Background
Undiagnosed diseases are defined as constellations of findings that remain refractory to medical diagnostic approaches. Undiagnosed diseases affect approximately 30 million Americans and include (a) rare diseases that are difficult to identify, (b) atypical presentations of known disorders, and (c) yet to be described diseases [
1]. Undiagnosed diseases typically manifest with objective findings, which are clinically measurable on physical examination or through medical testing and these provide tangible targets for further diagnostic approaches (e.g. dysmorphic facies, abnormal biochemical profiles, physical exam demonstrating weakness or abnormal gait). Approximately 80% of rare and undiagnosed disorders have a genetic basis [
1].
The National Institutes of Health established a multi-site network of clinical sites and core laboratories, the Undiagnosed Diseases Network (UDN), in 2013 [
2,
3] (
https://undiagnosed.hms.harvard.edu) to facilitate the diagnosis/research of undiagnosed and rare diseases. Network-wide, the UDN receives approximately 70 applications each month from adults and parents of children with unexplained illnesses. Application to the UDN is open to all individuals who complete the application with a referral letter from a healthcare provider. The clinical sites make decisions after a comprehensive review of an applicant’s medical records. The network accepts about half (51.8%) for further evaluation. UDN applicants have a wide range of objective and subjective (non-objective) symptoms; however we noticed that many applicants presented primarily or exclusively with subjective findings.
Subjective findings are non-objective, patient-reported symptoms that are not verifiable by physical exam or medical tests [
4‐
6] (e.g. pain, fatigue, weakness that is not substantiated by physical exam). Patients with subjective findings may fall under the diagnostic terms of functional disorder, central sensitivity syndrome, subjective health complaints or even carry the DSM5 diagnosis of somatic symptom disorder. It is difficult to estimate the number of patients affected by these disorders, although it represents a common conundrum in adult primary care medicine [
7‐
9]. Many patients with primarily/exclusively subjective findings may consider themselves to have undiagnosed diseases and while a small number may have underlying organic disease, the majority are not believed to do so [
6,
10].
Both patients with objective and subjective findings accrue substantial healthcare costs and seek opinions from multiple specialists, often undergoing extensive/invasive diagnostic testing in their search for a diagnosis [
11‐
14]. Both groups also express chaos in their lives, frustration with negative laboratory tests/procedures, and seek validation of their symptoms [
15]. This results in significant personal psychosocial and financial distress and a societal economic impact in both entities [
16‐
19]. However, the likely underlying causes for each group are different: Subjective findings have a number of predisposing risk factors and environmental triggers [
20,
21] and genetic factors are expected to play at most a modest role [
22]. Conversely, approximately 80% of undiagnosed disorders with clear objective findings have a genetic etiology [
1,
17,
23]. Thus, the diagnostic and management approaches for each group differ, with strategies focused on symptom management for the subjective group and further diagnostic pathways, including genomic sequencing for undiagnosed diseases with objective findings.
Utilizing the UDN applicant cohort, we characterize symptoms, referral patterns, and demographic factors among applicants that are and are not accepted for evaluation in the UDN. We sought to provide information to healthcare providers and patients regarding applicants that are suitable for further diagnostic avenues such as the UDN, but more importantly we hope to contribute to a discussion on the need for diagnostic/management/research pathways for applicants who suffer primarily/exclusively from subjective findings.
Discussion
Our findings indicate that many applicants that are not accepted to the UDN suffer primarily from subjective symptoms. Further, Not Accepted Applicants were more often adults who had experienced illness for a shorter proportion of their lives and had more non-neurological presentations. Although objective and subjective symptoms were seen in both groups, higher numbers of subjective symptoms were reported for Not Accepted Applicants relative to Accepted subjects. This is true regardless of whether an Accepted applicant was diagnosed by the UDN or not, indicating that a functional disorder was less likely in these remaining still-undiagnosed Accepted applicants, distinguishing them from the Not Accepted applicants. When objective findings were noted in the Not Accepted applicants, these were often unrelated to the reasons for applying to the UDN (e.g. iron deficiency anemia, abnormal thyroid profile) or were non-specific (e.g. positive anti-nuclear antibody). Taken together, we infer that Not Accepted subjects suffer primarily from subjective symptoms that are unlikely to be caused by or related to any objective findings. As such, these applicants are not candidates for further diagnostic efforts such as those offered by the UDN. Interestingly, the Not Accepted Applications took longer to review, perhaps due to a higher volume of medical records that needed to be reviewed to determine if there were features (such as objective findings beyond subjective symptoms) that would warrant acceptance, although we specifically did not ascertain the reasons for review time.
We also found that primary care physicians referred the largest proportion of applicants to the UDN, but that their referrals had fewer objective findings and were less likely to be accepted. We did not identify a clear reason for this finding, but given that there is no difference in the number of specialty consultations between Not Accepted Applicants and Accepted Applicants, a lack of access to specialists is unlikely. Instead, we presume this indicates that patients with non-objective symptoms continue to seek diagnostic efforts and additional referrals through their PCPs after consultations with specialists do not provide a diagnosis [
24].
In the context of the UDN, and perhaps more importantly in the setting of clinical practice, it is important to make a distinction between undiagnosed patients with and without objective findings. Undiagnosed patients with clear objective findings are expected to have a genetic basis in most instances; therefore these diseases can reasonably be expected to be solved (eventually) with additional tests, procedures, and genomic investigations. The UDN is one of several avenues available to pursue a unifying diagnosis. For patients with primarily/exclusively subjective symptoms, additional clinical or genomic investigations are likely to provide a concrete diagnosis in only a small minority (< 5%) of cases [
10,
25]. There is evidence that risk factors may play a part, such as stress, underlying mood disorders and viral infections, and there are several diagnostic terms, including “functional disorder,” “central sensitivity syndrome,” or “somatic symptom disorder” that may fit these individuals [
20,
21]. Whether these diagnoses have been discussed with these UDN applicants is not ascertainable from the data available, but it is certain that these applicants attribute their symptoms to a physical illness that requires additional diagnostic efforts.
Despite the dichotomy between undiagnosed patients with and without objective symptoms, the societal and personal impact is remarkably similar. Both groups incur high medical costs and the affected individuals are often significantly disabled. In our recent analysis of UDN narratives, all applicants expressed similar levels of chaos in their lives and frustration with negative laboratory tests/procedures and many stated that the UDN represented their last hopes for a diagnosis [
15].
Although the UDN provides recommendations for applicants and their physicians whenever appropriate, in many cases the onus of continuing medical investigation and treatment falls to primary care physicians, who themselves have limited resources, especially limited time, and few research avenues available to them in their efforts to diagnose/treat patients with subjective findings. There are some research studies that may be an option (
https://mecfs.ctss.nih.gov;
https://painconsortium.nih.gov), but there are only a few specific clinical programs (
http://www.chop.edu/centers-programs/center-amplified-musculoskeletal-pain-syndrome;
http://www.amazingkids.org/Medical-Services/pain-rehabilitation) to address non-objective symptoms, and they are treat primarily children. The diagnostic terms “functional disorder,” “central sensitivity syndrome,” or “somatic symptom disorder” were almost never identified in referral letters, indicating that PCPs may not be discussing these. Clearly more avenues for management of subjective symptoms are needed beyond the care that PCPs may be able to provide these patients.
This study has some limitations that future research efforts may address. We were unable to ascertain a comprehensive list of subjective/objective findings directly from medical records review. We may have under-ascertained primary care provider referrals because all mid-level providers were classified as “other” regardless of specialty. We were unable to speak with referring providers directly, and future studies that consider these discussions may provide additional insights into a physician’s motivations for referral. We were not able to follow applicants after a decision was made and so do not know if any of the Not Accepted applicants received a diagnosis. We also did not have socioeconomic status data available and these may have influenced the types of applications received.
Acknowledgements
We would like to acknowledge all members of the Undiagnosed Diseases Network: David R. Adams, Mercedes E. Alejandro, Patrick Allard, Euan A. Ashley, Mahshid S. Azamian, Carlos A. Bacino, Ashok Balasubramanyam, Hayk Barseghyan, Gabriel F. Batzli, Alan H. Beggs, Hugo J. Bellen, Jonathan A. Bernstein, Anna Bican, David P. Bick, Camille L. Birch, Devon Bonner, Braden E. Boone, Bret L. Bostwick, Lauren C. Briere, Donna M. Brown, Matthew Brush, Elizabeth A. Burke, Lindsay C. Burrage, Shan Chen, Gary D. Clark, Terra R. Coakley, Joy D. Cogan, Cynthia M. Cooper, Heidi Cope, William J. Craigen, Precilla D’Souza, Mariska Davids, Jean M. Davidson, Jyoti G. Dayal, Esteban C. Dell’Angelica, Shweta U. Dhar, Ani Dillon, Katrina M. Dipple, Laurel A. Donnell-Fink, Naghmeh Dorrani, Daniel C. Dorset, Emilie D. Douine, David D. Draper, Annika M. Dries, David J. Eckstein, Lisa T. Emrick, Christine M. Eng, Gregory M. Enns, Ascia Eskin, Cecilia Esteves, Tyra Estwick, Liliana Fernandez, Paul G. Fisher, Brent L. Fogel, Noah D. Friedman, William A. Gahl, Emily Glanton, Rena A. Godfrey, David B. Goldstein, Sarah E. Gould, Jean-Philippe F. Gourdine, Catherine A. Groden, Andrea L. Gropman, Melissa Haendel, Rizwan Hamid, Neil A. Hanchard, Lori H. Handley, Matthew R. Herzog, Ingrid A. Holm, Jason Hom, Ellen M. Howerton, Yong Huang, Howard J. Jacob, Mahim Jain, Yong-hui Jiang, Jean M. Johnston, Angela L. Jones, David M. Koeller, Isaac S. Kohane, Jennefer N. Kohler, Donna M. Krasnewich, Elizabeth L. Krieg, Joel B. Krier, Jennifer E. Kyle, Seema R. Lalani, C. Christopher Lau, Jozef Lazar, Brendan H. Lee, Hane Lee, Shawn E. Levy, Richard A. Lewis, Sharyn A. Lincoln, Allen Lipson, Sandra K. Loo, Joseph Loscalzo, Richard L. Maas, Ellen F. Macnamara, Calum A. MacRae, Valerie V. Maduro, Marta M. Majcherska, May Christine V. Malicdan, Laura A. Mamounas, Teri A. Manolio, Thomas C. Markello, Ronit Marom, Julian A. Martínez-Agosto, Shruti Marwaha, Thomas May, Allyn McConkie-Rosell, Colleen E. McCormack, Alexa T. McCray, Jason D. Merker, Thomas O. Metz, Matthew Might, Paolo M. Moretti, John J. Mulvihill, Jennifer L. Murphy, Donna M. Muzny, Michele E. Nehrebecky, Stan F. Nelson, J. Scott Newberry, John H. Newman, Sarah K. Nicholas, Donna Novacic, Jordan S. Orange, J. Carl Pallais, Christina GS. Palmer, Jeanette C. Papp, Neil H. Parker, Loren DM. Pena, John A. Phillips III, Jennifer E. Posey, John H. Postlethwait, Lorraine Potocki, Barbara N. Pusey, Chloe M. Reuter, Amy K. Robertson, Lance H. Rodan, Jill A. Rosenfeld, Jacinda B. Sampson, Susan L. Samson, Kelly Schoch, Molly C. Schroeder, Daryl A. Scott, Prashant Sharma, Vandana Shashi, Edwin K. Silverman, Janet S. Sinsheimer, Kevin S. Smith, Ariane G. Soldatos, Rebecca C. Spillmann, Kimberly LeBlanc, Joan M. Stoler, Nicholas Stong, Jennifer A. Sullivan, David A. Sweetser, Cynthia J. Tifft, Camilo Toro, Alyssa A. Tran, Tiina K. Urv, Zaheer M. Valivullah, Eric Vilain, Tiphanie P. Vogel, Daryl M. Waggott, Colleen E. Wahl, Nicole M. Walley, Chris A. Walsh, Michael F. Wangler, Patricia A. Ward, Katrina M. Waters, Bobbie-Jo M. Webb-Robertson, Monte Westerfield, Matthew T. Wheeler, Anastasia L. Wise, Lynne A. Wolfe, Elizabeth A. Worthey, Shinya Yamamoto, Yaping Yang, Guoyun Yu, Diane B. Zastrow, Chunli Zhao, Allison Zheng.