It is critical that applicants follow the instructions in the Research Instructions for 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.

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

With the completion of the human genome project and advances in genomic sequencing technologies, clinical genetic testing is becoming increasingly routine in clinical practice. Genome-scale sequencing inevitably leads 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 the 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 function.

The lack of an openly accessible database that captures genetic variants, their phenotypic and functional effects, and other clinical information has been a limiting factor in the clinical and research use of variant information. Recently, NIH has initiated a clinical genomics infrastructure to develop an openly accessible knowledge base to gather information and provide the structure for determining the clinical actionability of genetic variants through two initiatives: the Clinical Genomics Resources (ClinGen) supported by NHGRI, NCI and NICHD and the NLM database of clinical variation (ClinVar). ClinVar and ClinGen have formed a critical partnership to improve our knowledge of clinically relevant genomic variation. This partnership includes significant efforts in data sharing, data archiving, and collaborative curation to characterize and disseminate the clinical relevance of genomic variation. ClinVar is a publically and freely available database that aggregates information about genomic variation and its relationships to human health (http://www.ncbi.nlm.nih.gov/clinvar/). ClinGen is a central resource that defines the clinical relevance of genes and variants for use in precision medicine and research by standardizing clinical annotation and interpretation of variants and implementating evidence-based expert consensus for curation of their clinical validity and actionability (https://www.clinicalgenome.org/). This integrated infrastructure has been designed to support disease/disorder specific working groups to determine the clinical applicability of genes and/or variants utilizing genomic, clinical, and functional data. ClinGen has developed a Clinical Validity framework for identifying and assigning the level of evidence to support determination of a gene-disease relationship for variants, including utilizing variants that that are deposited into the ClinVar database. Although the framework will continue to evolve, the current framework includes five evidence levels ranging from: 1) definitive, where the role of the gene in this particular disease has been repeatedly demonstrated in both research and clinical diagnostic settings and has been upheld over time; 2) strong, where the role of the gene has been independently demonstrated in at least two separate studies; 3) moderate, where at least 3 unrelated probands with variants provide convincing evidence for disease causality and/or moderate experimental data supports the gene-disease association; 4) limited, where there is limited evidence to support a causal role with fewer than 3 observations of variants or limited experimental data and 5) no evidence reported. Finally, the framework includes an opportunity to address situations where conflicting evidence has been reported. The framework can be found at https://www.clinicalgenome.org/site/assets/files/2657/current_clinical_validity_classifications.pdf.

Sharing of genomic data is critical for the determination of clinical actionability of a gene or its variant. To that end, ClinVar is a submission-driven database that can receive submissions of varying complexity ranging from primary submitters for a single variant to assertions of clinical actionability prepared by expert panels. To date, over 209,000 records have been submitted to ClinVar. ClinVar utilizes a four star rating system for users of ClinVar to have additional information with regard to the level of review of the submissions. By default, ClinVar submissions have the review status single submitter - criteria not provided. However, submissions may obtain the status of single submitter - criteria provided, "expert panel," and "practice guideline." Each level requires accompanying evidence that is transparently and systematically evaluated (for information see: https://www.clinicalgenome.org/expert-groups/).

ClinGen has developed the infrastructure to aid expert groups in their determination of clinical applicability or actionability of specific gene/variant disease pairs through a user interface. This interface includes tools to ensure transparency by reviewers and a standardized method for data reporting. These tools include the gene validity classification system, clinical validity curation spreadsheet (https://www.clinicalgenome.org/working-groups/gene-curation/) and a pathogenicity calculator (http://calculator.clinicalgenome.org/site/cg-calculator). These tools have been tested by ClinGen-established expert panels that review gene/variants in cardiovascular diseases, cancer, inborn errors of metabolism and pharmacogenomics. This systematic process for analyzing supporting evidence also enables the uniform and streamlined compilation and presentation of the met criteria that facilitate review by expert panels, enable automated alerts when new evidence might cause a change in the clinical validity assessment, and provide consistency within the field.

Significant progress is being made in identifying genes of clinical relevance to NICHD. These include genes associated with reproductive and gynecological health, poor pregnancy outcomes, high risk newborn conditions, structural birth defects, intellectual and developmental disabilities, and susceptibility to infection. The ClinGen/ClinVar framework is available to be applied to assess the clinical actionability of genes and variants for conditions of priority to NICHD.

This FOA invites applications to establish Genomic Clinical Variant Expert Curation Panels. These panels will select clinical domains of high priority to NICHD, select candidate genes that will have a high impact on clinical practice in these high priority areas, analyze all relevant data utilizing the ClinGen resource tools and establish the clinical actionability of individual genes and/or variants to support clinical practice. For the purpose of this FOA, genes and variants should be associated with but not limited to: reproductive and gynecological health; poor pregnancy outcomes; high risk newborn conditions; intellectual and developmental disabilities; and susceptibility to infection. The Expert Curation Panels are expected to collaborate with the open databases ClinGen and ClinVar utilizing the ClinGen tools and submit their underlying data to these resources in order to share data with the field. Training on these tools will be provided by ClinGen staff for new curation groups. NICHD Expert Curation Panel PD/PIs and key staff will be expected to participate in ClinGen working groups and share curation procedures and outcomes with ClinGen and ClinVar.

The scope of this FOA is to establish Genomic Clinical Variant Expert Curation Panels in domains of high priority to NICHD that will select and review genes and their variants within the specified domain utilizing the procedures and tools developed by ClinGen and ClinVar, which have the potential for clinical applicability. The role of the expert panel is to evaluate the strength of evidence supporting the clinical significance or actionability of the selected genes to support clinical practice and submission to ClinVar.

1. Expert Panels are expected to focus on a clinical domain area within the scope of NICHD priorities that includes but is not limited to curation of variants associated with reproductive and gynecological health; poor pregnancy outcomes; high risk newborn conditions; structural birth defects; intellectual and developmental disabilities; and susceptibility to infection.

2. 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 Panel. If the gene(s) are already being examined by another expert panel then joint efforts with the existing panel should be established or justify the necessities of another panel.

3. 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/or co-chair (if needed). It is recommended that expert panels include medical professionals caring for patients relevant to the clinical domain 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 panels should represent multiple institutions, 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.

4. Expert Panels should be supported by staff members who will assist the curation process. This includes curation scientists, such as clinical fellows, genetic counselors, or researchers in the field, as well as bioinformatics specialists. This staff is expected to utilize ClinGen rules and tools to review existing information preparing summary materials for Expert Panel decision making. Experience with other expert curation panels indicates that the most successful groups have bioinformaticians and curation scientists, e.g. clinical fellows, genetic counselors, or researchers who undertake the initial curation that is then reviewed by the expert panel.

5. 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 ClinGen/Decipher meeting is encouraged.

6. Utilizing the ClinGen/ClinVar framework (https://www.clinicalgenome.org/working-groups/gene-curation/), Expert Panels are expected to define standard operating procedures for gene/variant assessment including variant assessment protocols, curation and review processes and policies for resolving differences. These standard operating procedures are expected to be based on ClinGen protocols and be shared with ClinGen. Training for use of ClinGen/ClinVar tools will be available through ClinGen either via webinars or in person. Expert curation panels are expected to deposit gene and variant calls and curation tools into the ClinGen/ClinVar interface.

7. The chair of the Clinical Variant Curation Panel, leaders of specific gene working groups, and key curation staff are expected to participate in ClinGen working groups, participate in monthly ClinGen webinars and attend the annual ClinGen/Decipher meeting.

8. Prior to submission of applications to this FOA, 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.

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

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made in response to this FOA.

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) (formerly CCR) 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 and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. 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.

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

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).

Buttons to access the online ASSIST system or to download application forms 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.

It is critical that applicants follow the instructions in the Research Instructions for the SF424 (R&R) Application Guide, including Supplemental Grant Application Instructions 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.

For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

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:

Danuta Krotoski, Ph.D.
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-496-5576
Email: krotoskd@mail.nih.gov

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 Panel chair and under exceptional circumstances the co-chair. Other panel experts can receive nominal consulting fees. In addition, funds can be used for meeting support including webinars and travel to face-to face meetings. It is expected that the PD(s)/PI(s) should attend the annual ClinGen/Decipher meeting and the PD(s)/PI(s) and key panel members and staff may participate in relevant ClinGen working groups as appropriate. A primary emphasis of the budget should be on supporting a project coordinator, biocurator(s) and bioinformatics specialist(s). Costs associated with training on ClinGen tools, development of ClinGen informatics interface, and integration with ClinGen/ClinVar should be included in the budget as consulting fees.

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 NICHD priorities 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 Panel as well as other key group members, including a project coordinator and clinical and informatics curators who will provide support for the Expert Panel. Describe the membership of the Expert Panel that will select and evaluate the clinical actionability 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. It is expected that the panel will reflect multiple institutions/organizations and takes into account work within the international context.

4. Describe how the Expert 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 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. If the gene(s)/variants are already being examined by another expert panel, justify the need for an additional panel or provide a plan for collaborative efforts.

6. Describe the standard operating procedures for gene-disease/gene variant assessments utilizing the ClinGen/ClinVar framework. Include the gene-disease/variant assessment protocol, curation and review process and policies for resolving differences. Describe the curation summaries prepared by curators, the process by which they will be reviewed by the Expert Panel rules, and the process used by the Expert Panel for decision making. Provide a plan for work-flow and timeline.

7. Describe plans for regular Expert 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 ClinGen/Decipher meeting is encouraged.

8. Describe plans for integration with ClinGen curation activities including plans for training on ClinGen curation procedures, sharing of gene and variant calls and curation tools into the ClinGen/ClinVar interface, and participation on ClinGen Clinical Domain, Biocurator and Informatics Working Groups.

9. Describe plans for interaction with ClinGen by the chair of the clinical domain expert panel and leaders of specific gene working groups to participate in ClinGen working groups, participate in monthly ClinGen webinars and attend the annual ClinGen/Decipher meeting.

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, with the following modification:

All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan and include plans for deposition of underlying variant calling data to ClinVar.

Appendix: Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

When conducting clinical research, follow all instructions for completing PHS Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

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

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.

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

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.

This initiative is not subject to intergovernmental review.

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

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

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 Applying Electronically. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues. 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.

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-13-030.

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research 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 NICHD Clinical Genomic Variant 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 NICHD. 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.

Does the project address an important problem or a critical barrier to progress in the field? Is there a strong scientific premise for the project? 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?

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or 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?

Do the investigators have appropriate experience and training, and have they demonstrated an ongoing record of accomplishments in managing clinical genetics programs or projects? Do the investigators demonstrate significant experience with coordinating collaborative basic and/or clinical research? Does the project include appropriate biocurator and bionformatics expertise? Will the proposed plan for forming the Expert Curation Panels and affiliated work groups reflect the breadth of expertise and institutional representation needed to assess the clinical actionability of the genes and/or variants they will select?

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

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators 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? Are an appropriate plan for work-flow and a well-established timeline proposed?

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 children, justified in terms of the scientific goals and research strategy proposed?

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?

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.

For research that involves human subjects but does not involve one of the six 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 six 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.

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 children 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.

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.

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.

Not Applicable

Not Applicable

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.

Not applicable

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).

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).

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.

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

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s), convened by NICHD, 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 Child Health and Human Development (NACHHD) Council. 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.

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.

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.

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 http://www.hhs.gov/ocr/civilrights/resources/laws/revisedlep.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and http://www.hhs.gov/ocr/civilrights/understanding/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at http://www.hhs.gov/ocr/office/about/rgn-hqaddresses.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.

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:

• 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 Variant Expert Curation Working Groups are met.
• Ensure effective interaction and coordination among Working Group 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.
• Coordinate and collaborate with the ClinGen and ClinVar Program as described above.
• 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 NICHD Genomic Clinical Variant 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 Clinical Variant Expert Curation Panels to achieve their goals.
• Coordinate the efforts of the NICHD Genomic Clinical Variant Expert Curation Panel with ClinGen, ClinVar and others engaged in similar and related activities.
• Serve on subgroups of the NICHD Genomic Clinical Variant 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 Clinical Variant 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.

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 progress report, 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.

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 registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, 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)

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact Center Telephone: 800-518-4726
Web ticketing system: https://grants-portal.psc.gov/ContactUs.aspx
Email: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-710-0267

Danuta Krotoski, Ph.D.
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-496-5576
Email: krotoskd@mail.nih.gov

Sherry Dupere, Ph.D.
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-496-1485
Email: duperes@mail.nih.gov

Bryan S. Clark, MBA
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-402-0915
Email: clarkb1@mail.nih.gov

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.