iSPHYNCS : Unsupervised Clustering in Questionnaires and Metadata Reveals Distinct Subtypes in the Narcolepsy Borderland

Journal of Sleep Research, vol. 35, pp. e70294

Abstract

The international Swiss Primary Hypersomnolence and Narcolepsy Cohort Study (iSPHYNCS) is a multicentre study aimed at identifying novel biomarkers for central disorders of hypersomnolence (CDH). We analysed questionnaires and metadata to uncover distinct clusters of participants and explore phenotypic variability within CDH. Data were collected from 227 patients with CDH and 33 healthy controls. Participants completed validated clinical questionnaires and study-specific questions addressing CDH-related symptoms such as excessive daytime sleepiness, fatigue, cataplexy, disrupted sleep, and sleep paralysis. Demographic metadata (age, gender, BMI) were included. After excluding participants with missing over 30% of data (n = 40), missing values were imputed using a multiple random forest algorithm. A robust clustering pipeline was employed: (1) random sampling of 60% of the dataset, (2) dimensionality reduction via UMAP, (3) K-means clustering, and (4) consensus clustering across 500 iterations. Post hoc analysis was performed to identify biomarkers in data not used for clustering. We identified four distinct clusters. One predominantly comprised healthy controls, while another primarily contained individuals with narcolepsy type 1 (NT1). Two clusters represented predominantly the narcolepsy borderland group (NBL), with one distinctly characterised by higher symptom severity and psychiatric comorbidities. The clustering pipeline produced reproducible results, with the NT1 and healthy control clusters serving as internal validation. The differentiation between the two NBL clusters aligns with prior studies, suggesting a possible NBL subtype marked by increased fatigue and psychiatric comorbidities. These findings emphasise the phenotypic heterogeneity of CDH and the potential for cluster-based approaches in management. Trial Registration: ClinicalTrials.gov identifier: NCT04330963.

Authors 20

1. Rafael Morand

   University of Bern · University Hospital of Bern

   Affiliation as printed

   ARTORG Center for Biomedical Engineering Research University of Bern Bern Switzerland

   Center for Experimental Neurology, Sleep Wake Epilepsy Center, NeuroTec, Department of Neurology, Inselspital, Bern University Hospital University of Bern Bern Switzerland

   Graduate School for Cellular and Biomedical Sciences University of Bern Bern Switzerland

   Sleep‐Wake Epilepsy Center, NeuroTec, Department of Neurology, Inselspital, Bern University Hospital University of Bern Bern Switzerland

2. Livia G. Fregolente corresponding

   University of Bern · University Hospital of Bern

   Affiliation as printed

   Graduate School for Health Sciences University of Bern Bern Switzerland

   Sleep‐Wake Epilepsy Center, NeuroTec, Department of Neurology, Inselspital, Bern University Hospital University of Bern Bern Switzerland

3. Julia van der Meer

   University of Bern · University Hospital of Bern

   Affiliation as printed

   Sleep‐Wake Epilepsy Center, NeuroTec, Department of Neurology, Inselspital, Bern University Hospital University of Bern Bern Switzerland

4. Elena Wenz

   University of Bern · University Hospital of Bern

   Affiliation as printed

   Graduate School for Health Sciences University of Bern Bern Switzerland

   Sleep‐Wake Epilepsy Center, NeuroTec, Department of Neurology, Inselspital, Bern University Hospital University of Bern Bern Switzerland

5. Annina Helmy

   University of Bern · University Hospital of Bern

   Affiliation as printed

   Center for Experimental Neurology, Sleep Wake Epilepsy Center, NeuroTec, Department of Neurology, Inselspital, Bern University Hospital University of Bern Bern Switzerland

   Graduate School for Cellular and Biomedical Sciences University of Bern Bern Switzerland

   Institute of Computer Science University of Bern Bern Switzerland

   Sleep‐Wake Epilepsy Center, NeuroTec, Department of Neurology, Inselspital, Bern University Hospital University of Bern Bern Switzerland

6. Lorenzo Brigato

   University of Bern

   Affiliation as printed

   ARTORG Center for Biomedical Engineering Research University of Bern Bern Switzerland

7. Jan D. Warncke

   University of Bern · University Hospital of Bern

   Affiliation as printed

   Sleep‐Wake Epilepsy Center, NeuroTec, Department of Neurology, Inselspital, Bern University Hospital University of Bern Bern Switzerland

8. Kseniia Zub

   University of Bern · University Hospital of Bern

   Affiliation as printed

   Sleep‐Wake Epilepsy Center, NeuroTec, Department of Neurology, Inselspital, Bern University Hospital University of Bern Bern Switzerland

9. Ramin Khatami

   University of Bern · University Hospital of Bern · Klinik Barmelweid

   Affiliation as printed

   Clinic Barmelweid Center for Sleep Medicine and Sleep Research Barmelweid Switzerland

   Sleep‐Wake Epilepsy Center, NeuroTec, Department of Neurology, Inselspital, Bern University Hospital University of Bern Bern Switzerland

10. Zhongxing Zhang

    Klinik Barmelweid

    Affiliation as printed

    Clinic Barmelweid Center for Sleep Medicine and Sleep Research Barmelweid Switzerland

11. Sigrid von Manitius

    Kantonsspital St. Gallen

    Affiliation as printed

    Department of Neurology Health Ostschweiz (HOCH), Kantonsspital St. Gallen St St. Gallen Switzerland

12. Silvia Miano

    Ospedale regionale di Lugano

    Affiliation as printed

    Sleep and Epilepsy Center, Neurocenter of Southern Switzerland, Regional Hospital (EOC) of Lugano Lugano Switzerland

13. Jens G Acker

    ZURZACH Care AG

    Affiliation as printed

    ZurzachCare, Clinic for Sleep Medicine Bad Zurzach Switzerland

14. Mathias Strub
    Affiliation as printed

    Centre for Sleep Medicine Basel Basel Switzerland

15. Ulf Kallweit

    Witten/Herdecke University

    Affiliation as printed

    Center for Narcolepsy and Hypersomnias, Professorship for Narcolepsy and Hypersomnolence Research, Department of Medicine University Witten/Herdecke Witten Germany

16. Gert Jan Lammers Aachen Department of Neurology

    Leiden University · Leiden University Medical Center · Stichting Epilepsie Instellingen Nederland

    Affiliation as printed

    Department of Neurology, Leiden University Medical Centre Leiden the Netherlands

    Sleep Wake Centre SEIN, Stichting Epilepsie Instellingen Nederland Heemstede the Netherlands

17. Athina Tzovara

    University of Bern · University Hospital of Bern

    Affiliation as printed

    Center for Experimental Neurology, Sleep Wake Epilepsy Center, NeuroTec, Department of Neurology, Inselspital, Bern University Hospital University of Bern Bern Switzerland

    Institute of Computer Science University of Bern Bern Switzerland

    Sleep‐Wake Epilepsy Center, NeuroTec, Department of Neurology, Inselspital, Bern University Hospital University of Bern Bern Switzerland

18. Claudio L. Bassetti

    University of Bern · University Hospital of Bern

    Affiliation as printed

    Sleep‐Wake Epilepsy Center, NeuroTec, Department of Neurology, Inselspital, Bern University Hospital University of Bern Bern Switzerland

19. Stavroula Georgia Mougiakakou

    University of Bern

    Affiliation as printed

    ARTORG Center for Biomedical Engineering Research University of Bern Bern Switzerland

20. Markus Helmut Schmidt

    University of Bern · University Hospital of Bern

    Affiliation as printed

    Center for Experimental Neurology, Sleep Wake Epilepsy Center, NeuroTec, Department of Neurology, Inselspital, Bern University Hospital University of Bern Bern Switzerland

    Sleep‐Wake Epilepsy Center, NeuroTec, Department of Neurology, Inselspital, Bern University Hospital University of Bern Bern Switzerland