A rare disease is a health condition that affects a small number of people compared with other prevalent diseases in the general population. While there is no universal definition of rare diseases, the concept of rare diseases in the current political and legislative framework is closely linked to a definition by point prevalence. Most jurisdictions include a prevalence threshold in at least one definition of rare diseases, whereas incidence as specification in a rare disease definition is seldomly used.(1)
In the European Union (EU), a disease is considered to be rare, if it affects less than 5 of 10,000 people. In the United States of America (USA) a rare disease is defined as affecting less than 200,000 inhabitants, translating to a prevalence of about 8-9 out of 10,000 people.(2) About 30 million people in both the EU and the USA are suffering from a disease that is considered a rare disease.(3, 4)
Orphanet is a 37-country network, aiming to increase knowledge of rare diseases. It was cofounded by the European Commission in 1997. As of 2020, classification and descriptions of 6,172 rare diseases (by the European definition) are included in the Orphanet database; 71.9% being genetic and the onset of symptoms occurring during childhood in 69,9%. About 85% of rare diseases are ultra-rare with a prevalence of less than 1 per 1,000,000.(2, 5)
Due to insufficient epidemiological data, lack of scientific publications and an absence of structured databases, the number of patients suffering from an uncharacterized disease is hard to estimate. In terms of uncharacterized genetic diseases, estimates state an unidentified underlying disease gene for at least 3,000 human Mendelian diseases, and the true number may be much higher.(6)
Many rare diseases are severe chronic conditions with a complex clinical presentation and a negative impact on life expectancy and quality of life.(7) Prevention and cure as well as adequate therapies exist only for a minority of rare diseases.(8)
Implications for Patients
Patients with rare diseases face a multitude of disease-related problems. Starting with delayed diagnosis, multiple doctor’s visits before a diagnosis is made, misleading diagnosis, lack of comprehensive information provided at the time of diagnosis, insufficient coordination of care, inadequate transition from paediatric to adult care, and low or non-existent access to medication due to poor knowledge or lacking research and clinical trials. Patient organizations play a vital role in improving these circumstances.(9, 10)
The diagnostic odyssey, that many patients affected by rare diseases experience, is often due to multiple causes: a non-specific clinical presentation involving multiple organ systems that seem to be unrelated, a general lack of awareness and physician training regarding rare diseases, missing standard diagnostic criteria, a limited number of specialists, uncoordinated patient journeys through the health-care system, that cause loss of information and increase the possibility of errors and sometimes limited access to diagnostic tools.(11-13)
The connection between undiagnosed and rare disease patients
It is important to state, that rare diseases remain not always undiagnosed and undiagnosed diseases are not always hidden rare diseases. The undiagnosed patient can be affected by a rare disease, a more common disease that presents atypically, by multiple diseases occurring simultaneously, including psychosomatic disorders or by a completely new and uncharacterized disease. Both undiagnosed and rare disease patients require broad interdisciplinary evaluation, access to modern information resources and special diagnostic techniques including molecular genetics. (14)Therefore, the centres for rare diseases across Germany offer visiting hours for undiagnosed patients with or without a suspected rare disease.
In terms of the diagnostic process, a disease can be delayed when the patient has not yet been referred to the appropriate expert. This can be caused by gatekeeping delays in primary care due to missing knowledge about rare diseases as well as systemic problems due to a lack of coordination, collaboration and adequate exchange of information between several healthcare providers.(11, 15-17) A complex diagnosis is defined by a non-conclusive phenotype and genomic profile, insufficient biomarkers, presentation of unspecific but common symptoms or the concurrent existence of more than one disease. In this case, the patient might require specific equipment and contact with a centre of expertise or a reference network. In case of a diagnostic impasse all available investigations have been carried out by experts and the patient and physicians may be facing a new, yet undescribed disorder.(11, 16, 17)
Implications for Physicians
Due to the large number of rare diseases, it is impossible for a single doctor to be familiar with all of them. Especially general practitioners, who are the first contact for many patients, feel insufficiently trained in detecting rare diseases and often lack close interdisciplinary collaboration.(15)
Implications for Researchers
For researchers, one of the main obstacles is to include an adequate number of patients in clinical trials. This is a problem with any rare disease but especially affects the ultra-rare diseases. To improve this situation, collaboration of multiple centres of expertise nationwide, in some cases internationally, is needed. Therefore, research networks have started to coordinate research projects and implement highly standardized structures of data collection and sharing.(3, 18, 19)
Implications for the Economy
Patients with rare diseases generate a lot of health care expenditures. Unnecessary costs occur especially during the time before a diagnosis is established: Multiple health care contacts over a period of up to 30 years have been documented.(10) Inadequate utilization of costly therapies due to incomplete diagnosis or false indication is another reason for waste of resources.
Actions for Rare Diseases
Initiated by patient organizations, rare diseases have gained attention in politics over the last decade. Driven by European legislative requirements, national strategies for the improvement of care in rare diseases had to be developed.(20) In Germany, the National Action Plan for People with Rare Diseases implemented 52 measures to improve health care for patients with rare diseases. Some examples are: Recommendations for the implementation of national centres of expertise, specific measures to accelerate time to diagnosis, research support, improvement of information management as well as suggestions on financing of these measures.(21)
Concerning research, the development of a registry toolbox for creating individual disease-specific registries was requested. This registry toolbox should make use of an open-source software with a defined minimal data scheme and an emphasis on interoperability on a national and international level as well as metadata management.(21) This project was conducted collaboratively by the Institute of Medical Biometrics, Epidemiology and Informatics of the University Medical Centre of the Johannes Gutenberg University Mainz and the University Hospital Frankfurt in 2013 as part of the German National Action Plan and yielded the “Open Source Registry System for Seltene Erkrankungen (OSSE)”. OSSE is an easily scalable and customizable framework for developing disease specific rare disease registries automatically connected to a meta data repository and fulfilling the FAIR data principles(22): Findable: By describing metadata, people and computers can interact with the data to search for specific records. Accessible: Data is stored long-term, with defined license and access conditions, both at the level of metadata as well as the level of the instance data. Interoperable: Data sets can be combined with other data sets. Reusable: Data can be used for further research using computational methods.. Further development of the OSSE registry framework is ongoing by the Medical Informatics Group (MIG) of the University Hospital Frankfurt.(21, 23-25)
To improve timely and correct diagnosis for patients with rare diseases, the development of a ‘registry for undiagnosed patients’ was also recommended by the German National Action Plan, taking into account that a high percentage of these ‘undiagnosed patients’ eventually are diagnosed to have a rare disease.(21)
Similar National strategies have been developed in most member states of the European Union as well as Norway, Switzerland and the UK.(26) Some international examples are: The National Institutes of Health Undiagnosed Diseases Program, which started in 2008(27); the “Nan-Byo” (which translates as “difficult and illness”), which was established in 1972 in Japan and extended in 2015 as Japan’s Initiative on Rare and Undiagnosed Diseases(28); In February 2020, the Australian government announced to provide funding for activities to implement the National Strategic Action Plan for Rare Diseases, which was developed by Rare Voices Australia.(29)
Registries for Rare Diseases
Registries in general and especially in the field of rare diseases can help to connect data from multiple health care providers (HCP), thus enlarging the data base for research questions, including epidemiology of rare diseases. However, disease-specific ICD-10 codes are not available for most rare diseases and Orpha-codes, OMIM-codes or alpha-IDs are not used in routine clinical care. Therefore, prevalence calculated from disease-specific registries have limited accuracy.(30, 31) And, of course, usually academia driven registries do not achieve sufficient representation of the whole disease population to allow calculation of prevalence.
Due to the fact that undiagnosed patients present with a wide variety of symptoms at different levels and specialities within the health care system, it is even more complicated to assess the number of undiagnosed patients.
Undiagnosed patients face specific problems caused by their lack of diagnosis. Such as long diagnostic odysseys and also a feeling of “not belonging anywhere” and self-doubt, which prevents access to self-help-groups and social support. Illustrating the feelings of suffering and loss, the inability to make plans, uncertainty, fear and rejection by clinicians and others, illness narratives of undiagnosed patients are from a chaotic type.(32) Therefore, it seems reasonable to create a registry addressing undiagnosed patients in order to create an opportunity to connect with others experiencing similar problems, shorten their path to diagnosis and by identifying chronic conditions at an earlier stage possibly producing savings to the health care system.(33)
As most medical registries focus on one specific disease or group of diseases, they contain disease-specific and disease-relevant data. Patients, who are not yet diagnosed do not fit into these registry schemes. Therefore, in this paper we focus on the question on how such a registry for undiagnosed patients can be built and which information it should contain.