Part 1. Overview Information

Key Dates

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.

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

Background

Clinical genetic testing is becoming increasingly routine in clinical practice and genome-scale sequencing is leading to the identification of many genomic variants with vastly differing clinical relevance. Many of these tests reveal a large number of variants of unknown significance (VUS) due to a variant’s rarity or to differences in the interpretation of its role by clinical laboratories or clinicians, potentially leading to inappropriate medical interventions.Though variants have been identified for certain Mendelian disorders, for the majority of the over 80 million variants in the human genome currently there is no clear understanding of their impact on human health.

NIH established a clinical genomics infrastructure to develop an openly accessible knowledge base that promotes data sharing and provides standardized infrastructure and tools for determining the clinical relevance of genetic variants through two initiatives: the Clinical Genomics Resources (ClinGen) and the Clinical Variant Database (ClinVar) of clinical variation. ClinVar is a publicly and freely available database maintained by the National Center for Biotechnology Information (NCBI) that aggregates information about genomic variation and its relationships to human health (http://www.ncbi.nlm.nih.gov/clinvar/). ClinGen is an NHGRI-funded central resource additionally supported by NCI and NICHD. ClinGen defines the clinical relevance of genes and variants for use in precision medicine and research by standardizing clinical annotation and interpretation of variants and implementing evidence-based expert consensus (https://www.clinicalgenome.org/). This integrated infrastructure supports disease/disorder specific expert panels to determine the clinical applicability of genes and/or variants utilizing genomic, clinical, computational, and functional data. ClinGen has developed a clinical validity framework for identifying and assigning the level of evidence to support determination of gene-disease relationships. Furthermore, they have implemented standard approaches for curation and interpretation of both sequence and copy number variants. Variants evaluated by ClinGen-endorsed expert panels are deposited in ClinVar. Based on its rigorous and transparent procedures, ClinGen has been recently recognized by the FDA as the first public genetic variant database that can be used to validate genetic variant information in regulatory submissions. The ClinGen framework and tools can be found at https://www.clinicalgenome.org/tools/#heading_0.

Sharing of genomic data is critical for the determination of clinical significance of a gene and its variants.To that end, ClinVar is a community submission-driven knowledgebase that can receive submissions of varying complexity ranging from primary submitters for a single variant to authoritative assertions of clinical significance prepared by expert panels. ClinVar utilizes a four-star rating system to provide information about the level of review of the submissions. ClinVar assigns three stars for ClinGen approved expert panel submissions. As a result of their FDA recognition, ClinGen expert panels submissions are additionally marked in ClinVar with an FDA Recognized Database label (https://www.ncbi.nlm.nih.gov/clinvar/variation/239906/). ClinGen has developed the procedures to support the formation of expert panels along with a suite of curation interfaces and tools to support their expert panel activities. These procedures, interfaces, and tools facilitate a systematic process for analyzing evidence in a uniform and streamlined manner by expert panels.

Currently ClinGen-established expert panels span a number of disease areas including: cardiovascular diseases, hearing loss, hemostasis/thrombosis, hereditary cancers, inborn errors of metabolism, neurodevelopmental disorders, neuromuscular disorders, and RASopathies. ClinGen continues to consider additional disease areas as new opportunities arise, as well as new genes or variants within existing domains (https://www.clinicalgenome.org/affiliation/).

This FOA invites applications to establish Genomic Expert Curation Panels. These panels may identify clinical domains of high priority to participating NIH Institutes and Centers (ICs), select candidate genes that will have a high impact on clinical practice in these high priority areas, analyze all relevant variant data utilizing the ClinGen procedures, interfaces, and tools to make determinations of clinical significance. Specific IC interests include:

• Eunice Kennedy Shriver National Institute of Child Health and Human Development: Of particular interest to NICHD are genes associated with gynecologic, andrologic and reproductive health, poor pregnancy outcomes, high risk newborn conditions, structural birth defects, intellectual and developmental disabilities, and susceptibility to infection.
• National Cancer Institute: Of interest to NCI are genes and variants potentially associated with inherited susceptibility to cancer development and/or to cancer response or resistance to therapy; these genes/variants should be curated across populations, with particular attention to underrepresented populations.
• National Institute of Mental Health: Of interest to NIMH are genes and variants associated with severe mental illnesses, such as autism and schizophrenia, within the mission of the NIMH.
• National Institute of Neurological Disorders and Stroke: Of interest to NINDS are genes and variants associated with neurological/neuromuscular diseases and stroke within the mission of the NINDS.
• National Eye Institute: Of interest to NEI are genes and variants associated with diseases of the visual system including those of the eye, central visual, and oculomotor pathways that are within the mission of the NEI

The Expert Curation Panels are required to collaborate with ClinGen and ClinVar utilizing the ClinGen suite of curation interfaces and tools and to submit their underlying data to these resources in order to share data with the field. Training on these tools is required and is provided through ClinGen online resources and/or staff for new curation groups. NIH Expert Curation Panel PD/PIs, coordinators and other key staff are expected to participate in ClinGen working groups and share curation procedures and outcomes with ClinGen and ClinVar.

Because of the large number of diseases and limited funds for this program, investigators are encouraged to form collaborations with other researchers in the same disease area and submit one application, rather than competing or complementary applications. Disease areas that have already established an Expert Curation Panel should provide compelling justification for the need for support through this initiative.

Scope

The scope of this FOA is to establish Expert Curation Panels in areas of high priority to the participating ICs. The Expert Curation Panel will select and review genes and their variants within the specified domain that have the potential for clinical applicability utilizing the procedures and tools developed by ClinGen. The role of the expert panel is to evaluate the strength of existing publicly available evidence supporting the clinical significance or actionability of the selected genes to support clinical practice and submission to ClinVar.

• Expert Curation Panels are expected to identify a clinical domain or genes/variants within the scope of the participating IC priorities ensuring that these do not duplicate current ClinGen-supported Expert Panel efforts (https://clinicalgenome.org/affiliation/).
• Genes and/or variants should be selected for curation based on their potential for clinical actionability. Depending on the number of genes or variants proposed, individual working groups may be established that will report to the Expert Curation Panel. If the gene(s) are already being examined by another expert panel, joint efforts with the existing panel should be established or justify the need for another panel.
• Panel members should reflect the breadth of expertise required to ascertain the clinical actionability of the genes identified and be led by a chair and co-chair (if needed). It is recommended that Expert Curation Panels include medical professionals caring for patients relevant to the disorder or disease, medical geneticists, clinical laboratory diagnosticians and/or molecular pathologists who report such findings, researchers relevant to the disease, and statisticians.
• Members of Expert Curation Panels should represent multiple institutions (at a minimum 3), be international in scope, and be considered by the community to be experts in the field. There is no predefined number of members for an expert panel.
• Expert Curation Panels should be supported by staff members who will assist the curation process. These include: a project coordinator, curation scientists, such as clinical fellows, genetic counselors, or researchers in the field, as well as bioinformatics specialists. This staff is required to utilize ClinGen rules and tools to review existing information preparing summary materials for Expert Curation Panel decision making. Experience with other expert curation panels indicates that the most successful groups have a project coordinator, bioinformaticians and curation scientists who undertake the initial curation that is then reviewed by the Expert Curation Panel.
• Panel meetings can occur remotely, though at least one annual face-to-face meeting is recommended. Scheduling this meeting either in association with a regularly attended professional meeting or in conjunction with the annual Curating the Clinical Genome Conference (https://www.clinicalgenome.org/about/events/curating-the-clinical-genome-2019/) is encouraged.
• Utilizing the ClinGen/ClinVar framework (https://clinicalgenome.org/curation-activities/), Expert Curation Panels are expected to define operating procedures for gene/variant assessment as described by ClinGen, which will include modification of the ACMG variant assessment guidelines, curation and review processes and policies for resolving differences. These standard operating procedures are expected to follow ClinGen protocols and be shared with ClinGen. Training for use of ClinGen/ClinVar tools is available through ClinGen, via online courses, webinars or in person. Expert curation panels are expected to deposit gene and variant calls and curation tools into the ClinGen/ClinVar interface.
• The chair of the Clinical Variant Curation Panel, leaders of specific gene working groups, coordinators and key curation staff are expected to be trained on ClinGen procedures and tools, participate in ClinGen working groups, participate in monthly ClinGen webinars and attend the annual ClinGen/Decipher meeting.
• Prior to submission of applications to this FOA, applicants are expected to be familiar with the policies and procedures published on the ClinGen website (https://www.clinicalgenome.org/start/). ClinGen will hold an informational webinar for all potential applicants to describe the resources and procedures used for curation and deposition into ClinGen/ClinVar databases.
• Potential applicants are encouraged to submit a Letter of Intent (LOI).

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

Section II. Award Information

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

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

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.

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.

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.

Currently funded PD(s)/PI(s)are eligible to apply but must provide a strong justification to be considered for support.,

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 Guideexcept 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:

Melissa A. Parisi, MD, PhD
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-435-6880
Email: [email protected]

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed 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. All instructions in the SF424 (R&R) Application Guide must be followed. All instructions in the SF424 (R&R) Application Guide must be followed. All instructions in the SF424 (R&R) Application Guide must be followed. All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed. Funds can be used to support partial salary of the Expert Curation Panel chair and, if applicable, the co-chair(s). Other panel experts can receive nominal consulting fees. The primary emphasis of the budget should be on supporting a project coordinator, biocurators, and bioinformatics specialists. Both domestic and international Expert Panel members can receive nominal consulting fees. Funds can also be used for meeting support and travel to face-to face meetings and the annual Curating the Clinical Genome Conference (https://clinicalgenome.org/about/events/) by the PI and other appropriate members. There may be additional costs associated with training on ClinGen tools. Regarding budgeting for consultants, if they will not be conducting a substantive portion of the research, their fees will not be considered to be a sub-award, and therefore, no indirect costs would be involved. If they are conducting a substantive portion of the research, a sub-contract will be required. All costs, including indirect costs, come from the parent award.

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

Research Strategy:

1. Describe the clinical domain(s) identified within the scope of priorities described by the participating ICs and identify the disease/disorder genes and/or variants selected for curation. Provide a justification for why this area is ready for analysis and why particular genes/variants were selected. Document their potential for clinical actionability.

2. Describe the leadership (including a chair and co-chair, if needed) and membership of the Expert Curation Panel as well as other key group members, including a project coordinator and clinical and informatics curators who will provide support for the Expert Curation Panel. Describe the membership of the Expert Curation Panel that will select and evaluate the clinical relevance of genes/variant to be curated. Include details about how each member will contribute to establishing the clinical actionability of the genes/variants being curated.

3. Provide a description of how you will ensure that the panel reflects multiple institutions and takes into account work within the international context.

4. Describe how the Expert Curation Panel will carry out its functions. Based on the number of genes or variants proposed, determine whether individual working groups focused on specific subsets of genes or variants will be established, and how these will be related to the Expert Curation Panel. Describe the work of these subgroups, key members that will provide oversight and those undertaking the process of curation. Ensure that there is adequate biocuration and operations staffing to accomplish the outlined goals of the expert panel. Include information about staff who will support the group and planned interactions with ClinGen.

5. Describe the procedures for gene-disease/gene variant assessments utilizing the ClinGen/ClinVar procedures and interfaces. Include the gene-disease/variant curation guideline development, curation review process and policies for resolving differences.

6. Describe the ClinGen training to be undertaken by the PI, experts, coordinator, curators, the curation summaries prepared by curators, the process by which they will be reviewed by the Expert Curation Panel rules, and the process used by the Expert Curation Panel for decision making. Provide a plan for work-flow and timeline.

7. Describe plans for regular Expert Curation Panel meetings both remote and face-to-face. At least one annual in-person meeting is recommended. Scheduling this meeting either at a regularly attended professional meeting or in conjunction with the annual Curating the Clinical Genome (https://www.clinicalgenome.org/about/events/curating-the-clinical-genome-2019/)meeting is encouraged.

8. Describe plans for integration with ClinGen working groups and curation activities.

9. Describe plans for interaction with ClinGen and participation in the relevant working groups, including the Coordinators, Curators, and Bioinformatics ClinGen working groups, monthly ClinGen webinars and attend the annual face to face meetings, e.g., Curating the Clinical Genome Conference.

10. If this is an application from an existing Expert Panel, provide a justification for the need for this panel, e.g. different group of genes.

Letters of Support:

Letters of support from Expert Curation Panel members who are not listed as key personnel should be included in the Letters of Support Section.

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 Expert Curation Panels, regardless of the amount of direct costs requested for any one year, are required to collaborate with ClinGen and ClinVar utilizing the ClinGen suite of curation interfaces and tools and to submit their underlying data to these resources in order to share data with the field. Applicants must describe plans for doing so in the Data Sharing Plan.

Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide. When involving human subjects research, clinical research, and/or NIH-definedclinical 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.

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, NIH. Applications that are incomplete or non-compliant will not be reviewed.

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

Section V. Application Review Information

1. Criteria

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

For this particular announcement, note the following:

The U24 mechanism invites applications to support research projects contributing to improvement of the capability of resources to serve biomedical research. The Genomic Expert Curation Panels provide an infrastructure within which panel members are able to utilize the tools developed by ClinGen and ClinVar to determine the clinical significance of individual genes and genomic variants to diseases or disorders of high priority to the participating ICs. Accordingly, the review will emphasize whether the Expert Curation Panels have the breadth of expertise and institutional representation to assess the clinical actionability of the genes and/or variants they have selected. Reviewers should also assess how well the Expert Curation Panels will utilize the ClinGen/ClinVar curation resources in their determination of clinical significance. Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed). Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

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 curation of the genes/variants selected make a significant contribution toclinical practice?

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?

Does the Expert Panel membershipinclude broad institutional and technical representation? Is there international representation? Is there adequate staffing to support the curation process?

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?

Howwell have the applicants described their utilization of the ClinGen/ClinVar procedures and suite of tools for curating genes/variants? For existing Expert Curation Panels, is the justification adequate for continued support, e.g. new group of genes/variants associated with the conditions being currently curated?

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?

Protections for Human Subjects

For research that involves human subjects but does not involve one of thecategories 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

Not Applicable

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 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:

• 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.

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. 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 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.

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.

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.

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.htmlhttps://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.htmlor 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.

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:

• Accept close coordination, cooperation, and participation of the NIH staff in the aspects of scientific and technical management of the project as described below.
• Ensure that all goals of the Genomic Expert Curation Panel are met.
• Ensure effective interaction and coordination among Expert Curation Panel Members, ClinGen, ClinVar staff and the NIH staff.
• Adhere to the NIH policies regarding intellectual property, data release and other applicable resource sharing policies as appropriate.
• Accept and participate in the cooperative nature of the ClinGen and ClinVar programs.
• Deposit gene and variant calls to ClinGen/ClinVar as appropriate and consistent with achieving the goals of the program.
• Awardees will retain custody of and have primary rights to the data 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:

Project Scientist(s) -- NIH staff will have the role of Project Scientist(s) through technical assistance, advice, and coordination. The Project Scientists' responsibilities are defined as follows:

• Participate in the group process of setting project priorities and making decisions on joint activities and standard practices within each Genomic Expert Curation Panel. The Project Scientist(s) will assist and facilitate the group process but not direct it.
• Negotiate goals and timelines with the awardees, as necessary.
• Serve as liaisons between the awardees, ClinGen, NIH, and the larger scientific community in helping the Genomic Expert Curation Panels to achieve their goals.
• Coordinate the efforts of the Genomic Expert Curation Panel with ClinGen, ClinVar and others engaged in similar and related activities.
• Serve on subgroups of the Genomic Expert Curation Panels as appropriate.
• Where warranted, co-author publications about the goals of this FOA, and of results of studies funded under this FOA.

Program Official Additionally, an Institute Program Official will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice. The Program Official will:

• Approve progress of award.
• Retain the option of recommending termination of project activities if they cannot be effectively pursued in a timely manner.
• Retain the option to recommend additional project activities by the Expert Panel within the constraints of the approved research and negotiated budget.

Areas of Joint Responsibility include:

None; all responsibilities are divided between awardees and NIH staff as described above.

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 arbitration. An Arbitration Panel composed of three members will be convened. It will have three members: a designee of the Genomic Expert Curation Panel 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 awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulations 42 CFR Part 50, Subpart D and HHS regulations 45 CFR Part 16.

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 agreementsare 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. eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threatensubmission 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:[email protected](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:[email protected]

Melissa A. Parisi, MD, PhD
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-435-6880
Email: [email protected]

Melissa Rotunno
National Cancer Institute (NCI)
Telephone: 240-276-7245
Email:[email protected]

Jonathan Pevsner, PhD
National Institute of Mental Health
Telephone: 301-728-5618
Email: [email protected]

Vicky Whittemore
National Institute of Neurological Disorders and Stroke
Telephone: 301-496-1917
Email: [email protected]

Grace Shen, Ph.D.
National Eye Institute (NEI)
Telephone: (301) 451-2020
Email: [email protected]

Baishali Maskeri, PhD
Center for Scientific Review (CSR)
Telephone: 301-827-2864
Email: [email protected]

Bryan Clark
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-435-6975
Email: clarkb1@mail.nih.gov

Terri Jarosik
National Institute of Mental Health (NIMH)
Telephone: 301-443-3858
Email: [email protected]

Chief Grants Management Officer
National Institute of Neurological Disorders and Stroke (NINDS)
Email: [email protected]

Karen Robinson-Smith
National Eye Institute (NEI)
Telephone: (301) 451-2020
Email: [email protected]

Section VIII. Other Information

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