Proteomic insights into the pathophysiology of periodic limb movements and restless legs syndrome.

OBJECTIVES: We used a high-throughput assay of 5000 plasma proteins to identify biomarkers associated with periodic limb movements (PLM) and restless legs syndrome (RLS) in adults. METHODS: Participants (n = 1410) of the Stanford Technology Analytics and Genomics in Sleep (STAGES) study had blood collected, completed a sleep questionnaire, and underwent overnight polysomnography with the scoring of PLMs. An aptamer-based array (SomaScan) was used to quantify 5000 proteins in plasma. A second cohort (n = 697) that had serum assayed using a previous iteration of SomaScan (1300 proteins) was used for replication and in a combined analysis (n = 2107). A 5% false discovery rate was used to assess significance. RESULTS: Multivariate analyses in STAGES identified 68 proteins associated with the PLM index after correction for multiple testing (ie, base model). Most significantly decreased proteins were iron-related and included Hepcidin (LEAP-1), Ferritin, and Ferritin light chain. Most significantly increased proteins included RANTES, Cathepsin A, and SULT 1A3. Of 68 proteins significant in the base model, 17 were present in the 1300 panel, and 15 of 17 were replicated. The most significant proteins in the combined model were Hepcidin (LEAP-1), Cathepsin A, Ferritin, and RANTES. Exploration of proteins in RLS versus non-RLS identified Cathepsin Z, Heme oxygenase 2 (HO-2), Interleukin-17A (upregulated in the combined cohort), and Megalin (upregulated in STAGES only) although results were less significant than for proteins associated with PLM index. CONCLUSIONS: These results confirm the association of PLM with low iron status and suggest the involvement of catabolic enzymes in PLM/RLS.

Proteomic Biomarkers of the Apnea Hypopnea Index and Obstructive Sleep Apnea: Insights into the Pathophysiology of Presence, Severity, and Treatment Response.

Obstructive sleep apnea (OSA), a disease associated with excessive sleepiness and increased cardiovascular risk, affects an estimated 1 billion people worldwide. The present study examined proteomic biomarkers indicative of presence, severity, and treatment response in OSA. Participants (n = 1391) of the Stanford Technology Analytics and Genomics in Sleep study had blood collected and completed an overnight polysomnography for scoring the apnea−hypopnea index (AHI). A highly multiplexed aptamer-based array (SomaScan) was used to quantify 5000 proteins in all plasma samples. Two separate intervention-based cohorts with sleep apnea (n = 41) provided samples pre- and post-continuous/positive airway pressure (CPAP/PAP). Multivariate analyses identified 84 proteins (47 positively, 37 negatively) associated with AHI after correction for multiple testing. Of the top 15 features from a machine learning classifier for AHI ≥ 15 vs. AHI < 15 (Area Under the Curve (AUC) = 0.74), 8 were significant markers of both AHI and OSA from multivariate analyses. Exploration of pre- and post-intervention analysis identified 5 of the 84 proteins to be significantly decreased following CPAP/PAP treatment, with pathways involving endothelial function, blood coagulation, and inflammatory response. The present study identified PAI-1, tPA, and sE-Selectin as key biomarkers and suggests that endothelial dysfunction and increased coagulopathy are important consequences of OSA, which may explain the association with cardiovascular disease and stroke.

Estimation of Apnea-Hypopnea Index Using Deep Learning On 3-D Craniofacial Scans.

Obstructive sleep apnea (OSA) is characterized by decreased breathing events that occur through the night, with severity reported as the apnea-hypopnea index (AHI), which is associated with certain craniofacial features. In this study, we used data from 1366 patients collected as part of Stanford Technology Analytics and Genomics in Sleep (STAGES) across 11 US and Canadian sleep clinics and analyzed 3D craniofacial scans with the goal of predicting AHI, as measured using gold standard nocturnal polysomnography (PSG). First, the algorithm detects pre-specified landmarks on mesh objects and aligns scans in 3D space. Subsequently, 2D images and depth maps are generated by rendering and rotating scans by 45-degree increments. Resulting images were stacked as channels and used as input to multi-view convolutional neural networks, which were trained and validated in a supervised manner to predict AHI values derived from PSGs. The proposed model achieved a mean absolute error of 11.38 events/hour, a Pearson correlation coefficient of 0.4, and accuracy for predicting OSA of 67% using 10-fold cross-validation. The model improved further by adding patient demographics and variables from questionnaires. We also show that the model performed at the level of three sleep medicine specialists, who used clinical experience to predict AHI based on 3D scan displays. Finally, we created topographic displays of the most important facial features used by the model to predict AHI, showing importance of the neck and chin area. The proposed algorithm has potential to serve as an inexpensive and efficient screening tool for individuals with suspected OSA.

Obstructive sleep apnea and driving: A Canadian Thoracic Society and Canadian Sleep Society position paper.

Untreated patients with obstructive sleep apnea (OSA) are at increased risk for motor vehicle collisions; however, it is unclear how this should be translated into fitness-to-drive recommendations. Accordingly, the Canadian Thoracic Society (CTS) Sleep Disordered Breathing Clinical Assembly and the Canadian Sleep Society (CSS) assembled a CTS-CSS working group to propose recommendations with regard to driving in patients with OSA. Recommendations for assessing fitness to drive in noncommercial drivers: 1. Severity of OSA alone is not a reliable predictor of collision risk and, therefore, should not be used in isolation to assess fitness to drive; 2. The severity of sleep apnea should be considered in the context of other factors to assess fitness to drive; 3. The decision to restrict driving is ultimately made by the motor vehicle licensing authority; however, they should take into account the information and recommendations provided by the sleep medicine physician and should follow provincial guidelines; 4. For patients prescribed continuous positive airway pressure (CPAP) therapy, objective CPAP compliance should be documented. Efficacy should also be documented in terms of reversing the symptoms and improvement in sleep apnea based on physiological monitoring; 5. For patients treated with surgery or an oral appliance, verification of adequate sleep apnea treatment should be obtained; and 6. A driver diagnosed with OSA may be recertified as fit to drive based on assessment of symptoms and demonstrating compliance with treatment. The assessment should be aligned with the provincial driver's license renewal period. Commercial vehicles: Assessment of fitness to drive should be more stringent for patients operating commercial vehicles. In general, the CTS-CSS working group was in agreement with the Medical Expert Panel recommendations to the Federal Motor Carrier Safety Administration in the United States; these recommendations were adapted for Canadian practitioners.

Canadian Sleep Society/Canadian Thoracic Society position paper on the use of portable monitoring for the diagnosis of obstructive sleep apnea/hypopnea in adults.

The present position paper on the use of portable monitoring (PM) as a diagnostic tool for obstructive sleep apnea/hypopnea (OSAH) in adults was based on consensus and expert opinion regarding best practice standards from stakeholders across Canada. These recommendations were prepared to guide appropriate clinical use of this new technology and to ensure that quality assurance standards are adhered to. Clinical guidelines for the use of PM for the diagnosis and management of OSAH as an alternative to in-laboratory polysomnography published by the American Academy of Sleep Medicine Portable Monitoring Task Force were used to tailor our recommendations to address the following: indications; methodology including physician involvement, physician and technical staff qualifications, and follow-up requirements; technical considerations; quality assurance; and conflict of interest guidelines. When used appropriately under the supervision of a physician with training in sleep medicine, and in conjunction with a comprehensive sleep evaluation, PM may expedite treatment when there is a high clinical suspicion of OSAH.