# Focus on the Undiagnosed Diseases Network

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Accelerating discovery and innovation in the way we diagnose and treat patients with previously undiagnosed diseases.

The Undiagnosed Diseases Network (UDN) is a research program that combines basic and clinical research services to understand health conditions for individuals and their families who have sought a clinical diagnosis without success. The program is supported by 17 Institutes and Centers at the National Institute of Health and is led by the National Institute of Neurological Disorders and Stroke (NINDS).  Launched by the NIH Office of the Director’s Common Fund in 2013, it has facilitated difficult diagnoses for more than 650 people in the past decade – providing answers to patients who have long searched for the cause of their symptoms. Team science and collaboration among UDN investigators has led to the discovery of hundreds of novel disease-associated genes and genomic variants, including the identification of new diseases and syndromes. Together, the UDN has built an international reputation for advancing disease research while establishing exemplary clinical practices for undiagnosed diseases.

## What are Undiagnosed Diseases?

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) previously described diseases that are not recognized due to very low incidence or prevalence; 2) yet-to-be-described disorders that have not been previously documented; and 3) rare variations of more common diseases. These conditions and the lack of a diagnosis 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. 

## History of the UDN

The National Human Genome Research Institute and the NIH Clinical Center established the intramural Undiagnosed Diseases Program (UDP) in 2008 to make progress in uncovering, understanding, and treating rare disorders. Based on the success of the UDP, the NIH Common Fund established the Undiagnosed Diseases Network (UDN) in FY 2013 (phase I) to achieve this type of cross-disciplinary approach to disease diagnosis in academic medical centers around the United States. The NIH Common Fund expanded the network in 2018 (phase II) to increase the availability of diagnostic services, foster opportunities for collaboration between laboratory and clinical investigators, provide resulting data and protocols to the broader community, and assess development of a sustainable national resource after Common Fund support ends. The UDN transitioned from Common Fund in 2023.

## The Next Phase

NIH is using a NIH-wide approach to support the UDN beyond 2023. The National Institute of Neurological Disorders and Stroke (NINDS) will oversee the Network in Phase III, which will launch in July 2023, with help from 17 different NIH Institutes and Centers along with the NIH Office of the Director. With help from patients, family members, patient advocacy groups, a Data Management and Coordinating Center (DMCC), several Clinical Sites, and other stakeholders, the NIH envisions the UDN evolving into a larger, diverse, and self-sustained network that fosters scientific discovery and provides expert diagnostic services for undiagnosed patients across the nation.

**The overarching goals of the UDN in Phase III include:**

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## Phase III UDN Priorities

              - Scale clinical capacity to engage more patients across the US by incorporating community and third-party payer support for patient services while NIH funds continue to support the research efforts.  
              - Expand access to the UDN for individuals and groups who historically have not benefited from modern diagnostic investigations due to racial, ethnic, socioeconomic, geographic or other systemic reasons. 
              - Continue to incorporate input from patients, caregivers and family members into the practice of the UDN.
              - Continue the fruitful genetic investigations, but expand to including other potential causal factors such as environmental insults, infectious, oncologic, immunologic, or complex multi-organ disorders.
              - Continue to develop health economics approaches to support the sustainability of the UDN approach to investigate persons with undiagnosed medical conditions.
              - Incorporate implementation science methods to facilitate the translation of UDN lessons- learned into the mainstream of medical care.  

## Phase III UDN

In FY2023, NINDS and 17 other NIH Institutes joined together to launch the Phase III Network as a Trans-NIH Initiative. NIH has awarded a cooperative agreement to establish a new UDN Data Management and Coordinating Center (DMCC), which will provide infrastructure and research support for a new network of clinical sites. The DMCC will also support Research Cores (genomic sequencing, model organisms screening center, metabolomic and proteomic analysis, etc.) based on the needs of the Network cases, via subawards. To ease the transition from Phase II to Phase III and ensure that applicants continue to have the opportunity to receive a diagnosis, eligible Phase II extramural clinical sites were also awarded an additional year of support under the Limited Competition for the Continuation of Clinical Sites for the Undiagnosed Diseases Network Notice of Funding Opportunity (NOFO). The intramural Undiagnosed Disease Program, housed within the NIH Clinical Center and currently supported as a UDN clinical site, will continue to receive support and oversight from multiple NIH Institutes and Centers. 

### More About Phase III UDN

Starting in 2023, additional, new Clinical sites with the appropriate infrastructure, expertise, and resources needed to conduct the clinical evaluation and DNA sequencing of participants enrolled at their sites can apply for designation as a Diagnostic Center of Excellence via an X01 Resource Access Program, the U01 PAR-23-289 NOFO, or through future NIH NOFOs. The Diagnostic Centers of Excellence will have access to the rich research capacity, data infrastructure and the DMCC subaward resources to enable diagnoses for the most difficult cases. Thus, these clinical sites will be poised to expand geographic coverage and reach individuals in the U.S. specifically from populations defined by the NIH to experience health disparities. If you have questions regarding NOFO PAR-23-289, please see our Frequently Asked Questions section below.

### Phase III Awardees

Explore our awardees for the Data Management Coordinating Center for Diagnostic Centers of Excellence RFA (RFA-NS-22-051), Limited Competition for the continuation of UDN Clinical Sites RFA (RFA-NS-23-004), and Diagnostic Centers of Excellence PAR (PAR-23-171).

### PAR-23-289 Diagnostic Centers of Excellence for the Undiagnosed Diseases Network (U01 Clinical Trial Not Allowed) Frequently Asked Questions:

Below you will find answers to the most frequently asked questions. If you do not find your answer, please email: UDNProgramStaff@ninds.nih.gov

**Q: What are the differences between the X01 award (**PAR-23-171: Diagnostic Centers of Excellence (X01 Clinical Trial Not Allowed) (nih.gov)**) and the U01 award (**PAR-23-289: Diagnostic Centers of Excellence for the Undiagnosed Diseases Network (U01 Clinical Trial Not Allowed) (nih.gov)**) mechanisms? What are the different expectations for the clinical sites under these awards?**

**A:** The X01 award is a resource access award that allows qualified clinical sites access to UDN and Data Management Coordinating Center (DMCC) resources but does not provide direct NIH funding. Resources include infrastructure, data management, and clinical research support including the option to apply for small subawards issued by the DMCC to support limited research activities. See RFA-NS-22-051 for more information about DMCC resources. X01 applicants must 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. X01 awardees will be required to enroll and perform comprehensive clinical evaluations for a minimum of 5 undiagnosed participants.  Both X01 and U01 awardees will receive the designation of Diagnostic Center of Excellence (DCoE). 

The U01 cooperative agreement award grants qualified clinical sites access to UDN and DMCC resources **and** provides up to $500,000 Direct Costs/year for up to 4 years to enroll and perform comprehensive clinical evaluations at their site and propose a research plan that meets the following Phase III priorities: 
              - Scale clinical capacity to engage more participants across the US by increasing diagnostic efficiencies and incorporating community and third-party payer support for patient services. 
              - Expand access to the UDN for individuals and groups who historically have not benefited from modern diagnostic investigations due to race, ethnicity, socioeconomic status, geographic location, sex/gender, linguistic or other systemic barriers. The U01 NOFO includes the requirement that sites partner with community collaborators that serve populations defined by the NIH to experience health disparities. 
              - Propose and develop innovative strategies to investigate other potential causal factors in undiagnosed diseases such as environmental insults, infectious, oncologic, immunologic, or complex genetic disorders.
              - Collaborate with the DMCC to survey and incorporate input from patients, caregivers and family members into the practice of the UDN to ensure participants consistently receive a high-quality experience.

**Q: Are X01 DCoEs able apply to PAR-23-289?**

**A:**Yes, X01 DCoEs are eligible to submit an application in response to PAR-23-289. However, X01 awardees that are successful in obtaining an U01 award will be required to relinquish the X01 access award. Institutions/PIs are allowed only one active Diagnostic Center of Excellence (DCoE) award at a time, whether awarded through the U01 or X01 grant mechanism.

**Q: Is there a minimum number of participants that clinical sites are required to enroll under this NOFO?**

**A:**Since NIH would like to move away from creating a fixed “ceiling” in the number of participants who are enrolled each year, the NOFO intentionally does not specify minimum annual enrollment requirements. ****Participant recruitment will be a joint effort between the Clinical Sites and the DMCC, with the expectation to expand access to populations that experience health disparities. Applicants are****expected to propose a reasonable number for participant enrollment at their site that is in line with the budget request, along with plans to expand enrollment as Network efficiencies are achieved. Since reviewers will be tasked with evaluating enrollment plans, we recommend that applicants justify their enrollment plans in their application. For example, a site’s participant enrollment plan may depend on many variables including complexity/difficulty of cases, how many participants lack insurance and require NIH funds for patient costs or travel, a site’s plans to move into potentially more expensive non-genomic strategies, etc. 

**Q: What resources will the DMCC provide to Clinical Sites?**

**A:** Please see RFA-NS-22-051 for a description of the resources that the DMCC is required to provide. In addition, more information can be found by by contacting the DMCC. 

**Q: How can Clinical Sites cover the costs for clinical sequencing and research sequencing? Can investigators include sequencing costs to their proposed grant budget under this NOFO?**

**A:** Clinical sequencing should be billed to insurance or covered through private foundation or institutional support, etc., whenever possible. The DMCC has established a Sequencing Core this year that can be used to cover the sequencing of participants who lack insurance coverage or when outside sources of support are not available.  Most types of research sequencing (i.e., WGS, WES, RNAseq) will be supported by the DMCC’s Sequencing Core and should not be included in the grant budget. More advanced types of genomic sequencing such as long-read sequencing will not be supported by the DMCC and can be included in the grant budget. If in future years a site’s sequencing requirements exceed the capacity of the DMCC’s Sequencing Core, the recipient can request to rebudget their funds to support these costs. 

**Q: Can participant travel costs be included in the grant budget?**

**A:** Applicants are expected to prioritize the use of NIH funds to cover patient costs and travel for un/underinsured participants who are economically disadvantaged. The goal is to provide UDN access to participants who otherwise would not be able to participate in the program.

**Q:****What bioinformatics expertise should individual clinical have?**

**A:** Clinical Sites are required to have advanced bioinformatics expertise to analyze human sequence data in addition to the ability to leverage novel, cutting edge informatics approaches. The DMCC also has bioinformatics expertise that will be shared with DCoEs as needed, for example, through virtual consultation meetings. 

**Q: How many sites will NIH fund?**

**A:** The number of Clinical Site U01 awards will depend on Congressional appropriations.  If resources are available, an NIH goal in Phase III is to expand the number of UDN Clinical Sites in the U.S. (e.g., 12-15).

**Q: What are NIH’s expectation for engaging and enrolling minority populations (e.g., percentage, minimum number, etc.) including establishing community partnerships to help achieve this goal?**

**A:** Although the NIH and UDN Steering Committee have not set a minimum percentage or number for enrolling minority populations, an NIH goal in Phase III is to expand access to the UDN for individuals and groups who historically have not benefited from modern diagnostic investigations due to race, ethnicity, socioeconomic status, geographic location, sex/gender, linguistic or other systemic barriers.  To help achieve this goal, we ask applicants to partner with community collaborators that serve populations defined by the NIH to experience health disparities, to develop cooperative and mutually beneficial partnerships with the community collaborators.  Site’s may vary in their capacity and/or unique opportunities to develop different types of community partnerships (e.g., based on geographical location or other factors). The U01 NOFO stipulates that “at least one of the partnerships must be a community healthcare organization that provides services for economically disadvantaged individuals who are under/uninsured.”

### Current Trans-NIH UDN Working Group Members

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## Contact

For questions about UDN, please contact Program Staff at UDNProgramStaff@ninds.nih.gov. 

For more information about the UDN or application process, individuals can contact the UDN Coordinating Center by:
              - Telephone                  - Toll-free from USA, Canada, Mexico: 1-844-RING UDN (746-4836)
                - From all other countries: 1-617-432-2344
              - Email: UDN@hms.harvard.edu

> Resources
UDN Coordinating Center Website

UDN Participant Engagement and Empowerment Resource (PEER)

Undiagnosed Diseases Network International (UDNI)

Undiagnosed Diseases Network Foundation