The NIH Undiagnosed Diseases Program

Abstract

ON MAY 19, 2008, THE NATIONAL INSTITUTES of Health (NIH) Undiagnosed Diseases Program (UDP) was launched to address an unmet need in the US health care system, ie, the diagnosis of mysterious, often multisystem diseases. A prime mover in initiating the program was the recognition by the NIH Office of Rare Diseases Research that it took 1 to 5 years to reach a proper diagnosis for 33% of patients with rare disorders and more than 5 years for 15% of these patients. Moreover, at least 6% of the inquiries to the Genetic and Rare Diseases Information Center were from individuals still seeking a diagnosis. A second critical motivation for establishing the program was to discover new diseases that would provide medically relevant insights into biochemistry, physiology, and cell biology. After receiving $280 000 in funding from the Office of Rare Diseases Research, and with the support of the National Human Genome Research Institute and the NIH Clinical Center, the program’s popularity and publicity increased rapidly, and the budget was increased to $1.9 million in fiscal year 2009 and to $3.5 million annually for fiscal years 2010 through 2012. Applications to the UDP require a summary letter from the referring clinician and complete medical records, including imaging and histologic slides of biopsy material. This material is reviewed by 1 to 5 consultants representing 25 different specialties, who offer opinions on the applicant’s suitability for admission. Accepted patients are scheduled for a week-long inpatient admission to the NIH Clinical Center. Diagnostic investigations include specialized, commercially available tests focused on candidate diagnoses, as well as generic studies using next-generation genetic analyses, eg, single-nucleotide polymorphism arrays and whole-exome sequencing. In the first 32 months of the UDP, more than 4700 inquiries were received, along with the medical records of more than 1700 individuals. Approximately 1000 cases were rejected, 400 were accepted, and the rest remain under consideration. DNA was collected from more than 300 family members of accepted patients; each person provided informed consent and was enrolled in protocol 76-HG-0238 (“Diagnosis and Treatment of Patients with Inborn Errors of Metabolism and Other Genetic Disorders”). For both the applicant pool and the accepted patients, several findings were apparent. Nearly half of the patients had neurologic problems, and approximately 40% were children; approximately 60% were female, including almost 70% of those aged 30 to 60 years (unpublished data). For patients admitted to the UDP service of the NIH Clinical Center (n=272), 20% to 25% received a diagnosis, whether on clinical, biochemical, pathologic, or molecular grounds. Two new disorders were described, several are in the process of being defined, and approximately 25 ultrarare and rare diseases were identified. New constellations of findings have been recognized to represent potentially novel diseases. The experience of the UDP has generated several important lessons and impressions. First, the brain represents the next frontier for medicine. The number of patients with neurologic problems nearly equaled the total number of patients from all other specialties combined. Neither patients nor physicians are satisfied with the diagnostic armamentarium generally available, and affected individuals frequently see several clinicians in search of understanding and relief. Neurologists are sometimes forced to use therapeutic maneuvers as a means of diagnosis; examples include the use of intravenous immune globulin or steroids for suspected inflammatory disease of the central nervous system and the use of L-dopamine for a possible neurotransmitter disorder. Treatment is often symptomatic. Second, some systemic problems in the current health care system are related to the diagnosis and care of chronic, mysterious illnesses and rare multisystem disorders. Patients often mention that the testing performed in a single week at the NIH Clinical Center (which charges no fees) would take more than a year to obtain under their insurance plans, in which approval is required for each step in serial testing. Uncertain diagnoses appear to be commonly made, either to satisfy patients or for billing purposes. At admission, UDP patients, far from lacking a