. 2022 Feb 14;17(1):47.

doi: 10.1186/s13023-022-02176-1.

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

Helge Hebestreit¹, Cornelia Zeidler², Christopher Schippers³, Martina de Zwaan⁴, Jürgen Deckert^{5

6}, Peter Heuschmann⁷, Christian Krauth⁸, Monika Bullinger⁹, Alexandra Berger¹⁰, Mark Berneburg¹¹, Lilly Brandstetter⁷, Anna Deibele¹², Jan Dieris-Hirche¹³, Holm Graessner¹⁴, Harald Gündel¹⁵, Stephan Herpertz¹³, Gereon Heuft¹⁶, Anne-Marie Lapstich⁸, Thomas Lücke¹⁷, Tim Maisch¹¹, Christine Mundlos^{18

19}, Andrea Petermann-Meyer²⁰, Susanne Müller²¹, Stephan Ott^{14

22}, Lisa Pfister⁵, Julia Quitmann⁹, Marcel Romanos²³, Frank Rutsch²⁴, Kristina Schaubert⁸, Katharina Schubert²⁵, Jörg B Schulz^{3

26}, Susann Schweiger²⁷, Oliver Tüscher²⁸, Kathrin Ungethüm⁷, Thomas O F Wagner¹⁰, Kirsten Haas⁷; ZSE-DUO working group

Collaborators, Affiliations

Collaborators

ZSE-DUO working group:
Federica Akkaya, Christine Babka, Lavinia Bârlescu, Anja Bärsch-Michelmann, Astrid Bergbreiter, Janika Blömeke, Leonie Böhm, Benita Böttger, Birgit Braun, Folke Brinkmann, Vanessa Britz, Holger Cario, Melisa Celiker, Moritz de Greck, Klaus-Michael Debatin, Katrin Dillmann-Jehn, Max Ertl, Monika Ettinger, Jutta Eymann, Jörg Frommer, Martina Gabrian, Anja Glode, Vega Gödecke, Corinna Grasemann, Eva Grauer, Helmut Greger, Astrid Haas, Martina Haase, Lea Haisch, Isabel Heinrich, Melissa Held, Julia Hennermann, Anne Herrmann-Werner, Julian Hett, Bettina Hilbig, Laura Holthöfer, Christiane Imhof, Titus Jacob, Florian Junne, Stefanie Karl, Jan Kassubek, Lisa Kick, Kevin-Thomas Koschitzki, Heike Krassort, Christian Kratz, Kaja Kristensen, Birgit Kropff, Julia Kuhn, Philipp Latzko, Thomas Loew, Delia Lorenz, Albert C Ludolph, Isabell Meyer Dos Santos, Torsten Meyer, Klaus Mohnike, Martina Monninger, Thomas Musacchio, Amalia Nicole Nanciu, Margret Nießen, Mariell Nöhre, Aikaterini Papagianni, Christina Pfeifer-Duck, Lea-Sophie Piduhn, Carina Rampp, Antonia Richter, Olaf Rieß, Annika Schmidt, Simone Schneider, Ludger Schoels, Martina Schwalba, Udo Selig, Astrid Spangenberger, Alexandra Sroka, Toni Steinbüchel, Sebastian Stösser, Steffi Suchant, Matthias Vogel, Daniela Volk, Christoph Vollmuth, Solange Volnov, Sabrina Walter, Bodo Warrings, Christine Weiler, Stefanie Witt, Kamil Kajetan Zajt, Lena Zeltner, Karola Zenker, Kailun David Zhang, Stephan Zipfel

Affiliations

¹ Center for Rare Diseases - Reference Center Northern Bavaria (ZESE), University Hospital Würzburg, Josef-Schneider-Str. 2, 97080, Würzburg, Germany. hebestreit@uni-wuerzburg.de.
² Center for Rare Diseases, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany.
³ Center for Rare Diseases, RWTH Aachen University Hospital, Pauwelsstraße 30, 52074, Aachen, Germany.
⁴ Department of Psychosomatic Medicine and Psychotherapy, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany.
⁵ Center for Rare Diseases - Reference Center Northern Bavaria (ZESE), University Hospital Würzburg, Josef-Schneider-Str. 2, 97080, Würzburg, Germany.
⁶ Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital, Margarete-Höppel-Platz 1, 97080, Würzburg, Germany.
⁷ Institute of Clinical Epidemiology and Biometry, University of Würzburg, Josef-Schneider-Str. 2, 97080, Würzburg, Germany.
⁸ Center for Health Economics Research Hannover and Institute for Epidemiology, Social Medicine and Health Systems Research, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany.
⁹ Department for Medical Psychology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.
¹⁰ Frankfurt Reference Centre for Rare Diseases, University Hospital Frankfurt, Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany.
¹¹ Center for Rare Diseases Regensburg, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93053, Regensburg, Germany.
¹² Department of Psychosomatic Medicine and Psychotherapy, University Hospital Magdeburg, Leipziger Straße 44, 39120, Magdeburg, Germany.
¹³ Department of Psychosomatic Medicine and Psychotherapy, LWL-University Clinic, Ruhr-University Bochum, Alexandrinenstraße 1-3, 44791, Bochum, Germany.
¹⁴ Centre for Rare Disease, University Hospital Tübingen, Calwerstr. 7, 72076, Tübingen, Germany.
¹⁵ Department of Psychosomatic Medicine and Psychotherapy, University Hospital Ulm, Albert.-Einstein-Allee 23, 89081, Ulm, Germany.
¹⁶ Department of Psychosomatic Medicine Und Psychotherapy, University Hospital Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany.
¹⁷ University Hospital of Pediatrics and Adolescent Medicine, Ruhr-University Bochum, Alexandrinenstr. 5, 44791, Bochum, Germany.
¹⁸ Allianz Chronischer Seltener Erkrankungen (ACHSE) e.V., c/o DRK Kliniken Berlin Mitte, Dronheimer Str. 39, 13359, Berlin, Germany.
¹⁹ ACHSE e.V., Berlin, Germany.
²⁰ Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Section Psychooncology, Center for Integrated Oncology - Aachen, Medical Faculty, RWTH Aachen University, Aachen, Germany.
²¹ Department of Neurology, University of Ulm, Oberer Eselsberg 45, 89081, Ulm, Germany.
²² Department of Psychosomatics and Psychotherapy, University Hospital Tübingen, Osianderstraße 5, 72076, Tübingen, Germany.
²³ Department of Child Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital Würzburg, Margarete-Höppel-Platz 1, 97080, Würzburg, Germany.
²⁴ Department of General Pediatrics, Muenster University Children's Hospital and Center for Rare Diseases, Muenster University Hospital, Albert-Schweitzer-Campus 1, Gebäude A1, 48149, Münster, Germany.
²⁵ Central German Competence Network for Rare Diseases, University Hospital Magdeburg, Leipziger Straße 44, 39120, Magdeburg, Germany.
²⁶ Department of Neurology, RWTH Aachen University, Pauwelsstraße 30, 52074, Aachen, Germany.
²⁷ Centre for Rare Disease and Institute for Human Genetics, University Medical Center, Johannes Gutenberg University, 55131, Mainz, Germany.
²⁸ Centre for Rare Disease and Department of Psychiatry and Psychotherapy, University Medical Center, Johannes Gutenberg University, 55131, Mainz, Germany.

PMID: 35164804
PMCID: PMC8842899
DOI: 10.1186/s13023-022-02176-1

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

Helge Hebestreit et al. Orphanet J Rare Dis. 2022.

. 2022 Feb 14;17(1):47.

doi: 10.1186/s13023-022-02176-1.

Authors

Collaborators

ZSE-DUO working group:
Federica Akkaya, Christine Babka, Lavinia Bârlescu, Anja Bärsch-Michelmann, Astrid Bergbreiter, Janika Blömeke, Leonie Böhm, Benita Böttger, Birgit Braun, Folke Brinkmann, Vanessa Britz, Holger Cario, Melisa Celiker, Moritz de Greck, Klaus-Michael Debatin, Katrin Dillmann-Jehn, Max Ertl, Monika Ettinger, Jutta Eymann, Jörg Frommer, Martina Gabrian, Anja Glode, Vega Gödecke, Corinna Grasemann, Eva Grauer, Helmut Greger, Astrid Haas, Martina Haase, Lea Haisch, Isabel Heinrich, Melissa Held, Julia Hennermann, Anne Herrmann-Werner, Julian Hett, Bettina Hilbig, Laura Holthöfer, Christiane Imhof, Titus Jacob, Florian Junne, Stefanie Karl, Jan Kassubek, Lisa Kick, Kevin-Thomas Koschitzki, Heike Krassort, Christian Kratz, Kaja Kristensen, Birgit Kropff, Julia Kuhn, Philipp Latzko, Thomas Loew, Delia Lorenz, Albert C Ludolph, Isabell Meyer Dos Santos, Torsten Meyer, Klaus Mohnike, Martina Monninger, Thomas Musacchio, Amalia Nicole Nanciu, Margret Nießen, Mariell Nöhre, Aikaterini Papagianni, Christina Pfeifer-Duck, Lea-Sophie Piduhn, Carina Rampp, Antonia Richter, Olaf Rieß, Annika Schmidt, Simone Schneider, Ludger Schoels, Martina Schwalba, Udo Selig, Astrid Spangenberger, Alexandra Sroka, Toni Steinbüchel, Sebastian Stösser, Steffi Suchant, Matthias Vogel, Daniela Volk, Christoph Vollmuth, Solange Volnov, Sabrina Walter, Bodo Warrings, Christine Weiler, Stefanie Witt, Kamil Kajetan Zajt, Lena Zeltner, Karola Zenker, Kailun David Zhang, Stephan Zipfel

Affiliations

¹ Center for Rare Diseases - Reference Center Northern Bavaria (ZESE), University Hospital Würzburg, Josef-Schneider-Str. 2, 97080, Würzburg, Germany. hebestreit@uni-wuerzburg.de.
² Center for Rare Diseases, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany.
³ Center for Rare Diseases, RWTH Aachen University Hospital, Pauwelsstraße 30, 52074, Aachen, Germany.
⁴ Department of Psychosomatic Medicine and Psychotherapy, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany.
⁵ Center for Rare Diseases - Reference Center Northern Bavaria (ZESE), University Hospital Würzburg, Josef-Schneider-Str. 2, 97080, Würzburg, Germany.
⁶ Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital, Margarete-Höppel-Platz 1, 97080, Würzburg, Germany.
⁷ Institute of Clinical Epidemiology and Biometry, University of Würzburg, Josef-Schneider-Str. 2, 97080, Würzburg, Germany.
⁸ Center for Health Economics Research Hannover and Institute for Epidemiology, Social Medicine and Health Systems Research, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany.
⁹ Department for Medical Psychology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.
¹⁰ Frankfurt Reference Centre for Rare Diseases, University Hospital Frankfurt, Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany.
¹¹ Center for Rare Diseases Regensburg, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93053, Regensburg, Germany.
¹² Department of Psychosomatic Medicine and Psychotherapy, University Hospital Magdeburg, Leipziger Straße 44, 39120, Magdeburg, Germany.
¹³ Department of Psychosomatic Medicine and Psychotherapy, LWL-University Clinic, Ruhr-University Bochum, Alexandrinenstraße 1-3, 44791, Bochum, Germany.
¹⁴ Centre for Rare Disease, University Hospital Tübingen, Calwerstr. 7, 72076, Tübingen, Germany.
¹⁵ Department of Psychosomatic Medicine and Psychotherapy, University Hospital Ulm, Albert.-Einstein-Allee 23, 89081, Ulm, Germany.
¹⁶ Department of Psychosomatic Medicine Und Psychotherapy, University Hospital Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany.
¹⁷ University Hospital of Pediatrics and Adolescent Medicine, Ruhr-University Bochum, Alexandrinenstr. 5, 44791, Bochum, Germany.
¹⁸ Allianz Chronischer Seltener Erkrankungen (ACHSE) e.V., c/o DRK Kliniken Berlin Mitte, Dronheimer Str. 39, 13359, Berlin, Germany.
¹⁹ ACHSE e.V., Berlin, Germany.
²⁰ Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Section Psychooncology, Center for Integrated Oncology - Aachen, Medical Faculty, RWTH Aachen University, Aachen, Germany.
²¹ Department of Neurology, University of Ulm, Oberer Eselsberg 45, 89081, Ulm, Germany.
²² Department of Psychosomatics and Psychotherapy, University Hospital Tübingen, Osianderstraße 5, 72076, Tübingen, Germany.
²³ Department of Child Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital Würzburg, Margarete-Höppel-Platz 1, 97080, Würzburg, Germany.
²⁴ Department of General Pediatrics, Muenster University Children's Hospital and Center for Rare Diseases, Muenster University Hospital, Albert-Schweitzer-Campus 1, Gebäude A1, 48149, Münster, Germany.
²⁵ Central German Competence Network for Rare Diseases, University Hospital Magdeburg, Leipziger Straße 44, 39120, Magdeburg, Germany.
²⁶ Department of Neurology, RWTH Aachen University, Pauwelsstraße 30, 52074, Aachen, Germany.
²⁷ Centre for Rare Disease and Institute for Human Genetics, University Medical Center, Johannes Gutenberg University, 55131, Mainz, Germany.
²⁸ Centre for Rare Disease and Department of Psychiatry and Psychotherapy, University Medical Center, Johannes Gutenberg University, 55131, Mainz, Germany.

PMID: 35164804
PMCID: PMC8842899
DOI: 10.1186/s13023-022-02176-1

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 .

Keywords: Cohort study; Mental health disorders; Rare diseases; Unclear diagnosis; Undetermined symptoms.

PubMed Disclaimer

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

**Fig. 1**
Standard diagnostic approach employed for people with a suspected rare disease in Centers for Rare Diseases and additional innovative elements established in the ZSE-DUO project

**Fig. 2**
Timeline of assessments at timepoints T0, T1 and T2 during the study. Recruitment and delivery of care in the standard care and the innovative care groups occurred in consequtive time periods

See this image and copyright information in PMC

References

1. European Commission. Rare diseases. https://ec.europa.eu/health/non_communicable_diseases/rare_diseases_en 2021. Accessed 20 SEP 2021.
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1. Boycott KM, Rath A, Chong JX, et al. International cooperation to enable the diagnosis of all rare genetic diseases. Am J Hum Genet. 2017;100:695–705. doi: 10.1016/j.ajhg.2017.04.003. - DOI - PMC - PubMed
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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

Collaborators

Affiliations

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

Collaborators

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Associated data

LinkOut - more resources

Full Text Sources

Medical