BACKGROUND AND OBJECTIVES: Recent studies fueled doubts as to whether all currently defined central disorders of hypersomnolence are stable entities, especially narcolepsy type 2 and idiopathic hypersomnia. New reliable biomarkers are needed, and the question arises of whether current diagnostic criteria of hypersomnolence disorders should be reassessed. The main aim of this data-driven observational study was to see whether data-driven algorithms would segregate narcolepsy type 1 and identify more reliable subgrouping of individuals without cataplexy with new clinical biomarkers. METHODS: We used agglomerative hierarchical clustering, an unsupervised machine learning algorithm, to identify distinct hypersomnolence clusters in the large-scale European Narcolepsy Network database. We included 97 variables, covering all aspects of central hypersomnolence disorders such as symptoms, demographics, objective and subjective sleep measures, and laboratory biomarkers. We specifically focused on subgrouping of patients without cataplexy. The number of clusters was chosen to be the minimal number for which patients without cataplexy were put in distinct groups. RESULTS: We included 1,078 unmedicated adolescents and adults. Seven clusters were identified, of which 4 clusters included predominantly individuals with cataplexy. The 2 most distinct clusters consisted of 158 and 157 patients, were dominated by those without cataplexy, and among other variables, significantly differed in presence of sleep drunkenness, subjective difficulty awakening, and weekend-week sleep length difference. Patients formally diagnosed as having narcolepsy type 2 and idiopathic hypersomnia were evenly mixed in these 2 clusters. DISCUSSION: Using a data-driven approach in the largest study on central disorders of hypersomnolence to date, our study identified distinct patient subgroups within the central disorders of hypersomnolence population. Our results contest inclusion of sleep-onset REM periods in diagnostic criteria for people without cataplexy and provide promising new variables for reliable diagnostic categories that better resemble different patient phenotypes. Cluster-guided classification will result in a more solid hypersomnolence classification system that is less vulnerable to instability of single features.

• MeSH
• idiopatická hypersomnie * diagnóza   MeSH
• kataplexie * diagnóza   MeSH
• lidé MeSH
• mladiství MeSH
• narkolepsie * diagnóza   farmakoterapie   MeSH
• poruchy nadměrné spavosti * diagnóza   epidemiologie   MeSH
• shluková analýza MeSH
• Check Tag
• lidé MeSH
• mladiství MeSH
• Publikační typ
• časopisecké články MeSH
• pozorovací studie MeSH
• práce podpořená grantem MeSH

PURPOSE: Narcolepsy type-1 (NT1) is a rare chronic neurological sleep disorder with excessive daytime sleepiness (EDS) as usual first and cataplexy as pathognomonic symptom. Shortening the NT1 diagnostic delay is the key to reduce disease burden and related low quality of life. Here we investigated the changes of diagnostic delay over the diagnostic years (1990-2018) and the factors associated with the delay in Europe. PATIENTS AND METHODS: We analyzed 580 NT1 patients (male: 325, female: 255) from 12 European countries using the European Narcolepsy Network database. We combined machine learning and linear mixed-effect regression to identify factors associated with the delay. RESULTS: The mean age at EDS onset and diagnosis of our patients was 20.9±11.8 (mean ± standard deviation) and 30.5±14.9 years old, respectively. Their mean and median diagnostic delay was 9.7±11.5 and 5.3 (interquartile range: 1.7-13.2 years) years, respectively. We did not find significant differences in the diagnostic delay over years in either the whole dataset or in individual countries, although the delay showed significant differences in various countries. The number of patients with short (≤2-year) and long (≥13-year) diagnostic delay equally increased over decades, suggesting that subgroups of NT1 patients with variable disease progression may co-exist. Younger age at cataplexy onset, longer interval between EDS and cataplexy onsets, lower cataplexy frequency, shorter duration of irresistible daytime sleep, lower daytime REM sleep propensity, and being female are associated with longer diagnostic delay. CONCLUSION: Our findings contrast the results of previous studies reporting shorter delay over time which is confounded by calendar year, because they characterized the changes in diagnostic delay over the symptom onset year. Our study indicates that new strategies such as increasing media attention/awareness and developing new biomarkers are needed to better detect EDS, cataplexy, and changes of nocturnal sleep in narcolepsy, in order to shorten the diagnostic interval.

• Klíčová slova
• cataplexy, diagnostic delay, machine learning, misdiagnosis, symptom onset,
• Publikační typ
• časopisecké články MeSH

Narcolepsy is a rare life-long disease that exists in two forms, narcolepsy type-1 (NT1) or type-2 (NT2), but only NT1 is accepted as clearly defined entity. Both types of narcolepsies belong to the group of central hypersomnias (CH), a spectrum of poorly defined diseases with excessive daytime sleepiness as a core feature. Due to the considerable overlap of symptoms and the rarity of the diseases, it is difficult to identify distinct phenotypes of CH. Machine learning (ML) can help to identify phenotypes as it learns to recognize clinical features invisible for humans. Here we apply ML to data from the huge European Narcolepsy Network (EU-NN) that contains hundreds of mixed features of narcolepsy making it difficult to analyze with classical statistics. Stochastic gradient boosting, a supervised learning model with built-in feature selection, results in high performances in testing set. While cataplexy features are recognized as the most influential predictors, machine find additional features, e.g. mean rapid-eye-movement sleep latency of multiple sleep latency test contributes to classify NT1 and NT2 as confirmed by classical statistical analysis. Our results suggest ML can identify features of CH on machine scale from complex databases, thus providing 'ideas' and promising candidates for future diagnostic classifications.

• MeSH
• biologické modely * MeSH
• databáze faktografické statistika a číselné údaje   MeSH
• datové soubory jako téma MeSH
• dospělí MeSH
• interpretace statistických dat MeSH
• lidé MeSH
• mladý dospělý MeSH
• narkolepsie klasifikace   diagnóza   patofyziologie   MeSH
• polysomnografie statistika a číselné údaje   MeSH
• řízené strojové učení * MeSH
• ROC křivka MeSH
• spánek REM fyziologie   MeSH
• spánková latence fyziologie   MeSH
• stochastické procesy MeSH
• vzácné nemoci klasifikace   diagnóza   patofyziologie   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND: Narcolepsy is a lifelong, rare neurological sleep disorder characterized by chronic, excessive attacks of daytime sleepiness. This disease is often extremely incapacitating, interfering with every aspect of life, in work and social settings. OBJECTIVE: The purpose of this study is to specify the treatment costs of patients in Central Europe (Czech Republic), while the attention is mainly paid to the drugs that were fully or partially covered by public health insurance. Furthermore, concomitant therapy is also evaluated, since it incurs a certain financial burden for patients and their family members. On the basis of the calculated costs, impact on the public budget is evaluated. PATIENTS AND METHODS: This study monitors the direct costs of the drugs for 13 patients, who represent ~1.3% of the total number of diagnosed patients in the Czech Republic, and evaluates the costs associated with their treatment during the period from January 9, 2011 to April 23, 2013. RESULTS: Most of the treatment costs (~80%) were covered by publicly available sources. This finding is also true for the concomitant therapy of comorbidities. Additional payments for the drugs constitute about 20% of the total costs.

• Klíčová slova
• cataplexy, cost, narcolepsy, orphan drug, rare disease, sodium oxybate,
• Publikační typ
• časopisecké články MeSH