Rare diseases are characterized by a common denominator that is the infrequency of their occurrence in the human population.
According to European Union criteria, rare diseases affect 5 per 10,000 persons in the EU population; in USA, rare diseases are defined as conditions that affect fewer than 200,000 individuals in the overall USA population, i.e. 320 million people.
Although the frequency of separate entities often seem negligible, in the EU rare diseases affect about 30 million people and an estimated 25 million to 30 million Americans.
Currently from 6000 to 8000 rare disorders are defined and many of them are waiting to be named in the future.
Patient populations for individual rare diseases are small and scattered; international collaborations and networks are crucial to pool resources fragmented across individual countries for a better diagnosis and treatment.
Undiagnosed rare diseases are conditions that elude diagnosis by a referring physician; some patients wait years for a definitive diagnosis. Undiagnosed rare diseases may include groups of unnamed disorders with common characteristics, phenotypically well described diseases, diseases with an unknown molecular basis or due to unknown, non-genetic factors.
In 2008, in the USA the NIH Undiagnosed Disease Program was established to provide a diagnosis for individuals waiting for a long time without success.
A second goal was to obtain insights into novel disease aethiopathogenesis. In 2013, the Common Fund of the NIH supported a nationwide Undiagnosed Diseases Network.
Nevertheless, the unmet needs of undiagnosed patients remain a global issue.
To begin to address this, the Common Fund, within the Office of the NIH Director, along with the Wilhelm Foundation, Sweden, has sponsored two International Conferences (Rome, September 29-30, 2014 and Budapest, June 26-27 2015). In attendance were representative of 16 countries and 4 continents. Afterwards an international network was formed, the Undiagnosed Diseases Network International-UDNI.
Principles
[from: D. Taruscio, et al., Undiagnosed Diseases Network International (UDNI): White paper for global actions to meet patient needs, Mol. Genet. Metab. (2015), http://dx.doi.org/10.1016/j.ymgme.2015.11.003]
Below are the general principles of the newly formed UDN International (UDNI).
1. Patients enrolled in the UDNI should be selected for the unique characteristics of their disorder and for its potential to inform new aspects of cell biology, pathogenetic mechanism(s) and therapy. Candidate patients should have been extensively examined already, so that obvious diagnoses have been eliminated.
2. Accepted patients should be thoroughly evaluated by the UDNI, preferably at no cost to the patient.
3. Patients should consent to share their data with other investigators within the group, according to the tenets of the Helsinki Declaration and/or of Good Clinical Practices. Patient phenotypes should be expressed using a standard ontology system in order to build up a highly integrated database.
3. Next-generation sequencing and other -omics analyses (e.g., proteomics, glycomics, lipidomics) should be performed on enrolled families/patients(trios or quartets when possible), and analyzed with some uniformity and according to state-of-the-art protocols. New tools will be applied in some cases, including when a non-genetic undiagnosed disease (e.g., rare infections or poisonings) is suspected. Return of results will conform to site-specific consents.
4. The -omics and phenotypic data should be shared among members of the UDNI.
5. Functional studies should be performed to substantiate causal relationships between a candidate gene and the phenotype and address novel therapies.
Practices
[from: D. Taruscio, et al., Undiagnosed Diseases Network International (UDNI): White paper for global actions to meet patient needs, Mol. Genet. Metab. (2015), http://dx.doi.org/10.1016/j.ymgme.2015.11.003]
The UDNI will adhere to the following best practices.
1. Applications will be specific to member sites, but should include core information described in Appendix A.
2. Clinical site evaluations will be comprehensive and include clinical and basic research approaches, including specimen collection for future studies, as described in Appendix B.
3. A list of clinical experts will be created for advice and referral both within the UDNIand outside of it.
4. A list of basic research topic experts will be compiled to serve as a potential collaborator pool; de-identified cases can be shared with these authorities if they have variants in genes within a particular basic researcher’s area of expertise.
5. The UDNI will maintain a website with information for physicians and patients.
6. The NIH UDN will make available its Manual of Operations to the UDNI.
Implementation of Principles and Practices
[from: D. Taruscio, et al., Undiagnosed Diseases Network International (UDNI): White paper for global actions to meet patient needs, Mol. Genet. Metab. (2015), http://dx.doi.org/10.1016/j.ymgme.2015.11.003]
The table below lists basic principles and their implementation in the NIH UDN. The UDNI is expected to operate under the same principles with similar approaches to implementation.
UDN Principles
UDN Implementation Approaches
(1) Engage centers of excellence
Seven centers of clinical excellence
Two centers of genomic sequencing excellence
One center of informatics excellence
(2) Foster a collaborative research community
Monthly steering committee conference calls
Regular face-to-face meetings
Ongoing working group activities, training and educational issues
Weekly clinical case review conference calls
(3) Establish a cooperative governance structure
Steering committee comprising the principal investigators of each center
All major decisions made by steering committee vote (one vote per center)
(4) Design a common research protocol
Central institutional review board
Protocol amended by agreement as necessary
Network-wide patient consents
(5) Provide a uniform patient experience
Patient portal for applying to the network
Network-wide acceptance criteria
Network-wide clinical evaluation methods
Patients can participate irrespective of their health insurance status
Patient advisory group
(6) Collect data in accordance with recognized data standards
Human Phenotype Ontology for clinical data
Genetic data consistent with National Center for Biotechnology Information standards
Biospecimens in accordance with UDN standard protocol
Standard environmental exposure survey
(7) Protect patient data, general ELSI issues
Security procedures for personally-identifiable information and personal health information in accordance with federal guidelines (Health Insurance Portability and Accountability Act, National Institute of Standards and Technology, and Federal Information Security Management Act)
(8) Expect broad data sharing
Data sharing and use agreement for freely sharing data within the network
De-identified data deposited in publicly available databases
(9) Stimulate dissemination of research results
Policies for publications, presentations, and UDN-related grant applications
(10) Ensure a high-functioning network
Executive committee meets weekly to review and monitor progress
Performance metrics for intermediate goals
Performance metrics for overall success of the network
Membership will be open to clinical investigators who serve undiagnosed disease patients from all countries. Members agree to adhere to the principles mentioned above.
Appendix A.
Applications in the UDNI should include:
1. Demographic information such as name, date of birth, gender, selfdescribed race and ethnicity, contact information;
2. Physician referral letter relating chief complaint, history, and what is undiagnosed;
3. Pertinent medical problems and prior diagnoses;
4. Medical records of physical examinations, hospitalizations, pertinent office visits, specialist consultations;
5. Laboratory test results;
6. Imaging on disks;
7. Biopsy slides when available;
8. Video of speech, gait, hand movements when impaired.