Department of Health and Human Services

Part 1. Overview Information

Participating Organization(s)

National Institutes of Health (NIH)

Components of Participating Organizations

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

National Institute of Dental and Craniofacial Research (NIDCR)

Division of Program Coordination, Planning and Strategic Initiatives, Office of Research Infrastructure Programs (ORIP)

Funding Opportunity Title
Screening and Functional Validation of Human Birth Defects Genomic Variants (R01 Clinical Trial Not Allowed)
Activity Code

R01 Research Project Grant

Announcement Type
New
Related Notices

None

Funding Opportunity Announcement (FOA) Number
PAR-21-229
Companion Funding Opportunity
None
Assistance Listing Number(s)
93.865, 93.121, 93.351
Funding Opportunity Purpose

Rapid advances in genotyping and next generation sequencing technologies have led to the identification of genetic variants that are associated with a wide variety of congenital defects including structural birth defects (SBDs), intellectual developmental disabilities (IDDs) and inborn errors of metabolism (IEMs). Large quantities of genomic data collected from pediatric birth defects cohorts are available to the research community through several databases such as the Database of Genotypes and Phenotypes (dbGaP), the Gabriella Miller Kids First Data Resource Portal, the European Genome-Phenome Archive and Clinical Genome Resource (ClinGen). The purpose of this initiative is to promote the screening, functional validation and characterization of birth defects-associated genetic variants identified through public facing databases and individual efforts using in-silico tools, appropriate animal models, in vitro systems or multi-pronged approaches. This initiative addresses a challenging gap between identifying sequence variations of potential interest and recognizing which of those variations have functional effects on the phenotype of interest.

Key Dates

Posted Date
May 05, 2021
Open Date (Earliest Submission Date)
May 05, 2021
Letter of Intent Due Date(s)

30 days prior to application due date(s)

The following table includes NIH standard due dates marked with an asterisk.
Application Due Dates Review and Award Cycles
New Renewal / Resubmission / Revision (as allowed) AIDS Scientific Merit Review Advisory Council Review Earliest Start Date
June 05, 2021 * July 05, 2021 * Not Applicable November 2021 January 2022 April 2022
February 05, 2022 * March 05, 2022 * Not Applicable July 2022 October 2022 December 2022
June 05, 2022 * July 05, 2022 * Not Applicable November 2022 January 2023 April 2023
February 05, 2023 * March 05, 2023 * Not Applicable July 2023 October 2023 December 2023
June 05, 2023 * July 05, 2023 * Not Applicable November 2023 January 2024 April 2024
February 05, 2024 * March 05, 2024 * Not Applicable July 2024 October 2024 December 2024
June 05, 2024 * July 05, 2024 * Not Applicable November 2024 January 2025 April 2025
February 05, 2025 * March 05, 2025 * Not Applicable July 2025 October 2025 December 2025

All applications are due by 5:00 PM local time of applicant organization. All types of non-AIDS applications allowed for this funding opportunity announcement are due on the listed date(s).

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
May 08, 2025
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 SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from NIH Guide for Grants and Contracts).

Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions.

Applications that do not comply with these instructions may be delayed or not accepted for review.

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

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

  3. Use Grants.gov Workspace to prepare and submit your application and eRA Commons to track your application.


  4. Table of Contents

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

Purpose/Research Objectives

Rapid advances in genotyping and next generation sequencing technologies have led to the identification of genetic variants that are associated with a wide variety of congenital defects including structural birth defects (SBDs), intellectual developmental disabilities (IDDs) and inborn errors of metabolism (IEMs). The purpose of this initiative is to promote the screening, functional validation and characterization of birth defects-associated genetic variants identified through public facing databases and individual efforts using in-silico tools, appropriate animal models, in vitro systems or multi-pronged approaches. The ultimate goal is to enhance the translation of basic knowledge gained from functional genomic approaches into the development of new, innovative, and efficacious strategies for the molecular diagnosis, treatment, and prevention of human birth defects.

Background

Annually, almost five percent of all live births in the United States (more than 180,000 babies) involve babies born with birth defects when broadly defined to include both structural and functional/ metabolic abnormalities. Birth defects are the leading cause of death in children within the first year of life and account for half of all pediatric hospitalizations. Structural birth defects have a great impact on public health, socioeconomics, and family life.

The genomic revolution holds promise for enabling the discovery of effective and targeted therapies based on the underlying genetic classification of conditions – the basis for precision medicine. Studies of developmental biology are revealing the underlying genetic networks essential to cell/tissue differentiation, morphogenesis, organogenesis, as well as functions of cells and cellular organelles. Disruptions in these fundamental developmental processes result in birth defects. The combined efforts of basic scientists studying the genetic networks and physician scientists sequencing patient cohorts together place the field of birth defects research on the verge of major advances.

The NIH has made significant investment in genomic studies and technologies to identify DNA sequence variations associated with a wide variety of birth defects. Among others, the Gabriella Miller Kids First Pediatric Research Program (Kids First), the Center for Mendelian Genomics (CMG), Pediatric Cardiac Genomics Consortium (PCGC), Deciphering Developmental Disorders (DDD) and the Undiagnosed Disease Network (UDN) are generating large-scale clinical and genetic data from patients and their families with syndromic and organ-specific developmental disorders. Data generated through whole genome sequencing, SNP and SV analysis, and whole-exome sequencing are available to the research community through several databases such as the Database of Genotypes and Phenotypes (dbGaP), the Kids First Data Resource Portal, the European Genome-phenome Archive and ClinVar.

Despite an explosion of data resources, researchers face a challenging gap between identifying birth defect-associated sequence variations and recognizing which of these variations have functional effects on the phenotype of interest. In order to pursue mechanistic studies of how specific genetic variants affect developmental pathways and gene networks leading to the observed phenotype, researchers must have effective methods to screen potential variants to identify the causal ones. Faster, less expensive, and more accurate gene-to-function screens are critical for accelerating the translation of genomic findings into greater understanding of structural developmental disorders.

Scope

This initiative encourages screening and functional validation of genomic variants associated with birth defects and invites grant applications proposing to identify and prioritize genomic variants through in-silico analyses and/or cell-based assays, and followed by functional validation and deep mechanistic studies of causal variants in appropriate model systems.

Criteria for responsive applications:

Applicants may propose non-hypothesis driven screening of variants to establish association with birth defects under investigation, or hypothesis-driven mechanistic studies to generate critical information on how variant functions affect the disease phenotypes, or a combination of both types of studies.

Variant selection:

  • Genomic variants may be selected from those available through public databases or identified via individual/group efforts such as ClinGen Expert Curation Panels.
  • Genomic variants must be statistically associated with the birth defect under investigation.
  • Genomic variants may affect coding and/or non-coding regions.
  • Genomic variations including, but not limited to single base pair substitutions, copy number variations (insertions or deletions) and chromosomal rearrangements can be investigated.
  • Applicants are encouraged to use available genomic, gene expression and phenotypic databases and resources, such as the International Genome Sample Resource-IGSR, the Encyclopedia of DNA Elements-ENCODE data portal, the Gene Expression Omnibus-GEO data resource, GenotypeTissue Expression-GTEx-database, model organism databases, and appropriate bioinformatics tools for variant selection.
  • Variant selection criteria may include, but are not limited to the following categories:
    • Variants prioritized based on existing clinical phenotyping data.
    • Variants selected through functional prediction or variant interpretation tools (e.g. CiviC, Open Cravat).
    • Variants known to be associated with gene expression patterns in relevant tissue(s) and cell types that could reasonably be connected to normal biology and the disorder in question.
    • Variants that currently lack functional annotation and need improved and/or high‐throughput functional assays to establish a connection with the human phenotype of interest.
    • Novel variants associated with functionally annotated genes but lacking an established connection with the human phenotype in question.
    • Variants known to be associated with epigenomic changes such as DNA methylation, histone modifications or DNase I hypersensitivity occurring in disease relevant cell types and potentially influencing gene regulation involved in the trait of interest.

Model Systems:

Novel and/or high throughput screening strategies to validate genomic variants may be based on:

  • Model organisms including but not limited to Drosophila, C. elegans, Xenopus, zebrafish, chick, mouse, or rat.
  • In vitro model systems include, but are not limited to, organoids, and patient-derived or genome engineered induced pluripotent stem cells and their differentiated derivatives of defined genotype.
  • A combination of in vitro and in vivo model systems (cell or tissue-based culture systems).

    In order to determine the optimal model systems best suited to study human conditions of interest, the investigators are encouraged to use the existing resources for animal models or in vitro systems. These include, but are not limited to, the database of Drosophila Genes and Genomes (FlyBase), core data resource for C. elegans and other nematodes (WormBase), Xenopus Biology & Genomics Resource (Xenbase), Zebrafish Model Organism Database (ZFIN), Mouse Gene Expression Database [GDX], Chick Gene Expression Database (GEISHA/Aviport), Rat Genome Database (RGD), the Collaborative Cross mouse strains, and the NIH Center for Regenerative Medicine (NIH CRM) databases.

Assays:

  • Assays should allow for direct functional measures of normal and altered biological processes and/or anatomic structure.
  • Assays should typically be conducted in vivo (in relevant animal-model) and/or in vitro (in cell- or tissue-based models).
  • Functional assays conducted in vitro or cell-free biochemical assays should be verified in vivo in an animal model.

Providing multiple lines of convergent evidence supporting functionality using a combination of in silico, in vitro, and in vivo models is encouraged.

Applicants are encouraged to provide a timeline for achieving the major goals stated in the application and describe metrics for evaluating achievement of the goals and what action will be taken, and when, if a goal is not met or significantly delayed.

Non-responsive applications: Projects with the following properties will be considered non-responsive, and will not be reviewed:

  • Projects proposing large scale sequencing of birth defects cohorts will be considered non-responsive to this FOA. Investigations should be focused on existing sequence data available through publicly available databases or identified via individual/group efforts such as ClinGen Expert Curation Panels.
  • Projects that do not test the function of human genomic variants.
  • Projects that do not test genomic variants associated with birth defects.
  • Projects proposing only cell-free biochemical assays to validate genomic variants.
  • Assays conducted exclusively in in vitro systems.
  • Assays not validated in an animal model

Research Interests of Participating NIH Institutes and Office

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

A high priority goal for NICHD, as stated in Theme 1 of the 2020 NICHD Strategic Plan, is to address the problem of birth defects by advancing our understanding of their etiology in order to improve prevention and treatment.

For this FOA, NICHD encourages applications proposing to screen, functionally validate, and characterize genetic variants associated with children born with the following conditions:

  • Structural birth defects (SBDs)
  • Intellectual developmental disabilities (IDDs)
  • Inborn errors of metabolism (IEMs)

Program Directors/Principal Investigators (PD/PIs) planning to submit applications to this FOA to be considered for funding from NICHD are strongly encouraged to contact the scientific contact prior to submission (see Scientific/Research Contacts in Section VII. Agency Contacts) to be advised on appropriateness of the intended research plans for this program, competitiveness of a potential application, and alignment with NICHD's program priorities.

National Institute of Dental and Craniofacial Research (NIDCR)

NIDCR encourages applications proposing studies that will generate insights into the developmental etiology of rare or common structural birth defects, affecting dental, oral, and craniofacial structures. Data available on the NIDCR-supported FaceBase Hub (www.facebase.org) may be utilized to support variant prioritization.

Program Directors/Principal Investigators (PD/PIs) planning to submit applications to this FOA to be considered for funding from NIDCR are strongly encouraged to contact the scientific contact prior to submission (see Scientific/Research Contacts in Section VII. Agency Contacts) to be advised on appropriateness of the intended research plans for this program, competitiveness of a potential application, and alignment with NIDCR's program priorities.

Office of Research Infrastructure Programs (ORIP)

ORIP encourages applications that are relevant to ORIP's mission to support research infrastructure and research-related resource programs, such as development of new technologies for generation and distribution of animal models of human diseases. The technologies to create animal models of human genetic variants associated with structural birth defects and related materials must have broad application to multiple NIH Institutes or Centers (ICs) to align with the ORIP’s trans-NIH mission. The following are examples of potential research topics:

  • Improving methods to rapidly and efficiently generate non-mosaic germline and somatic human genomic variants to model disease-specific genomic alterations (coding and not coding), including robust phenotyping to assess if species genetic changes recapitulate a human phenotype. Tools for a conditional and tissue specific genome modifications are of special interest.
  • Approaches for generation of complex genetic mutations or larger structural variants (SV) (deletions, duplications, inversions).
  • Combining model organism genomic modifications with phenotyping assays including detailed molecular analysis (omics profiling) which should be sufficiently integrative to assist high throughput interpretation of disease processes shared in model organisms and human patients.
  • Assess the effect of species genetic background of specific animal model species used to model a variant on the presentation and penetrance of a given phenotype.

Program Directors/Principal Investigators (PD/PIs) planning to submit applications to this FOA to be considered for funding from ORIP are strongly encouraged to contact the scientific contact prior to submission (see Scientific/Research Contacts in Section VII. Agency Contacts) to be advised on appropriateness of the intended research plans for this program, competitiveness of a potential application, and alignment with ORIP's program priorities.

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

Section II. Award Information

Funding Instrument

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

Application Types Allowed
New
Renewal
Resubmission
Revision

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

Clinical Trial?

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.

Award Budget

Application budgets are limited to $499,999 direct costs per year and need to reflect the actual needs of the proposed projects.

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 FOA.

Section III. Eligibility Information

1. Eligible Applicants

Eligible Organizations

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Local Governments

  • State Governments
  • County Governments
  • City or Township Governments
  • Special District Governments
  • Indian/Native American Tribal Governments (Federally Recognized)
  • Indian/Native American Tribal Governments (Other than Federally Recognized)

Federal Governments

  • Eligible Agencies of the Federal Government
  • U.S. Territory or Possession

Other

  • Independent School Districts
  • Public Housing Authorities/Indian Housing Authorities
  • Native American Tribal Organizations (other than Federally recognized tribal governments)
  • Faith-based or Community-based Organizations
  • Regional Organizations
  • Non-domestic (non-U.S.) Entities (Foreign Institutions)
Foreign Institutions

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.

Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are allowed. 

Required Registrations

Applicant organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

  • Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
  • 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.
  • eRA Commons - Applicants must have an active DUNS number to register in eRA Commons. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration, but 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 DUNS number and 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 his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH 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 SF424 (R&R) Application Guide.

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

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

The NIH will not accept duplicate or highly overlapping applications under review at the same time.  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 NOT-OD-11-101).

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 FOA. 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 SF424 (R&R) Application Guide except where instructed in this funding opportunity announcement 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.

Letter of Intent

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

  • Descriptive title of proposed activity
  • Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
  • Names of other key personnel
  • Participating institution(s)
  • Number and title of this funding opportunity

The letter of intent should be sent to:

Mahua Mukhopadhyay, Ph. D.
Telephone: 301-435-6886
Email: mukhopam@mail.nih.gov

Page Limitations

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.

Instructions for Application Submission

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

SF424(R&R) Cover

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

SF424(R&R) Project/Performance Site Locations

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

SF424(R&R) Other Project Information

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

SF424(R&R) Senior/Key Person Profile

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

R&R or Modular Budget

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

R&R Subaward Budget

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

PHS 398 Cover Page Supplement

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

PHS 398 Research Plan

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

Research Strategy:

Applicants should:

1) Describe the birth defect under investigation and the dataset from which variants will be selected, as well as the public database through which these data are accessible, where applicable.

2) Describe how in-silico analysis, in vivo analysis and/or cell-based assays will be used to identify and prioritize variants. Include an explanation of how gender differences will be accounted for.

3) Describe the assay(s) and/or model system(s) that will be used to validate the selected variants. Explain why this approach is expected to recapitulate or otherwise inform the phenotype under study. Using a combination of in silico, in vitro, and in vivo models is encouraged. If conducting in vitro or cell-free biochemical assays, explain how this will be verified in an in vivo animal model.

4) Explain why the data generated from this project will be of high value to the birth defects research community and/or potentially inform the development of strategies for the molecular diagnosis, treatment, or prevention of human birth defects.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide.

The following modifications also apply:

All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan

NICHD Plans for Sharing Human and Non-Human Data and/or Biospecimens

NICHD expects that data, biospecimens, and results of NICHD-funded research will be shared with the wider scientific community to the extent feasible and in a timely manner. NIH Data Sharing Policy expects the timely release and sharing of data to be no later than the acceptance for publication of the main findings from the final dataset. All NICHD applications, regardless of the amount of direct costs requested for any one year, are expected to include a Sharing Plan that addresses sharing of data as well as biospecimens, if applicable. Ideally, this plan would include submitting data or biospecimens to an appropriate repository. These plans will also be considered by program staff as award decisions are being made as appropriate and consistent with achieving the goals of the program.

Specifically, for human data, the NICHD encourages the use of the Data and Specimen Hub (DASH), a centralized resource for researchers to store and access de-identified data from studies funded by NICHD. They can also submit information about the location and availability of biospecimens to DASH, if applicable. Submission of data to the NICHD DASH is one way that grantees may meet the requirements of the NIH Data Sharing Policy and make study data available for secondary analyses. Information about DASH may be obtained at https://dash.nichd.nih.gov/

If use of DASH is not feasible, NICHD expects awardees to share data and/or biospecimens through other equivalent broad-sharing data and/or biospecimen repositories. For projects generating large-scale human genetic data, applicants should provide a Provisional or Institutional Certification specifying whether the individual-level data can be shared through an NIH approved repository, such as dbGaP, in line with the NIH Genomic Data Sharing Policy (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-14-124.html).

Appendix:
Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.
PHS Human Subjects and Clinical Trials Information

When involving human subjects research, clinical research, and/or NIH-defined clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered “Yes” to the question “Are Human Subjects Involved?” on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

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

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).All instructions in the SF424 (R&R) Application Guide must be followed.

PHS Assignment Request Form

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

Foreign Institutions

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

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

See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov.

4. Submission Dates and Times

Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time.  If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

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

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

7. Other Submission Requirements and Information

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide.  Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit How to Apply – Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. 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 FOA for information on registration requirements.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

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

Post Submission Materials

Applicants are required to follow the instructions for post-submission materials, as described in the policy. Any instructions provided here are in addition to the instructions in the policy.

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process.  Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

Overall Impact

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

Scored Review Criteria

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

Significance

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?

Will the data generated be of high value to the research community and potentially informative for translation of basic knowledge gained from functional genomic approaches into the development of strategies for the molecular diagnosis, treatment, or prevention of human birth defects?

Investigator(s)

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?

Innovation

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?

Approach

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?

  • Will the approach be effective in meeting the stated goals of the project (non-hypothesis driven screening of variants to establish association with the birth defect under investigation, hypothesis-driven mechanistic studies to generate critical information on how variant functions affect the disease phenotypes, or a combination of both types of studies)?
  • If functional assays are conducted in vitro or in cell-free systems, is there an effective plan to verify those data in vivo, in an animal model?
  • Will the study provide multiple lines of convergent evidence supporting functionality using a combination of two or more of the following model systems: in silico, in vitro, cell free and in vivo?
  • When applicable, is the approach designed to identify gender differences in variant susceptibility to the birth defect under investigation?

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

Environment

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

Additional Review Criteria

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

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, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

Inclusion of Women, Minorities, and Individuals Across the Lifespan

When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of individuals of all ages (including children and older adults) to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Biohazards

Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

Resubmissions

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

Renewals

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

Revisions

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

Additional Review Considerations

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

Applications from Foreign Organizations

Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.

Select Agent Research

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Resource Sharing Plans

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) Data Sharing Plan; (2) Sharing Model Organisms; and (3)  Genomic Data Sharing Plan (GDS).

Authentication of Key Biological and/or Chemical Resources:

For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

Budget and Period of Support

Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by the Center for Scientific Review, in accordance with NIH peer review policy and procedures, 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 . Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. The following will be considered in making funding decisions:

  • Scientific and technical merit of the proposed project as determined by scientific peer review.
  • Availability of funds.
  • Relevance of the proposed project to program priorities.

3. Anticipated Announcement and Award Dates

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

Section VI. Award Administration Information

1. Award Notices

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the recipient's business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website.  This includes any recent legislation and policy applicable to awards that is highlighted on this website.

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

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Recipients, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights laws that prohibit discrimination on the basis of race, color, national origin, disability, age and, in some circumstances, religion, conscience, and sex. This includes ensuring programs are accessible to persons with limited English proficiency. The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-providers/provider-obligations/index.html and http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html.

HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research. For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA.

Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 “Federal awarding agency review of risk posed by applicants.” This provision will apply to all NIH grants and cooperative agreements except fellowships.

Cooperative Agreement Terms and Conditions of Award

Not Applicable

3. Reporting

When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later.  All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000.  See the NIH Grants Policy Statement for additional information on this reporting requirement.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period.  The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS).  This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313).  As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available.  Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 – Award Term and Conditions for Recipient Integrity and Performance Matters.

Section VII. Agency Contacts

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

Application Submission Contacts

eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten submission by the due date, and post-submission issues)

Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-945-7573

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

Scientific/Research Contact(s)

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Mahua Mukhopadhyay, Ph.D.
Telephone: 301-435-6886
Email: mukhopam@mail.nih.gov

National Institute of Dental and Craniofacial Research (NIDCR)
Kathryn Stein, Ph.D.
Telephone: 301-827-4653
Email: kathryn.stein@nih.gov

Office of Research Infrastructure Programs (ORIP)
Oleg Mirochnitchenko, Ph.D.
Telephone: 301-435-0748
Email: oleg.mirochnitchenko@nih.gov

Peer Review Contact(s)

Center for Scientific Review
Email: FOA_ReviewContact@csr.nih.gov

Financial/Grants Management Contact(s)

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Margaret Young
Telephone: 301-642-4552
Email: margaret.young@nih.gov

National Institute of Dental and Craniofacial Research (NIDCR)
Diana Rutberg, MBA
Telephone: 301-594-4798
Email: rutbergd@mail.nih.gov

Office of Research Infrastructure Programs (ORIP)
Gavin Wilcom, M.I.M
Telephone: 301-435-0964
Email: wilkomg@mail.nih.gov

Section VIII. Other Information

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

Authority and Regulations

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


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