Creation of the Undiagnosed Diseases Network
In 2008, the National Institutes of Health established the Undiagnosed Diseases Program (UDP) in Bethesda, Maryland.1 The goal of this program is to provide a comprehensive evaluation for patients with rare or complex diseases in whom a diagnosis has previously eluded their medical providers. Applicants are selected based on the presence of objective signs and symptoms, availability of patients and relatives for evaluation, and likelihood of establishing a diagnosis. Patients are evaluated in Bethesda by a multidisciplinary team, and many also undergo genomic sequencing as part of the evaluation. Despite the complexity of referred cases, the UDP made diagnoses in 39 of the 160 patients evaluated in its first 2 years, including 2 previously undescribed syndromes.2
Based on the UDP’s success, the program was expanded nationally in 2015 by establishing the Undiagnosed Diseases Network (UDN). The UDN consists of an additional 11 clinical sites, a sequencing core facility, a central biorepository, a metabolomics core, 2 model organism facilities, and a coordinating center.3 This national expansion facilitates more overall evaluations and reduces the travel burden on participants. It also extends the available network of clinical and diagnostic expertise. Patients and providers submit cases via the online UDN Gateway portal. With an overall budget of $120,000,000, the ultimate goal is 450 clinical evaluations annually.3
Clinical evaluation of rare and undiagnosed diseases
Although the UDN’s primary focus is diagnosing rare diseases, we believe it also presents a unique opportunity for improving graduate medical education (GME) in the care of such patients. Most patients evaluated at UDN sites undergo genomic or other forms of -omic testing, such as transcriptomics and metabolomics. This type of evaluation has largely been restricted to research endeavors in the past. However, as the UDP and UDN illustrate, the boundary between clinical and research investigations is increasingly arbitrary. With steady reductions in cost, genomic sequencing is becoming more readily available not only as a diagnostic tool for clinicians but also as a direct-to-consumer option for patients. As a result, residency training programs must adapt to ensure trainees understand the role of genomic testing as well as the limitations of this and other -omic technologies.
The evaluation and management of patients with unexplained or rare disorders is not restricted to medical subspecialists. According to the Accreditation Council for Graduate Medical Education (ACGME) Internal Medicine Milestone Project, a residency graduation target for internal medicine trainees is the ability to care independently for patients with a “broad spectrum of clinical disorders, including undifferentiated syndromes.”4 The same document mentions that some exemplary trainees will ideally be capable of managing “unusual, rare, or complex disorders” by the time of graduation.4 However, there is little guidance to help training programs achieve these goals, and many clinicians who participate in GME have themselves not received adequate training on these topics.
Provider training in genetics and genomics
Given the increasing role of genetic evaluation in rare and undiagnosed diseases, it is essential that providers are trained in incorporating this tool into their armamentarium. However, in a contemporary survey of 597 internists and family medicine practitioners, more than half did not feel well-informed about genetic testing in general.5 Although 57% acknowledged receiving genetic training in medical school, 73% felt this training did not adequately prepare them to use genetic testing in clinical practice. Another survey of 382 internists and family practitioners found only 39% were aware of direct-to-consumer genetic testing, and only 15% felt prepared to answer questions about such testing.6 In light of these gaps in providers’ knowledge, the Inter-Society Coordinating Committee for Physician Education in Genomics released a set of key competencies in genomic medicine.7 These include the ability to collect and assess a thorough family history, recognize patterns of Mendelian inheritance, discuss the indications for and implications of genomic testing, and interpret genomic test results. Although not all practitioners would require proficiency in all these areas, the group hoped this would serve as a guiding document for GME programs.
Pilot residency training module
Given the breadth of both clinical and research expertise within the UDN, we feel it is ideally positioned to develop genomic teaching modules for residency training programs to help address this deficit in GME. At the Harvard UDN site (Brigham and Women’s Hospital, Massachusetts General Hospital, and Boston Children’s Hospital), we recently piloted such a module in the internal medicine residency program at Brigham and Women’s Hospital. This pilot involved a case of a 60-year-old gentleman with progressive right-sided weakness and alterations in sensation. Head imaging revealed multiple left-sided white matter lesions. Unfortunately, his symptoms progressed with resultant quadriparesis, dysphagia, and aphasia, and repeat brain imaging showed multiple new lesions. An extensive workup, including brain biopsy, revealed non-specific inflammation with no evidence of infection or malignancy, and his symptoms did not respond to steroid therapy. Of note, his identical twin brother was unaffected.
As part of his UDN evaluation, he was admitted to the internal medicine housestaff service. The residents responsible for his care were able to review his extensive history and prior workup, and to examine him with their attending physicians. A member of the UDN who is also a practicing medical geneticist then met with the housestaff over several days to discuss further the details of his case and the role of the UDN in his evaluation. These meetings also included a didactic session on the UDN itself as well as on key components of a family history and pedigree, whole exome and whole genome sequencing, and segregation analysis. These topics were all discussed as they pertained to this particular case. In addition to whole genome sequencing, this individual also underwent additional blood tests, imaging studies, and evaluation by various subspecialists and fellows. A final wrap-up conference involving the admitting team and all participating subspecialist services was organized by the UDN to summarize the patient’s clinical course and laboratory findings. At present, genome analysis is complete, and the UDN is coordinating additional functional assays to confirm a genetic cause of his illness. Even though the participating housestaff members had received genetics training in medical school, they found the experience particularly beneficial since they were incorporating genomic testing into the evaluation of a patient under their care rather than discussing a theoretical case. At present, we are further modifying our UDN site’s clinical pipeline so housestaff can participate in both the inpatient and outpatient evaluation.
Future Directions
Although this was a pilot program at a single institution, we hope this can serve as an impetus to develop similar programs at other UDN sites as well as additional clinical programs across the country. A strength of the UDN is the representation of numerous disciplines among the various clinical sites, including internal medicine, pediatrics, medical genetics, neurology, and numerous medical subspecialties. This presents an ideal opportunity to develop formal curricula (Table 1) for different training programs and test their efficacy. Sites should be encouraged to develop and test different educational approaches and collect data to determine which are most effective at improving genomics literacy among trainees. In particular, we believe that the UDN is well-positioned to involve trainees in not only the -omic but also the clinical evaluation and long-term management of such patients. Ultimately, these curricula should be made publicly available to ensure all trainees can benefit irrespective of the local expertise of the particular training program. Through efforts to improve the education of medical trainees, the UDN, in collaboration with other academic medical centers, may eventually achieve its mission of developing a sustainable program to improve the care of patients with undiagnosed diseases.
Table 1.
Key Components of Proposed Curriculum for Graduate Medical Education in Rare and Undiagnosed Diseases
| Didactics on whole exome/genome sequencing and other -omic technologies, interpretation of data, issues of privacy, and key terminology |
| Sessions with standardized patients focusing on family history |
| Interactive sessions on creating pedigrees and predicting modes of inheritance based on pedigrees |
| Expert discussion of prior clinical vignettes emphasizing differential diagnosis, diagnostic strategies, and principles of segregation analysis |
| Direct patient care as part of a multidisciplinary team |
| Case-based humanistic curriculum emphasizing issues regarding patients’ and providers’ response to lack of diagnosis, impact on daily lives, coping strategies, and planning for the future |
Acknowledgements
The authors would like to thank Meredith Hanna, Laurel Donnell-Fink, Joyce Hong, Christine Callahan, and Tom Licata for their invaluable assistance in evaluating and caring for patients within the UDN.
Appendix
Members of the UDN
| Members of the UDN | ||
|---|---|---|
| David R. Adams | Laurel A. Donnell-Fink | Angela L. Jones |
| Mercedes E. Alejandro | Naghmeh Dorrani | David M. Koeller |
| Patrick Allard | Daniel C. Dorset | Isaac S. Kohane |
| Euan A. Ashley | Emilie D. Douine | Jennefer N. Kohler |
| Mahshid S. Azamian | David D. Draper | Donna M. Krasnewich |
| Carlos A. Bacino | Annika M. Dries | Joel B. Krier |
| Ashok Balasubramanyam | David J. Eckstein | Jennifer E. Kyle |
| Hayk Barseghyan | Lisa T. Emrick | Seema R. Lalani |
| Gabriel F. Batzli | Christine M. Eng | C. Christopher Lau |
| Alan H. Beggs | Gregory M. Enns | Jozef Lazar |
| Babak Behnam | Ascia Eskin | Kimberly LeBlanc |
| Hugo J. Bellen | Cecilia Esteves | Brendan H. Lee |
| Jonathan A. Bernstein | Tyra Estwick | Hane Lee |
| Anna Bican | Liliana Fernandez | Shawn E. Levy |
| David P. Bick | Carlos Ferreira | Richard A. Lewis |
| Camille L. Birch | Elizabeth L. Fieg | Sharyn A. Lincoln |
| Devon Bonner | Paul G. Fisher | Sandra K. Loo |
| Braden E. Boone | Brent L. Fogel | Joseph Loscalzo |
| Bret L. Bostwick | Noah D. Friedman | Richard L. Maas |
| Lauren C. Briere | William A. Gahl | Ellen F. Macnamara |
| Donna M. Brown | Emily Glanton | Calum A. MacRae |
| Matthew Brush | Rena A. Godfrey | Valerie V. Maduro |
| Elizabeth A. Burke | David B. Goldstein | Marta M. Majcherska |
| Lindsay C. Burrage | Sarah E. Gould | May Christine V. Malicdan |
| Manish J. Butte | Jean-Philippe F. Gourdine | Laura A. Mamounas |
| Shan Chen | Catherine A. Groden | Teri A. Manolio |
| Gary D. Clark | Andrea L. Gropman | Thomas C. Markello |
| Terra R. Coakley | Melissa Haendel | Ronit Marom |
| Joy D. Cogan | Rizwan Hamid | Martin G. Martin |
| Cynthia M. Cooper | Neil A. Hanchard | Julian A. Martinez-Agosto |
| Heidi Cope | Lori H. Handley | Shruti Marwaha |
| William J. Craigen | Matthew R. Herzog | Thomas May |
| Precilla D'Souza | Ingrid A. Holm | Allyn McConkie-Rosell |
| Mariska Davids | Jason Hom | Colleen E. McCormack |
| Jean M. Davidson | Ellen M. Howerton | Alexa T. McCray |
| Jyoti G. Dayal | Yong Huang | Jason D. Merker |
| Esteban C. Dell'Angelica | Mahim Jain | Thomas O. Metz |
| Shweta U. Dhar | Yong-hui Jiang | Matthew Might |
| Katrina M. Dipple | Jean M. Johnston | Paolo M. Moretti |
| Marie Morimoto | Cynthia J. Tifft | |
| John J. Mulvihill | Camilo Toro | |
| Jennifer L. Murphy | Alyssa A. Tran | |
| Donna M. Muzny | Tiina K. Urv | |
| Michele E. Nehrebecky | Zaheer M. Valivullah | |
| Stan F. Nelson | Eric Vilain | |
| J. Scott Newberry | Tiphanie P. Vogel | |
| John H. Newman | Daryl M. Waggott | |
| Sarah K. Nicholas | Colleen E. Wahl | |
| Donna Novacic | Nicole M. Walley | |
| Jordan S. Orange | Chris A. Walsh | |
| J. Carl Pallais | Jijun Wan | |
| Christina GS. Palmer | Michael F. Wangler | |
| Jeanette C. Papp | Patricia A. Ward | |
| Neil H. Parker | Katrina M. Waters | |
| Loren DM. Pena | Bobbie-Jo M. Webb- | |
| John A. Phillips III | Robertson | |
| Jennifer E. Posey | Monte Westerfield | |
| John H. Postlethwait | Matthew T. Wheeler | |
| Lorraine Potocki | Anastasia L. Wise | |
| Barbara N. Pusey | Lynne A. Wolfe | |
| Chloe M. Reuter | Elizabeth A. Worthey | |
| Amy K. Robertson | Shinya Yamamoto | |
| Lance H. Rodan | Yaping Yang | |
| Jill A. Rosenfeld | Amanda J. Yoon | |
| Jacinda B. Sampson | Guoyun Yu | |
| Susan L. Samson | Diane B. Zastrow | |
| Kelly Schoch | Chunli Zhao | |
| Molly C. Schroeder | Allison Zheng | |
| Daryl A. Scott | ||
| Prashant Sharma | ||
| Vandana Shashi | ||
| Edwin K. Silverman | ||
| Janet S. Sinsheimer | ||
| Kevin S. Smith | ||
| Rebecca C. Spillmann | ||
| Joan M. Stoler | ||
| Nicholas Stong | ||
| Jennifer A. Sullivan | ||
| David A. Sweetser | ||
| Queenie K.-G. Tan |
Footnotes
Declarations of interest: none.
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