Balaji Goparaju

Sleep apnea in patients reporting insomnia or restless legs symptoms.

Insomnia and restless legs syndrome (RLS) are defined by self‐reported symptoms, and polysomnography (PSG) is not routinely indicated. Occult obstructive sleep apnea (OSA), common even in asymptomatic adults, may complicate management of patients presenting with insomnia or restless legs. To this end, we investigated objective sleep apnea metrics in a large retrospective cohort according to self‐reported symptom profiles.

Sleep–wake misperception in sleep apnea patients undergoing diagnostic versus titration polysomnography

OBJECTIVE Insomnia is commonly co-morbid with obstructive sleep apnea. Among patients reporting insomnia symptoms, sleep misperception occurs when self-reported sleep duration under-estimates objective measures. Misperception represents a clinical challenge since insomnia management is based entirely on patient self-report. We tested the hypothesis that misperception occurring in sleep apnea patients would improve with subsequent treatment. METHODS We compared subjective sleep-wake reports with objective sleep in adults with obstructive sleep apnea (n=405) in two nights of polysomnography (diagnostic and treatment) within a median interval of 92 days. RESULTS Sleep latency was generally over-estimated, while wake after sleep onset and number of awakenings were under-estimated. None of these estimations differed between diagnostic and treatment polysomnograms. We observed a large spectrum of total sleep time misperception values during the diagnostic polysomnogram, with one third of the cohort under-estimating their total sleep time by at least 60 min. Of those with >60 minute misperception, we observed improved total sleep time perception during treatment polysomnography. Improved perception correlated with improvements in self-reported sleep quality and response confidence. We found no polysomnogram or demographic predictors of total sleep time misperception for the diagnostic polysomnogram, nor did we find objective correlates of improved perception during titration. CONCLUSION Our results suggest that misperception may improve with treatment of obstructive sleep apnea in patients who also exhibit misperception. Within subject changes in misperception are consistent with misperception being, at least to some extent, a state characteristic, which has implications for management of patients with comorbid insomnia and sleep apnea.

Potential Underestimation of Sleep Apnea Severity by At-Home Kits: Rescoring In-Laboratory Polysomnography Without Sleep Staging

STUDY OBJECTIVES Home sleep apnea testing (HSAT) is increasingly available for diagnosing obstructive sleep apnea (OSA). One key limitation of most HSAT involves the lack of sleep staging, such that the respiratory event index is calculated using the total recording time (TRT) rather than total sleep time (TST). METHODS We performed a retrospective analysis of n = 838 diagnostic polysomnography (PSG) nights from our center; n = 444 with OSA (4% rule, apneahypopnea index (AHI) ≥ 5), and n = 394 with AHI < 5. We recalculated the AHI using time in bed (TIB) instead of TST, to assess the predicted underestimation risk of OSA severity. RESULTS Of all the patients with OSA, 26.4% would be reclassified as having less severe or no OSA after recalculating the AHI using TIB rather than TST. Of the n = 275 with mild OSA, 18.5% would be reclassified as not having OSA. The risk of underestimation was higher in those with moderate or severe OSA. Of the n = 119 moderate OSA cases, 40.3% would be reclassified as mild, and of the n = 50 severe OSA cases, 36.0% would be reclassified as moderate. Age strongly correlated with the degree of underestimation of the AHI, because age was significantly correlated with time awake during PSG. CONCLUSIONS The risk of sleep apnea underestimation is predicted to be substantial in a tertiary sleep center population. Phenotyping errors included risk of falsely negative results (from mild to normal), as well as category errors: moderate or severe moving to mild or moderate severity, respectively. Clinicians should recognize this underestimation limitation, which directly affects diagnostic phenotyping and thus therapeutic decisions. COMMENTARY A commentary on this article appears in this issue on page 531.

Large-Scale Automated Sleep Staging

Study Objectives Automated sleep staging has been previously limited by a combination of clinical and physiological heterogeneity. Both factors are in principle addressable with large data sets that enable robust calibration. However, the impact of sample size remains uncertain. The objectives are to investigate the extent to which machine learning methods can approximate the performance of human scorers when supplied with sufficient training cases and to investigate how staging performance depends on the number of training patients, contextual information, model complexity, and imbalance between sleep stage proportions. Methods A total of 102 features were extracted from six electroencephalography (EEG) channels in routine polysomnography. Two thousand nights were partitioned into equal (n = 1000) training and testing sets for validation. We used epoch-by-epoch Cohens kappa statistics to measure the agreement between classifier output and human scorer according to American Academy of Sleep Medicine scoring criteria. Results Epoch-by-epoch Cohens kappa improved with increasing training EEG recordings until saturation occurred (n = ~300). The kappa value was further improved by accounting for contextual (temporal) information, increasing model complexity, and adjusting the model training procedure to account for the imbalance of stage proportions. The final kappa on the testing set was 0.68. Testing on more EEG recordings leads to kappa estimates with lower variance. Conclusion Training with a large data set enables automated sleep staging that compares favorably with human scorers. Because testing was performed on a large and heterogeneous data set, the performance estimate has low variance and is likely to generalize broadly.

Big data in sleep medicine: prospects and pitfalls in phenotyping

Clinical polysomnography (PSG) databases are a rich resource in the era of “big data” analytics. We explore the uses and potential pitfalls of clinical data mining of PSG using statistical principles and analysis of clinical data from our sleep center. We performed retrospective analysis of self-reported and objective PSG data from adults who underwent overnight PSG (diagnostic tests, n=1835). Self-reported symptoms overlapped markedly between the two most common categories, insomnia and sleep apnea, with the majority reporting symptoms of both disorders. Standard clinical metrics routinely reported on objective data were analyzed for basic properties (missing values, distributions), pairwise correlations, and descriptive phenotyping. Of 41 continuous variables, including clinical and PSG derived, none passed testing for normality. Objective findings of sleep apnea and periodic limb movements were common, with 51% having an apnea–hypopnea index (AHI) >5 per hour and 25% having a leg movement index >15 per hour. Different visualization methods are shown for common variables to explore population distributions. Phenotyping methods based on clinical databases are discussed for sleep architecture, sleep apnea, and insomnia. Inferential pitfalls are discussed using the current dataset and case examples from the literature. The increasing availability of clinical databases for large-scale analytics holds important promise in sleep medicine, especially as it becomes increasingly important to demonstrate the utility of clinical testing methods in management of sleep disorders. Awareness of the strengths, as well as caution regarding the limitations, will maximize the productive use of big data analytics in sleep medicine.

Alternative remedies for insomnia: a proposed method for personalized therapeutic trials

Insomnia is a common symptom, with chronic insomnia being diagnosed in 5–10% of adults. Although many insomnia patients use prescription therapy for insomnia, the health benefits remain uncertain and adverse risks remain a concern. While similar effectiveness and risk concerns exist for herbal remedies, many individuals turn to such alternatives to prescriptions for insomnia. Like prescription hypnotics, herbal remedies that have undergone clinical testing often show subjective sleep improvements that exceed objective measures, which may relate to interindividual heterogeneity and/or placebo effects. Response heterogeneity can undermine traditional randomized trial approaches, which in some fields has prompted a shift toward stratified trials based on genotype or phenotype, or the so-called n-of-1 method of testing placebo versus active drug in within-person alternating blocks. We reviewed six independent compendiums of herbal agents to assemble a group of over 70 reported to benefit sleep. To bridge the gap between the unfeasible expectation of formal evidence in this space and the reality of common self-medication by those with insomnia, we propose a method for guided self-testing that overcomes certain operational barriers related to inter- and intraindividual sources of phenotypic variability. Patient-chosen outcomes drive a general statistical model that allows personalized self-assessment that can augment the open-label nature of routine practice. The potential advantages of this method include flexibility to implement for other (nonherbal) insomnia interventions.

Automated identification of epileptic seizures in EEG signals based on phase space representation and statistical features in the CEEMD domain

Abstract Epileptic seizure detection based on visual inspection by expert physicians is burdensome, and subject to error and bias. In this work, we present a novel method for the automated identification of epileptic seizure using a single-channel EEG signal. We utilize the complete ensemble empirical mode decomposition with adaptive noise (CEEMDAN) technique to devise an effective feature extraction scheme for physiological signal analysis, and construct the corresponding growth curve. Then, various statistical features are extracted from the growth curve as the feature set, and this is fed to the random forest classifier for completing the detection. The suitability of the extracted features is established through statistical measures and graphical analysis. The proposed method is evaluated for the well-known problem of classifying epileptic seizure and seizure-free signals using a publically available EEG database from the University of Bonn. To assess the performance of the classification method, 10-fold cross-validation is performed. Compared to state-of-the-art algorithms, the numerical results confirm the superior algorithm performance of the proposed scheme in terms of accuracy, sensitivity, specificity, and Cohen’s Kappa statistics.

Sleep Fragmentation Does Not Explain Misperception of Latency or Total Sleep Time.

STUDY OBJECTIVES Perception of sleep-wake times may differ from objective measures, although the mechanisms remain elusive. Quantifying the misperception phenotype involves two operational challenges: defining objective sleep latency and treating sleep latency and total sleep time as independent factors. We evaluated a novel approach to address these challenges and test the hypothesis that sleep fragmentation underlies misperception. METHODS We performed a retrospective analysis on patients with or without obstructive sleep apnea during overnight diagnostic polysomnography in our laboratory (n = 391; n = 252). We compared subjective and objective sleep-wake durations to characterize misperception. We introduce a new metric, sleep during subjective latency (SDSL), which captures latency misperception without defining objective sleep latency and allows correction for latency misperception when assessing total sleep time (TST) misperception. RESULTS The stage content of SDSL is related to latency misperception, but in the opposite manner as our hypothesis: those with > 20 minutes of SDSL had less N1%, more N3%, and lower transition frequency. After adjusting for misperceived sleep during subjective sleep latency, TST misperception was greater in those with longer bouts of REM and N2 stages (OSA patients) as well as N3 (non-OSA patients), which also did not support our hypothesis. CONCLUSIONS Despite the advantages of SDSL as a phenotyping tool to overcome operational issues with quantifying misperception, our results argue against the hypothesis that light or fragmented sleep underlies misperception. Further investigation of sleep physiology utilizing alternative methods than that captured by conventional stages may yield additional mechanistic insights into misperception. COMMENTARY A commentary on this article appears in this issue on page 1211.

Periodic limb movements of sleep: empirical and theoretical evidence supporting objective at-home monitoring.

Introduction Periodic limb movements of sleep (PLMS) may increase cardiovascular and cerebrovascular morbidity. However, most people with PLMS are either asymptomatic or have nonspecific symptoms. Therefore, predicting elevated PLMS in the absence of restless legs syndrome remains an important clinical challenge. Methods We undertook a retrospective analysis of demographic data, subjective symptoms, and objective polysomnography (PSG) findings in a clinical cohort with or without obstructive sleep apnea (OSA) from our laboratory (n=443 with OSA, n=209 without OSA). Correlation analysis and regression modeling were performed to determine predictors of periodic limb movement index (PLMI). Markov decision analysis with TreeAge software compared strategies to detect PLMS: in-laboratory PSG, at-home testing, and a clinical prediction tool based on the regression analysis. Results Elevated PLMI values (>15 per hour) were observed in >25% of patients. PLMI values in No-OSA patients correlated with age, sex, self-reported nocturnal leg jerks, restless legs syndrome symptoms, and hypertension. In OSA patients, PLMI correlated only with age and self-reported psychiatric medications. Regression models indicated only a modest predictive value of demographics, symptoms, and clinical history. Decision modeling suggests that at-home testing is favored as the pretest probability of PLMS increases, given plausible assumptions regarding PLMS morbidity, costs, and assumed benefits of pharmacological therapy. Conclusion Although elevated PLMI values were commonly observed, routinely acquired clinical information had only weak predictive utility. As the clinical importance of elevated PLMI continues to evolve, it is likely that objective measures such as PSG or at-home PLMS monitors will prove increasingly important for clinical and research endeavors.

Heart rate phenotypes and clinical correlates in a large cohort of adults without sleep apnea

Background Normal sleep is associated with typical physiological changes in both the central and autonomic nervous systems. In particular, nocturnal blood pressure dipping has emerged as a strong marker of normal sleep physiology, whereas the absence of dipping or reverse dipping has been associated with cardiovascular risk. However, nocturnal blood pressure is not measured commonly in clinical practice. Heart rate (HR) dipping in sleep may be a similar important marker and is measured routinely in at-home and in-laboratory sleep testing. Methods We performed a retrospective cross-sectional analysis of diagnostic polysomnography in a clinically heterogeneous cohort of n=1047 adults without sleep apnea. Results We found that almost half of the cohort showed an increased HR in stable nonrapid eye movement sleep (NREM) compared to wake, while only 13.5% showed a reduced NREM HR of at least 10% relative to wake. The strongest correlates of HR dipping were younger age and male sex, whereas the periodic limb movement index (PLMI), sleep quality, and Epworth Sleepiness Scale (ESS) scores were not correlated with HR dipping. PLMI was however significantly correlated with metrics of impaired HR variability (HRV): increased low-frequency power and reduced high-frequency power. HRV metrics were unrelated to sleep quality or the ESS value. Following the work of Vgontzas et al, we also analyzed the sub-cohort with insomnia symptoms and short objective sleep duration. Interestingly, the sleep–wake stage-specific HR values depended upon insomnia symptoms more than sleep duration. Conclusion While our work demonstrates heterogeneity in cardiac metrics (HR and HRV), the population analysis suggests that pathological signatures of HR (nondipping and elevation) are common even in this cohort selected for the absence of sleep apnea. Future prospective work in clinical populations will further inform risk stratification and set the stage for testing interventions.