Department of Health and Human Services
Part 1. Overview Information
Participating Organization(s)

National Institutes of Health (NIH)

Components of Participating Organizations

National Human Genome Research Institute (NHGRI)

Funding Opportunity Title

Mendelian Genomics Research Centers (U01 - Clinical Trial Optional)

Activity Code

U01 Research Project – Cooperative Agreements

Announcement Type

New

Related Notices

January 24, 2020 - Notice of Pre-Application Webinars for the Mendelian Genomics Research Centers (RFA-HG-20-007) and Mendelian Genomics Data Coordinating Center (RFA-HG-20-008). See Notice NOT-HG-20-018.

NOT-OD-19-128, Changes to NIH Requirements Regarding Proposed Human Fetal Tissue Research.

NOT-OD-19-137, Clarifying Competing Application Instructions and Notice of Publication of Frequently Asked Questions (FAQs) Regarding Proposed Human Fetal Tissue Research.

Funding Opportunity Announcement (FOA) Number

RFA-HG-20-007

Companion Funding Opportunity
Catalog of Federal Domestic Assistance (CFDA) Number(s)

93.172 

Funding Opportunity Purpose

The purpose of this Funding Opportunity is to establish a consortium aimed at significantly increasing the proportion of Mendelian conditions with an identified genetic cause. A key objective of the Mendelian Genomics Research Centers is to develop and apply approaches to discover causal genes underlying Mendelian conditions for which a candidate gene was not identified using whole exome sequencing alone.

Key Dates
Posted Date

January 10, 2020

Open Date (Earliest Submission Date)

March 16, 2020

Letter of Intent Due Date(s)

March 16, 2020

Application Due Date(s)

April 15, 2020

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) No late applications will be accepted for this Funding Opportunity Announcement.

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.

AIDS Application Due Date(s)

Not applicable

Scientific Merit Review

July 2020

Advisory Council Review

October 2020

Earliest Start Date

December 2020

Expiration Date

April 16, 2020

Due Dates for E.O. 12372

Not Applicable

Required Application Instructions

It is critical that applicants follow 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 the 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 1. Overview Information
    Part 2. Full Text of the Announcement

    Section I. 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. Funding Opportunity Description

    This Funding Opportunity Announcement is to establish a consortium aimed at significantly increasing the proportion of Mendelian disorders with an identified genetic cause through enhanced data sharing, collaboration, and an increased focus on the application of new technologies, sequencing strategies, and analytical approaches.

    Background

    Mendelian conditions are rare, and generally caused by highly penetrant mutations in single genes. Identifying genes and causal genetic variants associated with human Mendelian diseases will advance our understanding of the genomics of disease and inform the development of diagnostic tests or therapeutic strategies for these conditions. The application of next-generation sequencing to Mendelian conditions has had an enormous impact on the pace of Mendelian gene discovery. Today, close to 300 Mendelian disease genes are identified per year, primarily using whole exome sequencing.

    Although tremendous progress has been made in advancing our understanding of the genetic cause of Mendelian conditions, much work remains to be done. One challenge is the high rate of unsolved cases, i.e., known Mendelian conditions for which whole exome sequencing did not identify an underlying genetic cause. It has been reported that in clinical diagnostic laboratories, the genetic cause of suspected Mendelian disorders is successfully identified in between 20-40% of cases. Even in research programs like the NHGRI-funded Centers for Mendelian Genomics, which used a stringent selection process aimed at choosing cases with the highest likelihood of being solved, approximately one third of the cases sequenced had no identified candidate gene, and only half of the cases analyzed had enough supporting evidence to be classified as truly solved. Some of these cases might be solved with re-analysis or by identifying additional individuals with the same underlying condition, but many of them may reflect cases of more complex genetic inheritance, mutations that are located outside of coding regions in functional genomic elements, structural variants, or other mechanisms that are not amenable to being identified using whole exome analysis.

    An additional challenge is the need for more scalable approaches to functional validation of candidate variants, both to prioritize among a list of potential candidates, and to confirm suggestive variant/phenotype associations. Once a candidate variant(s) is identified, additional experiments must often be done to raise the association from the tier 2 (i.e., suggestive) to tier 1 (i.e., confirmed) level, including demonstrating that the candidate variant does in fact impact protein function in relevant pathways, and recapitulating the phenotype in a model organism. These types of corroborative data are necessary before researchers can begin additional investigation into the underlying biology of the disease, and before the findings can be translated into diagnostic testing.

    One of the most significant challenges in this field are the barriers to data sharing. Data sharing will be especially important for solving cases that were not solved after initial whole exome sequencing, not only because it can assist in identifying additional related cases, but because it allows other researchers to apply novel analytical approaches that may prove successful. The data sharing culture among the rare disease research community has been moving in the direction of increased openness, and it is important to continue this trajectory. Challenges to data sharing include historic samples that have restrictive data use limitations, or have limited phenotype information, making the data less useful for further analysis. There are also limitations to the available platforms for responsible sharing of participant and patient data. There is a need to move the field towards increased, but still responsible data sharing, focusing on samples with sufficient supporting phenotypic data that have been consented for broad data sharing, and the development of an infrastructure that will enable secure, but accessible sharing of genomic and phenotypic data from individuals with Mendelian conditions among researchers across the globe.

    Scope and Objectives of this Research Program

    The Mendelian Genomics Research Centers (MGRCs) will be a key element of the Mendelian Genomics Research Consortium, which is composed of two FOAs, of which this FOA is one:

    RFA-HG-20-007, Mendelian Genomics Research Centers (U01 Clinical Trial Optional)

    RFA-HG-20-008, Mendelian Genomics Data Coordinating Center (U24 Clinical Trial Not Allowed)

    The major objectives of the MGRCs are:

    Discovery of causal genes underlying Mendelian conditions, particularly those not identified using whole exome sequencing.

    The MGRCs will use state-of-the-art sequencing technologies to uncover the causal genes underlying Mendelian disorders and traits. Although many of these are expected to represent novel gene/phenotype associations, discoveries that are not novel will also be reported, in order to add to the evidence base for variant interpretation. Applicants are encouraged to perform CAP-accredited and/or CLIA-certified sequencing or validation of findings and return clinical variant reports to collaborating clinicians and patients, when applicable.

    A key outcome of this program will be the development of approaches to identify the causal gene or variant for Mendelian conditions for which a candidate gene was not identified using whole exome sequencing alone. The MGRCs will be expected to apply new technologies or more comprehensive sequencing, and to develop novel analytical approaches or other strategies that can be used to solve these more complex cases. Using infrastructure developed by the Mendelian Genomics Data Coordinating Center (MGDCC), the MGRCs should work collaboratively both within the consortium, as well as with other participating groups, to identify the causal gene for as many of these initially unsolved Mendelian conditions as possible.

    Consistent with the high priority placed on data sharing within this program, applicants should work to identify individual cases or cohorts of individuals with Mendelian disorders for sequencing or re-analysis that are consented for general research use through controlled access, or for unrestricted access, and for which detailed clinical and phenotypic data and metadata are available to be shared. The MGRCs may need to work with potential collaborators to obtain the appropriate consent and associated data for samples which have already been collected. Consistent with the high priority placed on increasing diversity in human genomics research by NHGRI, applicants should ensure these efforts include cases and cohorts from diverse and underrepresented populations.

    Development of approaches to inform variant interpretation, functional follow-up of candidate variants

    Variants that lie outside of coding regions, particularly those within regulatory regions or other functional genomic elements, may play important roles in Mendelian disease, either as modifiers or the primary causal variant. It can be challenging to determine which of the many candidate variants that may be identified in these regions using more comprehensive sequencing approaches might warrant additional investigation, or are likely to play causal roles in disease. Moreover, proving the causality of a variant for disease is extremely challenging; the definitive criteria have not yet been established.

    The MGRCs should develop and apply a pipeline to characterize variants that are associated with disease. This pipeline could include computational steps to identify candidate causal variants and modifier loci and prioritize them for further investigation. It could also include experimental approaches to characterize candidate variants, such as higher-throughput systems that test many candidates, or more physiological systems, such as animal models, that evaluate fewer, high-priority candidates.

    Dissemination of findings from the Mendelian Genomics Research Consortium

    Data generated by the MGRCs will be submitted to the Mendelian Genomics Data Coordination Center (MGDCC), who will be responsible for depositing the complete, quality controlled data into an NIH-designated repository, such as the NHGRI Genomic Data Science Analysis, Visualization, and Informatics Lab-space (AnVIL).The MGDCC will work with the MGRCs to define a process and standards for the submission of sequence data, associated metadata, and phenotypic data to the MGDCC. These standards will enable high-throughput submissions and integration with processes and pipelines of the MGRCs. Through this process, the Consortium will define the minimal data to be included for each sample and the level of harmonization expected. The MGRCs will be expected to work closely with the MGDCC to resolve validation errors, to ensure submitted data meets the agreed-upon standards.

    The MGRCs will also work with the MGDCC to report information on ongoing collaborations and samples under investigation. This information will be made available to NIH and all MGRCs to ensure transparency and facilitate coordinated analyses across cohorts. Finally, the MGRCs will work with the MGDCC to disseminate findings and increase the impact of the Mendelian Genomics Research Consortium through outreach and collaboration with other national and international groups.

    Program Formation and Governance

    The awards funded under this FOA will be cooperative agreements. The Mendelian Genomics Research Centers will be required to interact closely with the other MGRCs, the Mendelian Genomics Data Coordinating Center (MGDCC), and with NIH staff in order to fully achieve the goals of the Mendelian Genomics Research Consortium.

    The MGRCs will also be expected to work closely with the MGDCC to establish data formats and standards, to track and catalog collaborations and incoming samples, report findings, and coordinate the transfer of sequence, variant, and phenotypic data to the MGDCC, who will be responsible for sharing these data more broadly.

    A Steering Committee will be the main governing body of the Mendelian Genomics Research Consortium. The Steering Committee will be composed of the PD/PI(s) from each of the funded MGRCs and the Coordinating Center, and NIH program staff. In addition to the PD(s)/PI(s), key personnel from each MGRC, including pre- and post-doctoral trainees, will be eligible to attend Steering Committee meetings. The Steering Committee will establish subcommittees or working groups, in order to facilitate collaborative work and standardize approaches, or to achieve other goals of the Consortium. The MGRCs and MGDCC will be expected to play an active role in these working groups, which may include (but are not limited to) groups focused on specific cross-consortium activities, such as data harmonization, analysis of unsolved cases, variant interpretation, functional follow-up, outreach and education, ollaborative efforts with outside groups, or international data sharing. The Steering Committee will also work to define and prioritize research needs to be supported through the opportunity fund. An external scientific panel will be formed after awards are made to provide recommendations and advice.

    Data Sharing in this Initiative

    Consistent with the goals of this program, NHGRI expects that centers will prioritize samples for which detailed phenotype data is available, and that have been consented for the broadest possible data sharing, such as consent for unrestricted access, or for general research use and broad sharing through controlled access. Consent language should also avoid restrictions on the types of users who may access the data. Additional guidance on informed consent can be found in the NHGRI Informed Consent Resource.   

    Genomic and associated data from this project will be submitted to the Mendelian Genomics Data Coordination Center, which will be responsible for ensuring its deposition into the appropriate NIH-designated repositories, such as the NHGRI Genomic Data Science Analysis, Visualization, and Informatics Lab-space (AnVIL). This includes all metadata and descriptive information (e.g., protocols or methodologies used) needed to support future use of the data, as well as detailed phenotype data (e.g., clinical data, environmental data, demographic variables, and any non-genotype data). The MGDCC will also deposit information about genomic variation into ClinVar, Matchmaker Exchange, and other resources, as appropriate.

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

    Section II. Award Information
    Funding Instrument

    Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH scientific or program staff will assist, guide, coordinate, or participate in project activities. See Section VI.2 for additional information about the substantial involvement for this FOA.

    Application Types Allowed

    New

    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?

    Optional: Accepting applications that either propose or do not propose clinical trial(s)

    Need help determining whether you are doing a clinical trial?

    Funds Available and Anticipated Number of Awards

    NHGRI intends to commit $9M in FY 2020-2025 to fund 3-5 awards.

    Award Budget
    Application budgets are limited to $2M direct costs and must reflect the actual needs of the proposed project.
    Award Project Period

     The total award period for this FOA is 5 years (FY2021-2025). 

    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)

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

    Other

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

    Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.

    Non-domestic (non-U.S.) components of U.S. Organizations are not 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.
    • 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. 
    • 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 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:

    Lisa Helbling Chadwick, Ph.D.
    National Human Genome Research Institute (NHGRI)
    Telephone: 301-435-7275
    Email: lisa.chadwick@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.

    Effective management of this center requires a significant commitment by the Program Director(s)/Principal Investigator(s). For an application proposing a single PD/PI, that PD/PI is expected to devote at least 3 person months annually to the project. If multi-PDs/PIs are proposed, then one PD/PI is expected to commit at least 3 person months annually and the other(s) should devote sufficient time to serve his/her proposed role.

    MGRC budgets should include costs required for active participation in the consortium, including regular teleconferences and meetings of the Steering Committee and its working groups. Applicants should also budget for the PD(s)/PI(s) and 3-5 other key personnel from the Center to attend one annual meeting of the full consortium and one additional in-person meeting per year (i.e. a Steering Committee meeting, analysis-focused meetings, etc.).

    R&R Subaward Budget

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

    PHS 398 Cover Page Supplement

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

    PHS 398 Research Plan

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

    Applicants should describe their plans to address the major objectives of the Mendelian Genomics Research Centers, described in Section I above. Without duplicating information contained in the biosketches, relevant previous experience should be described succinctly.

    A. Discovery of causal genes underlying Mendelian conditions, particularly those not identified using whole exome sequencing

    Specific points that applicants should address include, but are not limited to:

    • How they will work to identify individual cases or cohorts of individuals with Mendelian conditions for sequencing or re-analysis, that have been consented for general research use through controlled access, and for which detailed clinical and phenotypic data and metadata are available to be shared, this should include a description of how they will communicate data sharing requirements and expectations with any collaborators or sample providers.
    • A proposal for specific phenotypic data (e.g., clinical data, environmental data, demographic variables and any non-genotype data), descriptive information and metadata to be collected and shared as part of their proposal, including a description of how they will work with the Mendelian Genomics Research Consortium governance as a whole to establish and implement final data sharing requirements and consortium policies.
    • Strategies that will be used to ensure the proposed work includes individual cases or cohorts of individuals with Mendelian conditions from diverse and underserved populations
    • The facilities, sequencing platform(s), and analytical pipelines that will be used for the proposed activities, including sequence coverage, file hierarchy and structure, quality assessment of primary sequences, and variant identification
    • If clinical sequencing or validation and return of results is proposed, include a description of College of American Pathologists (CAP)-accredited and/or Clinical Laboratory Improvement Amendments (CLIA)-certified exome and genome sequence generation, including the facilities and instrumentation to be utilized for sequencing, and plans for clinical reports
    • Specific, innovative approaches that will be applied towards identifying the causal genes for Mendelian conditions that were not identified using whole exome sequencing, including a commitment to working collaboratively with the entire Consortium and any associated groups on solving these cases
    • Capability for developing, improving, and integrating new discovery approaches, methods, and technologies that lead to improved data quality, efficiency, and costs

    B. Development of approaches to inform variant interpretation, functional follow-up of candidate variants

    Applicants should describe a pipeline to identify and characterize candidate variants and confirm suggestive variant/phenotype associations. This pipeline may include, but is not limited to, the following features:

    • Computational analysis to identify candidate causal and modifier loci
    • Computational prioritization of variants for experimental follow up
    • Experimental assays to characterize elements.  These may range from high-throughput assays to broadly survey a large number of candidate functional elements (e.g., massively parallel reporter assays or CRISPR library screens) to lower throughput assays to characterize candidate functional elements in more physiological systems (e.g., transgenic animals)
    • Assays may characterize function along the continuum from molecular phenotypes (e.g., transcription, splicing) to organismal phenotypes (e.g., height, brain anatomy)

    Applicants should include justification of the chosen pipeline and indicate how it will contribute to the goal of increasing the proportion of Mendelian conditions with an identified genetic cause. Applicants should describe how they will collaborate with other members of the Mendelian Genomics Research Consortium to share standards, protocols and best practices for variant interpretation and functional follow-up and how they will achieve flexibility to adapt or integrate new approaches as necessary.

    C. Dissemination of findings from the Mendelian Genomics Research Consortium

    Applicants should describe their commitment to communicating, collaborating and coordinating with the Mendelian Genomics Data Coordination Center to establish data formats and standards, track and catalog collaborations and incoming samples, report findings, and coordinate the transfer and rapid release of sequence, variant, and phenotypic data to the MGDCC.

    Applicants should describe a pipeline for submitting sequence, phenotype, and other relevant data to the MGDCC, and discuss their commitment to adapting this pipeline if needed in order to better integrate with the needs of the larger Consortium, including demonstrating flexibility in their pipelines that may be needed to support enhanced data sharing with the broader research community as the opportunity arises over the course of the project.  

    Applicants should include a description of proposed joint outreach activities, (such as training workshops, conference centers, collaborations with other national and international consortia, etc) with the goal of ensuring data and methods developed by the Consortium are disseminated to and used by the broader research community.

    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.

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

    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. 

    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.

    A proposed Clinical Trial application may include study design, methods, and intervention that are not by themselves innovative but address important questions or unmet needs. Additionally, the results of the clinical trial may indicate that further clinical development of the intervention is unwarranted or lead to new avenues of scientific investigation.

    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?

    Specific to this FOA: Will this project make a significant contribution to the overall goals of the Mendelian Genomics Research Consortium? Is there a high likelihood that the proposed activities will ultimately increase the success rate for discovery of causal genes for human Mendelian conditions?

    In addition, for applications involving clinical trials

    Are the scientific rationale and need for a clinical trial to test the proposed hypothesis or intervention well supported by preliminary data, clinical and/or preclinical studies, or information in the literature or knowledge of biological mechanisms? For trials focusing on clinical or public health endpoints, is this clinical trial necessary for testing the safety, efficacy or effectiveness of an intervention that could lead to a change in clinical practice, community behaviors or health care policy?  For trials focusing on mechanistic, behavioral, physiological, biochemical, or other biomedical endpoints, is this trial needed to advance scientific understanding?

    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?

    Specific to this FOA: Do the PD(s)/PI(s) and the research team have the required expertise in the sequencing methods proposed, and interpretation of these data?

    Does the team have the necessary expertise in developing and applying approaches to identify, prioritize, and characterize candidate variants?  

    In addition, for applications involving clinical trials

    With regard to the proposed leadership for the project, do the PD/PI(s) and key personnel have the expertise, experience, and ability to organize, manage and implement the proposed clinical trial and meet milestones and timelines? Do they have appropriate expertise in study coordination, data management and statistics? For a multicenter trial, is the organizational structure appropriate and does the application identify a core of potential center investigators and staffing for a coordinating center?

    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?

    Specific to this FOA: Does the application propose innovative solutions that will advance Mendelian gene discovery studies more broadly? Does the application propose novel approaches for cases in which a candidate gene was not identified using whole exome sequencing alone?  Will the approaches proposed move the field of Mendelian gene discovery beyond the current state-of-the-art?

    In addition, for applications involving clinical trials

    Does the design/research plan include innovative elements, as appropriate, that enhance its sensitivity, potential for information or potential to advance scientific knowledge or clinical practice?

    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?

    Specific to this FOA:

    Does the applicant present approaches that will significantly increase the proportion of Mendelian cases that are solved?

    Have the applicants presented a feasible plan for obtaining samples or data from individuals with Mendelian conditions that have been consented for general research use through controlled access, and for which detailed clinical and phenotypic data and metadata are available to be shared?  Does the applicant propose to collect sufficient phenotypic data, metadata and descriptive information to facilitate cross-consortium analyses?  Does the applicant provide strategies that will ensure the inclusion of diverse and underserved populations?

    Will the proposed pipeline for variant characterization help confirm suggestive gene/phenotype associations? Does the application include a plan for coordinating and communicating with the MGDCC? Is the center willing to share raw and derived data files with the MGDCC in order to enable genomic data harmonization and release?

    Is there sufficient flexibility in the approaches proposed to allow the center to adapt to the needs of the Consortium?

    In addition, for applications involving clinical trials

    Does the application adequately address the following, if applicable

    Study Design

    Is the study design justified and appropriate to address primary and secondary outcome variable(s)/endpoints that will be clear, informative and relevant to the hypothesis being tested? Is the scientific rationale/premise of the study based on previously well-designed preclinical and/or clinical research? Given the methods used to assign participants and deliver interventions, is the study design adequately powered to answer the research question(s), test the proposed hypothesis/hypotheses, and provide interpretable results? Is the trial appropriately designed to conduct the research efficiently? Are the study populations (size, gender, age, demographic group), proposed intervention arms/dose, and duration of the trial, appropriate and well justified?

    Are potential ethical issues adequately addressed? Is the process for obtaining informed consent or assent appropriate? Is the eligible population available? Are the plans for recruitment outreach, enrollment, retention, handling dropouts, missed visits, and losses to follow-up appropriate to ensure robust data collection? Are the planned recruitment timelines feasible and is the plan to monitor accrual adequate? Has the need for randomization (or not), masking (if appropriate), controls, and inclusion/exclusion criteria been addressed? Are differences addressed, if applicable, in the intervention effect due to sex/gender and race/ethnicity?

    Are the plans to standardize, assure quality of, and monitor adherence to, the trial protocol and data collection or distribution guidelines appropriate? Is there a plan to obtain required study agent(s)? Does the application propose to use existing available resources, as applicable?

    Data Management and Statistical Analysis

    Are planned analyses and statistical approach appropriate for the proposed study design and methods used to assign participants and deliver interventions? Are the procedures for data management and quality control of data adequate at clinical site(s) or at center laboratories, as applicable? Have the methods for standardization of procedures for data management to assess the effect of the intervention and quality control been addressed? Is there a plan to complete data analysis within the proposed period of the award?

    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?   

    In addition, for applications involving clinical trials

    If proposed, are the administrative, data coordinating, enrollment and laboratory/testing centers, appropriate for the trial proposed?

    Does the application adequately address the capability and ability to conduct the trial at the proposed site(s) or centers? Are the plans to add or drop enrollment centers, as needed, appropriate?

    If international site(s) is/are proposed, does the application adequately address the complexity of executing the clinical trial?     

    If multi-sites/centers, is there evidence of the ability of the individual site or center to: (1) enroll the proposed numbers; (2) adhere to the protocol; (3) collect and transmit data in an accurate and timely fashion; and, (4) operate within the proposed organizational structure?

    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.

    Study Timeline

    Specific to applications involving clinical trials

    Is the study timeline described in detail, taking into account start-up activities, the anticipated rate of enrollment, and planned follow-up assessment? Is the projected timeline feasible and well justified? Does the project incorporate efficiencies and utilize existing resources (e.g., CTSAs, practice-based research networks, electronic medical records, administrative database, or patient registries) to increase the efficiency of participant enrollment and data collection, as appropriate?

    Are potential challenges and corresponding solutions discussed (e.g., strategies that can be implemented in the event of enrollment shortfalls)?

    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

    Not applicable

    Renewals

    Not applicable

    Revisions

    Not applicable

    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

    Not applicable.

    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 NHGRI, 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:

    • 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.
    • Will receive a written critique.

    Appeals of initial peer review will not be accepted for applications submitted in response to this FOA.

    Applications will be assigned  to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the National Advisory Council for Human Genome Research. 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 grantee’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.

    Individual awards are based on the application submitted to, and as approved by, the NIH and are subject to the IC-specific terms and conditions identified in the NoA. 

    ClinicalTrials.gov: If an award provides for one or more clinical trials. By law (Title VIII, Section 801 of Public Law 110-85), the "responsible party" must register and submit results information for certain “applicable clinical trials” on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov). NIH expects registration and results reporting of all trials whether required under the law or not. For more information, see https://grants.nih.gov/policy/clinical-trials/reporting/index.htm

    Institutional Review Board or Independent Ethics Committee Approval: Grantee institutions must ensure that all 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.  Data and Safety

    Monitoring Requirements: The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or -supported human biomedical and behavioral intervention studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&R) and PHS 398).

    Investigational New Drug or Investigational Device Exemption Requirements: Consistent with federal regulations, clinical research projects involving the use of investigational therapeutics, vaccines, or other medical interventions (including licensed products and devices for a purpose other than that for which they were licensed) in humans under a research protocol must be performed under a Food and Drug Administration (FDA) investigational new drug (IND) or investigational device exemption (IDE). 

    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, Grantees, 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 law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency.  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. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/index.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-individuals/section-1557/index.html; and https://www.hhs.gov/civil-rights/for-providers/laws-regulations-guidance/index.html.  Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see https://www.hhs.gov/civil-rights/for-individuals/disability/index.html. 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. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

    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

    The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Part 75, and other HHS, PHS, and NIH grant administration policies.

    The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

    The PD(s)/PI(s) will have the primary responsibility for:

    • Determining research approaches, designing protocols, setting project milestones, and conducting research.
    • Timely transfer of detailed genomic, phenotypic, family history, clinical, and related data to the MGDCC, using agreed-upon formats and processes, in order to facilitate dissemination of data through databases such as AnVILdbGaP, or ClinVar.
    • Preparing abstracts, presentations and publications and collaborating consortium-wide in making the public and professionals aware of the program.
    • Assessing and disseminating data, protocols, consent materials, and methods developed for or derived from the MGRCs within and outside the Consortium.
    • Adhering to policies regarding data access, publication, and intellectual property established by the NIH and the Mendelian Genomics Research Consortium Steering Committee.
    • Abiding by common definitions, protocols, and procedures, as chosen by majority vote of the Steering Committee.
    • Submitting periodic progress reports in a standard format, as agreed upon by NIH and the Steering Committee
    • Attending and participating in Steering Committee and other working group meetings and accepting and implementing decisions made by these groups.
    • Ensuring their site receives the appropriate approvals for sharing of data between their site, the MGDCC, and selected data repositories such as AnVILdbGaP, and ClinVar.

    Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.

    NIH staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

    The Project Scientist(s) will have substantial scientific and programmatic involvement during the conduct of this activity through technical assistance, advice, and coordination.  However, the role of NIH staff will be to facilitate and not to direct the activities.  It is anticipated that decisions in all activities will be reached by consensus of the Mendelian Genomics Research Consortium, and that NIH staff will be given the opportunity to offer input to this process.  The Project Scientist(s) will participate as members of the Steering Committee and will have one vote. 

    The Project Scientist(s) will have the following substantial involvement:

    • Participating with the other Steering Committee members in addressing issues that arise with planning, operation, assessment, and data analysis.? The Project Scientist(s) will assist and facilitate the group process and not direct it.
    • Serving as a liaison, helping to coordinate activities, including acting as a liaison to other NIH Institutes/Centers, and as an information resource for the awardees. The Project Scientist(s) will also help coordinate the efforts of the Consortium with other groups conducting similar efforts.
    • Attending all Steering Committee meetings as a voting member and all Working Group meetings, assisting in developing operating guidelines, quality control procedures, and consistent policies for dealing with situations that require coordinated action. 
    • Reporting periodically on Consortium progress to the National Advisory Council of Human Genome Research Institute.
    • Assisting awardees in the development, if needed, of policies for dealing with situations that require coordinated action.
    • Providing advice in the management and technical performance of the award.
    • Assisting in promoting the availability of the data and related resources developed in the course of this program to the scientific community at large. ?
    • Participating in data analyses, interpretations, and, where warranted, co-authorship of the publication of results of studies conducted through the program. ?
    • Serve as a liaison between the awardees and the External Scientific Panel and the National Advisory Council for Human Genome Research.
    • Lend relevant expertise and overall knowledge of NHGRI-sponsored research to facilitate the selection of scientists not affiliated with the awardee institutions who are to serve on the External Scientific Panel.
    • Serve on subcommittees of the Steering Committee, working groups and the External Scientific Panel, as appropriate.
    • Additionally, an agency program official or IC program director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.
    • The Program Official may withhold or reduce support from any awardee that fails to achieve its goals or comply with the Terms and Conditions of Award.
    • Other NHGRI staff may assist the awardee as designated by the Program Official.?
    • The assigned program director may also serve as an NHGRI Project Scientist.

    Dispute Resolution:

    Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

    Areas of Joint Responsibility include

    The Mendelian Genomics Research Centers will be required to interact closely with the other MGRCs, the Mendelian Genomics Data Coordinating Center (MGDCC), and with NIH staff in order to fully achieve the goals of the Mendelian Genomics Research Consortium.

    The MGRCs will also be expected to work closely with the MGDCC to establish data formats and standards, to track and catalog collaborations and incoming samples, report findings, and coordinate the transfer of sequence, variant, and phenotypic data to the MGDCC, who will be responsible for sharing these data more broadly.

    A Steering Committee will be the main governing body of the Mendelian Genomics Research Consortium. The Steering Committee will be composed of the PD/PI(s) from each of the funded MGRCs and the Coordinating Center, and NIH program staff. In addition to the PD(s)/PI(s), key personnel from each MGRC, including pre- and post-doctoral trainees, will be eligible to attend Steering Committee meetings. The Steering Committee will establish subcommittees or working groups, in order to facilitate collaborative work and standardize approaches, or to achieve other goals of the Consortium. The MGRCs and MGDCC will be expected to play an active role in these working groups, which may include (but are not limited to) groups focused on specific cross-consortium activities, such as analysis of unsolved cases, variant interpretation, functional follow-up, outreach and education, or international data sharing. The Steering Committee will also work to define and prioritize research needs to be supported through the opportunity fund.

    NHGRI and the grantees will work with and provide information to an External Scientific Panel (ESP). The ESP will be responsible for reviewing and evaluating the progress of the members of the Mendelian Genomics Research Consortium toward meeting their individual and collective goals. The ESP will provide recommendations to the Director, NHGRI Division of Genome Sciences and Director, NHGRI. The ESP is composed of four to six senior scientists with relevant expertise who are not P.I.s of a cooperative agreement involved in the Consortium. The membership of the ESP may be enlarged permanently or on an ad hoc basis as needed.

    The ESP will meet at least once a year. During part of this meeting, there will be a joint meeting with the Steering Committee to allow the ESP members to interact directly with the awardees. The ESP will make recommendations regarding progress of the Consortium and present advice about changes, if any, which may be necessary in the Consortium to the Director, NHGRI Division of Genome Sciences and Director, NHGRI.

    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)

    Lisa Helbling Chadwick, Ph.D.
    National Human Genome Research Institute (NHGRI)
    Telephone: 301-435-7275
    Email: lisa.chadwick@nih.gov

    Peer Review Contact(s)

    Rudy Pozzatti, Ph.D.
    National Human Genome Research Institute (NHGRI)
    Telephone: 301-402-8739
    Email: pozzattr@exchange.nih.gov

    Financial/Grants Management Contact(s)

    Devon Bumbray-Quarles
    National Human Genome Research Institute (NHGRI)
    Telephone: 301-451-7928
    Email: devon.bumbray-quarles@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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