Part 1. Overview Information

Key Dates

All applications are due by 5:00 PM local time of applicant organization.

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

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 NOFO or in a Notice from NIH Guide for Grants and Contracts).

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

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

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

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



Table of Contents
Key Dates
Part 2. Full Text of Announcement
Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

Background

Undiagnosed diseases are defined as long-standing symptoms or elusive medical conditions that have not been diagnosed despite extensive clinical evaluation. Undiagnosed diseases are often due to rare conditions and can include: 1) not recognized, previously described diseases due to very low incidence or prevalence; 2) yet-to-be-described disorders; and 3) rare variations of more common diseases. These conditions present difficult problems for patients, their families, and physicians resulting in a high emotional, physical, and financial burden to patients who may spend many years seeking a diagnosis and path to treatment. Diagnoses in these difficult cases require teams of clinicians and scientists with a wide variety of special expertise. Scientific advances springing from these diagnoses require an organized approach to testing, data analysis, and validation in patients with similar rare conditions or in model organisms.

In 2008, the NIH established an intramural Undiagnosed Diseases Program (UDP) to aid individuals plagued by longstanding medical conditions that elude medical diagnosis. Using a team science approach, comprehensive clinical phenotyping and cutting-edge diagnostic and genomic technologies, the UDP was successful in ending the diagnostic odyssey for many individuals with rare, challenging, and difficult-to-diagnose diseases. Based on the success of the UDP, the NIH Common Fund announced in 2012 an expansion of the UDP to form a nation-wide network the Undiagnosed Diseases Network (UDN) - composed of the NIH UDP and extramural Clinical Sites. Phase I (FY2013-2017) of the UDN included seven Clinical Sites including the UDP, a Coordinating Center, and Core Laboratories to facilitate diagnoses (genome sequencing, testing variants in model organisms, metabolomics, and a biorepository). In Phase II (FY2018-2022), the number of Clinical Sites was expanded to twelve. Since the launch of Phase I, the UDN has been very successful in achieving its objectives by: providing over 600 diagnoses; discovering hundreds of novel disease-associated genes and genomic variants, including new diseases and syndromes; and building an international reputation for establishing exemplary clinical practices, standards, and pipelines for genomics-based diagnoses.

In Phase II, the network was tasked to develop a framework that would continue the mission of the UDN after NIH Common Fund support ends in 2023. To have a broader impact on the clinical practice of undiagnosed diseases in the United States (US), the NIH envisions the UDN evolving into a larger, self-sustained network that, with public and private partners, can provide expert diagnostic services for undiagnosed patients across the nation and foster scientific discovery. The network will also seek to implement strategies that will expand equity and access to health disparity populations. In this new model, the new Network (henceforth referred to as the Network in this NOFO) will consist of an NIH-supported Data Management Coordinating Center (DMCC), the UDP, highly qualified and collaborative clinical sites, patients with undiagnosed diseases (referred to as participants in this NOFO), patient advocacy groups, and the NIH and other stakeholders including external funding providers and/or resource providers (e.g., Cores or private partnerships that conduct genomics sequencing, gene function studies or other diagnostic services).

The purpose of this NOFO is to solicit proposals from highly qualified clinical sites in the US to join the Network through an X01 Resource Access Program award. Accepted sites will be designated as a Diagnostic Center of Excellence (DCoE) and will be responsible for generating participant clinical, phenotypic and sequencing data to be submitted to the DMCC through a Data Use Agreement with the Center. X01 recipients will have access to DMCC resources and infrastructure including access to high-quality phenotypic and genotypic data and collaboration with highly skilled physicians, researchers, and bioinformaticians. Using team science, DCoEs will be able to collaborate with Network members to implement strategies that will expand equity and access to health disparity populations and increase the discovery of new disease-associated genes and genomic variants, immunologic and metabolic abnormalities, as well as environmental insults that are causative in previously undiagnosed patients. DCoEs will be invited to submit their most challenging, unsolved cases for acceptance into the Network, and partner in their evaluation with the Network’s virtual case review committee(s), which will be coordinated by the DMCC.

Successful applicants will demonstrate that they have the appropriate expertise and a track record of diagnosing rare and difficult-to-diagnose disorders, along with the infrastructure and resources needed to conduct the clinical evaluation and DNA sequencing of participants enrolled at their sites. Specifically, applicants will be expected to demonstrate the expertise, independent resources (e.g., institutional support, plans for billing insurance, obtaining support from outside partnerships, etc.), and capacity to:

• Enroll a minimum of 5 participants per year who are accepted into the Network, although some sites may have the capacity to enroll more participants. Typically, only the most difficult, unsolved cases will be accepted into the Network (e.g., those cases requiring specialized, non-routine diagnostic testing procedures or collaboration among a team of clinicians and researchers).
• Perform comprehensive clinical evaluations of undiagnosed participants enrolled at their site including medical record review, routine and specialized diagnostic testing procedures, consultations, and referral to other sites with necessary expertise if appropriate.
• Have the resources (in-house or outsourced) to perform DNA and/or RNA sequencing and re-analysis of existing genome-sequencing data.
• Capability to work with Network data stored in a cloud architecture, such as AnVIL.
• Have the genomics capability including medical genetics and associated informatics expertise needed to identify pathogenic variants from human genomics sequence data. This includes the infrastructure to return genetic results to study participants and provide post-test genetic counseling.
• Demonstrate sufficient clinical metabolomics and other omics expertise to interpret or re-interpret lab and research-grade findings.
• Have sufficient clinical staff to review medical records from applicants (so as to enroll a minimum of five cases per year into the Network) and to rigorously discuss the results to arrive at a diagnosis or to interrogate candidate genes.
• Collect and store DNA, fibroblasts from skin biopsies, and other biological specimens produced by clinical evaluations as needed for the diagnosis.
• Organize incoming records and return results to participants, family members, and referring physicians.
• Support a site coordinator or equivalent position to serve as the DCoE’s point of contact for data sharing, case coordination, collaboration, data retrieval for research projects and patient follow-up.

Additional Information

(1) The X01 mechanism does not provide budgetary support for the proposed activities. Successful X01 applications will receive access to DMCC resources and Network data (discussed above), and will have the option to apply for small research grants issued by the DMCC as subawards to DCoE sites (see: RFA-NS-22-051 for more information). The DMCC will provide at least $500,000 Direct Costs (DC) in year 1 and $1M DC per year in years 2-5 to support Network research activities. The subawards (typically in the range of $25-50K DC each) are intended to support: 1) some of the DCoEs costs associated with on-site coordination and submitting data to the Network; and 2) pilot research projects such as very early-stage gene function studies in model systems and clinical genomics/metabolomics investigations that are needed to facilitate a participant’s diagnosis. Subawards cannot support clinical trials.

(2) Successful applicants to this NOFO will be expected to incorporate the Network’s infrastructure and operational procedures into their proposed study plans, including coordination, collaboration, and data management through the DMCC and signing onto any agreements or Memoranda of Understanding established by the Network Steering Committee in the next phase of the UDN (see Network Governance below). In addition, DCoEs will be expected to work with the DMCC and Steering Committee to develop Network protocols, a Manual of Operations, and participate in Steering Committee, Case Review, diagnostic consultation, and Working Group meetings as established by the Steering Committee.

(3) Successful applicants will be required to consent participants and use a single-IRB managed by the NIH UDP that is consistent with NIH’s Single IRB Policy as described in NOT-OD-16-094 to ethically review Network-wide protocols involving human subjects research.

(4) To gain access to DMCC resources, X01 recipients will be required to submit relevant participant datasets generated at their Site (e.g., clinical, phenotypic, genomic, environmental, covariates, metadata, etc.) to the DMCC through a Data Use Agreement with the Center. The Network’s Steering Committee will develop and implement Network-wide approaches for data submission from DCoEs and timelines including data standards and formatting requirements, along with standards for data use by Network members. The DMCC is responsible for submitting de-identified data to national repositories as required in RFA-NS-22-051.

(5) DCoEs are encouraged to use innovative approaches that increase the efficiency, yield, and cost-effectiveness of the diagnosis (e.g., remote visits, tiered evaluation strategies, use of innovative tools or strategies for record review, etc.), while still providing a comprehensive and expeditious clinical evaluation.

(6) Although DCoEs are encouraged to enroll participants with disorders in any clinical specialty (similar to current UDN operations: UDN Manual of Operations), sites have the option to specialize in one or more areas of clinical practice (e.g., pediatrics, neurology, cardiology, gastroenterology, immunology, metabolism, environmentally-linked or infectious diseases, etc.).

(7) Applicants are strongly encouraged to enroll participants from health disparity populations and/or to partner with medical institutions that serve under/uninsured and health disparity populations.

Network Governance.

Network governance will be managed by the Steering Committee, with advice from an External Advisory Committee. The External Advisory Committee will be named by the NIH and the Network Steering Committee (members defined below) and will serve in an advisory capacity by reviewing network activities and making recommendations to the Steering Committee, the NIH and other stakeholders regarding process and substantive issues that arise during network operations. The Network Steering Committee may establish subcommittees and working groups to facilitate development, implementation, and monitoring of specific Network functions as needed.

The Network Steering Committee will be composed of the following voting members:

• The contact PD/PI of NIH-awarded DCoEs and the UDP PI
• The contact PD/PI of the DMCC
• A representative from the participating undiagnosed diseases patient advocacy group(s). The patient advocacy groups will have one collective vote
• NIH Program Official(s)/Projects Scientist(s) from participating Institutes. NIH will have one collective vote
• As the Network evolves, other key stakeholders may be invited to serve on the Steering Committee as appropriate (e.g., outside funding or resource partners)

The Network Steering Committee will identify scientific and policy issues that need to be addressed at the network level, as well as broad issues in the field of rare, undiagnosed diseases research that can be addressed by the Network. It will also ensure dissemination of undiagnosed diseases clinical practice and research knowledge to the wider scientific community.

Applications Not Responsive to this NOFO

Applications that propose clinical trials will be considered non-responsive and will not be reviewed.

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 NOFO.

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)

Local Governments

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

Federal Government

• 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.

• System for Award Management (SAM) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
  • NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
  • Unique Entity Identifier (UEI)- A UEI is issued as part of the SAM.gov registration process. The same UEI must be used for all registrations, as well as on the grant application.
• eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their Grants.gov registration; all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with their organization to develop an application for support. Individuals from diverse backgrounds, including underrepresented racial and ethnic groups, individuals with disabilities, and women are always encouraged to apply for NIH support. See, Reminder: Notice of NIH's Encouragement of Applications Supporting Individuals from Underrepresented Ethnic and Racial Groups as well as Individuals with Disabilities, NOT-OD-22-019.

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.

Applications for the X01 DCoE award may be submitted by individuals located at the same institution as an applicant or PD/PI of the DMCC [submitted under RFA-NS-22-051: Data Management Coordinating Center for Diagnostic Centers of Excellence (U2C Clinical Trial Not Allowed) ], but an individual may not be the PD/PI of both a DCoE and the DMCC. An applicant organization will not be awarded more than one DCoE that is active at the same time (either through this X01 PAR, RFA-NS-23-004 [Limited Competition for the Continuation of Clinical Sites for the Undiagnosed Diseases Network (U01 Clinical Trial Not Allowed)], or future NIH funding announcements that support UDN DCoEs).

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

Only one application per institution (normally identified by having a unique UEI or NIH IPF number) is allowed.The NIH will not accept duplicate or highly overlapping applications under review at the same time, per 2.3.7.4 Submission of Resubmission Application. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see 2.3.9.4 Similar, Essentially Identical, or Identical Applications)

Section IV. Application and Submission Information

1. Requesting an Application Package

The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this NOFO. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide except where instructed in this notice of funding opportunity 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:

Argenia Doss
Telephone: 301-827-1373
Email: argenia.doss@nih.gov

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

For this specific NOFO, the Research Strategy section is limited to no more than 6 pages.

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

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

Total Federal Funds Requested: Enter $0.

Total Federal & Non-Federal Funds: Enter $0.

Estimated Program Income: Enter $0.

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

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

Facilities and Other Resources:

In addition to the information required in the standard instructions, applicants should describe the relevant institutional facilities, resources and services that can be leveraged for accomplishing the goals of the proposed program and Network (e.g., informatics/computational platforms, data storage and security resources, consultative and statistical resources, communication platforms, etc.).

Other Attachments: Applicants must provide the following additional materials in support of their application. The attachment must be uploaded as a separate PDF using the indicated filenames (which will serve as application bookmarks). Applications that do not include this attachment will be considered incomplete and will not be reviewed.

Attachment (Required - 2 pages maximum): Applicants should describe existing or planned resources available to the applicant, such as clinical and laboratory facilities, institutional support, plans for billing third party payers, private funding sources, federal grants, or resource partnerships, etc., that will be leveraged to conduct the clinical evaluation of participants and support the associated diagnostic costs [use file name External Sources of Support ].

In addition, a table must be included that lists the external sources of support or resources to be used to perform the activities listed below, including the dollar amount and length of each commitment (start and end date of the support or partnership) if applicable:

• Clinical evaluation of enrolled participants including routine and specialized diagnostic testing procedures, consultations with other clinicians and specialists, return of information to participants, counseling and referrals for participants, etc.
• Review of medical records from applicants (so as to enroll a minimum of five cases per year into the Network) and ensuring sufficient clinical staff time to discuss medical records and associated test results to arrive at a diagnosis or develop a diagnostic strategy.
• DNA sequencing (whole genome and/or exome), and staff time for re-analysis of existing genome-sequencing data if needed.
• Support for a site coordinator (or equivalent position) to serve as the DCoE’s point of contact for data sharing, case coordination, collaboration with the Network, data retrieval for research projects, coordinating site IRB requirements and participant consent, patient follow-up and return of information to referring physicians, etc.
• Participation in Network activities as described in Section I. Funding Opportunity Description (Additional Information, bullet #1), including protected time for key personnel to attend Network meetings.

Applications that do not include this table will not be reviewed.

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

Include a single Biographical Sketch for each Senior/Key person listed in the application.

Address the following elements in the relevant Biographical Sketches:

• Knowledge and prior experiences of the PD(s)/PI(s) and key personnel in leading and managing projects involving the clinical practice and research of rare and undiagnosed diseases.
• Clinical expertise in managing and diagnosing patients with difficult-to-diagnose conditions including expertise and knowledge of advanced diagnostic testing strategies, detailed clinical phenotyping, DNA sequencing, clinical genomics/metabolomics and other specialized clinical and laboratory testing used to diagnose challenging cases; include specialties/subspecialties of physicians if applicable.
• Expertise in medical genetics including bioinformatics expertise to identify pathogenic variants from human DNA sequence data and other clinical genomics, metabolomics, immunologic and/or exposome investigations.
• Provide examples where the PD(s)/PI(s) collaborate with teams of scientists to make difficult diagnoses and disseminate findings to network members and/or the broader undiagnosed/rare disease research community.

R&R Budget

Not Applicable

R&R Subaward Budget

Not Applicable

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:

Specific Aims: The Specific Aims should refer directly to the X01 request and should clearly and concisely describe the potential impact of the proposed research.

Research Strategy

Describe any prior experience and success of your site in: recruiting, enrolling and completing the evaluation of participants with rare and/or difficult-to-diagnose disorders, including those from health disparity populations. Describe your site’s track record of success in diagnosing rare and difficult-to-diagnose disorders.

Provide a timeline to recruit, enroll, and complete the clinical evaluation of at least 5 affected Network participants per year, including the number of individuals your site expects to enroll from health disparity populations. Note: in the Planned Inclusion Enrollment Report (in PHS Human Subjects and Clinical Trials Information), include only affected individuals (not family members).

In addition, describe the overall strategy, methodology, analyses, and independent resources (e.g., institutional support, plans for billing insurance, obtaining support from outside partnerships, etc., as described and depicted in the required table in Facilities and Other Resources) to be used to accomplish the specific aims of the project, including how the following will be accomplished:

• Performing comprehensive clinical evaluations, consenting, medical record review, routine and specialized diagnostic testing procedures, clinical metabolomics and other omics expertise to interpret or re-interpret lab findings, consultations, genetic counseling, return of results to participants, and referral to other sites with necessary expertise if appropriate.
• Conducting DNA and/or RNA sequencing (in-house or outsourced) if appropriate including having associated informatics and medical genetics expertise needed to identify pathogenic variants from human genomics sequence data; describe other specialized or advanced diagnostic testing procedures available at your site (e.g., for diagnosing immunologic and metabolic abnormalities, environmental insults that may be causative in previously undiagnosed patients).
• Collecting and storing DNA, fibroblasts from skin biopsies, and other biological specimens produced by clinical evaluations as needed for the diagnosis.
• Describe bioinformatics approaches to be used including innovative strategies capable of identifying rare and novel diagnoses. Include plans for how bioinformatics infrastructure, capabilities, and computational resources in place (or readily obtainable) as described in Facilities and Other Resources will be leveraged.
• Describe plans including outreach efforts to recruit and enroll participants from health disparity populations and/or to partner with medical institutions that serve under/uninsured and health disparity populations.
• Describe unique strengths such as systems- or disease-specific clinical expertise available at your site, including the specific area(s) of clinical practice that your site intends to pursue.
• Describe approaches to increase the efficiency, yield, and cost-effectiveness of the diagnosis (e.g., remote visits, tiered evaluation strategies, use of innovative tools or strategies for record review, etc.), while still providing a comprehensive and expeditious clinical evaluation; and willingness and approach for making such expertise available Network-wide.

To gain access to DMCC resources, X01 recipients must agree to submit all relevant participant datasets generated at their Site (e.g., clinical, phenotypic, genomic, environmental, covariates, metadata, etc.) to the DMCC through a Data Use Agreement with the Center. The Network’s Steering Committee will develop and implement Network-wide approaches for data submission from DCoEs and timelines including data standards and formatting requirements, along with standards for data use by Network members. The DMCC is responsible for submitting de-identified data to national repositories as required in RFA-NS-22-051.

Integration and collaboration are essential to the success of the Network. Applicants should describe their willingness and plans to:

• Adhere to Network-wide policies and procedures for the key DCoE functions (described above and in Section I. Funding Opportunity Description) including Network-defined timelines for: recruitment and enrollment of participants into the Network; data collection, and accurate submission of data and scientific variables such as phenotype, genotype, and environmental exposures data to the DMCC.
• Participate in and abide by Network Steering Committee decisions (as outlined in Section 1. Funding Opportunity Description), Data Use Agreements, Memoranda of Understanding or other agreements potentially needed for data and resource sharing within and outside the Network.
• Collaborate with the DMCC, other DCoEs, and Network members to develop and implement Network protocols, a Manual of Operations, and participate in Steering Committee, Case Review, diagnostic consultation, and Working Group meetings as established by the Steering Committee.
• Participate in a Network that uses a single IRB managed by the NIH UDP.

Assessment, Dissemination, and Outreach

Applicants are encouraged to propose a plan to collaborate with the DMCC and other DCoEs to assess and disseminate data, protocols, consent materials, and methods developed by the Network. Examples include:

• Collaborating with the DMCC to develop and implement appropriate educational and outreach materials for participants, clinicians, and other researchers in the field of undiagnosed diseases research.
• Conducting training activities at your site to expose students, fellows, staff, and faculty to the Network model.

Letters of Support: Institutional and other external commitments proposed in application to fund or support the clinical evaluation, diagnostic testing, DNA sequencing, evaluation of uninsured participants, and sustaining the program beyond this grant award support are encouraged.

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.

Other Plan(s):

Note: Effective for due dates on or after January 25, 2023, the Data Management and Sharing Plan will be attached in the Other Plan(s) attachment in FORMS-H application forms packages.

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

• A Data Management and Sharing Plan form is not applicable for this NOFO.

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

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

Study Record: PHS Human Subjects and Clinical Trials Information

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

In the Planned Inclusion Enrollment Report(s), only include affected individuals (i.e., the probands and not family members).

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.

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

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.

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 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 form. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this NOFO for information on registration requirements.

The applicant organization must ensure that the unique entity identifier provided on the application is the same identifier used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the 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.

Use of Common Data Elements in NIH-funded Research

Many NIH ICs encourage the use of common data elements (CDEs) in basic, clinical, and applied research, patient registries, and other human subject research to facilitate broader and more effective use of data and advance research across studies. CDEs are data elements that have been identified and defined for use in multiple data sets across different studies. Use of CDEs can facilitate data sharing and standardization to improve data quality and enable data integration from multiple studies and sources, including electronic health records. NIH ICs have identified CDEs for many clinical domains (e.g., neurological disease), types of studies (e.g., genome-wide association studies (GWAS)), types of outcomes (e.g., patient-reported outcomes), and patient registries (e.g., the Global Rare Diseases Patient Registry and Data Repository). NIH has established a Common Data Element (CDE) Resource Portal" (https://cde.nlm.nih.gov/home) to assist investigators in identifying NIH-supported CDEs when developing protocols, case report forms, and other instruments for data collection. The Portal provides guidance about and access to NIH-supported CDE initiatives and other tools and resources for the appropriate use of CDEs and data standards in NIH-funded research. Investigators are encouraged to consult the Portal and describe in their applications any use they will make of NIH-supported CDEs in their projects.

Applicants are required to follow the instructions for post-submission materials, as described 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 administrative review system.

For this particular announcement, note the following:

The X01 Resource Access Program invites eligible institutions to seek access to NIH research resources, which are specified in each X01 NOFO. This includes programs where institutions will request access to submit to the resource (e.g., high throughput screening assays) as well as programs where access to a specific NIH research resource is needed to conduct certain research. Important factors in the administrative review of X01 applications are the need for, and potential benefit of, gaining access to the resource, specifications for any assays proposed, timelines for completion and plans for follow-on studies.

Overall Impact

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

Scored Review Criteria

Not applicable.

Significance

Not applicable.

Investigator(s)

Not applicable.

Innovation

Not applicable.

Approach

Not applicable.

Not Applicable.

Environment

Not applicable.

Review Criteria

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

• Will this project make a significant contribution to the overall goals and objectives of the Network and assist in the diagnosis of participants who suffer from rare or difficult-to-diagnose diseases while expanding access to health disparity populations?
• Are the applicants effectively using their independent resources (e.g., institutional support, billing insurance, obtaining outside support, etc.) to support the clinical evaluation and other associated diagnostics costs when indicated and to achieve the aims of the project?
• Have the PD(s)/PI(s) and research team demonstrated that they have:
  • the required experience and expertise in evaluating and successfully diagnosing difficult-to-diagnose participants and are they recognized within and outside their institutions as expert diagnosticians?
  • a track record of meeting enrollment milestones?
  • a track record of working collaboratively and disseminating findings?
  • the appropriate experience in managing complex projects involving teams of scientists that include those at medical institutions who serve under/uninsured and health disparity populations?
  • a track record of collecting, analyzing, and publishing phenotypic and genomic data?
• Have the applicants proposed a feasible plan to enroll a minimum of 5 participants per year into the Network?
• Have the applicants proposed effective and state-of-the-art approaches for the diagnosis of participants enrolled at their site; have they proposed creative new strategies that have the potential to increase the efficiency, yield, and cost-effectiveness of the diagnosis, while still providing a comprehensive and expeditious clinical evaluation of participants?
• Are the bioinformatics approaches described state-of-the-art and likely to provide the best utilization of the data produced for the Network?
• Does the applicant have an effective plan for recruiting and enrolling participants from under/uninsured and health disparity populations, including those from racially/ethnically minority populations, from urban and rural areas who are economically disadvantaged and medically underserved, and/or with limited English proficiency?
• Have the applicants agreed to submit all relevant participant datasets (e.g., clinical, phenotypic, genomic, environmental, covariates, and other relevant data and metadata) to the DMCC through a Data Use Agreement with the Center?
• 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?

Protections for Human Subjects

For research that involves human subjects but does not involve one of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

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

Inclusion of Women, Minorities, and Individuals Across the Lifespan

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

Vertebrate Animals

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

Renewals

For Renewals, the committee will consider the progress made in the last award 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

Not Applicable.

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.

2. Review and Selection Process

Applications submitted to this notice of funding opportunity will be administratively reviewed using the criteria shown above.

Following the initial administrative review, applications will receive a second level of review by the UDN Trans-NIH Working Group, the NINDS Director and other participating Institute Directors. The following will be considered in making award decisions:

• Scientific and technical merit of the proposed project as determined in the administrative review
• Capacity of the Network
• Relevance of the proposed project to program priorities.

3. Anticipated Announcement and Award Dates

After the administrative review of the application is completed, NIH program staff will inform applicant(s) of the review outcome and start date if selected for award.

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.

An X01 does not result in a Notice of Award (NoA). Rather, selected applicants will receive access to resources provided by the Data Management Coordinating Center for Diagnostic Centers of Excellence (RFA-NS-22-051). Successful applicants will receive instructions for next steps.

2. Administrative and National Policy Requirements

An X01 does not result in a Notice of Award. Instead, successful applicants will receive instructions on accessing the resources described in this NOFO.

Not Applicable

3. Data Management and Sharing

Note: The NIH Policy for Data Management and Sharing is effective for due dates on or after January 25, 2023.

Consistent with the NIH Policy for Data Management and Sharing, when data management and sharing is applicable to the award, recipients will be required to adhere to the Data Management and Sharing requirements as outlined in the NIH Grants Policy Statement. Upon the approval of a Data Management and Sharing Plan, it is required for recipients to implement the plan as described.

4. Reporting

Not applicable. An X01 does not result in a Notice of Award. Instead, successful applicants will receive instructions on accessing the resources described in this NOFO.

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 threaten submission by the due date, and post-submission issues)

Finding Help Online: https://www.era.nih.gov/need-help (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-480-7075

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

Argenia Doss
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-827-1373
Email: argenia.doss@mail.nih.gov

Laura Mamounas
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-5745
Email: mamounal@ninds.nih.gov

Jason Wan, PhD
NIDCR - NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH
Phone: (301) 594-9898
E-mail: jasonwan@mail.nih.gov

Nahed El Kassar, MD, PhD
NHLBI - NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
Phone: 301-495-0054
E-mail: nahed.elkassar@nih.gov

Srikanth Nadadur, PhD
NIEHS - NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
Phone: 984-287-3296
E-mail: nadadurs@mail.nih.gov

Stacy E. Ferguson, Ph.D.
National Institute of Allergy and Infectious Diseases (NIAID)
Phone: 240-627-3504
Email: fergusonst@niaid.nih.gov

Jyoti Dayal
NHGRI - NATIONAL HUMAN GENOME RESEARCH INSTITUTE
Phone: 301.480.2307
E-mail: jyotig@nhgri.nih.gov

Tiina K Urv
NCATS - NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
Phone: (301) 402-7015
E-mail: urvtiin@mail.nih.gov

Melissa Parisi, MD, PhD
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-435-6880
Email: parisima@mail.nih.gov

Faye H Chen, PhD
NIAMS - NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
Phone: 301-594-5055
E-mail: chenf1@mail.nih.gov

Sangeeta Bhargava
NEI - NATIONAL EYE INSTITUTE
Phone: 301-435-8175
E-mail: bhargavas@nei.nih.gov

Argenia Doss
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-827-1373
Email: argenia.doss@mail.nih.gov

Chief Grants Management Officer
National Institute of Neurological Disorders and Stroke (NINDS)
Email: ChiefGrantsManagementOfficer@mail.nih.gov

Gabriel Hidalgo, MBA
NIDCR - NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH
Phone: 301-827-4630
E-mail: hidalgoge@mail.nih.gov

Tracee Foster
NHLBI - NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
Phone: 301.827-8030
E-mail: gilchrit@mail.nih.gov

Jenny L Greer
NIEHS - NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
Phone: 984.287.3332
E-mail: jenny.greer@nih.gov

Tamia Powell
National Institute of Allergy and Infectious Diseases (NIAID)
Phone: 240-669-2982
E-mail: tamia.powell@nih.gov

Deanna L Ingersoll
NHGRI - NATIONAL HUMAN GENOME RESEARCH INSTITUTE
Phone: 301-435-7858
E-mail: deanna.ingersoll@nih.gov

David Madoo
National Center for Advancing Translational Sciences (NCATS)
Phone: 301-761-6703
Email: david.madoo@nih.gov

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

Sahar Rais-Danai
NIAMS - NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
Phone: 301-594-5032
E-mail: sahar.rais-danai@nih.gov

Karen Robinson Smith
NEI - NATIONAL EYE INSTITUTE
Phone: 301-435-8178
E-mail: kyr@nei.nih.gov

Section VIII. Other Information

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

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 and 2 CFR Part 200.