Impact case study database

4.1 New diagnostic testing approaches have been designed, developed and implemented in regional laboratories serving Amish communities.

The Exeter team developed targeted tests for the 20 commonest genetic causes of disease among the Amish and shared methodologies with three regional certified diagnostic laboratories. In collaboration with PlexSeq Diagnostics (Cleveland), the team developed a new comprehensive, rapid, multiplexed, low-cost approach to diagnostic testing, based on blood-spot-derived DNA. This technology now provides an expandable custom panel assay that tests 178 OWI-Amish gene mutations in parallel. This ‘Amish panel test’ is embedded in the Wisconsin State Laboratory of Hygiene, for newborn screening, diagnostic and carrier testing [5.1, 5.2].

4.2 Establishment of regional specialist healthcare clinics for genetic disease.

Prior to 2013, there were no specialist clinics providing healthcare for inherited diseases in OWI-Amish communities. The Exeter-led Amish research programme Windows of Hope [5.3] worked alongside clinician-led community initiatives to develop specialist clinics in Ohio (New Leaf Center’s Clinic for Special Children, opened 2014) [5.2, 5.4] and Wisconsin (Center for Special Children at La Farge Medical Clinic, opened 2015) [5.2, 5.5]. These clinics serve a combined Amish population of >100,000, although many patients also travel from out of state to access this specialised care. As a consequence of Exeter-led research, local clinicians are now able to recognise a patient’s disorder and order a cost-effective (~$50) genetic test, enabling diagnoses for ~50% of families [5.2, 5.4, 5.5]. Dr Baple and Professor Crosby support regular clinics for patients at both sites, translating research discoveries directly into clinical care and have improved the diagnostic rates from <15% (2013) to ~70% (2020). Early precise diagnosis combined with improved clinical understanding has led to more effective treatment and screening for disease complications [5.2].

4.3 Reductions in healthcare costs.

Many Amish live below the federal poverty threshold and have no health insurance. The standard clinical evaluation to diagnose a child with neurodevelopmental disability costs an average of US$19,000 (ranging from $9,000 to $35,000), excluding professional fees, indirect institutional expenses and genome sequencing . The cost of the new systematic diagnostic genetic testing pathway designed by the Exeter team for Amish children affected by developmental disorders, ranges from $300 (clinic visit plus targeted genetic test) to $2250 (including targeted test, Amish panel test, genome sequencing, and clinic visit). This testing pathway has saved at least $16,750 per diagnosis for the 950 OWI-Amish patients who have been diagnosed, totalling at least $15 million since 2013 **[**costs provided by Amish specialist clinics and referenced in 5.2 and 5.6]. Since 2013, 72 patients were diagnosed with disorders affecting neurological and cognitive function in whom early genetic diagnosis and treatment has prevented or reduced neurodisability, unnecessary hospitalisation and investigations. Examples include diagnosis, prevention, and treatment of hypoglycaemia and seizures in KPTN-related disorder, and prevention of metabolic stroke in the Amish variant of propionic acidaemia, which is not reliably detected through metabolic newborn screening. The lifetime cost savings for these patients are estimated to be more than $90 million **[**costs from Centers for Disease Control and Prevention, 2004 and Amish specialist clinics, 2020 referenced in 5.2 and 5.6].

4.4 Education initiatives for the public, healthcare professionals, and the Amish community.

Four MRC Medical Research Foundation grants [5.7] funded educational and community initiatives developed and delivered by the Exeter research team between 2014-2019. Few requests for genetic tests for diseases prevalent within the OWI-Amish were received from family doctors, local or specialist clinicians prior to 2014. More than 300 requests were made between 2018-2020 by clinical providers in Wisconsin following the education initiatives [ 5.2]:

(i) The Exeter Windows of Hope Website includes a database of all known Amish/Mennonite inherited disorders and describes a systematic approach to defining differential diagnoses, accessing diagnostic testing and tailoring treatment [5.3].

(ii) Continuing Medical Education (CME) accredited symposia for health, education and social care professionals were developed and delivered by the Exeter research team, alongside local and subspecialty clinical experts, each attended by >50 specialists. Over 96% of attendees reported improved knowledge and understanding of Amish genetic disease. Feedback included: “ I have learnt the importance of early diagnosis to provide the best medical care and outcome and avoid unnecessary costly hospital stays” [5.2, 5.3, 5.5].

(iii) Family meetings and disease-specific literature. Over 1000 Amish have attended >14 disease-specific events (2013-2020). Information brochures for 30 disorders have been developed, with 1000s printed and used by the specialist clinics, family practices and special education schools serving the Amish [, 5.2, 5.3, 5.4, 5.5, 5.8].

(iv) A Massive Open Online Course, “Genomic Medicine and Research: A Community Approach”. The first course (2019) attracted 386 medical, academic, social science and legal participants, along with patients and families affected by genetic disease. The Medical Director of the New Leaf Clinic tells course attendees: “ I can quickly focus the tests I order when seeing a child with an unknown cause of developmental delay because of the work that’s done through the research in Exeter. It is the best example of translational work that I have seen in 15 years of practice.” [5.2, 5.8]

Together, these initiatives have inspired local clinics and the Amish community to develop disease registries so that new research findings are now quickly shared. Numerous media outlets have reported how the educational programme has not only improved Amish healthcare outcomes, but also reduced stigma and misunderstanding and changed attitudes towards rare genetic disease and genetic testing among the Amish, healthcare providers and the public [5.2, 5.4, 5.5, 5.7, 5.8, 5.9].

4.5 Genetic discoveries in the Amish have been translated into diagnostic and clinical benefits worldwide.

Almost all the novel disorders described by the Exeter group have subsequently also been identified outside the Amish population. The research team have produced accessible information for families about the diseases they have defined in response to requests from support groups, including the National Organization for Rare Disorders (NORD), an international patient advocacy organisation [5.10]. Prof Crosby and Dr Baple are scientific and clinical advisors to the KPTN Alliance Family Support Group and also developed the Troyer syndrome clinical guidelines, adopted by clinicians worldwide and accessed through US National Center for Biotechnology Information [5.10].