Persistent sleep-disordered breathing independently contributes to metabolic syndrome in prepubertal children.

BACKGROUND: Obstructive sleep apnea (OSA) is a risk factor for metabolic syndrome (MetS) in adults, but its association in prepubertal children is still questionable due to the relatively limited cardiometabolic data available and the phenotypic heterogeneity. OBJECTIVE: To identify the role of OSA as a potential mediator of MetS in prepubertal children. METHODS: A total of 255 prepubertal children from the Childhood Adenotonsillectomy Trial were included, with standardized measurements taken before OSA treatment and 7 months later. MetS was defined if three or more of the following criteria were present: adiposity, high blood pressure, elevated glycemia, and dyslipidemia. A causal mediation analysis was conducted to assess the effect of OSA treatment on MetS. RESULTS: OSA treatment significantly impacted MetS, with the apnea-hypopnea index emerging as mediator (p = .02). This mediation role was not detected for any of the individual risk factors that define MetS. We further found that the relationship between MetS and OSA is ascribable to respiratory disturbance caused by the apnea episodes, while systemic inflammation as measured by C-reactive protein, is mediated by desaturation events and fragmented sleep. In terms of evolution, patients with MetS were significantly more likely to recover after OSA treatment (odds ratio = 2.56, 95% confidence interval [CI] 1.20-5.46; risk ratio = 2.06, 95% CI 1.19-3.54) than the opposite, patients without MetS to develop it. CONCLUSION: The findings point to a causal role of OSA in the development of metabolic dysfunction, suggesting that persistent OSA may increase the risk of MetS in prepubertal children. This mediation role implies a need for developing screening for MetS in children presenting OSA symptoms.

ECG-based convolutional neural network in pediatric obstructive sleep apnea diagnosis.

Obstructive sleep apnea (OSA) is a prevalent respiratory condition in children and is characterized by partial or complete obstruction of the upper airway during sleep. The respiratory events in OSA induce transient alterations of the cardiovascular system that ultimately can lead to increased cardiovascular risk in affected children. Therefore, a timely and accurate diagnosis is of utmost importance. However, polysomnography (PSG), the standard diagnostic test for pediatric OSA, is complex, uncomfortable, costly, and relatively inaccessible, particularly in low-resource environments, thereby resulting in substantial underdiagnosis. Here, we propose a novel deep-learning approach to simplify the diagnosis of pediatric OSA using raw electrocardiogram tracing (ECG). Specifically, a new convolutional neural network (CNN)-based regression model was implemented to automatically predict pediatric OSA by estimating its severity based on the apnea-hypopnea index (AHI) and deriving 4 OSA severity categories. For this purpose, overnight ECGs from 1,610 PSG recordings obtained from the Childhood Adenotonsillectomy Trial (CHAT) database were used. The database was randomly divided into approximately 60%, 20%, and 20% for training, validation, and testing, respectively. The diagnostic performance of the proposed CNN model largely outperformed the most accurate previous algorithms that relied on ECG-derived features (4-class Cohen's kappa coefficient of 0.373 versus 0.166). Specifically, for AHI cutoff values of 1, 5, and 10 events/hour, the binary classification achieved sensitivities of 84.19%, 76.67%, and 53.66%; specificities of 46.15%, 91.39%, and 98.06%; and accuracies of 75.92%, 86.96%, and 91.97%, respectively. Therefore, pediatric OSA can be readily identified by our proposed CNN model, which provides a simpler, faster, and more accessible diagnostic test that can be implemented in clinical practice.

Pediatric sleep apnea: Characterization of apneic events and sleep stages using heart rate variability.

Heart rate variability (HRV) is modulated by sleep stages and apneic events. Previous studies in children compared classical HRV parameters during sleep stages between obstructive sleep apnea (OSA) and controls. However, HRV-based characterization incorporating both sleep stages and apneic events has not been conducted. Furthermore, recently proposed novel HRV OSA-specific parameters have not been evaluated. Therefore, the aim of this study was to characterize and compare classic and pediatric OSA-specific HRV parameters while including both sleep stages and apneic events. A total of 1610 electrocardiograms from the Childhood Adenotonsillectomy Trial (CHAT) database were split into 10-min segments to extract HRV parameters. Segments were characterized and grouped by sleep stage (wake, W; non-rapid eye movement, NREMS; and REMS) and presence of apneic events (under 1 apneic event per segment, e/s; 1-5 e/s; 5-10 e/s; and over 10 e/s). NREMS showed significant changes in HRV parameters as apneic event frequency increased, which were less marked in REMS. In both NREMS and REMS, power in BW2, a pediatric OSA-specific frequency domain, allowed for the optimal differentiation among segments. Moreover, in the absence of apneic events, another defined band, BWRes, resulted in best differentiation between sleep stages. The clinical usefulness of segment-based HRV characterization was then confirmed by two ensemble-learning models aimed at estimating apnea-hypopnea index and classifying sleep stages, respectively. We surmise that basal sympathetic activity during REMS may mask apneic events-induced sympathetic excitation, thus highlighting the importance of incorporating sleep stages as well as apneic events when evaluating HRV in pediatric OSA.

Slow EEG Oscillation to Characterize Pediatric Sleep Apnea and Associated Cognitive Impairments.

Previous studies have suggested that the typical slow oscillations (SO) characteristics during sleep could be modified in the presence of pediatric obstructive sleep apnea (OSA). Here, we evaluate whether these modifications are significant and if they may reflect cognitive deficits. We recorded the overnight electroencephalogram (EEG) of 294 pediatric subjects (5-9 years old) using eight channels. Then, we divided the cohort in three OSA severity groups (no OSA, mild, and moderate/severe) to characterize the corresponding SO using the spectral maximum in the slow wave sleep (SWS) band δ1: 0.1-2 Hz (Maxs o), as well as the frequency where this maximum is located (FreqMaxso). Spectral entropy (SpecEn) from δ1 was also included in the analyses. A correlation analysis was performed to evaluate associations of these spectral measures with six OSA-related clinical variables and six cognitive scores. Our results indicate that Maxso could be used as a moderate/severe OSA biomarker while providing useful information regarding verbal and visuo-spatial impairments, and that FreqMaxso emerges as an even more robust indicator of visuospatial function. In addition, we uncovered novel insights regarding the ability of SpecEn in δ1 to characterize OSA-related disruption of sleep homeostasis. Our findings suggest that the information from SO may be useful to automatically characterize moderate/severe pediatric OSA and its cognitive consequences. Clinical Relevance- This study contributes towards reaching an objective quantifiable and automated assessment of the potential cognitive consequences of pediatric sleep apnea.

Heart rate variability as a potential biomarker of pediatric obstructive sleep apnea resolution.

STUDY OBJECTIVES: Pediatric obstructive sleep apnea (OSA) affects cardiac autonomic regulation, altering heart rate variability (HRV). Although changes in classical HRV parameters occur after OSA treatment, they have not been evaluated as reporters of OSA resolution. Specific frequency bands (named BW1, BW2, and BWRes) have been recently identified in OSA. We hypothesized that changes with treatment in these spectral bands can reliably identify changes in OSA severity and reflect OSA resolution. METHODS: Four hundred and four OSA children (5-9.9 years) from the prospective Childhood Adenotonsillectomy Trial were included; 206 underwent early adenotonsillectomy (eAT), while 198 underwent watchful waiting with supportive care (WWSC). HRV changes from baseline to follow-up were computed for classical and OSA-related frequency bands. Causal mediation analysis was conducted to evaluate how treatment influences HRV through mediators such as OSA resolution and changes in disease severity. Disease resolution was initially assessed by considering only obstructive events, and was followed by adding central apneas to the analyses. RESULTS: Treatment, regardless of eAT or WWSC, affects HRV activity, mainly in the specific frequency band BW2 (0.028-0.074 Hz). Furthermore, only changes in BW2 were specifically attributable to all OSA resolution mediators. HRV activity in BW2 also showed statistically significant differences between resolved and non-resolved OSA. CONCLUSIONS: OSA treatment affects HRV activity in terms of change in severity and disease resolution, especially in OSA-related BW2 frequency band. This band allowed to differentiate HRV activity between children with and without resolution, so we propose BW2 as potential biomarker of pediatric OSA resolution. CLINICAL TRIAL REGISTRATION: Childhood Adenotonsillectomy Trial, NCT00560859, https://sleepdata.org/datasets/chat.

Pediatric Sleep Apnea: The Overnight Electroencephalogram as a Phenotypic Biomarker.

Pediatric obstructive sleep apnea (OSA) is a prevalent disorder that disrupts sleep and is associated with neurocognitive and behavioral negative consequences, potentially hampering the development of children for years. However, its relationships with sleep electroencephalogram (EEG) have been scarcely investigated. Here, our main objective was to characterize the overnight EEG of OSA-affected children and its putative relationships with polysomnographic measures and cognitive functions. A two-step analysis involving 294 children (176 controls, 57% males, age range: 5-9 years) was conducted for this purpose. First, the activity and irregularity of overnight EEG spectrum were characterized in the typical frequency bands by means of relative spectral power and spectral entropy, respectively: δ1 (0.1-2 Hz), δ2 (2-4 Hz), θ (4-8 Hz), α (8-13 Hz), σ (10-16 Hz), ß1 (13-19 Hz), ß2 (19-30 Hz), and γ (30-70 Hz). Then, a correlation network analysis was conducted to evaluate relationships between them, six polysomnography variables (apnea-hypopnea index, respiratory arousal index, spontaneous arousal index, overnight minimum blood oxygen saturation, wake time after sleep onset, and sleep efficiency), and six cognitive scores (differential ability scales, Peabody picture vocabulary test, expressive vocabulary test, design copying, phonological processing, and tower test). We found that as the severity of the disease increases, OSA broadly affects sleep EEG to the point that the information from the different frequency bands becomes more similar, regardless of activity or irregularity. EEG activity and irregularity information from the most severely affected children were significantly associated with polysomnographic variables, which were coherent with both micro and macro sleep disruptions. We hypothesize that the EEG changes caused by OSA could be related to the occurrence of respiratory-related arousals, as well as thalamic inhibition in the slow oscillation generation due to increases in arousal levels aimed at recovery from respiratory events. Furthermore, relationships between sleep EEG and cognitive scores emerged regarding language, visual-spatial processing, and executive function with pronounced associations found with EEG irregularity in δ1 (Peabody picture vocabulary test and expressive vocabulary test maximum absolute correlations 0.61 and 0.54) and ß2 (phonological processing, 0.74; design copying, 0.65; and Tow 0.52). Our results show that overnight EEG informs both sleep alterations and cognitive effects of pediatric OSA. Moreover, EEG irregularity provides new information that complements and expands the classic EEG activity analysis. These findings lay the foundation for the use of sleep EEG to assess cognitive changes in pediatric OSA.

Erratum: Martín-Montero et al. Bispectral Analysis of Heart Rate Variability to Characterize and Help Diagnose Pediatric Sleep Apnea. Entropy 2021, 23, 1016.

The author wishes to make the following correction to this paper [...].

Bispectral Analysis of Heart Rate Variability to Characterize and Help Diagnose Pediatric Sleep Apnea.

Pediatric obstructive sleep apnea (OSA) is a breathing disorder that alters heart rate variability (HRV) dynamics during sleep. HRV in children is commonly assessed through conventional spectral analysis. However, bispectral analysis provides both linearity and stationarity information and has not been applied to the assessment of HRV in pediatric OSA. Here, this work aimed to assess HRV using bispectral analysis in children with OSA for signal characterization and diagnostic purposes in two large pediatric databases (0-13 years). The first database (training set) was composed of 981 overnight ECG recordings obtained during polysomnography. The second database (test set) was a subset of the Childhood Adenotonsillectomy Trial database (757 children). We characterized three bispectral regions based on the classic HRV frequency ranges (very low frequency: 0-0.04 Hz; low frequency: 0.04-0.15 Hz; and high frequency: 0.15-0.40 Hz), as well as three OSA-specific frequency ranges obtained in recent studies (BW1: 0.001-0.005 Hz; BW2: 0.028-0.074 Hz; BWRes: a subject-adaptive respiratory region). In each region, up to 14 bispectral features were computed. The fast correlation-based filter was applied to the features obtained from the classic and OSA-specific regions, showing complementary information regarding OSA alterations in HRV. This information was then used to train multi-layer perceptron (MLP) neural networks aimed at automatically detecting pediatric OSA using three clinically defined severity classifiers. Both classic and OSA-specific MLP models showed high and similar accuracy (Acc) and areas under the receiver operating characteristic curve (AUCs) for moderate (classic regions: Acc = 81.0%, AUC = 0.774; OSA-specific regions: Acc = 81.0%, AUC = 0.791) and severe (classic regions: Acc = 91.7%, AUC = 0.847; OSA-specific regions: Acc = 89.3%, AUC = 0.841) OSA levels. Thus, the current findings highlight the usefulness of bispectral analysis on HRV to characterize and diagnose pediatric OSA.

Heart rate variability spectrum characteristics in children with sleep apnea.

BACKGROUND: Classic spectral analysis of heart rate variability (HRV) in pediatric sleep apnea-hypopnea syndrome (SAHS) traditionally evaluates the very low frequency (VLF: 0-0.04 Hz), low frequency (LF: 0.04-0.15 Hz), and high frequency (HF: 0.15-0.40 Hz) bands. However, specific SAHS-related frequency bands have not been explored. METHODS: One thousand seven hundred and thirty-eight HRV overnight recordings from two pediatric databases (0-13 years) were evaluated. The first one (981 children) served as training set to define new HRV pediatric SAHS-related frequency bands. The associated relative power (RP) were computed in the test set, the Childhood Adenotonsillectomy Trial database (CHAT, 757 children). Their relationships with polysomnographic variables and diagnostic ability were assessed. RESULTS: Two new specific spectral bands of pediatric SAHS within 0-0.15 Hz were related to duration of apneic events, number of awakenings, and wakefulness after sleep onset (WASO), while an adaptive individual-specific new band from HF was related to oxyhemoglobin desaturations, arousals, and WASO. Furthermore, these new spectral bands showed improved diagnostic ability than classic HRV. CONCLUSIONS: Novel spectral bands provide improved characterization of pediatric SAHS. These findings may pioneer a better understanding of the effects of SAHS on cardiac function and potentially serve as detection biomarkers. IMPACT: New specific heart rate variability (HRV) spectral bands are identified and characterized as potential biomarkers in pediatric sleep apnea. Spectral band BW1 (0.001-0.005 Hz) is related to macro sleep disruptions. Spectral band BW2 (0.028-0.074 Hz) is related to the duration of apneic events. An adaptive spectral band within the respiratory range, termed ABW3, is related to oxygen desaturations. The individual and collective diagnostic ability of these novel spectral bands outperforms classic HRV bands.

Assessment of Airflow and Oximetry Signals to Detect Pediatric Sleep Apnea-Hypopnea Syndrome Using AdaBoost.

The reference standard to diagnose pediatric Obstructive Sleep Apnea (OSA) syndrome is an overnight polysomnographic evaluation. When polysomnography is either unavailable or has limited availability, OSA screening may comprise the automatic analysis of a minimum number of signals. The primary objective of this study was to evaluate the complementarity of airflow (AF) and oximetry (SpO2) signals to automatically detect pediatric OSA. Additionally, a secondary goal was to assess the utility of a multiclass AdaBoost classifier to predict OSA severity in children. We extracted the same features from AF and SpO2 signals from 974 pediatric subjects. We also obtained the 3% Oxygen Desaturation Index (ODI) as a common clinically used variable. Then, feature selection was conducted using the Fast Correlation-Based Filter method and AdaBoost classifiers were evaluated. Models combining ODI 3% and AF features outperformed the diagnostic performance of each signal alone, reaching 0.39 Cohens's kappa in the four-class classification task. OSA vs. No OSA accuracies reached 81.28%, 82.05% and 90.26% in the apnea-hypopnea index cutoffs 1, 5 and 10 events/h, respectively. The most relevant information from SpO2 was redundant with ODI 3%, and AF was complementary to them. Thus, the joint analysis of AF and SpO2 enhanced the diagnostic performance of each signal alone using AdaBoost, thereby enabling a potential screening alternative for OSA in children.