Part 1. Overview Information

Key Dates

It is critical that applicants follow the Multi-Project (M) Instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

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 500 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. Participating NIH Institutes and Centers intend to support a Data Management and Coordinating Center (DMCC) that will provide infrastructure and research support for a new network (henceforth referred to as the Network in this FOA) of clinical sites, designated Diagnostic Centers of Excellence (DCoEs) and the UDP. Sites across the US that provide expert diagnostic services for undiagnosed diseases will be solicited to join a collaborative effort that is coordinated by the DMCC to promote 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. In this new model, the new Network will consist of the DMCC, the UDP, highly qualified and collaborative DCoEs, patients with undiagnosed diseases (referred to as participants in this FOA), patient advocacy groups, and the NIH and other stakeholders including external funding providers and/or resource providers (e.g., Cores). A DCoE is defined as one or more clinical sites within the US that are willing to submit their most challenging, unsolved diagnostic cases for acceptance into the Network, and participate in the evaluation by the Network’s virtual consultation committees. DCoEs 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. In FY2023, through a future RFA, clinical sites will be invited to join the Network by applying for an NIH X01 Resource Access Program award (or other NIH funding mechanisms) and will be selected amongst the respondents. Since DCoEs will not receive direct NIH funds through the X01 mechanism, DCoEs must have the appropriate infrastructure, expertise, and independent resources required to evaluate participants and conduct DNA sequencing and other specialized testing as needed. To qualify as a DCoE, each site will be expected to enroll a minimum of 5 participants per year, although some sites may have the capacity to enroll more participants. Initially, we expect that the DMCC will be coordinating the activities of at least 10-15 DCoEs, depending on the number of qualified X01 applications submitted to the NIH. However, NIH’s long-term vision is to see the Network expand to include DCoEs across the US in order to provide expert diagnostics services to diverse undiagnosed patient populations and, through strategic partnerships with patient advocacy groups and other stakeholders, to make important scientific discoveries while improving clinical practice for undiagnosed patients.

Research Scope and Objectives

This FOA solicits applications to develop and implement a DMCC for a new Network of DCoEs. The DMCC will provide:

1. A coordination infrastructure to foster communication and collaboration among Network physicians, researchers, undiagnosed diseases participants and patient advocacy groups, the NIH and other stakeholders or resource providers, and outreach to engage the broader undiagnosed diseases community.
2. A centralized resource to support data collection, facilitate curation and ensure submission of high-quality participant data to a designated NIH repository.
3. Bioinformatics and other expertise to aid Network investigators in designing gene function studies in model organisms or cell-based systems and clinical genomics/metabolomics expertise as needed to facilitate a diagnosis.
4. Small subawards to support: DCoE data sharing, and pilot research projects to catalyze new discoveries in undiagnosed diseases (e.g., through gene function studies in model organisms or non-routine clinical genomics, metabolomics, immunologic and exposome investigations, performed by DCoE investigators and their collaborators).

DMCC Structure

The DMCC will have three Cores:

I. Administrative Core

The Administrative Core is the managing component of the DMCC, charged with supervising DMCC governance and policies, evaluating progress, and enacting continuous improvements in the quality and efficiency of its activities. The Administrative Core is also responsible for overseeing all decision-making processes, managing the DMCC budget, interacting with NIH, and responding to the evolving needs of the participating DCoEs, including the UDP, research collaborators, undiagnosed diseases participants and patient advocacy groups, and stakeholders including external funding or resource providers.

The Administrative Core will:

• Establish a Steering Committee consisting of Network members, the NIH, and other stakeholders. The Steering Committee will have monthly recurring virtual meetings to advise on significant network decisions.
• In conjunction with NIH program staff and the Network Steering Committee, establish an External Advisory Committee that will provide guidance to the DMCC, Steering Committee, DCoEs, UDP, and other Network members. The Network may plan for other committees or subcommittees as needed to support decision-making processes.
• Provide overall coordination and management of network activities including regular communication and scheduling/hosting meetings as needed with the Steering Committee, External Advisory Committee, DCoEs and their affiliates, UDP, NIH, undiagnosed patient advocacy groups, resource providers, and other funding partners and stakeholders.
• Work with the NIH UDP and DCoEs to manage Network-wide clinical research protocols reviewed by a single IRB, informed consent documents, and clinical research protocols pertaining to network activities.
• Develop and maintain a manual of operations for the Network.
• Provide oversight and coordination of all DMCC Cores (Data Management Core and Clinical Research Core descriptions below).
• Assist the DMCC Cores and Network in the development and design of innovative research approaches, protocols, policies, and strategies.
• In collaboration with Network members, assess the outcomes of the Network’s model.
• Develop and maintain a public-facing portal that is equipped to receive applications from participants seeking to be accepted into the Network; the Administrative Core will also develop a resource for linking participants with participating DCoEs, the UDP, other participants, and relevant stakeholders or private disease foundations that can provide support or insight into their disease.
• Implement a sustainability plan that will fully support the DMCC when the award ends. This can include established partnerships, grants, institutional and philanthropic support, and private donations.

The Administrative Core will also be responsible for outreach, patient engagement and knowledge dissemination; the Administrative Core will:

• Work with NIH program staff to expand the Network, for example by identifying and recruiting highly qualified clinical sites to join the Network, including those that serve underserved and health disparity populations in the US.
• Assist the Network in recruiting diverse participants including those from health disparity populations, identifying barriers that cause health disparities in the undiagnosed diseases patient population, and solutions to these barriers.
• Assist the Network in disseminating educational materials for students, researchers, and participants via virtual workshops, webinars, brochures, and posting content online.
• Assist DCoEs and the UDP in hosting and tracking network-sponsored virtual training activities for individuals at all career levels (e.g., students, fellows, staff, and faculty) and individuals from groups underrepresented in the health-related sciences
• Support the development of research grant applications from Network investigators to fund follow-up studies on new discoveries.
• Provide an environment where participants can receive guidance or an update on their cases and interact with other Network participants.
• Help build complementary relationships between the participating DCoEs/UDP and outside strategic partners (such as rare disease foundations and undiagnosed diseases patient advocacy groups, philanthropic organizations, third-party payers, 501(c)(3) organizations, industry partners, and other outside funding or resource providers), while respecting intellectual property considerations and patient privacy policies.
• Incorporate participant experiences, perspectives, needs and priorities into decisions and activities of the Network, for example, by actively engaging patient advocacy groups such as the UDN Foundation (UDNF) and UDN Participant Engagement and Empowerment Resource (PEER).
• Organize and coordinate annual?meetings to enhance communication?and collaboration between Network members and the broader undiagnosed diseases scientific and patient community.

II. Data Management Core

The Data Management Core will establish and maintain efficient web- or cloud-based data systems and the infrastructure necessary for timely collection, submission, and analysis of high-quality phenotypic, exposure, genomic, and other specialized clinical research data obtained from the DCoEs and UDP. While using existing UDN data sharing standards and processes (see UDN Manual of Operations) as a guide, the Data Management Core will assist Network members in establishing common investigative and data collection/sharing protocols to be used by the DCoEs and the UDP. These protocols should facilitate data sharing across the Network and enhance the scientific and diagnostic value of the resulting information. The Data Management Core will also work with the Phase II UDN Coordinating Center to ensure that data (phenotypic, genomic, metabolomic, and associated metadata) from UDN participants accepted during Phases I and II are available for secondary analysis within the DMCC data repository.

The Data Management Core will:

• Plan for, establish, and maintain an efficient electronic data system(s) necessary for tracking participant enrollment, timely collection, submission, and analysis of high-quality phenotypic, exposure, genomic, and other specialized clinical and laboratory data from the DCoEs and the UDP. The system(s) should allow for real-time tracking of data quality and facilitates remote monitoring.
• Anticipate and resolve emerging issues relating to data submissions and sharing.
• Have a plan for archiving data, maintaining confidentiality and addressing privacy issues, back-up systems robust enough to prevent unauthorized access and a loss of data following natural and human causes.
• Create standardized data collection templates and ensure that standardized notation for metadata (e.g., controlled vocabularies or ontologies) is used to enable dataset harmonization for secondary research analyses.
• Validate DCoE and UDP participant data using the agreed-upon Network standards. If validations errors are found, the Data Management Core will work with DCoEs and the UDP to resolve the errors.
• Collect sample-level tracking information, information on ongoing collaborations by the DCoEs and UDP, and outcomes. This information will be made available to NIH, all DCoEs, and UDP to ensure transparency and facilitate coordinated analyses of data across the Network.
• Submit validated data to the appropriate NIH-designated controlled-access repositories and other appropriate resources. Controlled-access data such as de-identified sequence data, associated metadata, and phenotypic data must be registered in dbGaP and deposited into the NIH AnVIL. Variant information must be made available through services such as Matchmaker Exchange. Both novel and previously known variant interpretations must be made available through resources such as ClinVar to add to the evidence base for variant interpretation. The Data Management Core will work with the Steering Committee and NIH staff to define other specific repositories for sharing non-genomic data. All data submissions should adhere to the FAIR principles (Findable, Accessible, Interoperable, and Reusable). Timelines for submissions will be defined by the Network but are expected to be on a rolling and frequent basis such as monthly.
• Ensure data generated by the Network adheres to the NIH Data Access Policies, including informed consent of research participants. The Network is expected to use a process that provides consent for general research use (GRU) purposes.
• Enhance and support methods that allow the DCoEs, UDP, and others in the larger ecosystem of undiagnosed and rare disease research to collaborate on cases. The Data Management Core will develop, obtain approval of, and implement any Network-level data sharing policies. When storing and permitting controlled access to genomic data, included datasets must be consistent with the NIH Genomic Data Sharing Policy, the NIH Data Management and Sharing Policy, and the NIH Notice for Use of Cloud Computing Services for Storage and Analysis of Controlled-Access Data Subject to the NIH Genomic Data Sharing Policy.
• Advise the DCoEs and UDP on bioinformatics approaches and innovative techniques capable of identifying rare and novel diagnoses.
• Leverage bioinformatics infrastructure and computational resources provided by AnVIL to facilitate the development and sharing of bioinformatics tools for analyzing de-identified participant data.
• Provide statistical expertise and advice to the Network Steering Committee regarding optimal approaches to analyze data.

As appropriate, the Data Management Core is encouraged to make use of the following NIH Resources:

• NIH Common Data Elements Repository (https://cde.nlm.nih.gov/home)
• PhenX Toolkit (https://www.phenxtoolkit.org/)
• NINDS Common Data Elements (https://www.commondataelements.ninds.nih.gov/#page=Default)
• Science and Technology Research Infrastructure for Discovery, Experimentation, and Sustainability (STRIDES) (https://datascience.nih.gov/strides)

III. Clinical Research Support Core

The Clinical Research Support Core will provide resources intended to assist the DCoEs and the UDP in the diagnosis of Network participants and expand our knowledge of rare and difficult-to-diagnose diseases. The Clinical Research Support Core will:

• Establish and manage a Case Review Committee that includes representatives from the DCoEs and UDP, the NIH, other stakeholders as appropriate, and additional experts or consultants who attend on an ad hoc basis to advise on particular cases under discussion (the current UDN Manual of Operations can be used as a guide). DCoEs will submit their most challenging, unsolved cases for discussion by the Case Review Committee followed by a recommendation of whether the participant meets criteria for acceptance into the Network and possible next steps for determining a diagnosis. Additional virtual consultation meetings may be organized by the Clinical Research Support Core as needed to discuss a particular case with clinical specialists, medical genetics and informatics consultants, and gene function/model organism or metabolomics experts. The Network’s Steering Committee will establish the frequency of Case Review Committee and virtual consultation meetings, membership, and the criteria for accepting applications into the Network.

• Provide bioinformatics and other expertise to aid DCoE researchers in the design of gene function studies (e.g., in model organisms) and non-routine clinical genomics, metabolomics, multi-omics, immunologic and exposome investigations. Although DCoEs will be required to have medical genetics and informatics expertise to identify pathogenic variants from human DNA sequence data, sites may vary in their ability to select or design optimal approaches and assays for gene function studies in model organisms or non-routine clinical genomic and metabolomic investigations needed to facilitate a participant’s diagnosis. In the current UDN, the Model Organisms Screening Centers provide valuable bioinformatics advice to UDN clinical sites through their Initial Variant Review Informatics Team followed by recommendations of appropriate model organisms to study candidate variants (see UDN Manual of Operations for more details). Similarly, the current UDN Metabolomics Core provides advice and informatics guidance on metabolomics approaches and assays, in addition to glycomics, lipidomics, and mitochondrial expertise. To provide these types of informatics resources to Network DCoEs, the DMCC Clinical Research Support Core will have on board experts (as personnel on grant and/or as ad hoc consultants) to advise DCoEs in: medical genetics; bioinformatics of designing and conducting gene function studies in a variety of model systems (e.g., mouse, Drosophila, zebrafish, C. elegans, human cell-based models); and non-routine clinical genomics or metabolomics investigations. Since DCoEs will be expected to conduct the investigations in their own laboratories and/or with outside collaborators (or through clinical laboratories), the Clinical Research Support Core’s informatics experts will also assist DCoEs in identifying basic researchers (or laboratories) who may be interested in collaborating with the DCoE and are qualified to perform the work (e.g., using online resources such as ModelMatcher). DCoEs can apply to the DMCC for funds to support these research investigations as described below.

• Provide subawards to DCoE sites and/or their collaborators to support data sharing and pilot research projects. The DMCC will be required to set aside at least $500,000 Direct Costs (DC) in year 1 and $1M DC per year in years 2-5 to provide small subawards to DCoEs and/or collaborating laboratories. The subawards 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 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. Pilot funds, typically no more than $25-50K DC per project, are not intended to support more advanced research proposals (e.g., characterizing a gene or genomic variant already known to cause the participant’s disease) since these types of proposals can be submitted to the NIH using standard grant mechanisms. Subaward recipients must be a DCoE PD/PI and/or collaborating directly with a DCoE, and ideally propose a project that has the potential to develop competitive research applications to the NIH or other funding agencies. The Clinical Research Support Core will develop an efficient, rapid, and unbiased process to solicit, evaluate, and prioritize funding proposals for subawards (e.g., through standing committees or editorial-style reviews), subject to approval by the NIH. Once subawards are made, the core will manage and track subaward milestones and deliverables.

Program Formation and Governance

The administrative structure of the DMCC will provide leadership and assistance to the entire Network. The award funded under this FOA will be a cooperative agreement (see Section VI for Cooperative Agreement Terms and Conditions of Award). Because this is a cooperative agreement, extensive collaboration and management input from the NIH will occur regarding DMCC activities. The DMCC will be expected to propose measurable milestones and timelines in the application which will be used to assess progress and in consideration for funding of non-competing award years. To ensure that NIH’s investment in the DMCC is valuable, the NIH may negotiate and revise the milestones at the time of the award (e.g., by requiring: a minimum number of DCoEs to join the Network; a minimum number of participants to enroll each year; and measurable research outcomes).This overall structure is intended to ensure that participating DCoEs, the NIH and UDP, participants, undiagnosed diseases patient advocacy groups, and stakeholders including external (non-NIH) funding or resource providers are well-served by the DMCC resource.

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 U2C award
• 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 FOA

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 FOA.

Section III. Eligibility Information

1. Eligible Applicants

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Local Governments

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

Federal Governments

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

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. SAM registrations prior to fall 2021 were updated to include a UEI. For applications due on or after January 25, 2022, the UEI must be provided on the application forms (e.g., FORMS-G); the same UEI must be used for all registrations, as well as on the grant application.

• eRA Commons - Once the unique organization identifier (UEI after April 2022) is established, organizations can register with eRA Commons in tandem with completing their full SAM and Grants.gov registrations; 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 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. See, 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 DMCC grant may be submitted by individuals located at the same institution as an applicant for a DCoE award submitted under a future RFA entitled Diagnostic Centers of Excellence (X01 Clinical Trial Not Allowed) or other NIH DCoE funding mechanism but an individual may not be the PD/PI of both the DMCC and a DCoE.

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

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

The NIH will not accept duplicate or highly overlapping applications under review at the same time, 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 or an institutional system-to-system solution. A button to apply using ASSIST is available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

It is critical that applicants follow the Multi-Project (M) Instructions in the SF424 (R&R) Application Guide, except where instructed in this funding opportunity announcement to do otherwise and where instructions in the Application Guide are directly related to the Grants.gov downloadable forms currently used with most NIH opportunities. 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: [email protected]

Page Limitations

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

Instructions for the Submission of Multi-Component Applications

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing a multi-component application.

Overall Component

When preparing your application, use Component Type Overall .

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

SF424(R&R) Cover (Overall)

Complete entire form.

PHS 398 Cover Page Supplement (Overall)

Note: Human Embryonic Stem Cell lines from other components should be repeated in cell line table in Overall component.

Research & Related Other Project Information (Overall)

Follow standard instructions.

Project Summary /Abstract: Briefly describe the overall theme, goals, and objectives of the DMCC, including:

• Organizational structure
• Synergy among Cores

Facilities & Other Resources: All aspects of Facilities and Other Resources should be covered here, under Overall component. Indicate, however, to which cores the specific items listed here would be relevant (and group them accordingly). 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 (e.g., informatics/computational platforms, data storage and security resources, consultative and statistical resources, communication platforms, etc.) and Network. Specify whether such resources are in place (or readily obtainable) and on what basis such resources will be available to the DMCC, UDP/DCoE investigators (e.g., freely available, fee-for-service, etc.). Applicants should also describe any partnerships, institutional resources or commitments that could be leveraged to support the DMCC and Network. Include any other sources of support that will help the DMCC and Network be successful.

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

Attachment 1 (Required 1 page maximum): A table listing of available partnerships and infrastructures and the resource(s)/support that they will provide the DMCC and/or Network [use file name Partnerships and Infrastructure ]. Include the dollar amount (if applicable) and the duration of the commitment. Examples include partnerships with rare or undiagnosed diseases patient advocacy groups, existing collaborations with clinical sites that have expertise in diagnosing difficult-to-diagnose diseases, and partnerships with non-profit and for-profit organizations that can provide support for a patient web portal, genomic sequencing, data analyses, site coordinator, participant travel, clinical evaluations for under insured participants, gene function/metabolomics studies, the development of tools for genomic research, etc.

Attachment 2 (Required 4 pages maximum): DMCC Sustainability Plan [use file name Sustainability Plan ]. In this FOA, applicants must have a sustainability plan. Applicants are encouraged to creatively engage the scientific and operational problems that need to be addressed for the Network to be a sustainable success. NIH recognizes that the approach to diagnosis and investigation developed by the UDN during Phase I and II is only one model and cannot be sustained in perpetuity. New ideas and alternative approaches proposed by the DMCC are sought to refine and enhance the care of patients and the science generated from careful study of their cases. Propose a plan for sustainability to include:

• Established partnerships, grants, and donations that will support DMCC activities; The DMCC will be required to submit an updated sustainability plan to NIH by the end of year 4.
• A timeline for implementing the proposed sustainability plan.
• An evaluation plan that will determine if the sustainability plan is successful.

Applicants must discuss alternatives and defend the approaches they favor and describe their willingness to implement approaches agreed upon by the Network as a whole to move towards sustainability after the DMCC award ends in FY27.

Attachment 3 (Required 2 pages maximum): Summary of Senior/Key Personnel [use file name Summary of Personnel ]

This attachment should summarize which personnel fulfill the required and strongly encouraged areas of expertise. This includes but is not limited to:

• Leadership and project management of rare/undiagnosed disease networks
• Building diagnostic tools and sharing in an open-access environment
• Advanced genomics and bioinformatics expertise required for analyzing and interpreting data gathered from patients with rare and/or undiagnosed diseases
• Developing and maintaining web/cloud-based systems that allow for data sharing between multiple organizations
• Developing and managing network protocols reviewed by a single IRB
• Bioinformatics expertise in gene function studies conducted in model systems and non-routine clinical genomics/metabolomics investigations designed to facilitate a participant’s diagnosis
• Conducting unbiased reviews of grant proposals (e.g., for gene function or clinical genomics studies) and issuing subawards to sites
• Assessing network operations
• Developing partnerships with clinical sites, third party payers, philanthropic organizations, patients with undiagnosed diseases, patient advocacy groups, for-profit and non-profit organizations that have interest in providing support for the Network
• Outreach and communication with undiagnosed patients and patient advocacy groups, and disseminating knowledge about undiagnosed diseases to the broader community

Project/Performance Site Locations (Overall)

Enter primary site only.

A summary of Project/Performance Sites in the Overall section of the assembled application image in eRA Commons compiled from data collected in the other components will be generated upon submission.

Research and Related Senior/Key Person Profile (Overall)

Include only the Project Director/Principal Investigator (PD/PI) and any multi-PDs/PIs (if applicable to this FOA) for the entire application.

Describe the knowledge and prior experiences of the PD(s)/PI(s) in leading and managing large, complex, multi-site programs involving teams of scientists, including projects involving the clinical practice and research of rare and undiagnosed diseases. Include examples that reflect the PD(s)/PI(s) ability to collect, store, and analyze phenotypic and genomic data from undiagnosed/rare disease patients. Also provide examples where the PD(s)/PI(s) collaborate with teams of scientists and disseminate findings to network members and the broader undiagnosed/rare disease research community. The contact PD/PI must commit and maintain through the life of the award a minimum of 3.6 person-months (30% of full-time professional effort) to this program. For applications with multiple PDs/PIs, a minimum of 2.4 person-months (20%) effort is required for the Contact PD/PI and 1.2 person-months (10%) for each additional PD/PI. The required levels of effort may reflect an aggregate of the effort across the entire project.

A summary of Senior/Key Persons followed by their Biographical Sketches in the Overall section of the assembled application image in eRA Commons will be generated upon submission.

Budget (Overall)

The only budget information included in the Overall component is the Estimated Project Funding section of the SF424 (R&R) Cover.

A budget summary in the Overall section of the assembled application image in eRA Commons compiled from detailed budget data collected in the other components will be generated upon submission.

PHS 398 Research Plan (Overall)

Specific Aims: List each aim for the DMCC and how it supports the objectives of this research program as described in Section I. Funding Opportunity Description.

Research Strategy: Describe the overall strategies for reaching the goals of the DMCC for the proposed performance period of the application, including:

• The overall strategy, methodology, and analyses to be used to accomplish the specific aims of the project.
• The DMCC’s objectives for: facilitating clinical research performed by the DCoEs, UDP and collaborators; providing data management and sharing of data/resources among Network members; coordinating Network-wide activities; improving participants experiences by incorporating the perspectives of participants and undiagnosed diseases patient advocacy groups into network activities and decisions; engaging outside stakeholders (e.g., non-NIH funding and resource partnerships) to help support Network and clinical activities in the transition to a sustainable national resource; and serving as a conduit of rare and undiagnosed diseases related information to the research community and the general public.
• A succinct outline of the structure and function of each Core based on the requirements described in Section I. Funding Opportunity Description, and how the DMCC will coordinate activities across the Cores.
• Plans to work with other members of the Network Steering Committee and NIH, with guidance from the External Advisory Committee, to define a mode of operation that best matches the specific needs and capabilities of individual DCoEs accepted into the Network and ensures the fair, equitable, cost-effective, and timely distribution of DMCC resources to Network members.
• Plans for evaluating DMCC and Network progress, including receiving feedback from Network members and participants, and enacting continuous improvements in the quality and efficiency of its activities.
• Any innovations and improvements from the current UDN model (see UDN Manual of Operations) designed to: enhance the quality, efficiency and evaluation of Network-wide operations; assist DCoEs and the UDP in improving the efficiency and yield of diagnostic services performed by the Network; and transition the Network to a sustainable national resources that serves undiagnosed patient populations across the US.
• Plans to work with NIH program staff and other stakeholders to identify and recruit highly qualified clinical sites to join the Network as DCoEs through the NIH X01 or other future NIH support mechanism. We strongly encourage applicants to include letters from a minimum of 5 clinical sites stating their interest to join the new network and describing their sites qualifications to serve as DCoEs (as outlined in NOT-NS-22-072).

Integration and collaboration among Network members are essential tasks to accomplish the goals of the new Network and will require coordination assistance from the DMCC. Highlighting the synergy and expertise of the team as a whole (and not duplicative of the information provided in individual biosketches), applicants should describe:

• Prior experience of the team in working as a coordinating center, or as part of a research network, or other collaborative activities to meet individual and group goals, including examples of prior collaborative efforts and/or participation in networks or consortia particularly those involving rare, undiagnosed diseases research.
• Their team's experience and expertise in the proposed approaches, and ideas for potential alternatives to performing the various DMCC tasks of this FOA. Additional tasks that are not detailed here but, in the applicant’s view, are essential to network operations should be noted and potential approaches described.

Include a sub-section labeled: Health Disparities

A lack of insurance and access to health services is a major contributor to health disparities in the undiagnosed diseases population. In this section, describe how the Core will assist the Network in recruiting participants from health disparity populations, identifying barriers that cause health disparities in the undiagnosed patient population, and solutions to these barriers. In this context, efforts are encouraged to address the needs of racially/ethnically minority populations and those from urban and rural areas who are poor and medically underserved, who continue to suffer disproportionately from undiagnosed diseases.

Include a sub-section labeled: Milestones and Timelines

In this sub-section, describe the overall DMCC Milestones including the timeline for the overall program with brief descriptions of how the goals of each of the proposed specific aims will be achieved annually. The overall milestones must be well-described, specific, measurable, quantitative when appropriate, scientifically justified, and signal the achievement of a specific aim. The overall milestones should be connected to the performance benchmarks or progress of each Core. Milestones should include clear indicators of a program's continued success or emergent difficulties and will be used to evaluate the application not only in peer review but also in consideration for funding of non-competing award years. NINDS Program Officials may negotiate and revise the Milestones at the time of the award, for example by requiring: a minimum number of DCoEs to join the Network; a minimum number of participants to enroll each year; and measurable research outcomes.

The Responsibilities of the DMCC are described in Section VI.2, Administrative and National Policy Requirements. Applicants should indicate their willingness to cooperate with other awardees in the development and design of research approaches, procedures, policies, and strategies to be applied to this program. Applicants should also describe their ability to adapt to unique needs and unexpected circumstances that may arise as the Network evolves towards sustainability.

Letters of Support: All letters of support for the entire application should be provided under Overall component. DMCC Applicants and their institutions should indicate their willingness to participate in a network that uses a single IRB to review Network-wide research protocols. Institutional commitments to sustaining the DMCC functions beyond NIH grant support should be clearly documented. Letters should also be included that reflect any additional resources and partnerships that will be employed to achieve the goals of the DMCC, including transition of the Network to a sustainable national resource that serves diverse undiagnosed patient populations in the US. Letters should include those from partnering health care institutions and any other organizations that may be involved in the participant engagement or in supporting Network functions (e.g., relevant patient advocacy groups and other health interest groups, non-profits, industry partners or philanthropic organizations), but not formally part of the DMCC. Letters from a minimum of 5 clinical sites in the US stating their interest to join the new network and describing their site’s qualifications to serve as a DCoE (as outlined in NOT-NS-22-072) are strongly 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.

The following modifications also apply:

• All applications, regardless of the amount of direct costs requested for any one year, must address a Data Sharing Plan.
• Data Sharing under this FOA is required to increase the value of the significant public investment in the creation and operation of the Network. Consistent with achieving the goals of the program, NIH expects that datasets from the Network will be widely shared with the scientific community for research, while carefully observing standards of patient privacy, confidentiality, and management of health information.
• Information such as study protocols, descriptions, bioinformatics tools, and publications are expected to be made available to the public through open access databases, public web sites, etc. De-identified sequence data, associated metadata, and phenotypic data must be registered in dbGaP and deposited into AnVIL. The Data Sharing Plan must describe how the afore-mentioned issues will be addressed while providing optimal data sharing.
• Applicants should also describe plans for sharing software and analysis tools.
• The Data Sharing Plan should be provided only under the Overall component, but it must cover all the activities of the DMCC.

Appendix:

Only limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.

PHS Human Subjects and Clinical Trials Information (Overall)

When involving human subjects research, clinical research, and/or NIH-defined clinical trials 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, there must be at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record within the application. The study record(s) must be included in the component(s) where the work is being done, unless the same study spans multiple components. To avoid the creation of duplicate study records, a single study record with sufficient information for all involved components must be included in the Overall component when the same study spans multiple components.

Study Record: PHS Human Subjects and Clinical Trials Information

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

Delayed Onset Study

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

PHS Assignment Request Form (Overall)

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

Administrative Core

When preparing your application, use Component Type Administrative Core.

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

SF424 (R&R) Cover (Administrative Core)

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Use "Administrative Core" as the title for this component
• Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (Administrative Core)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Administrative Core)

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations? questions.

Vertebrate Animals: Answer only the Are Vertebrate Animals Used? question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Project /Performance Site Location(s) (Administrative Core)

List all performance sites that apply to the specific component.

Research & Related Senior/Key Person Profile (Administrative Core)

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Core Lead and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.
• The DMCC PD/PI (contact PD/PI for applications with multiple PDs/PIs) must be designated as the Administrative Core Lead.
• Address the following elements in the relevant Biographical Sketches: describe the experiences of Administrative Core key personnel in managing complex, multi-site projects involving teams of scientists in rare, undiagnosed diseases research.

Budget (Administrative Core)

Budget forms appropriate for the specific component will be included in the application package.

DMCC Administrator: Based on the complexity of the DMCC, applicants may propose a budget for a DMCC Administrator to manage day-to-day operations.

In-person meetings: Include a budget for one in-person meeting per year that provides travel funds for key stakeholders (e.g., External Advisory Committee (EAC) members and senior key personnel).

PHS 398 Research Plan (Administrative Core)

Specific Aims: Outline the specific aims for the Administrative Core.

Research Strategy: In lieu of the standard Research Strategy sub-sections (Significance, Innovation, Approach), use the sub-sections defined below to describe the administrative and organizational responsibilities of the proposed Administrative Core. Applications should also highlight aspects of the proposed activities of the Administrative Core that address the significance and innovation of the approaches.

Sub-section A. Leadership, Outreach, and Participant Engagement

Outline the organization of the leadership structure and overall DMCC structure (provide relevant organizational diagrams). Address the major responsibilities of the Administrative Core as described in Section I. Funding Opportunity Description, for example:

• Establishing an External Advisory Committee (EAC) consisting of scientific, clinical, and patient advocacy group representatives. Specific committee members should not be named in the grant application. Please refer to Program Formation and Governance in Section I. Funding Opportunity Description for more information on the EAC role. The EAC should meet at least once a year, beginning in the first year of the award. The Administrative Core will be responsible for scheduling, hosting, and managing the EAC meetings.
• Establishing a Steering Committee that will serve as the main scientific body of the program. Please refer to Program Formation and Governance in Section I. Funding Opportunity Description for more information on Steering Committee voting members and responsibilities. Specific committee members should not be named in the grant application. Plan to include at least one in-person meeting with the EAC and Steering Committee per year beginning in the second year of the award. The Administrative Core will be responsible for scheduling, hosting, and managing the Steering Committee meetings. Additional Steering Committee or EAC meetings as established in the Manual of Operations can be virtual.
• Developing and maintaining a public-facing portal that is equipped to receive applications from potential participants and/or their referring care providers seeking to join the Network and linking participants to participating DCoEs or the UDP.
• Supporting activities performed by the DMCC cores spanning from: outreach to participants, engagement, and communication; development and implementation of study protocols; collection of medical records; data management and sharing; organizing Case Review and Virtual Consultations meetings; reviewing and issuing subawards to DCoE sites and/or their collaborators to support data sharing and pilot research projects; and other responsibilities of the cores.
• Fostering synergy and integration of the three cores of the DMCC; provide efficiency in management of large-scale collaborative research efforts (including logistical services and organizational support) involving multiple institutions, if required.
• Working with the UDP and DCoEs to implement and manage relevant IRB protocols and consent documents. The Network will use a single IRB at the NIH to accelerate IRB approval of Network-wide clinical research protocols. The UDP will be the lead of the protocol.
• Working with the Network Steering Committee and EAC to assist the Network in the development and design of innovative research approaches, protocols, policies, and strategies including establishing a manual of operations for the Network.
• Identifying and solving operational problems involving participant recruitment and enrollment, data collection, quality assurance and refinement of protocols.
• Promoting collaborations between Network and non-Network clinicians and laboratory scientists to facilitate participants diagnoses and advance new research discoveries.
• Developing and implementing plans for coordinating, facilitating, and supporting the activities of the Network in collaboration with other DCoE investigators and NIH program officials.
• Describing how the DMCC will meaningfully incorporate participant experiences, perspectives, needs and priorities into decisions and activities of the Network.
• Describing plans to work with NIH program staff, Network members, resource providers, and other stakeholders to identify and recruit highly qualified clinical sites to join the Network with the goal of expanding the Network into a nationwide resource that serves diverse undiagnosed patient populations.
• Developing and implementing plans for assessing the outcomes of the Network’s model.

Sub-section B. Dissemination and Outreach

Propose a plan for dissemination and outreach to include:

• Developing an environment for linking Network participants with Network members including DCoEs and the UDP, other participants, patient advocacy groups, and non-Network members that could enhance their experience with the Network and provide insight into their disease or potential treatment options.
• Helping to build complementary relationships between the Network and outside strategic partners including: rare disease foundations and undiagnosed diseases patient advocacy groups; philanthropic organizations; third-party payers; 501(c)(3) organizations; industry partners; other government and outside funding or resource providers; developing a process to recruit these stakeholders to join the Network.
• Developing and implementing appropriate educational and outreach materials for participants, clinicians, researchers, and the broader undiagnosed diseases community.
• An approach for disseminating protocols, consent materials, and Network-derived best practices with the broader undiagnosed diseases community.
• Assisting the DCoEs and UDP with hosting and tracking virtual training activities for individuals at all career levels (e.g., students, fellows, staff, and faculty) and from groups underrepresented in the health-related sciences.
• Adhering to policies regarding data access, publication, and intellectual property established by the NIH and the Steering Committee for the Network.

Sub-section C. Center Logistics and Communication

Describe the communication strategies to ensure bidirectional exchange of logistical information, findings, and insights, including lessons learned and best practices between:

• DMCC cores;
• DMCC leadership (multiple PD(s)/PI(s) and other key personnel within the DMCC);
• DMCC and the DCoEs, UDP, and other Network scientists and investigators;
• DMCC and across the Network including the Steering Committee, EAC, Network participants and patient advocacy groups;
• DMCC, the NIH, and other stakeholders providing support and/or resources to the Network.

State who will be the lead for each level of communication.

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, must address a Data Sharing Plan.

Resource Sharing Plans should only be included in the Overall component.

Appendix: Only limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.

PHS Human Subjects and Clinical Trials Information (Administrative Core)

When involving human subjects research, clinical research, and/or NIH-defined clinical trials 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 a Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

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

Delayed Onset Study

Note: Delayed 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

Data Management Core

When preparing your application, use Component TypeData Management Core.

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

SF424 (R&R) Cover (Data Management Core)

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Data Management Core
• Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (Data Management Core)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Data Management Core)

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations? questions.

Vertebrate Animals: Answer only the Are Vertebrate Animals Used? question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Project /Performance Site Location(s) (Data Management Core)

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

Research & Related Senior/Key Person Profile (Data Management Core)

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Core Lead and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons who are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.
• For Cores with multiple leads, in the Project Director/Principal Investigator section of the form, use Project Role of 'Other (Specify)' and designate the role under 'Other Project Role Category' as 'Core Co-Lead' and provide a valid eRA Commons ID in the Credential field. For other co-leaders, in the additional Senior/Key Profiles section, use Project Role of 'Other (Specify)' and provide the role under 'Other Project Role Category' as 'Core Co-Lead' and provide a valid eRA Commons ID in the Credential field.
• In the relevant Biographical Sketches, describe the qualifications and expertise of Senior/Key persons in:
  • Establishing and maintaining a web- or cloud-based database gathered from rare disease patients, and/or in the management and sharing of clinical and phenotypic data from large, multi-site programs in rare, undiagnosed diseases research.
  • Building and sharing diagnostic tools to analyze genomic data.
  • Advanced genomics, multi-omics, and associated bioinformatic skills required for analyzing/interpreting these data.

Budget (Data Management Core)

Budget forms appropriate for the specific component will be included in the application package.

The DMCC will need to budget for computation, storage, and egress charges. The Data Management core will work with the other cores to determine the appropriate budget for administrative costs.

PHS 398 Research Plan (Data Management Core)

Specific Aims: List each aim for the Data Management Core and how it supports the overall objectives of the DMCC.

Research Strategy: Address how the Data Management Core will facilitate the development of web- or cloud-based management systems for the collection, storage, and quality control of data; promote the use of high-quality data standards; and provide a portal for data use and sharing, as described in Section I. Funding Opportunity Description. Describe the delivery of services and materials to Network members and the broader research community that ensures consistent data quality, fair access by users and efficient use of the resources by the Network. Applications should highlight aspects of the proposed activities of the Data Management Core that speak to the significance and innovation of the approach. Applicants must describe their plans for data collection at all levels of participant involvement in addition to tracking participant inquiries, medical chart reviews, detailed clinical evaluations, DNA sequencing data, and the outcomes of clinical genomics, metabolomics, multi-omics, and gene function investigations. The applicant should address how the Core will:

• Plan for, establish, and maintain efficient web- or cloud-based data systems necessary for tracking participant enrollment, timely collection, submission, and analysis of high-quality phenotypic, exposure, genomic, and other specialized clinical and laboratory data. The system(s) should allow for real-time tracking of data quality and facilitate remote monitoring.
• Assist the Network in the rigorous collection of phenotypic data; standardizing approaches; defining and monitoring data quality standards; and collecting short- and long-term follow-up data on outcomes.
• Anticipate and resolve emerging issues as it relates to data submissions and sharing.
• Obtain approval for and implement any Network-level data sharing policies.
• Advise the DCoEs and UDP on bioinformatics approaches and innovative techniques capable of identifying rare and novel diagnoses. This will ensure the best utilization of the data produced by the Network.
• Facilitate the use of Common Data Elements and standardized phenotyping protocols including the PhenX toolkit.
• Disseminate protocols, bioinformatics tools, and resources to Network and non-Network members.
• Promote collaboration and data sharing by registering sequence data, associated metadata, and phenotypic data in dbGaP and depositing de-identified data from all Network participants (~75 cases per year) in relevant open and controlled-access databases such as AnVIL, ClinVar, Matchmaker Exchange, PhenomeCentral, etc.
• Ensure data sharing adheres to patient privacy, confidentiality, and existing regulations on management of health information and consistent with the FAIR principles, NIH Data Access Policies, and HIPAA regulations. Please refer to Data Management Core in Section I. Funding Opportunity Description for more information.
• Develop and implement plans for archiving data and back-up systems robust enough to prevent loss of data following natural and human causes should be described along with ability to meet requirements.
• Address how human subject data will be handled, maintained, and protected.
• Leverage bioinformatics infrastructure and capabilities and computational resources in place (or readily obtainable) as described in Facilities and Other Resources to facilitate development and sharing of bioinformatics approaches.
• Leverage bioinformatics infrastructure and computational resources provided by AnVIL to facilitate the development and sharing of bioinformatics tools for analyzing de-identified the new Network’s and UDN Phase I-II participant data.

Performance Benchmarks

Applicants must provide a clear set of benchmarks for success. These benchmarks should address the aims of the Data Management Core. Applicants should include plans for critically evaluating and revising these benchmarks on a regular basis. The inclusion of a proposed timeline for implementing components and processes of the Core is encouraged. In addition, applicants must describe how they will prioritize their activities to ensure that the Overall DMCC milestones will be achieved. Applicants must also describe what action will be taken, and when, if a benchmark is not met or is significantly delayed. In addition, applicants should identify potential problems and alternative strategies to accomplish Data Management Core goals.

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, must address a Data Sharing Plan.

Resource Sharing Plans should only be included in the Overall component.

Appendix: Only limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

PHS Human Subjects and Clinical Trials Information (Data Management Core)

When involving NIH-defined human subjects research, clinical research, and/or clinical trials 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 a Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

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

Delayed Onset Study

Note: Delayed 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.

Clinical Research Support Core

When preparing your application, use Component Type Clinical Research Support Core.

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

SF424 (R&R) Cover (Clinical Research Support Core)

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Clinical Research Support Core
• Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (Clinical Research Support Core)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Clinical Research Support Core)

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations? questions.

Vertebrate Animals: Answer only the Are Vertebrate Animals Used? question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Project /Performance Site Location(s) (Clinical Research Support Core)

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

Research & Related Senior/Key Person Profile (Clinical Research Support Core)

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Core Lead and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons who are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used
• For Cores with multiple leads, in the Project Director/Principal Investigator section of the form, use Project Role of 'Other (Specify)' and designate the role under 'Other Project Role Category' as 'Core Co-Lead' and provide a valid eRA Commons ID in the Credential field. For other co-leaders, in the additional Senior/Key Profiles section, use Project Role of 'Other (Specify)' and provide the role under 'Other Project Role Category' as 'Core Co-Lead' and provide a valid eRA Commons ID in the Credential field.
• Address the following elements in the relevant Biographical Sketches:
  • Qualifications of Project Lead(s) and other key personnel in managing complex, multi-site programs in rare, undiagnosed diseases research.
  • Expertise and knowledge of advanced diagnostic testing strategies including detailed clinical phenotyping, DNA sequencing, clinical genomics/metabolomics and other specialized clinical and laboratory testing used to diagnose challenging cases.
  • Expertise in medical genetics including informatics expertise to identify pathogenic variants from human DNA sequence data and other clinical genomics, metabolomics, immunologic and/or exposome investigations.
  • Bioinformatics expertise to analyze candidate pathogenic variants in a variety of model systems (e.g., mouse, Drosophila, zebrafish, C. elegans, human cell-based models), and experience in designing and conducting gene function studies in these models.
  • Experience in managing the unbiased technical review of grant proposals (e.g., for gene function studies) and issuing subawards to awardee institutions.

Budget (Clinical Research Support Core)

Budget forms appropriate for the specific component will be included in the application package.

The budget should include a detailed justification for key personnel under this core. The person months for each member of the center staff related to this core should be included here. It is possible to have overlapped personnel under different components, as long as their total efforts do not exceed 100%.

The DMCC will be required to set aside at least $500,000 Direct Costs (DC) in year 1 and $1M DC per year in years 2-5 to provide small subawards to DCoEs and/or collaborating laboratories as described in Section I. Funding Opportunity Description. These funds should be presented in the Other Direct Costs category under the heading " DMCC Subaward Fund".

Include costs to administratively manage resource subawards. Include costs for any consultant or subcontractor directly supporting this core's activities (e.g., subject matter expert, project manager, information services). As this core is expected to scale up and down over the course of the period of performance, based on available funding and approved subprojects, application budgets should plan a minimum level of activity needed to support 5-50 subawards per year.

PHS 398 Research Plan (Clinical Research Support Core)

Specific Aims: Describe the specific aims of the Clinical Research Core and how these goals will assist the Network in diagnosing participants and expanding our knowledge of undiagnosed diseases.

Research Strategy: Describe the function of the Clinical Research Core as a resource to the DCoEs/UDP and Network, including not only the delivery of services and resources but the process for ensuring the consistent quality of services, fair access by users and efficient use of the resources by the Network. The research strategy must clearly present the facilities, techniques, and professional skills that the core will provide to the DCoEs and UDP, along with any innovations that may improve the quality of services and facilitate participant diagnoses. The inclusion of a timeline for establishing the various components of the core is strongly encouraged. Include the sub-sections below.

Sub-section A: Virtual Case Review Committee and Consultations

• Provide plans for establishing and maintaining a Case Review Committee and other virtual consultation meetings, including plans for scheduling meetings, identifying committee members, and ensuring that informatics experts and other consultants are available to inform DCoEs/UDP about possible next steps in the diagnoses of their cases. More information about the responsibilities and members of the committee(s) can be found under Clinical Research Support Core in Section I. Funding Opportunity Description. Unless listed as personnel or consultants on the grant application, external committee members should not be named in the application.
• Provide plans for including informatics experts and consultants (who may be listed as personnel on the grant application or as external ad hoc consultants) to advise DCoEs/UDP in: medical genetics; bioinformatics of conducting gene function studies in various model systems (e.g., mouse, Drosophila, zebrafish, C. elegans, xenopus, human cell-based models, etc.); non-routine clinical genomics or metabolomics investigations; and other specialized clinical or laboratory diagnostic testing. Discuss strategies to match DCoE/UDP clinicians with basic researchers (within or outside the Network) who may be interested in collaborating to solve cases. Describe how the Clinical Research Support Core will ensure the DCoEs/UDP will have fair and equitable access to consultation resources.
• Describe how the Clinical Research Support Core will work with the Administrative Core to ensure that the application and case review process for undiagnosed participants are efficient and not burdensome for the participant or DCoEs/UDP, and that each participant who applies to the Network will have a similar high-quality experience.
• Describe how outcomes will be communicated with applicants and participants.
• Include plans to improve operations such as surveys for receiving feedback from participants and DCoEs/UDP about the application and case review process.

Sub-section B: Set-Aside Funds for Collaborative Trans-Network Projects:

• Describe an efficient, rapid and unbiased process to solicit, review, and prioritize funding proposals for subawards (e.g., to support data sharing and pilot research projects as described under Clinical Research Support Core in Section I. Funding Opportunity Description); for example, possible approaches include using an external editorial-style review process and/or establishing a standing committee to review proposals. Subawards cannot support clinical trials.
• Describe the applicant’s experience and plans for issuing subawards to awardee institutions.
• Describe approaches to monitor subaward timelines, milestones, and deliverables, and procedures if a subaward is under-performing.
• Describe how data and findings from the subawards will be shared with the Network and broader scientific community.

Sub-section C: Performance Benchmarks

Outline benchmarks that will document progress towards the achievement of the Overall DMCC milestones. Applicants must include plans for critically evaluating and revising these benchmarks on a regular basis. Applicants must also describe what action will be taken, and when, if a benchmark is not met or is significantly delayed. In addition, applicants should identify potential problems and alternative strategies to accomplish Clinical Research Support Core goals.

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, must address a Data Sharing Plan.

Resource Sharing Plans should only be included in the Overall component.

Appendix: Only limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.

PHS Human Subjects and Clinical Trials Information (Clinical Research Support Core)

When involving NIH-defined human subjects research, clinical research, and/or clinical trials 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 a Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

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

Delayed Onset Study

Note: Delayed 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.

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

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

4. Submission Dates and Times

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

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

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

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

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

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

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

7. Other Submission Requirements and Information

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

For information on how your application will be automatically assembled for review and funding consideration after submission go to: http://grants.nih.gov/grants/ElectronicReceipt/files/Electronic_Multi-project_Application_Image_Assembly.pdf.

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) and component Project Leads must include their eRA Commons ID in the Credential fieldof 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.

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

See more tips for avoiding common errors.

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

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.

Prior Consultation with Scientific/Research Staff

Consultation with relevant NIH Scientific/Research staff is strongly encouraged, not later than the Letter of Intent due date. This is not the same as the Letter of Intent and should be included as a separate communication to the Scientific/Research Contacts (see Section VII). If requested by the applicants, staff can advise whether the proposed project meets the goals of this FOA and the mission of NINDS and discuss responsiveness questions. Staff will not evaluate the technical and scientific merit of the proposed project; technical and scientific merit will be determined during peer review using the review criteria indicated in this FOA. During the consultation phase, if the proposed project does not meet the programmatic needs of this FOA, applicants will be strongly encouraged to consider other Funding Opportunities.

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 participants 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. Investigators are encouraged to consult the NIH CDE Repository and describe in their applications any use they will make of CDEs (e.g., Human Phenotype Ontology, PhenX, etc.) in their projects, when applicable. 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 diseases), 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) Repository Resource Portal" (http://cde.nih.gov/) 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.

Post Submission Materials

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

Section V. Application Review Information

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

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

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

Significance

Does the project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Specific to this FOA: Does the proposed DMCC address the overall goals, objectives and needs of the new Network and assist in the diagnosis of participants who suffer from undiagnosed diseases? Is the scope of activities proposed for the DMCC appropriate to meet those needs? Will the DMCC’s conceptual design and overall operating plan provide the required strategy and resources to advance the diagnoses of undiagnosed diseases and catalyze new research discoveries? Do the applicants propose effective plans to transition the Network to a sustainable national resource that serves diverse undiagnosed patient populations?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

Specific to this FOA: Do the PD(s)/PI(s) and research team have the appropriate experience and demonstrate a record of accomplishments in leading and managing large, multi-center, collaborative networks in undiagnosed/rare diseases? Do they have a strong track record of coordinating and working collaboratively with teams of scientists, and disseminating findings to network members and the broader undiagnosed/rare diseases community? Do they have experience collecting, analyzing, and publishing phenotypic and genomic data in undiagnosed/rare diseases?

Innovation

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

Specific to this FOA: Does the applicant propose new approaches and strategies that would facilitate clinical research performed by the DCoEs, UDP, and collaborators and improve the current UDN model? As new technologies become available, is the research team poised to recognize when they are sufficiently developed and validated to be added to the Network protocols? Are the bioinformatics approaches described innovative and likely to provide the best utilization of the data produced by the Network? Will this research advance the use of genomics, related technologies and the use of Common Data Elements (e.g., Human Phenotype Ontology terms, PhenX Toolkit) and protocols in the clinical management of patients with rare or yet to be described diseases?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

Specific to this FOA:

• Are the overall strategies, operational plan, workflow, and organizational structure well-reasoned and appropriate to accomplish the goals of the Network and DMCC? Does the DMCC propose cutting edge, innovative approaches capable of solving rare, novel and challenging diagnoses and catalyzing new research discoveries in undiagnosed diseases?
• Are the three cores not only individually meritorious but also complementary to the other components of the DMCC and well positioned to serve the overall needs of the Network? Is there an adequate plan for evaluating and modifying the resource in response to user feedback and to technological and scientific advances?
• Does the applicant propose an appropriate plan to attract and recruit DCoEs to join the Network? Is the DMCC’s overall operational plan tailored to serve the specific needs and capabilities of individual DCoEs accepted into the Network and ensure the fair, equitable, cost-effective, and timely distribution of DMCC resources to Network members?
• Will the DMCC’s design and operating plan provide ample opportunity for communication and collaboration across the Network?
• Does the proposed plan meaningfully incorporate participant experiences, perspectives, needs and priorities into decisions and activities of the Network?
• Does the applicant provide an effective plan to partner with external stakeholders, patient advocacy groups, resource providers, for-profit and non-profit organizations with the goal of developing a sustainable national resource that serves diverse populations suffering from undiagnosed diseases? Is the proposed sustainability plan feasible?
• Are there appropriate plans for the DMCC to collaborate with and otherwise contribute to the broader undiagnosed/rare disease research communities including the sharing of Network data and resources as warranted? Do the proposed outreach activities and educational resources serve the needs of these communities?
• Is the plan for sharing data and bioinformatics tools with Network members, the broader research community including participants and/or stakeholders appropriate? Is the plan consistent with the NIH’s data sharing policies?
• How well does the Data Sharing Plan provide a summary of the shared data, a description of the data standards, a plan for the data archiving, and a timeline for data submission to the archive and sharing data with the research community?

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

Environment

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

Specific to this FOA: Will the institutional environment in which the DMCC will operate contribute to the probability of success in facilitating the research network it serves? Will the DMCC benefit from unique features of the institutional environment, infrastructure, or personnel? Are institutional resources and infrastructure being committed or leveraged? Have the applicants identified outside partnerships and/or sources of support that can contribute to the sustained success of the Network? Are adequate resources available within the scientific environment to support electronic information handling? Are the bioinformatics infrastructure and capabilities, computational resources equipment, and infrastructure available, in place (or readily obtainable), and adequate to support the project?

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.

Review Criteria for the Administrative Core

• Does the Administrative Core provide effective leadership, management, technical expertise, and plans for outreach and communication to ensure that it meets the needs of the DMCC and Network?
• Is there a plan for working with the UDP to manage a Network-wide clinical research protocol(s) reviewed by a single IRB?
• Are there appropriate plans to establish and manage a Network Steering Committee and External Advisory Committee, and do they serve the overall needs of the Network?
• Does the applicant provide an environment where participants can receive guidance or an update on their cases and interact with other Network participants?
• Will the plan for recruiting DCoEs and participants be effective?
• Will the plan for recruiting participants from health disparity populations be effective?
• Will the public-facing portal for receiving participant applications be effective?
• Does the applicant provide stringent and feasible methods for evaluating the DMCC and Network outcomes?

Review Criteria for the Data Management Core

• Does the Data Management Core propose effective methods for the timely collection, storage, and analysis of high-quality phenotypic, genomic, exposure, and other specialized clinical research data obtained from Network DCoEs the UDP, and participating resource providers?
• Does the Core provide adequate leadership, bioinformatics support and technical expertise to ensure that it meets its stated goals, including facilitating participant diagnoses and catalyzing new research discoveries within the Network?
• Are the Core personnel experienced in establishing common investigative and data collection protocols that can be used by multiple clinical sites involved in diagnosing undiagnosed diseases? Is the staffing and other resources available to the Core sufficient to meet the anticipated needs of the Network?
• Are the plans for standardizing, validating, and harmonizing data submitted by the DCoEs, UDP, and participating resource providers feasible? Does it include the use of Common Data Elements (e.g., Human Phenotype Ontology terms, PhenX Toolkit)?
• Is the plan for oversight and prioritization of user requests for core services adequate and fair?
• Does the Core propose a feasible and sufficient plan to protect human subjects and their data?

Review Criteria for the Clinical Research Support Core

• Does the Clinical Research Support Core provide effective leadership, bioinformatics support and technical expertise to ensure that it meets its stated goals, including facilitating participant diagnoses and catalyzing new research discoveries within the Network? Does the applicant propose an effective (e.g., web portal), efficient and streamlined process for DCoEs and the UDP to review applications and accept participants into the Network?
• Is there an effective process for communicating outcomes to participants? Are there plans in place to receive feedback from participants about the application review process and improve operations when possible?
• Is the plan for managing the Case Review and other virtual consultation committees effective, as well as fair and equitable to all stakeholders? Does the plan facilitate participant diagnoses or provide insights into potential next steps for solving cases?
• Does the core provide an effective plan for providing informatics expertise to Network members on medical genetics; conducting gene function studies in various model systems (e.g., mouse, Drosophila, zebrafish, C. elegans, xenopus, human cell-based models, etc.); non-routine clinical genomics or metabolomics investigations; and other specialized clinical or laboratory diagnostic testing? Are the personnel and/or consultants named in the application, including their time and effort, appropriate to meet the specialized needs of the Network?
• Are the plans for soliciting, reviewing, prioritizing and issuing subawards streamlined, rapid and efficient? Is there an effective plan for tracking subaward milestones and deliverables to ensure that research goals are met?

Protections for Human Subjects

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

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

Inclusion of Women, Minorities, and Individuals Across the Lifespan

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

Vertebrate Animals

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

Biohazards

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

Resubmissions

Not Applicable

Renewals

Not Applicable

Revisions

Not Applicable

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.

Milestones

Does the application provide appropriate milestones that will need to be met to accomplish the work set out above in a five-year time frame? Are the milestones for the DMCC robust and associated with clear, measurable and quantitative criteria for success? Will the overall milestones provide adequate information to evaluate annual progress of the DMCC as a whole? Are the timelines proposed for achieving the milestones realistic and inclusive of necessary steps, but also efficient without adding unnecessary steps? Are there additional key components that need to have milestones?

Applications from Foreign Organizations

Not Applicable

Select Agent Research

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

Resource Sharing Plans

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

Authentication of Key Biological and/or Chemical Resources:

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

Budget and Period of Support

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

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by the National Institute of Neurological Disorders and Stroke, in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications will receive a written critique.

Applications may undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.

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

Applications will be assigned to the National Institute of Neurological Disorders and Stroke (NINDS). 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 Neurological Disorders and Stroke (NANDS) 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.

3. Anticipated Announcement and Award Dates

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

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

Section VI. Award Administration Information

1. Award Notices

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

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

Recipients must comply with any funding restrictions described in Section IV.6. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

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

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

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Recipients, and Activities, including of note, but not limited to:

• Federalwide Research Terms and Conditions
• Prohibition on Certain Telecommunications and Video Surveillance Services or Equipment
• Acknowledgment of Federal Funding

If a recipient is successful and receives a Notice of Award, in accepting the award, the recipient agrees that any activities under the award are subject to all provisions currently in effect or implemented during the period of the award, other Department regulations and policies in effect at the time of the award, and applicable statutory provisions.

Should the applicant organization successfully compete for an award, recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights laws that prohibit discrimination on the basis of race, color, national origin, disability, age and, in some circumstances, religion, conscience, and sex (including gender identity, sexual orientation, and pregnancy). This includes ensuring programs are accessible to persons with limited English proficiency and persons with disabilities. The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-providers/provider-obligations/index.html https://www.hhs.gov/civil-rights/for-individuals/nondiscrimination/index.html.

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

Recipients of FFA must ensure that their programs are accessible to persons with limited English proficiency. For guidance on meeting the legal obligation to take reasonable steps to ensure meaningful access to programs or activities by limited English proficient individuals see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/fact-sheet-guidance/index.html and https://www.lep.gov.

• For information on an institution's specific legal obligations for serving qualified individuals with disabilities, including reasonable accommodations and making services accessible to them, see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html.

• HHS funded health and education programs must be administered in an environment free of sexual harassment, see https://www.hhs.gov/civil-rights/for-individuals/sex-discrimination/index.html; For information about NIH's commitment to supporting a safe and respectful work environment, who to contact with questions or concerns, and what NIH's expectations are for institutions and the individuals supported on NIH-funded awards, please see https://grants.nih.gov/grants/policy/harassment.htm.

• For guidance on administering programs in compliance with applicable federal conscience protection and associated anti-discrimination laws see https://www.hhs.gov/conscience/conscience-protections/index.html and https://www.hhs.gov/conscience/religious-freedom/index.html.

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

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 and 2 CFR Part 200.206 Federal awarding agency review of risk posed by applicants. This provision will apply to all NIH grants and cooperative agreements except fellowships.

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 2 CFR 200, 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 recipients 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 recipients for the project as a whole, although specific tasks and activities may be shared among the recipients and the NIH as defined below.

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

• Determining research approaches, designing protocols, setting project milestones, and conducting research.
• Establishing and coordinating activities for the following committees and panels:
  • An External Advisory Committee that will provide guidance to the Network’s Steering Committee and PD(s)/PI(s) and participate as appropriate in evaluating subaward applications
  • A Steering Committee that will provide guidance to Network PD(s)/PI(s), and make decisions on behalf of the network
  • A Virtual Case Review Committee that will review undiagnosed participant applications and recommend whether a participant would benefit from entering the network; other virtual consultation panels as needed to assist DCoEs and the UDP in the diagnosis
• Organizing and participating in group activities, including a network-wide Steering Committee and working groups as needed.
• Providing protocols, reports and data in a timely fashion as agreed upon by the Steering Committee.
• Collecting and compiling all data from Network participants for quality control and compilation in a network-wide dataset to be made available to all DCoEs (including the NIH UDP), as agreed upon by the Steering Committee and deposited in database repositories such as dbGaP and AnVIL.
• Assessing and disseminating data, protocols, consent materials, and methods developed by the Network with non-Network members.
• Developing and implementing appropriate educational materials for participants, clinicians, and other researchers.
• Adhering to policies regarding data access, publication, and intellectual property established by the NIH and the Steering Committee.
• Abiding by common definitions, protocols, and procedures, as chosen by majority vote of the Steering Committee.
• Accepting and complying with study policies established by NIH and with additional non-conflicting policies approved by the Steering Committee.
• Submitting periodic progress reports in a standard format, as agreed upon by the Steering Committee and NIH.
• Attending and participating in Steering Committee meetings and accepting and implementing decisions by the NIH, as appropriate.

• Facilitating collaborative interactions between DMCC personnel, NIH staff, Steering Committee members, External Advisory Committee members, resource providers and external stakeholders as appropriate to foster collaborations and exchange information and ideas to accelerate progress towards the goals of the DMCC.
• Organizing and participating in regular meetings or phone calls of the Steering Committee, External Advisory Committee, and other committees as needed. The membership, frequency, and governance of these meetings will be negotiated with NINDS staff after funding decisions have been made.
• Hosting and organizing, with programmatic and logistical input from the Steering Committee, annual meetings of DMCC investigators, DCoE recipients, and external subject matter experts, and attending and reporting on DMCC progress at these meetings. This includes providing agendas and minutes. The PI(s)/PD(s) must plan at least one in-person meeting per year with the External Advisory Committee, Steering Committee, and DCoE PIs/PDs.
• Completing quarterly and annual progress reports and providing written evidence of progress when requested by NINDS staff. This will include and is not limited to information on evaluations, samples in pipelines, conditions being studied, sequencing status, data submission status, discoveries, and publications. Much of this information should be extracted from data the DCoE submit to the DMCC, but some information will need to be collected specifically for these reports. The frequency, timing, and method for collecting this information will be determined in close collaboration with NIH and the Network.
• Preparing abstracts, presentations, and publications and collaborating with DCoE recipients and other stakeholders to make the public and scientific community aware of this resource.
• Making data, software, and access to the Network’s de-identifiable data broadly available and with minimal financial cost to biomedical researchers and educators in the non-profit sector, such as institutions of education, research institutions, and government laboratories.
• Data/software ownership and transition to another grantee:
  • A fundamental objective of this cooperative agreement is to ensure that the valuable data, products, and resources provided by the DMCC remain available without interruption to the research community if recipient withdraws or otherwise can no longer manage the resource or the award is terminated by the NIH.
  • Consistent with 45 C.F.R. 75.322, the recipient will own the data generated and software developed by the recipient, and it will be able to continue to use these data and software upon expiration or termination of the award. NIH will have unrestricted cost-free access and use of the data, resources and software generated by the recipient, including the right to transfer said data and/or software to other NIH-funded and/or managed resource projects, at the NIH's sole reasonable discretion upon termination or expiration of this cooperative agreement.
  • Ownership of the data and software that may be hosted (but not created) by the DMCC remains with the data and software providers.
  • Open Source Technology: Capabilities and software built as part of the new Network must be delivered under an open source model. Organizations may propose to use proprietary platforms, so long as the requirements for data transparency and interoperability are maintained.
  • Recipients will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.

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

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

• Participating with the other Steering Committee members in addressing issues that arise with Network planning, operation, assessment, and data analysis. The Project Scientist(s) will assist and facilitate the group process and not direct it.
• Serving as a liaison, helping to coordinate activities, including acting as a liaison to other NIH Institutes/Centers, and as an information resource for the recipients. The Project Scientist(s) will also help coordinate the efforts of the Network with other groups conducting similar efforts.
• Attending all Steering Committee meetings as a voting member and all Working Group meetings, assisting in developing operating guidelines, quality control procedures, and consistent policies for dealing with situations that require coordinated action. The Project Scientist(s) will be responsible for working with the grantee as needed to manage the logistic aspects of the Network.
• Reporting periodically on the Network’s progress to the NIH Trans-NIH Working Group, and to the National Advisory Neurological Disorders and Stroke Council.
• Reviewing funding subawards proposals put forth by the DMCC.
• Obtaining final approval from NIH staff on subawards.
• Serving on subcommittees of the Steering Committee and Working Groups as appropriate.
• If needed, assist recipients in developing policies for addressing situations that require coordinated action.
• Providing advice in the management and technical performance of the award.
• Assisting in promoting the availability of the data and related resources developed in the course of this program to the scientific community at large. Other Trans-NIH Working Group staff may assist the recipient as designated by the Program Official.
• Discussing proposed milestones with the applicant prior to funding an application to resolve concerns raised by the NINDS review panel or NINDS program staff. A final set of NINDS-approved milestones will be specified prior to award.
• Participating in External Advisory Committee meetings.
• Ensure compliance with the NINDS mission and NIH policies and procedures.
• Monitoring the project on a regular basis. Monitoring may include regular communication with DMCC PD(s)/PI(s) or team, periodic site visits, meetings, fiscal review, evaluation of progress reports, and other stewardship activities.
• Formally assessing DMCC progress on an annual basis, including evaluating progress toward achievement of milestones. NINDS program staff may consult with independent experts as necessary. If justified, future milestones may be revised based on data and information obtained during the previous budget period. If, based on the progress report, a project does not meet the milestones, funding for the project may be reduced or discontinued. In addition to milestones, the decision regarding continued funding will also be based on overall DMCC progress, NINDS portfolio balance and program priorities, the number of actively participating diagnostic centers, and availability of funds.
• Additionally, an agency program official or IC program director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice. The assigned Program Official may also serve as an NIH Working Group Project Scientist(s) to assist the recipient.

Areas of Joint Responsibility include:

Close interaction among the participating investigators will be required, as well as significant involvement from the NIH, to manage, assess, and disseminate the Network’s model. Changes to existing policies and procedures may be developed jointly by the recipient and NINDS staff and must be in compliance with relevant HHS, PHS, and NIH policies. While network membership requirements, frequency of meetings, and governance will be negotiated with NINDS staff after funding decisions have been made, the recipients and the Project Scientist(s) will meet in person with the program Steering Committee at least per year. The Steering Committee will have monthly recurring virtual meetings to advise on significant network decisions and share information on data resources, methodologies, analytical tools, as well as data and preliminary results. PDs/PIs, key co-investigators and pre- and post-doctoral trainees, especially those who are members of under-represented minority groups or those from different but related disciplines, are eligible to attend these meetings.

The Steering Committee will serve as the main scientific body of the program. Each DCoE (including the UDP), the DMCC, and the patient advocacy group representative will have one vote and the NIH Program Scientist(s) together will have one vote. The Steering Committee may establish working groups as needed to address particular issues, which will include representatives from the Network, the NIH and possibly other experts. The Network’s Steering Committee will have the overall responsibility of assessing and prioritizing the progress of the various working groups and other needed subcommittees. The DMCC Recipient agrees to work collaboratively with the Steering Committee to:

• Enhance the quality, efficiency and evaluation of Network-wide operations; assist DCoEs and the UDP in improving the efficiency and yield of diagnostic services performed by the Network; and transition the Network to a sustainable national resource that serves broad and diverse populations across the US.
• Identify and recruit highly qualified clinical sites to join the Network through the X01 or other NIH application processes
• Provide for secure, accurate and timely data submission to data repositories
• Assess and disseminate the Network’s model to the broader undiagnosed diseases community
• Collaborate with other relevant NINDS and NIH programs, as needed, to promote synergy and consistency among similar projects.

Dispute Resolution:

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

Multi-site clinical research studies

• Any third-party collaboration should be governed by a research collaboration agreement (e.g. CTA, RCA, MOU, etc.) with terms that ensure the collaboration is conducted in accordance with the Cooperative Agreement, applicable NIH policies and procedures.

Any third party in the study, including access to any study data; study results; using the name of the study; or the name/logo of the Network, NIH or any NIH institute, is permitted only after concurrence by the PO who may consult with others at NIH, including the Technology Advancement Office.

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

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement. NIH FOAs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 45 CFR Part 75.301 and 2 CFR Part 200.301.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for recipients of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All recipients 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 the threshold. See the NIH Grants Policy Statement for additional information on this reporting requirement.

In accordance with the regulatory requirements provided at 45 CFR 75.113and 2 CFR Part 200.113 and Appendix XII to 45 CFR Part 75 and 2 CFR Part 200, 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 75and 2 CFR Part 200 Award Term and Condition for Recipient Integrity and Performance Matters.

Section VII. Agency Contacts

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

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

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

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: [email protected] (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: [email protected]

Argenia Doss, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-827-1373
Email: [email protected]

John A. Peyman, Ph. D.
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-627-3544
Email: [email protected]

Sangeeta Bhargava
National Eye Institute (NEI)
Phone: 301-435-8175
E-mail: [email protected]

Jyoti Dayal
National Human Genome Research Institute (NHGRI)
Phone: 301.480.2307
E-mail: [email protected]

Faye H Chen, PhD
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Phone: 301-594-5055
E-mail: [email protected]

Chief, Scientific Review Branch
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9223
Email: [email protected]

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

Laura Pone
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-669-2951
Email: [email protected]

Karen Robinsonsmith
National Eye Institute (NEI)
Phone: (301) 451-2020
E-mail: [email protected]

Section VIII. Other Information

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

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75 and 2 CFR Part 200.