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Gold-standard sleep scoring as performed by human technicians is based on a subset of PSG signals, namely the EEG, EOG, and EMG. The PSG, however, consists of many more signal derivations that could potentially be used to perform sleep staging, including cardiac and respiratory modalities. Leveraging this variety in signals would offer advantages, for example by increasing reliability, resilience to signal loss, and application to long-term non-obtrusive recordings. This paper proposes a deep generative foundation model for fully automatic sleep staging from a plurality of sensors and any combination thereof. We trained a score-based diffusion model with a transformer backbone using a dataset of 1947 expert-labeled overnight sleep recordings with 36 different signals, including neurological, cardiac, and respiratory signals. We achieve zero-shot inference on any sensor set by using a novel Bayesian factorization of the score function across the sensors, i.e., it does not require retraining on specific combinations of signals. On single-channel EEG, our method reaches the performance limit in terms of PSG inter-rater agreement (5-class accuracy 85.6%, kappa 0.791). At the same time, the method offers full flexibility to use any sensor set derived from other modalities, for example, as typically used in home recordings that include finger PPG, nasal cannula and thoracic belt (5-class accuracy 79.0%, kappa of 0.697), or by combining derivations not typically used for sleep staging such as the tibialis and sternocleidomastoid EMG (5-class accuracy 71.0%, kappa of 0.575). Additionally, we propose a novel interpretability metric in terms of information gain per sensor and show that this is linearly correlated with classification performance. Lastly, our foundation model allows for post-hoc addition of entirely new sensor modalities by merely training a score estimator on the novel input.

PURPOSE: Comorbid insomnia often occurs in patients with obstructive sleep apnea (OSA), referred to as COMISA. Cortical arousals manifest as a common feature in both OSA and insomnia, often accompanied by elevated heart rate (HR). Our objective was to evaluate the heart rate response to nocturnal cortical arousals in patients with COMISA and patients with OSA alone.METHODS: We analyzed data from patients with COMISA and from patients with OSA matched for apnea-hypopnea index. Sleep staging and analysis of respiratory events and cortical arousals were performed using the Philips Somnolyzer automatic scoring system. Beat-by-beat HR was analyzed from the onset of the cortical arousal to 30 heartbeats afterwards. HR responses were divided into peak and recovery phases. Cortical arousals were separately evaluated according to subtype (related to respiratory events and spontaneous) and duration (3-6 s, 6-10 s, 10-15 s).RESULTS: A total of 72 patients with COMISA and 72 patients with OSA were included in this study. There were no overall group differences in the number of cortical arousals with and without autonomic activation. No significant differences were found for spontaneous cortical arousals. The OSA group had more cortical arousals related to respiratory events (21.0 [14.8-30.0] vs 16.0 [9.0-27.0], p = 0.016). However, the COMISA group had longer cortical arousals (7.2 [6.4-7.8] vs 6.7 [6.2-7.7] s, p = 0.024) and the HR recovery phase was prolonged (52.5 [30.8-82.5] vs 40.0 [21.8-55.5] beats/min, p = 0.017). Both the peak and the recovery phase for longer cortical arousals with a duration of 10-15 s were significantly higher in patients with COMISA compared to patients with OSA (47.0 [27.0-97.5] vs 34.0 [21.0-71.0] beats/min, p = 0.032 and 87.0 [47.0-132.0] vs 71.0 [43.0-103.5] beats/min, p = 0.049, respectively).CONCLUSIONS: The HR recovery phase after cortical arousals related to respiratory events is prolonged in patients with COMISA comp

Non-rapid eye movement parasomnia disorders, also called disorders of arousal, are characterized by abnormal nocturnal behaviours, such as confusional arousals or sleep walking. Their pathophysiology is not yet fully understood, and objective diagnostic criteria are lacking. It is known, however, that behavioural episodes occur mostly in the beginning of the night, after an increase in slow-wave activity during slow-wave sleep. A better understanding of the prospect of such episodes may lead to new insights in the underlying mechanisms and eventually facilitate objective diagnosis. We investigated temporal dynamics of transitions from slow-wave sleep of 52 patients and 79 controls. Within the patient group, behavioural and non-behavioural N3 awakenings were distinguished. Patients showed a higher probability to wake up after an N3 bout ended than controls, and this probability increased with N3 bout duration. Bouts longer than 15 min resulted in an awakening in 73% and 34% of the time in patients and controls, respectively. Behavioural episodes reduced over sleep cycles due to a reduction in N3 sleep and a reducing ratio between behavioural and non-behavioural awakenings. In the first two cycles, N3 bouts prior to non-behavioural awakenings were significantly shorter than N3 bouts advancing behavioural awakenings in patients, and N3 awakenings in controls. Our findings provide insights in the timing and prospect of both behavioural and non-behavioural awakenings from N3, which may result in prediction and potentially prevention of behavioural episodes. This work, moreover, leads to a more complete characterization of a prototypical hypnogram of parasomnias, which could facilitate diagnosis.

Pregnancy complications are associated with abnormal maternal autonomic regulation. Subsequently, thoroughly understanding maternal autonomic regulation during healthy pregnancy may enable the earlier detection of complications, in turn allowing for the improved management thereof. Under healthy autonomic regulation, reciprocal interactions occur between the cardiac and respiratory systems, i.e., cardiorespiratory coupling (CRC). Here, we investigate, for the first time, the differences in CRC between healthy pregnant and nonpregnant women. We apply two algorithms, namely, synchrograms and bivariate phase-rectified signal averaging, to nighttime recordings of ECG and respiratory signals. We find that CRC is present in both groups. Significantly less ( P < 0.01) cardiorespiratory synchronization occurs in pregnant women (11% vs. 15% in nonpregnant women). Moreover, there is a smaller response in the heart rate of pregnant women corresponding to respiratory inhalations and exhalations. In addition, we stratified these analyses by sleep stages. As each sleep stage is governed by different autonomic states, this stratification not only amplified some of the differences between groups but also brought out differences that remained hidden when analyzing the full-night recordings. Most notably, the known positive relationship between CRC and deep sleep is less prominent in pregnant women than in their nonpregnant counterparts. The decrease in CRC during healthy pregnancy may be attributable to decreased maternal parasympathetic activity, anatomical changes to the maternal respiratory system, and the increased physiological stress accompanying pregnancy. This work offers novel insight into the physiology of healthy pregnancy and forms part of the base knowledge needed to detect abnormalities in pregnancy. NEW & NOTEWORTHY We compare CRC, i.e., the reciprocal interaction between the cardiac and respiratory systems, between healthy pregnant and nonpregnant women for

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) and insomnia frequently co-occur, making diagnosis and treatment challenging. We investigated differences in sleep structure between patients with OSA, insomnia, and comorbid insomnia and sleep apnea (COMISA) to identify characteristics that can be used to improve the diagnosis of COMISA.METHODS: We obtained polysomnography data of 326 patients from the Sleep and OSA Monitoring with Non-Invasive Applications database. The group included patients with OSA (n = 199), insomnia (n = 47), and COMISA (n = 80). We compared statistics related to sleep structure between the 3 patient groups.RESULTS: Wake after sleep onset was significantly shorter for the OSA group (median: 60.0 minutes) compared to the COMISA (median: 83.3 minutes, P < .01) and the insomnia (median: 83.5 minutes, P = .01) groups. No significant differences were found in the total number of awakenings and the number of short (up to and including 2 minutes) and medium-length awakenings (2.5 up to and including 4.5 minutes). However, the number of long awakenings (5 minutes or longer) and wake after sleep onset containing only long awakenings was significantly lower for patients with OSA (median: 2 awakenings and 25.5 minutes) compared to patients with COMISA (median: 3 awakenings, P < .01 and 43.3 minutes, P < .001) or with insomnia (median: 3 awakenings, P < .01 and 56.0 minutes, P < .001). Total sleep time was significantly longer and sleep efficiency was significantly higher for the OSA group (median: 418.5 minutes and 84.4%) compared to both the COMISA (median: 391.5 minutes, P < .001 and 77.3%, P < .001) and the insomnia (median: 381.5 minutes, P < .001 and 78.2%, P < .001) groups. The number of sleep-stage transitions during the night for patients with COMISA (median: 194.0) was lower compared to that for patients with OSA (median: 218.0, P < .01) and higher compared to that for patients with insomnia (median

Background: People with intellectual disabilities (ID) have a higher risk of sleep disorders. Polysomnography (PSG) remains the diagnostic gold standard in sleep medicine. However, PSG in people with ID can be challenging, as sensors can be burdensome and have a negative influence on sleep. Alternative methods of assessing sleep have been proposed that could potentially transfer to less obtrusive monitoring devices. The goal of this study was to investigate whether analysis of heart rate variability and respiration variability is suitable for the automatic scoring of sleep stages in sleep-disordered people with ID. Methods: Manually scored sleep stages in PSGs of 73 people with ID (borderline to profound) were compared with the scoring of sleep stages by the CardioRespiratory Sleep Staging (CReSS) algorithm. CReSS uses cardiac and/or respiratory input to score the different sleep stages. Performance of the algorithm was analysed using input from electrocardiogram (ECG), respiratory effort and a combination of both. Agreement was determined by means of epochper-epoch Cohen’s kappa coefficient. The influence of demographics, comorbidities and potential manual scoring difficulties (based on comments in the PSG report) was explored. Results: The use of CReSS with combination of both ECG and respiratory effort provided the best agreement in scoring sleep and wake when compared with manually scored PSG (PSG versus ECG = kappa 0.56, PSG versus respiratory effort = kappa 0.53 and PSG versus both = kappa 0.62). Presence of epilepsy or difficulties in manually scoring sleep stages negatively influenced agreement significantly, but nevertheless, performance remained acceptable. In people with ID without epilepsy, the average kappa approximated that of the general population with sleep disorders. Conclusions: Using analysis of heart rate and respiration variability, sleep stages can be estimated in people with ID. This could in the future lead to less obtrusive measurements of

In many domains, multivariate event sequence data is collected focused around an entity (the case). Typically, each event has multiple attributes, for example, in healthcare a patient has events such as hospitalization, medication, and surgery. In addition to the multivariate events, also the case (a specific attribute, e.g., patient) has associated multivariate data (e.g., age, gender, weight). Current work typically only visualizes one attribute per event (label) in the event sequences. As a consequence, events can only be explored from a predefined case-centric perspective. However, to find complex relations from multiple perspectives (e.g., from different case definitions, such as doctor), users also need an event- and attribute-centric perspective. In addition, support is needed to effortlessly switch between and within perspectives. To support such a rich exploration, we present FlexEvent: an exploration and analysis method that enables investigation beyond a fixed case-centric perspective. Based on an adaptation of existing visualization techniques, such as scatterplots and juxtaposed small multiples, we enable flexible switching between different perspectives to explore the multivariate event sequence data needed to answer multi-perspective hypotheses. We evaluated FlexEvent with three domain experts in two use cases with sleep disorder and neonatal ICU data that show our method facilitates experts in exploring and analyzing real-world multivariate sequence data from different perspectives.

Objective: The recently-introduced hypnodensity graph provides a probability distribution over sleep stages per data window (i.e. an epoch). This work explored whether this representation reveals continuities that can only be attributed to intraand inter-rater disagreement of expert scorings, or also to co-occurrence of sleep stagede-pendent features within one epoch. Approach: We proposed a simplified model for time series like the ones measured during sleep, and a second model to describe the annotation process by an expert. Generating data according to these models, enabled controlled experiments to investigate the interpretation of the hypnodensity graph. Moreover, the influence of both the supervised training strategy, and the used softmax non-linearity were investigated. Polysomnography recordings of 96 healthy sleepers (of which 11 were used as independent test set), were subsequently used to transfer conclusions to real data. Main results: A hypnodensity graph, predicted by a supervised neural classifier, represents the probability with which the sleep expert(s) assigned a label to an epoch. It thus reflects annotator behavior, and is thereby only indirectly linked to the ratio of sleep stage-dependent features in the epoch. Unsupervised training was shown to result in hypnodensity graph that were slightly less dependent on this annotation process, resulting in, on average, higher-entropy distributions over sleep stages (Hunsupervised = 0.41 vs Hsupervised = 0.29). Moreover, pre-softmax predictions were, for both training strategies, found to better reflect the ratio of sleep stage-dependent characteristics in an epoch, as compared to the post-softmax counterparts (i.e. the hypnodensity graph). In real data, this was observed from the linear relation between pre-softmax N3 predictions and the amount of delta power. Significance: This study provides insights in, and proposes new, representa

Sleep staging is the process by which an overnight polysomnographic measurement is segmented into epochs of 30 seconds, each of which is annotated as belonging to one of five discrete sleep stages. The resulting scoring is graphically depicted as a hypnogram, and several overnight sleep statistics are derived, such as total sleep time and sleep onset latency. Gold standard sleep staging as performed by human technicians is time-consuming, costly, and comes with imperfect inter-scorer agreement, which also results in inter-scorer disagreement about the overnight statistics. Deep learning algorithms have shown promise in automating sleep scoring, but struggle to model inter-scorer disagreement in sleep statistics. To that end, we introduce a novel technique using conditional generative models based on Normalizing Flows that permits the modeling of the inter-rater disagreement of overnight sleep statistics, termed U-Flow. We compare U-Flow to other automatic scoring methods on a hold-out test set of 70 subjects, each scored by six independent scorers. The proposed method achieves similar sleep staging performance in terms of accuracy and Cohen's kappa on the majority-voted hypnograms. At the same time, U-Flow outperforms the other methods in terms of modeling the inter-rater disagreement of overnight sleep statistics. The consequences of inter-rater disagreement about overnight sleep statistics may be great, and the disagreement potentially carries diagnostic and scientifically relevant information about sleep structure. U-Flow is able to model this disagreement efficiently and can support further investigations into the impact inter-rater disagreement has on sleep medicine and basic sleep research.

Sleep is characterized by an intricate variation of brain activity over time. Measuring these temporal sleep dynamics is relevant for elucidating healthy and pathological sleep mechanisms. The rapidly increasing possibilities for obtaining and processing sleep registrations have led to an abundance of data, which can be challenging to analyze and interpret. This review provides a structured overview of approaches to represent temporal sleep dynamics, categorized based on the way the source data is compressed. For each category of representations, we describe advantages and disadvantages. Standard human-defined 30-s sleep stages have the advantages of standardization and interpretability. Alternative human-defined representations are less standardized but offer a higher temporal resolution (in case of microstructural events such as sleep spindles), or reflect non-categorical information (for example spectral power analysis). Machine-learned representations offer additional possibilities: automated sleep stages are useful for handling large quantities of data, while alternative sleep stages obtained from clustering data-driven features could aid finding new patterns and new possible clinical interpretations. While newly developed sleep representations may offer relevant insights, they can be difficult to interpret in for example a clinical context. Therefore, there should always be a balance between developing these sophisticated sleep analysis techniques and maintaining clinical explainability.

Continuous monitoring with an ever-increasing number of sensors has become ubiquitous across many application domains. Acquired data are typically high-dimensional and difficult to interpret, but they are also hypothesized to lie on a lower-dimensional manifold. Many deep learning (DL) models aim to identify this manifold, but do not promote structure nor interpretability. We propose the SOM-CPC model, which jointly optimizes Contrastive Predictive Coding (CPC), and a Self-Organizing Map (SOM) to find such an organized manifold. We address a largely unexplored and challenging set of scenarios comprising high-rate time series, and show on synthetic and real-life medical and audio data that SOM-CPC outperforms strong baseline models that combine DL with SOMs. SOM-CPC has great potential to expose latent patterns in high-rate data streams, and may therefore contribute to a better understanding of many different processes and systems.

Sleep stage classification is an important tool for the diagnosis of sleep disorders. Because sleep staging has such a high impact on clinical outcome, it is important that it is done reliably. However, it is known that uncertainty exists in both expert scorers and automated models. On average, the agreement between human scorers is only 82.6%. In this study, we provide a theoretical framework to facilitate discussion and further analyses of uncertainty in sleep staging. To this end, we introduce two variants of uncertainty, known from statistics and the machine learning community: aleatoric and epistemic uncertainty. We discuss what these types of uncertainties are, why the distinction is useful, where they arise from in sleep staging, and provide recommendations on how this framework can improve sleep staging in the future.

Lieke WA Hermans,1 Marta Regis,2 Pedro Fonseca,1,3 Bertram Hoondert,4 Tim RM Leufkens,3 Sebastiaan Overeem,1,4 Merel M van Gilst1,4 1Department of Electrical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands; 2Department of Mathematics and Computer Science, Eindhoven University of Technology, Eindhoven, the Netherlands; 3Philips Research, Eindhoven, the Netherlands; 4Sleep Medicine Center Kempenhaeghe, Heeze, the NetherlandsCorrespondence: Lieke WA HermansDepartment of Electrical Engineering, Eindhoven University of Technology, De Zaale, 5600, MB Eindhoven, the NetherlandsEmail l.w.a.hermans@tue.nlIntroduction: Assessing objective measures of sleep fragmentation could yield important features reflecting impaired sleep quality in people with insomnia. Survival analysis allows the specific examination of the stability of NREM sleep, REM sleep and wake. The objective of this study was to assess the differences between survival dynamics of NREM sleep, REM sleep and wake between people with insomnia and healthy controls.Methods: We analyzed retrospective polysomnography recordings from 86 people with insomnia and 94 healthy controls. For each participant, survival dynamics of REM sleep, NREM sleep and wake were represented using Weibull distributions. We used lasso penalized parameter selection in combination with linear regression to analyze the difference between participant groups with respect to the Weibull scale and shape parameters, while correcting for age, sex, total sleep time and relevant interaction effects.Results: Significant effects of group were found for the NREM scale parameter, and for the wake scale and shape parameters. Results indicated that people with insomnia had less stable NREM sleep and more stable wake after sleep onset compared to healthy controls. Additionally, the altered distribution of wake segment lengths indicated an increased difficulty to fall asleep after longer awakenings in the insomnia group. However, the

Bernice M Wulterkens,1,2,&ast; Pedro Fonseca,1,2,&ast; Lieke WA Hermans,1 Marco Ross,3 Andreas Cerny,3 Peter Anderer,3 Xi Long,1,2 Johannes P van Dijk,1,4 Nele Vandenbussche,4 Sigrid Pillen,1,4 Merel M van Gilst,1,4 Sebastiaan Overeem1,4 1Department of Electrical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands; 2Philips Research, Eindhoven, the Netherlands; 3Sleep and Respiratory Care, Home Healthcare Solutions, Philips Austria GmbH, Vienna, Austria; 4Sleep Medicine Center Kempenhaeghe, Heeze, the Netherlands&ast;These authors contributed equally to this workCorrespondence: Bernice M WulterkensEindhoven University of Technology, Department of Electrical Engineering, Room Flux 7.104, PO BOX 513, Eindhoven, 5600 MB, the NetherlandsEmail b.m.wulterkens@tue.nlPurpose: There is great interest in unobtrusive long-term sleep measurements using wearable devices based on reflective photoplethysmography (PPG). Unfortunately, consumer devices are not validated in patient populations and therefore not suitable for clinical use. Several sleep staging algorithms have been developed and validated based on ECG-signals. However, translation from these techniques to data derived by wearable PPG is not trivial, and requires the differences between sensing modalities to be integrated in the algorithm, or having the model trained directly with data obtained with the target sensor. Either way, validation of PPG-based sleep staging algorithms requires a large dataset containing both gold standard measurements and PPG-sensor in the applicable clinical population. Here, we take these important steps towards unobtrusive, long-term sleep monitoring.Methods: We developed and trained an algorithm based on wrist-worn PPG and accelerometry. The method was validated against reference polysomnography in an independent clinical population comprising 244 adults and 48 children (age: 3 to 82 years) with a wide variety of sleep disorders.Results: The classifier a