NIH Names New Clinical Sites in Undiagnosed Diseases Network

The National Institutes of Health has awarded grants to six medical centers across the United States to select from the most difficult-to-solve medical cases and together develop effective approaches to diagnose them. The sites will conduct clinical evaluation and scientific investigation in cases that involve patients with prolonged undiagnosed conditions.

Each clinical site will contribute local medical expertise to the NIH Undiagnosed Diseases Network (UDN). The network includes and is modeled after an NIH pilot program that has enrolled people with intractable medical conditions from nearly every state, the District of Columbia, and seven foreign countries. The network builds on a program at the NIH clinical center in Bethesda, Md, that for the past 6 years has evaluated hundreds of patients and provided many diagnoses for rare conditions, often using genomic approaches.

“Newly developed methods for genome sequencing now provide us amazingly powerful approaches for deciphering the causes of rare undiagnosed conditions,” said Eric D. Green, MD, PhD, director of the National Human Genome Research Institute (NHGRI). “Along with robust clinical evaluations, genomics will play a central role in the UDN’s mission.”

Undiagnosed diseases are conditions that even skilled physicians cannot diagnose despite extensive clinical investigation. They may not be recognized by doctors because they are rarely seen, are previously undescribed, or are rare forms of more common diseases.

The NIH Common Fund awarded 4-year grants of approximately $7.2 million (pending available funds) to each of the six medical centers around the country. James M. Anderson, MD, PhD, director of the NIH division of program coordination, planning, and strategic initiatives, announced in an NIH telebriefing that the six newly awarded sites join a clinical site already established at NIH in pursuing cutting-edge diagnoses. In addition, this past December, NIH selected Harvard Medical School as the UDN coordinating center for the multi-institution network.

“The NIH Undiagnosed Diseases Network has the potential to transform medicine and serve as a catalyst for new discoveries,” said Anderson. “It is an ideal NIH Common Fund program—the only one focused on diagnoses of rare disorders.”

The following institutions were awarded grants to establish UDN clinical sites:

• Baylor College of Medicine, Houston; principal investigator (PI), Brendan H.L. Lee, MD, PhD.
• Boston Children’s Hospital, Brigham and Women’s Hospital, and Massachusetts General Hospital, Boston; PI, Joseph Loscalzo, MD, PhD.
• Duke University, Durham, NC; PIs, Vandana Shashi, MD; David B. Goldstein, PhD.
• Stanford University, Stanford, Calif; PIs, Euan A. Ashley, MD, DPhil; Jonathan Bernstein, MD, PhD; Paul Graham Fisher, MD.
• University of California, Los Angeles; PIs, Eric J. Vilain, MD, PhD; Katrina M. Dipple, MD, PhD; Stanley Nelson, MD; and Christina Palmer, CGC, PhD.
• Vanderbilt University Medical Center, Nashville; PIs, John A. Phillips III, MD; John H. Newman, MD.

“This type of program can invigorate a medical center anywhere in the country and in the world,” said William A. Gahl, MD, PhD, clinical director at NHGRI, director of the NIH-based Undiagnosed Diseases Program (UDP), and co-coordinator of the UDN working group. “Often, patients have a lot of physical complaints and no objective diagnoses. Our goal is to use the latest tools to make a diagnosis that spans the clinical, pathological, and biochemical spectrum to uncover the basic genetic defect.”

Since 2008, the UDP has explored this fascinating area of medical research and acquired practical insights in the process of enrolling approximately 600 undiagnosed children and adults in its clinical protocols. The multidisciplinary clinical and research team diagnosed approximately 100 patients (20% to 25% of those evaluated), discovered two unknown diseases, and identified 15 genes not previously associated with any other human disease. A combination of genomic and clinical analyses contributed to the diagnoses.

By including an additional six clinical sites, the NIH UDN will both draw upon the unique expertise of new clinical research groups and cultivate opportunities for collaboration among a larger group of expert laboratory and clinical investigators. Physicians within the network will collect and share high-quality clinical and laboratory data, including genomic information, clinical observations, and documentation of environmental exposures. They will also benefit from common protocols designed to improve the level of diagnosis and care for patients with undiagnosed diseases.

“The UDN will look at diseases across all clinical specialties using new tools and methods of analysis for the identification of new diseases,” said Anastasia L. Wise, PhD, a program director in NHGRI’s division of genomic medicine and co-coordinator of the UDN working group that oversees the development and implementation of the UDN. “The network will facilitate collaboration and shared use of genomic tools among the sites.”

Based on the NIH UDP experience, the UDN coordinating center at Harvard Medical School has begun paving the way for the new UDN clinical sites to begin accepting patients. Among the coordinating efforts are the preparation of draft protocols and operating guidelines, and the definition of an initial framework of common practices across the network. The network will share systems for data collection and develop common approaches to patient selection, evaluation, and diagnosis.

Each new clinical site may have variations in handling health insurance coverage for clinical testing and care. However, no patient will be turned away from participation in the UDN based on lack of health insurance coverage.

“We believe that there is a substantial unmet demand for the diagnoses of conditions that have perplexed skillful physicians,” said Isaac Kohane, MD, PhD, professor of pediatrics at Harvard Medical School and Boston Children’s Hospital, and principal investigator of the coordinating center. “We want to address inquiries from physicians and patients throughout the country who require these services and, in doing so, create a 21st-century model for diagnosis and treatment in this genomic and information-intensive era.”

UDN investigators will share genomic data from UDN patients with the research community through multiple public repositories. Network-wide data sharing will observe standards of patient privacy, confidentiality, and management of health information.

The network will start up and test its operating procedures during its first year. It will progressively expand recruitment of patients so that by the summer of 2017 the rate of admissions at each new clinical site will be about 50 patients per year. For a period this summer, referrals from clinicians on behalf of undiagnosed patients may continue to be made through the existing NIH application pipeline.

Instructions on applying to the UDN on behalf of a patient can be found at rarediseases.info.nih.gov/undiagnosed. For more information about the UDN, including related funding announcements, visit the NIH Common Fund. Additional information about NHGRI can be found at www.genome.gov.