iSPHYNCS: Unsupervised clustering in questionnaires and metadata reveals distinct subtypes in the narcolepsy borderland
Abstract
Abstract Objective The international Swiss Primary Hypersomnolence and Narcolepsy Cohort Study (iSPHYNCS) is a multicenter study aimed at identifying novel biomarkers for central disorders of hypersomnolence (CDH). We analyzed questionnaires and metadata to uncover distinct clusters of participants and explore phenotypic variability within CDH. Methods 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. Results 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 characterized by higher symptom severity and psychiatric comorbidities. Conclusions 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 emphasize the phenotypic heterogeneity of CDH and the potential for cluster-based approaches in management. Statement of Significance Central disorders of hypersomnolence (CDH) are complex and heterogeneous, challenging conventional diagnostic frameworks. This study employed an innovative clustering pipeline to identify four distinct phenotypic clusters within a large, multicenter cohort. The identification of a subtype in the narcolepsy borderland group with a high psychiatric burden adds critical insights into the variability of CDH and underscores the need for personalized diagnostic and therapeutic strategies. The internal validation of clusters through healthy controls and NT1 phenotypes enhances confidence in the pipeline’s robustness. Furthermore, the study highlights the potential for integrating clinical data to define disease severity and developing therapeutic strategies. These findings pave the way for novel approaches to understanding and managing CDH.
Authors 18
-
Rafael Morand corresponding
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
-
University of Bern · University Hospital of Bern
Affiliation as printed
Graduate School for Health Sciences, University of Bern, Switzerland
Sleep-Wake Epilepsy Center, NeuroTec, Department of Neurology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
-
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
-
University of Bern · University Hospital of Bern
Affiliation as printed
Graduate School for Health Sciences, University of Bern, Switzerland
Sleep-Wake Epilepsy Center, NeuroTec, Department of Neurology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
-
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
-
Affiliation as printed
ARTORG Center for Biomedical Engineering Research, University of Bern, Bern, Switzerland
-
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
-
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
-
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
-
Affiliation as printed
Department of Neurology, Health Ostschweiz (HOCH), Kantonsspital St. Gallen St, Gallen, Switzerland
-
Affiliation as printed
Sleep and Epilepsy Center, Neurocenter of Southern Switzerland, Regional Hospital (EOC) of Lugano, Lugano, Switzerland
-
Affiliation as printed
ZurzachCare, Clinic for Sleep Medicine, Bad Zurzach, Switzerland
-
Affiliation as printed
Center for Narcolepsy and Hypersomnias, Professorship for Narcolepsy and Hypersomnolence Research, Department of Medicine, University Witten/Herdecke, Witten, Germany
-
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
-
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
-
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
-
Affiliation as printed
ARTORG Center for Biomedical Engineering Research, University of Bern, Bern, Switzerland
-
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
Cited by 0 stored of 0
No patents citing this paper on Lens.org (checked 2026-10-11).