Dual guidance structure for evaluation of patients with unclear diagnosis in centers for rare diseases (ZSE-DUO): study protocol for a controlled multi-center cohort study
Authors: Hebestreit Helge , Zeidler Cornelia , Schippers Christopher , de Zwaan Martina , Deckert Jürgen , Heuschmann Peter , Krauth Christian , Bullinger Monika , Berger Alexandra , Berneburg Mark , Brandstetter Lilly , Deibele Anna , Dieris-Hirche Jan , Graessner Holm , Gündel Harald , Herpertz Stephan , Heuft Gereon , Lapstich Anne-Marie , Lücke Thomas , Maisch Tim , Mundlos Christine , Petermann-Meyer Andrea , Müller Susanne , Ott Stephan , Pfister Lisa , Quitmann Julia , Romanos Marcel , Rutsch Frank , Schaubert Kristina , Schubert Katharina , Schulz Jörg B. , Schweiger Susann , Tüscher Oliver , Ungethüm Kathrin , Wagner Thomas O. F. , Haas Kirsten ,   ZSE-DUO working group, Akkaya Federica , Babka Christine , Bârlescu Lavinia , Bärsch-Michelmann Anja , Bergbreiter Astrid , Blömeke Janika , Böhm Leonie , Böttger Benita , Braun Birgit , Brinkmann Folke , Britz Vanessa , Cario Holger , Celiker Melisa , de Greck Moritz , Debatin Klaus-Michael , Dillmann-Jehn Katrin , Ertl Max , Ettinger Monika , Eymann Jutta , Frommer Jörg , Gabrian Martina , Glode Anja , Gödecke Vega , Grasemann Corinna , Grauer Eva , Greger Helmut , Haas Astrid , Haase Martina , Haisch Lea , Heinrich Isabel , Held Melissa , Hennermann Julia , Herrmann-Werner Anne , Hett Julian , Hilbig Bettina , Holthöfer Laura , Imhof Christiane , Jacob Titus , Junne Florian , Karl Stefanie , Kassubek Jan , Kick Lisa , Koschitzki Kevin-Thomas , Krassort Heike , Kratz Christian , Kristensen Kaja , Kropff Birgit , Kuhn Julia , Latzko Philipp , Loew Thomas , Lorenz Delia , Ludolph Albert C. , dos Santos Isabell Meyer , Meyer Torsten , Mohnike Klaus , Monninger Martina , Musacchio Thomas , Nanciu Amalia Nicole , Nießen Margret , Nöhre Mariell , Papagianni Aikaterini , Pfeifer-Duck Christina , Piduhn Lea-Sophie , Rampp Carina , Richter Antonia , Rieß Olaf , Schmidt Annika , Schneider Simone , Schoels Ludger , Schwalba Martina , Selig Udo , Spangenberger Astrid , Sroka Alexandra , Steinbüchel Toni , Stösser Sebastian , Suchant Steffi , Vogel Matthias , Volk Daniela , Vollmuth Christoph , Volnov Solange , Walter Sabrina , Warrings Bodo , Weiler Christine , Witt Stefanie , Zajt Kamil Kajetan , Zeltner Lena , Zenker Karola , Zhang Kailun David , Zipfel Stephan 
Published: February 2022

Abstract
Background
In individuals suffering from a rare disease the diagnostic process and the confirmation of a final diagnosis often extends over many years. Factors contributing to delayed diagnosis include health care professionals' limited knowledge of rare diseases and frequent (co-)occurrence of mental disorders that may complicate and delay the diagnostic process. The ZSE-DUO study aims to assess the benefits of a combination of a physician focusing on somatic aspects with a mental health expert working side by side as a tandem in the diagnostic process.

Study design
This multi-center, prospective controlled study has a two-phase cohort design.

Methods
Two cohorts of 682 patients each are sequentially recruited from 11 university-based German Centers for Rare Diseases (CRD): the standard care cohort (control, somatic expertise only) and the innovative care cohort (experimental, combined somatic and mental health expertise). Individuals aged 12 years and older presenting with symptoms and signs which are not explained by current diagnoses will be included. Data will be collected prior to the first visit to the CRD’s outpatient clinic (T0), at the first visit (T1) and 12 months thereafter (T2).

Outcomes
Primary outcome is the percentage of patients with one or more confirmed diagnoses covering the symptomatic spectrum presented. Sample size is calculated to detect a 10 percent increase from 30% in standard care to 40% in the innovative dual expert cohort. Secondary outcomes are (a) time to diagnosis/diagnoses explaining the symptomatology; (b) proportion of patients successfully referred from CRD to standard care; (c) costs of diagnosis including incremental cost effectiveness ratios; (d) predictive value of screening instruments administered at T0 to identify patients with mental disorders; (e) patients’ quality of life and evaluation of care; and f) physicians’ satisfaction with the innovative care approach.

Conclusions
This is the first multi-center study to investigate the effects of a mental health specialist working in tandem with a somatic expert physician in CRDs. If this innovative approach proves successful, it will be made available on a larger scale nationally and promoted internationally. In the best case, ZSE-DUO can significantly shorten the time to diagnosis for a suspected rare disease.
Trial registration ClinicalTrials.gov; Identifier: NCT03563677; First posted: June 20, 2018, https://clinicaltrials.gov/ct2/show/NCT03563677.