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Traditional sleep staging categorizes sleep and wakefulness into five coarse-grained classes, overlooking subtle variations within each stage. It provides limited information about the duration of arousal and may hinder research on sleep fragmentation and relevant sleep disorders. To address this issue, we propose a deep learning method for automatic and scalable annotation of continuous sleep depth index (SDI) using existing discrete sleep staging labels. Our approach was validated using polysomnography from over 10,000 recordings across four large-scale cohorts. The results showcased a strong correlation between the decrease in sleep depth index and the increase in duration of arousal. Specific case studies indicated that the sleep depth index captured more nuanced sleep structures than conventional sleep staging. Gaussian mixture models based on the digital biomarkers extracted from the sleep depth index identified two subtypes of sleep, where participants in the disturbed sleep group had a higher prevalence of sleep apnea, insomnia, poor subjective sleep quality, hypertension, and cardiovascular disease. The disturbed subtype was associated with a 42% (hazard ratio 1.42, 95% CI 1.24-1.62) increased risk of mortality and a 29% (hazard ratio 1.29, 95% CI 1.00-1.67) increased risk of fatal cardiovascular disease. Our study underscores the utility of the proposed method for continuous sleep depth annotation, which could reveal more detailed information about the sleep structure and yield novel digital biomarkers for routine clinical use in sleep medicine., Comment: working in progress

The ability to assess sleep at home, capture sleep stages, and detect the occurrence of apnea (without on-body sensors) simply by analyzing the radio waves bouncing off people's bodies while they sleep is quite powerful. Such a capability would allow for longitudinal data collection in patients' homes, informing our understanding of sleep and its interaction with various diseases and their therapeutic responses, both in clinical trials and routine care. In this article, we develop an advanced machine learning algorithm for passively monitoring sleep and nocturnal breathing from radio waves reflected off people while asleep. Validation results in comparison with the gold standard (i.e., polysomnography) (n=849) demonstrate that the model captures the sleep hypnogram (with an accuracy of 81% for 30-second epochs categorized into Wake, Light Sleep, Deep Sleep, or REM), detects sleep apnea (AUROC = 0.88), and measures the patient's Apnea-Hypopnea Index (ICC=0.95; 95% CI = [0.93, 0.97]). Notably, the model exhibits equitable performance across race, sex, and age. Moreover, the model uncovers informative interactions between sleep stages and a range of diseases including neurological, psychiatric, cardiovascular, and immunological disorders. These findings not only hold promise for clinical practice and interventional trials but also underscore the significance of sleep as a fundamental component in understanding and managing various diseases., Comment: The first two authors contributed equally to this work

Epileptiform activity (EA) is associated with worse outcomes including increased risk of disability and death. However, the effect of EA on the neurologic outcome is confounded by the feedback between treatment with anti-seizure medications (ASM) and EA burden. A randomized clinical trial is challenging due to the sequential nature of EA-ASM feedback, as well as ethical reasons. However, some mechanistic knowledge is available, e.g., how drugs are absorbed. This knowledge together with observational data could provide a more accurate effect estimate using causal inference. We performed a retrospective cross-sectional study with 995 patients with the modified Rankin Scale (mRS) at discharge as the outcome and the EA burden defined as the mean or maximum proportion of time spent with EA in six-hour windows in the first 24 hours of electroencephalography as the exposure. We estimated the change in discharge mRS if everyone in the dataset had experienced a certain EA burden and were untreated. We combined pharmacological modeling with an interpretable matching method to account for confounding and EA-ASM feedback. Our matched groups' quality was validated by the neurologists. Having a maximum EA burden greater than 75% when untreated had a 22% increased chance of a poor outcome (severe disability or death), and mild but long-lasting EA increased the risk of a poor outcome by 14%. The effect sizes were heterogeneous depending on pre-admission profile, e.g., patients with hypoxic-ischemic encephalopathy (HIE) or acquired brain injury (ABI) were more affected. Interventions should put a higher priority on patients with an average EA burden higher than 10%, while treatment should be more conservative when the maximum EA burden is low., Comment: 4 Figures

Objective: Sleep related respiratory abnormalities are typically detected using polysomnography. There is a need in general medicine and critical care for a more convenient method to automatically detect sleep apnea from a simple, easy-to-wear device. The objective is to automatically detect abnormal respiration and estimate the Apnea-Hypopnea-Index (AHI) with a wearable respiratory device, compared to an SpO2 signal or polysomnography using a large (n = 412) dataset serving as ground truth. Methods: Simultaneously recorded polysomnographic (PSG) and wearable respiratory effort data were used to train and evaluate models in a cross-validation fashion. Time domain and complexity features were extracted, important features were identified, and a random forest model employed to detect events and predict AHI. Four models were trained: one each using the respiratory features only, a feature from the SpO2 (%)-signal only, and two additional models that use the respiratory features and the SpO2 (%)-feature, one allowing a time lag of 30 seconds between the two signals. Results: Event-based classification resulted in areas under the receiver operating characteristic curves of 0.94, 0.86, 0.82, and areas under the precision-recall curves of 0.48, 0.32, 0.51 for the models using respiration and SpO2, respiration-only, and SpO2-only respectively. Correlation between expert-labelled and predicted AHI was 0.96, 0.78, and 0.93, respectively. Conclusions: A wearable respiratory effort signal with or without SpO2 predicted AHI accurately. Given the large dataset and rigorous testing design, we expect our models are generalizable to evaluating respiration in a variety of environments, such as at home and in critical care., Comment: Co-First Authors: Wolfgang Ganglberger, Abigail A. Bucklin Co-Senior Authors: Robert J. Thomas, M. Brandon Westover

The gold standard to assess respiration during sleep is polysomnography; a technique that is burdensome, expensive (both in analysis time and measurement costs), and difficult to repeat. Automation of respiratory analysis can improve test efficiency and enable accessible implementation opportunities worldwide. Using 9,656 polysomnography recordings from the Massachusetts General Hospital (MGH), we trained a neural network (WaveNet) based on a single respiratory effort belt to detect obstructive apnea, central apnea, hypopnea and respiratory-effort related arousals. Performance evaluation included event-based and recording-based metrics - using an apnea-hypopnea index analysis. The model was further evaluated on a public dataset, the Sleep-Heart-Health-Study-1, containing 8,455 polysomnographic recordings. For binary apnea event detection in the MGH dataset, the neural network obtained an accuracy of 95%, an apnea-hypopnea index $r^2$ of 0.89 and area under the curve for the receiver operating characteristics curve and precision-recall curve of 0.93 and 0.74, respectively. For the multiclass task, we obtained varying performances: 81% of all labeled central apneas were correctly classified, whereas this metric was 46% for obstructive apneas, 29% for respiratory effort related arousals and 16% for hypopneas. The majority of false predictions were misclassifications as another type of respiratory event. Our fully automated method can detect respiratory events and assess the apnea-hypopnea index with sufficient accuracy for clinical utilization. Differentiation of event types is more difficult and may reflect in part the complexity of human respiratory output and some degree of arbitrariness in the clinical thresholds and criteria used during manual annotation., Comment: 11 pages, 6 figures, 6 tables, \c{opyright}2020 IEEE

Dementia is under-recognized in the community, under-diagnosed by healthcare professionals, and under-coded in claims data. Information on cognitive dysfunction, however, is often found in unstructured clinician notes within medical records but manual review by experts is time consuming and often prone to errors. Automated mining of these notes presents a potential opportunity to label patients with cognitive concerns who could benefit from an evaluation or be referred to specialist care. In order to identify patients with cognitive concerns in electronic medical records, we applied natural language processing (NLP) algorithms and compared model performance to a baseline model that used structured diagnosis codes and medication data only. An attention-based deep learning model outperformed the baseline model and other simpler models., Comment: Machine Learning for Health (ML4H) at NeurIPS 2020 - Extended Abstract

Mediation analysis allows one to use observational data to estimate the importance of each potential mediating pathway involved in the causal effect of an exposure on an outcome. However, current approaches to mediation analysis with multiple mediators either involve assumptions not verifiable by experiments, or estimate the effect when mediators are manipulated jointly which precludes the practical design of experiments due to curse of dimensionality, or are difficult to interpret when arbitrary causal dependencies are present. We propose a method for mediation analysis for multiple manipulable mediators with arbitrary causal dependencies. The proposed method is clinically relevant because the decomposition of the total effect does not involve effects under cross-world assumptions and focuses on the effects after manipulating (i.e. treating) one single mediator, which is more relevant in a clinical scenario. We illustrate the approach using simulated data, the "framing" dataset from political science, and the HIV-Brain Age dataset from a clinical retrospective cohort study. Our results provide potential guidance for clinical practitioners to make justified choices to manipulate one of the mediators to optimize the outcome., Comment: 15 pages, 2 figures in main text, 1 figure in supplemental, 4 tables in main text

Objective Brain Age Index (BAI), calculated from sleep electroencephalography (EEG), has been proposed as a biomarker of brain health. This study quantifies night-to-night variability of BAI and establishes probability thresholds for inferring underlying brain pathology based on a patient's BAI. Methods 86 patients with multiple nights of consecutive EEG recordings were selected from Epilepsy Monitoring Unit patients whose EEGs reported as being within normal limits. BAI was calculated for each 12-hour segment of patient data using a previously described algorithm, and night-to-night variability in BAI was measured. Results The within-patient night-to-night standard deviation in BAI was 7.5 years. Estimates of BAI derived by averaging over 2, 3, and 4 nights had standard deviations of 4.7, 3.7, and 3.0 years, respectively. Conclusions Averaging BAI over n nights reduces night-to-night variability of BAI by a factor of the square root of n, rendering BAI more suitable as a biomarker of brain health at the individual level. Significance With increasing ease of EEG acquisition including wearable technology, BAI has the potential to track brain health and detect deviations from normal physiologic function. In a clinical setting, BAI could be used to identify patients who should undergo further investigation or monitoring., Comment: 18 pages, 6 figures, 2 tables

Study Objective: Sleep is reflected not only in the electroencephalogram but also in heart rhythms and breathing patterns. Therefore, we hypothesize that it is possible to accurately stage sleep based on the electrocardiogram (ECG) and respiratory signals. Methods: Using a dataset including 8,682 polysomnographs, we develop deep neural networks to stage sleep from ECG and respiratory signals. Five deep neural networks consisting of convolutional networks and long short-term memory networks are trained to stage sleep using heart and breathing, including the timing of R peaks from ECG, abdominal and chest respiratory effort, and the combinations of these signals. Results: ECG in combination with the abdominal respiratory effort achieve the best performance for staging all five sleep stages with a Cohen's kappa of 0.600 (95% confidence interval 0.599 -- 0.602); and 0.762 (0.760 -- 0.763) for discriminating awake vs. rapid eye movement vs. non-rapid eye movement sleep. The performance is better for young participants and for those with a low apnea-hypopnea index, while it is robust for commonly used outpatient medications. Conclusions: Our results validate that ECG and respiratory effort provide substantial information about sleep stages in a large population. It opens new possibilities in sleep research and applications where electroencephalography is not readily available or may be infeasible, such as in critically ill patients., Comment: Contains supplementary material at the end. Sleep 2019

The human electroencephalogram (EEG) of sleep undergoes profound changes with age. These changes can be conceptualized as "brain age", which can be compared to an age norm to reflect the deviation from normal aging process. Here, we develop an interpretable machine learning model to predict brain age based on two large sleep EEG datasets: the Massachusetts General Hospital sleep lab dataset (MGH, N = 2,621) covering age 18 to 80; and the Sleep Hearth Health Study (SHHS, N = 3,520) covering age 40 to 80. The model obtains a mean absolute deviation of 8.1 years between brain age and chronological age in the healthy participants in the MGH dataset. As validation, we analyze a subset of SHHS containing longitudinal EEGs 5 years apart, which shows a 5.5 years difference in brain age. Participants with neurological and psychiatric diseases, as well as diabetes and hypertension medications show an older brain age compared to chronological age. The findings raise the prospect of using sleep EEG as a biomarker for healthy brain aging.

Efficient label acquisition processes are key to obtaining robust classifiers. However, data labeling is often challenging and subject to high levels of label noise. This can arise even when classification targets are well defined, if instances to be labeled are more difficult than the prototypes used to define the class, leading to disagreements among the expert community. Here, we enable efficient training of deep neural networks. From low-confidence labels, we iteratively improve their quality by simultaneous learning of machines and experts. We call it Human And Machine co-LEarning Technique (HAMLET). Throughout the process, experts become more consistent, while the algorithm provides them with explainable feedback for confirmation. HAMLET uses a neural embedding function and a memory module filled with diverse reference embeddings from different classes. Its output includes classification labels and highly relevant reference embeddings as explanation. We took the study of brain monitoring at intensive care unit (ICU) as an application of HAMLET on continuous electroencephalography (cEEG) data. Although cEEG monitoring yields large volumes of data, labeling costs and difficulty make it hard to build a classifier. Additionally, while experts agree on the labels of clear-cut examples of cEEG patterns, labeling many real-world cEEG data can be extremely challenging. Thus, a large minority of sequences might be mislabeled. HAMLET has shown significant performance gain against deep learning and other baselines, increasing accuracy from 7.03% to 68.75% on challenging inputs. Besides improved performance, clinical experts confirmed the interpretability of those reference embeddings in helping explaining the classification results by HAMLET., Comment: Removed KDD template

Sleep disorders, such as sleep apnea, parasomnias, and hypersomnia, affect 50-70 million adults in the United States (Hillman et al., 2006). Overnight polysomnography (PSG), including brain monitoring using electroencephalography (EEG), is a central component of the diagnostic evaluation for sleep disorders. While PSG is conventionally performed by trained technologists, the recent rise of powerful neural network learning algorithms combined with large physiological datasets offers the possibility of automation, potentially making expert-level sleep analysis more widely available. We propose SLEEPNET (Sleep EEG neural network), a deployed annotation tool for sleep staging. SLEEPNET uses a deep recurrent neural network trained on the largest sleep physiology database assembled to date, consisting of PSGs from over 10,000 patients from the Massachusetts General Hospital (MGH) Sleep Laboratory. SLEEPNET achieves human-level annotation performance on an independent test set of 1,000 EEGs, with an average accuracy of 85.76% and algorithm-expert inter-rater agreement (IRA) of kappa = 79.46%, comparable to expert-expert IRA.