continuation) to domestic or foreign entities that involve foreign subawards/subcontracts.

All NIH-funded research involving foreign subawards/subcontracts must be submitted in response to a NOFO that is specifically designated for funded international collaborations. This new requirement was effective, May 1, 2025. Applications involving foreign subawards/subcontracts submitted in response to this NOFO will be deemed noncompliant and will not be considered for funding.

This policy applies to all monetary international collaborations resulting in foreign subawards/subcontracts, however, it does not preclude unfunded international collaborations or foreign components , funding for foreign consultants, or procurement of unique equipment or supplies from foreign vendors. 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 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 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 How to Apply - 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. 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: Examples of research projects can include, but are not limited to: Describe the scientific question to be addressed and the proposed study design for investigating the genetic basis and omics signature(s) of the target heart, lung, blood or sleep disorder(s) Describe the proposed specific phenotypic measures and how these will be determined Describe the relevance of the proposed phenotype(s) to heart, lung, blood, or sleep abnormalities Discuss plans to leverage existing TOPMed data and/or how proposed data will potentially complement existing TOPMed studies Describe plans for sharing and integrating, including sharing all omics and related phenotypic data with the broader research community through a public NIH-designated database and ensuring that all human subjects used in the application are appropriately consented for data-sharing.

Describe the biospecimens available for the project, including any details (e.g., number, sampling, purification, storage, used by any omics assay) that are informative for the assessment of whether the samples are suitable for the requested omics assay(s) List all phenotypic and environmental data that can be shared with the broad scientific community, including data not directly related to specific aims of the application Propose a timeline for delivery of biospecimens to the omics center Indicate how many families and/or sporadic cases are available for follow-up studies Identify how the proposed omics data and phenotypes will intersect with and complement data and phenotypes already contributed to the TOPMed program If applicable, describe any characteristics of the original study or population which would make its data of particular value for the overall NHLBI TOPMed omics data library, such as special or extreme (disease or resilient) phenotypes, the study of populations underrepresented in existing data sets, with rich phenotypic data as generic control group If existing omics data from elsewhere will be used as part of the application, provide information regarding the data generation and sources Letters of Support : Provide letters of support from any collaborators who will contribute necessary biospecimens or data.

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 . All instructions in the How to Apply - Application Guide must be followed, with the following additional instructions: A Data Management and Sharing Plan is not applicable for this NOFO. 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 NHLBI, NIH. Applications that are incomplete or non-compliant 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 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 NOFO, note the following: The X01 Resource Access Program invites eligible institutions to seek access to NIH research resources, which are specified in each X01 NOFO. This includes programs where institutions will request access to submit to the resource (e.g., high throughput screening assays) as well as programs where access to a specific NIH research resource is needed to conduct certain research.

Important factors in the peer review of X01 applications are the need for, and potential benefit of, gaining access to the resource, specifications for any assays proposed, timelines for completion and plans for follow-on studies.

Each X01 application will be evaluated and selected based on both its scientific merit for enriching the study itself and its potential to contribute towards the assembly of a large collection of datasets for general use by the scientific community.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

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

Does the project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved?

How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field? To what extent can the proposed study phenotype(s) be expected to contribute significantly to HLBS health or biological understanding?

How are the proposed studies likely to provide important new information about genetic variants or other molecular markers important in human health or disease? Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training?

If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance, and organizational structure appropriate for the project?

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense?

Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed? Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed project?

Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed?

Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects? If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2)