Internal Deadline: Contact RII.
LOI: 30 days prior to application due date, but is not required.
External Deadline: May 15, 2024
Recurring Deadlines: May 15, 2025
Award Type: “Other.” A mechanism that is not a grant or cooperative agreement. Examples include access to research resources or pre-applications.
Estimated Number of Awards: Funds are not awarded via the X01 mechanism. The total number of approvals for access to DMCC and Network resources is dependent on the number of meritorious applications and the capacity of the Network.
Anticipated Award Amount: Not Applicable; funds are not awarded via the X01 mechanism.
Who May Serve as PI: Standard NIH requirements.
Link to Award: https://grants.nih.gov/grants/guide/pa-files/PAR-23-171.html
Process for Limited Submissions
PIs must submit their application as a Limited Submission through the Research Initiatives and Infrastructure (RII) Application Portal: https://rii.usc.edu/oor-portal/. Use the template provided here: RII Limited Submission Applicant Template
Materials to submit include:
- (1) Two-Page Proposal Summary (0.5” margins; single-spaced; font type: Arial, Helvetica, or Georgia typeface; font size: 11 pt). Page limit includes references and illustrations. Pages that exceed the 2-page limit will be excluded from review. You must use the template linked above.
- (2) CV – (5 pages maximum)
Note: The portal requires information about the PIs in addition to department and contact information, including the 10-digit USC ID#, Gender, and Ethnicity. Please have this material prepared before beginning this application.
Undiagnosed diseases are defined as long-standing symptoms or elusive medical conditions that have not been diagnosed despite extensive clinical evaluation. Undiagnosed diseases are often due to rare conditions and can include: 1) not recognized, previously described diseases due to very low incidence or prevalence; 2) yet-to-be-described disorders; and 3) rare variations of more common diseases. These conditions present difficult problems for patients, their families, and physicians resulting in a high emotional, physical, and financial burden to patients who may spend many years seeking a diagnosis and path to treatment. Diagnoses in these difficult cases require teams of clinicians and scientists with a wide variety of special expertise. Scientific advances springing from these diagnoses require an organized approach to testing, data analysis, and validation in patients with similar rare conditions or in model organisms.
In 2008, the NIH established an intramural Undiagnosed Diseases Program (UDP) to aid individuals plagued by longstanding medical conditions that elude medical diagnosis. Using a team science approach, comprehensive clinical phenotyping and cutting-edge diagnostic and genomic technologies, the UDP was successful in ending the “diagnostic odyssey” for many individuals with rare, challenging, and difficult-to-diagnose diseases. Based on the success of the UDP, the NIH Common Fund announced in 2012 an expansion of the UDP to form a nation-wide network – the Undiagnosed Diseases Network (UDN) – composed of the NIH UDP and extramural Clinical Sites. Phase I (FY2013-2017) of the UDN included seven Clinical Sites including the UDP, a Coordinating Center, and Core Laboratories to facilitate diagnoses (genome sequencing, testing variants in model organisms, metabolomics, and a biorepository). In Phase II (FY2018-2022), the number of Clinical Sites was expanded to twelve. Since the launch of Phase I, the UDN has been very successful in achieving its objectives by: providing over 600 diagnoses; discovering hundreds of novel disease-associated genes and genomic variants, including new diseases and syndromes; and building an international reputation for establishing exemplary clinical practices, standards, and pipelines for genomics-based diagnoses.
In Phase II, the network was tasked to develop a framework that would continue the mission of the UDN after NIH Common Fund support ends in 2023. To have a broader impact on the clinical practice of undiagnosed diseases in the United States (US), the NIH envisions the UDN evolving into a larger, self-sustained network that, with public and private partners, can provide expert diagnostic services for undiagnosed patients across the nation and foster scientific discovery. The network will also seek to implement strategies that will expand equity and access to health disparity populations. In this new model, the new Network (henceforth referred to as the “Network” in this NOFO) will consist of an NIH-supported Data Management Coordinating Center (DMCC), the UDP, highly qualified and collaborative clinical sites, patients with undiagnosed diseases (referred to as “participants” in this NOFO), patient advocacy groups, and the NIH and other stakeholders including external funding providers and/or resource providers (e.g., Cores or private partnerships that conduct genomics sequencing, gene function studies or other diagnostic services).
The purpose of this NOFO is to solicit proposals from highly qualified clinical sites in the US to join the Network through an X01 Resource Access Program award. Accepted sites will be designated as a “Diagnostic Center of Excellence (DCoE)” and will be responsible for generating participant clinical, phenotypic and sequencing data to be submitted to the DMCC through a Data Use Agreement with the Center. X01 recipients will have access to DMCC resources and infrastructure including access to high-quality phenotypic and genotypic data and collaboration with highly skilled physicians, researchers, and bioinformaticians. Using team science, DCoEs will be able to collaborate with Network members to implement strategies that will expand equity and access to health disparity populations and increase the discovery of new disease-associated genes and genomic variants, immunologic and metabolic abnormalities, as well as environmental insults that are causative in previously undiagnosed patients. DCoEs will be invited to submit their most challenging, unsolved cases for acceptance into the Network, and partner in their evaluation with the Network’s virtual case review committee(s), which will be coordinated by the DMCC.
Successful applicants will demonstrate that they have the appropriate expertise and a track record of diagnosing rare and difficult-to-diagnose disorders, along with the infrastructure and resources needed to conduct the clinical evaluation and DNA sequencing of participants enrolled at their sites. Specifically, applicants will be expected to demonstrate the expertise, independent resources (e.g., institutional support, plans for billing insurance, obtaining support from outside partnerships, etc.), and capacity to:
- Enroll a minimum of 5 participants per year who are accepted into the Network, although some sites may have the capacity to enroll more participants. Typically, only the most difficult, unsolved cases will be accepted into the Network (e.g., those cases requiring specialized, non-routine diagnostic testing procedures or collaboration among a team of clinicians and researchers).
- Perform comprehensive clinical evaluations of undiagnosed participants enrolled at their site including medical record review, routine and specialized diagnostic testing procedures, consultations, and referral to other sites with necessary expertise if appropriate.
- Have the resources (in-house or outsourced) to perform DNA and/or RNA sequencing and re-analysis of existing genome-sequencing data.
- Capability to work with Network data stored in a cloud architecture, such as AnVIL.
- Have the genomics capability including medical genetics and associated informatics expertise needed to identify pathogenic variants from human genomics sequence data. This includes the infrastructure to return genetic results to study participants and provide post-test genetic counseling.
- Demonstrate sufficient clinical metabolomics and other omics expertise to interpret or re-interpret lab and research-grade findings.
- Have sufficient clinical staff to review medical records from applicants (so as to enroll a minimum of five cases per year into the Network) and to rigorously discuss the results to arrive at a diagnosis or to interrogate candidate genes.
- Collect and store DNA, fibroblasts from skin biopsies, and other biological specimens produced by clinical evaluations as needed for the diagnosis.
- Organize incoming records and return results to participants, family members, and referring physicians.
- Support a site coordinator or equivalent position to serve as the DCoE’s point of contact for data sharing, case coordination, collaboration, data retrieval for research projects and patient follow-up.
(1) The X01 mechanism does not provide budgetary support for the proposed activities. Successful X01 applications will receive access to DMCC resources and Network data (discussed above), and will have the option to apply for small research grants issued by the DMCC as subawards to DCoE sites (see: RFA-NS-22-051 for more information). The DMCC will provide at least $500,000 Direct Costs (DC) in year 1 and $1M DC per year in years 2-5 to support Network research activities. The subawards (typically in the range of $25-50K DC each) are intended to support: 1) some of the DCoEs’ costs associated with on-site coordination and submitting data to the Network; and 2) pilot research projects such as very early-stage gene function studies in model systems and clinical genomics/metabolomics investigations that are needed to facilitate a participant’s diagnosis. Subawards cannot support clinical trials.
(2) Successful applicants to this NOFO will be expected to incorporate the Network’s infrastructure and operational procedures into their proposed study plans, including coordination, collaboration, and data management through the DMCC and signing onto any agreements or Memoranda of Understanding established by the Network Steering Committee in the next phase of the UDN (see “Network Governance” below). In addition, DCoEs will be expected to work with the DMCC and Steering Committee to develop Network protocols, a Manual of Operations, and participate in Steering Committee, Case Review, diagnostic consultation, and Working Group meetings as established by the Steering Committee.
(3) Successful applicants will be required to consent participants and use a single-IRB managed by the NIH UDP that is consistent with NIH’s Single IRB Policy as described in NOT-OD-16-094 to ethically review Network-wide protocols involving human subjects research.
(4) To gain access to DMCC resources, X01 recipients will be required to submit relevant participant datasets generated at their Site (e.g., clinical, phenotypic, genomic, environmental, covariates, metadata, etc.) to the DMCC through a Data Use Agreement with the Center. The Network’s Steering Committee will develop and implement Network-wide approaches for data submission from DCoEs and timelines including data standards and formatting requirements, along with standards for data use by Network members. The DMCC is responsible for submitting de-identified data to national repositories as required in RFA-NS-22-051.
(5) DCoEs are encouraged to use innovative approaches that increase the efficiency, yield, and cost-effectiveness of the diagnosis (e.g., remote visits, tiered evaluation strategies, use of innovative tools or strategies for record review, etc.), while still providing a comprehensive and expeditious clinical evaluation.
(6) Although DCoEs are encouraged to enroll participants with disorders in any clinical specialty (similar to current UDN operations: UDN Manual of Operations), sites have the option to specialize in one or more areas of clinical practice (e.g., pediatrics, neurology, cardiology, gastroenterology, immunology, metabolism, environmentally-linked or infectious diseases, etc.).
(7) Applicants are strongly encouraged to enroll participants from health disparity populations and/or to partner with medical institutions that serve under/uninsured and health disparity populations.
Visit our Institutionally Limited Submission webpage for more updates and other announcements.