Single-nucleus RNA-seq identifies one galanin neuronal subtype in mouse preoptic hypothalamus activated during recovery from sleep deprivation.

The preoptic area of the hypothalamus (POA) is essential for sleep regulation. However, the cellular makeup of the POA is heterogeneous, and the molecular identities of the sleep-promoting cells remain elusive. To address this question, this study compares mice during recovery sleep following sleep deprivation to mice allowed extended sleep. Single-nucleus RNA sequencing (single-nucleus RNA-seq) identifies one galanin inhibitory neuronal subtype that shows upregulation of rapid and delayed activity-regulated genes during recovery sleep. This cell type expresses higher levels of growth hormone receptor and lower levels of estrogen receptor compared to other galanin subtypes. single-nucleus RNA-seq also reveals cell-type-specific upregulation of purinergic receptor (P2ry14) and serotonin receptor (Htr2a) during recovery sleep in this neuronal subtype, suggesting possible mechanisms for sleep regulation. Studies with RNAscope validate the single-nucleus RNA-seq findings. Thus, the combined use of single-nucleus RNA-seq and activity-regulated genes identifies a neuronal subtype functionally involved in sleep regulation.

Perturbation of the insomnia WDR90 GWAS locus pinpoints rs3752495 as a causal variant influencing distal expression of neighboring gene, PIG-Q.

Although genome wide association studies (GWAS) have identified loci for sleep-related traits, they do not directly uncover the underlying causal variants and corresponding effector genes. The majority of such variants reside in non-coding regions and are therefore presumed to impact cis-regulatory elements. Our previously reported 'variant-to-gene mapping' effort in human induced pluripotent stem cell (iPSC)-derived neural progenitor cells (NPCs), combined with validation in both Drosophila and zebrafish, implicated PIG-Q as a functionally relevant gene at the insomnia 'WDR90' GWAS locus. However, importantly that effort did not characterize the corresponding underlying causal variant. Specifically, our previous 3D genomic datasets nominated a shortlist of three neighboring single nucleotide polymorphisms (SNPs) in strong linkage disequilibrium within an intronic enhancer region of WDR90 that contacted the open PIG-Q promoter. We sought to investigate the influence of these SNPs collectively and then individually on PIG-Q modulation to pinpoint the causal "regulatory" variant. Starting with gross level perturbation, deletion of the entire region in NPCs via CRISPR-Cas9 editing and subsequent RNA sequencing revealed expression changes in specific PIG-Q transcripts. Results from individual luciferase reporter assays for each SNP in iPSCs revealed that the region with the rs3752495 risk allele induced a ~2.5-fold increase in luciferase expression. Importantly, rs3752495 also exhibited an allele specific effect, with the risk allele increasing the luciferase expression by ~2-fold versus the non-risk allele. In conclusion, our variant-to-function approach and in vitro validation implicates rs3752495 as a causal insomnia variant embedded within WDR90 while modulating the expression of the distally located PIG-Q.

Nocturnal gastro-oesophageal reflux and respiratory symptoms are increased in sleep apnoea: comparison with the general population.

AIM: To assess respiratory symptoms and nocturnal gastro-oesophageal reflux (nGER) among untreated obstructive sleep apnoea (OSA) patients, compared with the general population. Also, if nGER associates differently with respiratory symptoms among OSA patients. METHODS: 2 study cohorts were included: 822 newly diagnosed subjects with moderate-severe OSA and 738 Icelandic general population study participants. All participants answered the same questionnaires. Those reporting nGER symptoms at least once per week were defined as 'with nGER'; those without nGER symptoms and without nGER medication were defined as 'no nGER'; and other participants were defined as having 'possible nGER'. Propensity score-based weights were used to minimise confounding and selection bias and facilitate causal interpretations. RESULTS: The prevalence of nGER among OSA patients was 14.1%, compared with 5.8% in the general population. This increased prevalence in OSA was not explained by differences in age, gender, body mass index, smoking, hypertension and diabetes (adjusted OR (95% CI)=3.79 (2.24 to 6.43)). OSA patients 'with nGER' and with 'possible nGER' reported more wheezing (44% and 44% vs 25%, respectively) and productive cough (47% and 42% vs 29%, respectively), compared with OSA patients with 'no nGER'. The same pattern was seen in the general population, although with a generally lower prevalence. The effect of nGER on respiratory symptoms was similar between the two cohorts. CONCLUSION: nGER was more often reported among untreated moderate-severe OSA patients than in the general population. Participants with nGER had more wheezing and productive cough, both among untreated OSA patients and in the general population.

Polysomnographic characteristics of excessive daytime sleepiness phenotypes in obstructive sleep apnea: results from the international sleep apnea global interdisciplinary consortium.

STUDY OBJECTIVES: Excessive daytime sleepiness (EDS) is a major symptom of obstructive sleep apnea (OSA). Traditional polysomnographic (PSG) measures only partially explain EDS in OSA. This study analyzed traditional and novel PSG characteristics of two different measures of EDS among patients with OSA. METHODS: Sleepiness was assessed using the Epworth Sleepiness Scale (>10 points defined as "risk of dozing") and a measure of general sleepiness (feeling sleepy ≥ 3 times/week defined as "feeling sleepy"). Four sleepiness phenotypes were identified: "non-sleepy," "risk of dozing only," "feeling sleepy only," and "both at risk of dozing and feeling sleepy." RESULTS: Altogether, 2083 patients with OSA (69% male) with an apnea-hypopnea index (AHI) ≥ 5 events/hour were studied; 46% were "non-sleepy," 26% at "risk of dozing only," 7% were "feeling sleepy only," and 21% reported both. The two phenotypes at "risk of dozing" had higher AHI, more severe hypoxemia (as measured by oxygen desaturation index, minimum and average oxygen saturation [SpO2], time spent < 90% SpO2, and hypoxic impacts) and they spent less time awake, had shorter sleep latency, and higher heart rate response to arousals than "non-sleepy" and "feeling sleepy only" phenotypes. While statistically significant, effect sizes were small. Sleep stages, frequency of arousals, wake after sleep onset and limb movement did not differ between sleepiness phenotypes after adjusting for confounders. CONCLUSIONS: In a large international group of patients with OSA, PSG characteristics were weakly associated with EDS. The physiological measures differed among individuals characterized as "risk of dozing" or "non-sleepy," while "feeling sleepy only" did not differ from "non-sleepy" individuals.

Telemedicine management of obstructive sleep apnea disorder in China: a randomized, controlled, non-inferiority trial.

PURPOSE: Previous studies assessed different components of telemedicine management pathway for OSA instead of the whole pathway. This randomized, controlled, and non-inferiority trial aimed to assess whether telemedicine management is clinically inferior to in-person care in China. METHODS: Adults suspected of OSA were randomized to telemedicine (web-based questionnaires, self-administered home sleep apnea test [HSAT], automatically adjusting positive airway pressure [APAP], and video-conference visits) or in-person management (paper questionnaires, in-person HSAT set-up, APAP, and face-to-face visits). Participants with an apnea-hypopnea index (AHI) ≥ 15 events/hour received APAP for 3 months. The non-inferiority analysis was based on the change in Functional Outcomes of Sleep Questionnaire (FOSQ) score and APAP adherence. Cost-effectiveness analysis was performed. RESULTS: In the modified intent-to-treat analysis set (n = 111 telemedicine, 111 in-person), FOSQ scores improved 1.73 (95% confidence interval [CI], 1.31-2.14) points with telemedicine and 2.05 (1.64-2.46) points with in-person care. The lower bound of the one-sided 95% non-inferiority CI for the difference in change between groups of - 0.812 was larger than the non-inferiority threshold of - 1. APAP adherence at 3 months was 243.3 (223.1-263.5) minutes/night for telemedicine and 241.6 (221.3-261.8) minutes/night for in-person care. The lower bound of the one-sided 95% non-inferiority CI of - 22.2 min/night was higher than the non-inferiority delta of - 45 min/night. Telemedicine had lower total costs than in-person management (CNY 1482.7 ± 377.2 vs. 1912.6 ± 681.3; p < 0.0001), driven by patient costs, but no significant difference in QALYs. CONCLUSIONS: Functional outcomes and adherence were not clinically inferior in patients managed by a comprehensive telemedicine approach compared to those receiving in-person care in China. CLINICAL TRIAL REGISTRATION: https://www.chictr.org.cn , Registration number ChiCTR2000030546. Retrospectively registered on March 06, 2020.

Long-term health outcomes for patients with obstructive sleep apnea: placing the Agency for Healthcare Research and Quality report in context-a multisociety commentary.

This multisociety commentary critically examines the Agency for Healthcare Research and Quality (AHRQ) final report and systematic review on long-term health outcomes in obstructive sleep apnea. The AHRQ report was commissioned by the Centers for Medicare & Medicaid Services and particularly focused on the long-term patient-centered outcomes of continuous positive airway pressure, the variability of sleep-disordered breathing metrics, and the validity of these metrics as surrogate outcomes. This commentary raises concerns regarding the AHRQ report conclusions and their potential implications for policy decisions. A major concern expressed in this commentary is that the AHRQ report inadequately acknowledges the benefits of continuous positive airway pressure for several established, long-term clinically important outcomes including excessive sleepiness, motor vehicle accidents, and blood pressure. While acknowledging the limited evidence for the long-term benefits of continuous positive airway pressure treatment, especially cardiovascular outcomes, as summarized by the AHRQ report, this commentary reviews the limitations of recent randomized controlled trials and nonrandomized controlled studies and the challenges of conducting future randomized controlled trials. A research agenda to address these challenges is proposed including study designs that may include both high quality randomized controlled trials and nonrandomized controlled studies. This commentary concludes by highlighting implications for the safety and quality of life for the millions of people living with obstructive sleep apnea if the AHRQ report alone was used by payers to limit coverage for the treatment of obstructive sleep apnea while not considering the totality of available evidence. CITATION: Patil SP, Billings ME, Bourjeily G, et al. Long-term health outcomes for patients with obstructive sleep apnea: placing the Agency for Healthcare Research and Quality report in context-a multisociety commentary. J Clin Sleep Med. 2024;20(1):135-149.

Identifying clusters of patient comorbidities associated with obstructive sleep apnea using electronic health records.

STUDY OBJECTIVES: The objectives of this study were to understand the relative comorbidity burden of obstructive sleep apnea (OSA), determine whether these relationships were modified by sex or age, and identify patient subtypes defined by common comorbidities. METHODS: Cases with OSA and noncases (controls) were defined using a validated electronic health record (EHR)-based phenotype and matched for age, sex, and time period of follow-up in the EHR. We compared prevalence of the 20 most common comorbidities between matched cases and controls using conditional logistic regression with and without controlling for body mass index. Latent class analysis was used to identify subtypes of OSA cases defined by combinations of these comorbidities. RESULTS: In total, 60,586 OSA cases were matched to 60,586 controls (from 1,226,755 total controls). Patients with OSA were more likely to have each of the 20 most common comorbidities compared with controls, with odds ratios ranging from 3.1 to 30.8 in the full matched set and 1.3 to 10.2 after body mass index adjustment. Associations between OSA and these comorbidities were generally stronger in females and patients with younger age at diagnosis. We identified 5 distinct subgroups based on EHR-defined comorbidities: High Comorbidity Burden, Low Comorbidity Burden, Cardiovascular Comorbidities, Inflammatory Conditions and Less Obesity, and Inflammatory Conditions and Obesity. CONCLUSIONS: Our study demonstrates the power of leveraging the EHR to understand the relative health burden of OSA, as well as heterogeneity in these relationships based on age and sex. In addition to enrichment for comorbidities, we identified 5 novel OSA subtypes defined by combinations of comorbidities in the EHR, which may be informative for understanding disease outcomes and improving prevention and clinical care. Overall, this study adds more evidence that OSA is heterogeneous and requires personalized management. CITATION: Te TT, Keenan BT, Veatch OJ, Boland MR, Hubbard RA, Pack AI. Identifying clusters of patient comorbidities associated with obstructive sleep apnea using electronic health records. J Clin Sleep Med. 2024;20(4):521-533.

Positive airway pressure treatment affects respiratory symptoms and gastro-oesophageal reflux: the Icelandic Sleep Apnea Cohort Study.

Aim: To study the effect of positive airway pressure (PAP) treatment on nocturnal gastro-oesophageal reflux (nGOR) and respiratory symptoms among clinical obstructive sleep apnoea (OSA) patients. Methods: 822 patients newly diagnosed with OSA referred for PAP treatment were recruited. 732 patients had a 2-year follow-up visit with continuous PAP compliance data (366 full PAP users, 366 partial/non-PAP users). They answered questionnaires, including reporting of nGOR, sleep and respiratory symptoms and general health. Patients with nGOR symptoms once a week or more were defined as "with nGOR". Those without nGOR symptoms and nGOR medication were defined as "no nGOR". Others were defined as "possible nGOR". Results: At 2-year follow-up, PAP treatment among full users resulted in decreased nGOR (adjusted OR 0.58, 95% CI 0.40-0.86) and wheezing (adjusted OR 0.56, 95% CI 0.35-0.88) compared with partial/non-PAP users. Decreased nGOR, among both full and partial/non-users of PAP treatment, was associated with a decrease in productive morning cough (adjusted OR 4.70, 95% CI 2.22-9.99) and a decrease in chronic bronchitis (adjusted OR 3.86, 95% CI 1.74-8.58), but not decreased wheezing (adjusted OR 0.90, 95% CI 0.39-2.08). A mediation analysis found that PAP treatment directly led to a decrease in wheezing, not mediated through nGOR. Conversely, PAP treatment decreased productive cough mediated through a decrease in nGOR. Conclusion: In an unselected group of OSA patients, PAP treatment for 2 years was associated with a decrease in nGOR and respiratory symptoms. The PAP treatment itself was associated with less wheezing. A decrease in nGOR through PAP treatment was associated with a decrease in productive cough.

The need to promote sleep health in public health agendas across the globe.

Healthy sleep is essential for physical and mental health, and social wellbeing; however, across the globe, and particularly in developing countries, national public health agendas rarely consider sleep health. Sleep should be promoted as an essential pillar of health, equivalent to nutrition and physical activity. To improve sleep health across the globe, a focus on education and awareness, research, and targeted public health policies are needed. We recommend developing sleep health educational programmes and awareness campaigns; increasing, standardising, and centralising data on sleep quantity and quality in every country across the globe; and developing and implementing sleep health policies across sectors of society. Efforts are needed to ensure equity and inclusivity for all people, particularly those who are most socially and economically vulnerable, and historically excluded.

Unmasking Heterogeneity of Sleep Apnea.

Sleep apnea is heterogeneous in multiple dimensions. There are different physiological risk factors that may have clinical relevance. However, assessing them is challenging. An approach to ascertain them using a simple model of ventilatory control has been proposed. It is based, however, on untenable assumptions. There are limited validation data and reproducibility is not stellar. There are also different symptom subtypes. They have been found in multiple population-based and clinical cohorts worldwide. Symptomatic benefit from therapy is most marked in the excessively sleepy subtype. This group may also be the group at increased CV risk from obstructive sleep apnea.

Perturbation of the insomnia WDR90 GWAS locus pinpoints rs3752495 as a causal variant influencing distal expression of neighboring gene, PIG-Q.

Although genome wide association studies (GWAS) have been crucial for the identification of loci associated with sleep traits and disorders, the method itself does not directly uncover the underlying causal variants and corresponding effector genes. The overwhelming majority of such variants reside in non-coding regions and are therefore presumed to impact the activity of cis-regulatory elements, such as enhancers. Our previously reported 'variant-to-gene mapping' effort in human induced pluripotent stem cell (iPSC)-derived neural progenitor cells (NPCs), combined with validation in both Drosophila and zebrafish, implicated PIG-Q as a functionally relevant gene at the insomnia 'WDR90' locus. However, importantly that effort did not characterize the corresponding underlying causal variant at this GWAS signal. Specifically, our genome-wide ATAC-seq and high-resolution promoter-focused Capture C datasets generated in this cell setting brought our attention to a shortlist of three tightly neighboring single nucleotide polymorphisms (SNPs) in strong linkage disequilibrium in a candidate intronic enhancer region of WDR90 that contacted the open PIG-Q promoter. The objective of this study was to investigate the influence of the proxy SNPs collectively and then individually on PIG-Q modulation and to pinpoint the causal "regulatory" variant among the three SNPs. Starting at a gross level perturbation, deletion of the entire region harboring all three SNPs in human iPSC-derived neural progenitor cells via CRISPR-Cas9 editing and subsequent RNA sequencing revealed expression changes in specific PIG-Q transcripts. Results from more refined individual luciferase reporter assays for each of the three SNPs in iPSCs revealed that the intronic region with the rs3752495 risk allele induced a ~2.5-fold increase in luciferase expression (n=10). Importantly, rs3752495 also exhibited an allele specific effect, with the risk allele increasing the luciferase expression by ~2-fold compared to the non-risk allele. In conclusion, our variant-to-function approach and subsequent in vitro validation implicates rs3752495 as a causal insomnia risk variant embedded at the WDR90-PIG-Q locus.

Five-year Transitions of Symptom Subtypes in Untreated Obstructive Sleep Apnea.

Objectives: It is unknown if symptom subtypes of obstructive sleep apnea (OSA) transition over time and what clinical factors may predict transitions. Methods: Data from 2,643 participants of the Sleep Heart Health Study with complete baseline and 5-year follow-up visits were analyzed. Latent Class Analysis on 14 symptoms at baseline and follow up determined symptom subtypes. Individuals without OSA (AHI<5) were incorporated as a known class at each time point. Multinomial logistic regression assessed the effect of age, sex, body mass index (BMI) and AHI on specific class transitions. Results: The sample consisted of 1,408 women (53.8%) and mean (SD) age 62.4 (10.5) years. We identified four OSA symptom subtypes at both baseline and follow-up visits: minimally symptomatic, disturbed sleep, moderately sleepy and excessively sleepy . Nearly half (44.2%) of the sample transitioned to a different subtype from baseline to follow-up visits; transitions to moderately sleepy were the most common (77% of all transitions). A five-year older age was associated with a 6% increase in odds to transit from excessively sleepy to moderately sleepy [OR (95% CI) = 1.06 (1.02, 1.12)]. Women had 2.35 times higher odds (95% CI: 1.27, 3.27) to transition from moderately sleepy to minimal symptoms . A 5-unit increase in BMI was associated with 2.29 greater odds (95% CI: 1.19, 4.38) to transition from minimal symptoms to excessively sleepy . Interpretation: While over half of the sample did not transition their subtype over 5 years, among those who did, the likelihood of transitioning between subtypes was significantly associated with a higher baseline age, higher baseline BMI and with women, but was not predicted by AHI. Clinical Trials: Sleep Heart Health Study (SHHS) Data Coordinating Center, (SHHS) https://clinicaltrials.gov/ct2/show/NCT00005275 , NCT00005275. Statement of significance: There is very little research assessing symptom progression and its contributions to clinical heterogeneity in OSA. In a large sample with untreated OSA, we grouped common OSA symptoms into subtypes and assessed if age, sex, or BMI predicted transitions between the subtypes over 5 years. Approximately half the sample transitioned to a different symptom subtype and improvements in symptom subtype presentation were common. Women and older individuals were more likely to transition to less severe subtypes, while increased BMI predicted transition to more severe subtype. Determining whether common symptoms like disturbed sleep or excessive daytime sleepiness occur early in the course of the disease or as a result of untreated OSA over an extended period can improve clinical decisions concerning diagnosis and treatment.

Pleiotropic effects of a high confidence Autism Spectrum Disorder gene, arid1b, on zebrafish sleep.

Sleep fulfills critical functions in neurodevelopment, such as promoting synaptic plasticity, neuronal wiring, and brain connectivity which are critical phenomena in Autism Spectrum Disorder (ASD) pathophysiology. Sleep disturbance, specifically insomnia, accompanies ASD and is associated with more severe core symptoms (e.g., social impairment). It is possible that focusing on identifying effective ways to treat sleep problems can help alleviate other ASD-related symptoms. A body of evidence indicates shared mechanisms and neurobiological substrates between sleep and ASD and investigation of these may inform therapeutic effects of improving sleep at both behavioral and molecular levels. In this study, we tested if sleep and social behavior were different in a zebrafish model with the arid1b gene mutated compared to controls. This gene was selected for study as expert curations conducted for the Simons Foundation for Autism Research Institute (SFARI) Gene database define it is as a 'high confidence' ASD gene (i.e., clearly implicated) encoding a chromatin remodeling protein. Homozygous arid1b mutants displayed increased arousability and light sleep compared to their heterozygous and wild type counterparts, based on testing a mechano-acoustic stimulus presenting different vibration frequencies of increasing intensity to detect sleep depth. In addition, decreased social preference was observed in arid1b heterozygous and homozygous mutant zebrafish. The behavioral phenotypes reported in our study are in line with findings from mouse models and human studies and demonstrate the utility of zebrafish as a vertebrate model system with high throughput phenotyping in the investigation of changes in sleep in models relevant to ASD. Furthermore, we demonstrate the importance of including assessments of arousal threshold when studying sleep using in vivo models.

Cost-effectiveness of a 3-year tele-messaging intervention for positive airway pressure use.

OBJECTIVES: To evaluate the cost-effectiveness of a 3-year tele-messaging intervention for positive airway pressure (PAP) use in obstructive sleep apnea (OSA). STUDY DESIGN: A post hoc cost-effectiveness analysis (from US payers' perspective) of data from a 3-month tele-OSA trial, augmented with 33 months of epidemiologic follow-up. METHODS: Cost-effectiveness was compared among 3 groups of participants with an apnea-hypopnea index of at least 15 events/hour: (1) no messaging (n = 172), (2) messaging for 3 months (n = 124), and (3) messaging for 3 years (n = 46). We report the incremental cost (2020 US$) per incremental hour of PAP use and the fraction probability of acceptability based on a willingness-to-pay threshold of $1825 per year ($5/day). RESULTS: The use of 3 years of messaging had similar mean annual costs ($5825) compared with no messaging ($5889; P = .89) but lower mean cost compared with 3 months of messaging ($7376; P = .02). Those who received messaging for 3 years had the highest mean PAP use (4.11 hours/night), followed by no messaging (3.03 hours/night) and 3 months of messaging (2.84 hours/night) (all P < .05). The incremental cost-effectiveness ratios indicated that 3 years of messaging showed lower costs and greater hours of PAP use compared with both no messaging and 3 months of messaging. Based on a willingness-to-pay threshold of $1825, there is a greater than 97.5% chance (ie, 95% confidence) that 3 years of messaging is acceptable compared with the other 2 interventions. CONCLUSIONS: Long-term tele-messaging is highly likely to be cost-effective compared with both no and short-term messaging, with an acceptable willingness-to-pay threshold. Future long-term cost-effectiveness studies in a randomized controlled trial setting are warranted.

Obesity does not modify the effect of continuous positive airway pressure on insulin resistance in adults with obstructive sleep apnoea.

This study found no evidence that obesity significantly modifies the effect of 4 months of CPAP treatment on HOMA-IR. Longer duration of CPAP treatment may be needed in order to reduce insulin resistance and determine whether obesity modifies the effect. https://bit.ly/3CtX7jZ.

Facial and Intraoral Photographic Traits Related to Sleep Apnea in a Clinical Sample with Genetic Ancestry Analysis.

Rationale: Craniofacial and pharyngeal morphology influences risk for obstructive sleep apnea (OSA). Quantitative photography provides phenotypic information about these anatomical factors and is feasible in large samples. However, whether associations between morphology and OSA severity differ among populations is unknown. Objectives: The aim of this study was to examine this question in a large sample encompassing people from different ancestral backgrounds. Methods: Participants in SAGIC (Sleep Apnea Global Interdisciplinary Consortium) with genotyping data were included (N = 2,393). Associations between photography-based measures and OSA severity were assessed using linear regression, controlling for age, sex, body mass index, and genetic ancestry. Subgroups (on the basis of 1000 Genomes reference populations) were identified: European (EUR), East Asian, American, South Asian, and African (AFR). Interaction tests were used to assess if genetically determined ancestry group modified these relationships. Results: Cluster analysis of genetic ancestry proportions identified four ancestrally defined groups: East Asia (48.3%), EUR (33.6%), admixed (11.7%; 46% EUR, 27% Americas, and 22% AFR), and AFR (6.4%). Multiple anatomical traits were associated with more severe OSA independent of ancestry, including larger cervicomental angle (standardized ß [95% confidence interval (CI)] = 0.11 [0.06-0.16]; P < 0.001), mandibular width (standardized ß [95% CI] = 0.15 [0.10-0.20]; P < 0.001), and tongue thickness (standardized ß [95% CI] = 0.06 [0.02-0.10]; P = 0.001) and smaller airway width (standardized ß [95% CI] = -0.08 [-0.15 to -0.002]; P = 0.043). Other traits, including maxillary and mandibular depth angles and lower face height, demonstrated different associations with OSA severity on the basis of ancestrally defined subgroups. Conclusions: We confirm that multiple facial and intraoral photographic measurements are associated with OSA severity independent of ancestral background, whereas others differ in their associations among the ancestrally defined subgroups.

Variant-to-gene mapping followed by cross-species genetic screening identifies GPI-anchor biosynthesis as a regulator of sleep.

Genome-wide association studies (GWAS) in humans have identified loci robustly associated with several heritable diseases or traits, yet little is known about the functional roles of the underlying causal variants in regulating sleep duration or quality. We applied an ATAC-seq/promoter focused Capture C strategy in human iPSC-derived neural progenitors to carry out a "variant-to-gene" mapping campaign that identified 88 candidate sleep effector genes connected to relevant GWAS signals. To functionally validate the role of the implicated effector genes in sleep regulation, we performed a neuron-specific RNA interference screen in the fruit fly, Drosophila melanogaster, followed by validation in zebrafish. This approach identified a number of genes that regulate sleep including a critical role for glycosylphosphatidylinositol (GPI)-anchor biosynthesis. These results provide the first physical variant-to-gene mapping of human sleep genes followed by a model organism-based prioritization, revealing a conserved role for GPI-anchor biosynthesis in sleep regulation.

Association Between Positive Airway Pressure Adherence and Health Care Costs Among Individuals With OSA.

BACKGROUND: The impact of positive airway pressure (PAP) therapy for OSA on health care costs is uncertain. RESEARCH QUESTION: Are 3-year health care costs associated with PAP adherence in participants from the Tele-OSA clinical trial? STUDY DESIGN AND METHODS: Participants with OSA and prescribed PAP in the Tele-OSA study were stratified into three PAP adherence groups based on usage patterns over 3 years: (1) high (consistently ≥ 4 h/night), (2) moderate (2-3.9 h/night or inconsistently ≥ 4 h/night), and (3) low (< 2 h/night). Using data from 3 months of the Tele-OSA trial and 33 months of posttrial follow up, average health care costs (2020 US dollars) in 6-month intervals were derived from electronic health records and analyzed using multivariable generalized linear models. RESULTS: Of 543 participants, 25% were categorized as having high adherence, 22% were categorized as having moderate adherence, and 52% were categorized as having low adherence to PAP therapy. Average PAP use mean ± SD was 6.5 ± 1.0 h, 3.7 ± 1.2 h, and 0.5 ± 0.5 h for the high, moderate, and low adherence groups, respectively. The high adherence group had the lowest average covariate-adjusted 6-month health care costs ± SE ($3,207 ± $251) compared with the moderate ($3,638 ± $363) and low ($4,040 ± $304) adherence groups. Significant cost differences were observed between the high and low adherence groups ($832; 95% CI, $127 to $1,538); differences between moderate and low adherence were nonsignificant ($401; 95% CI, -$441 to $1,243). INTERPRETATION: In participants with OSA, better PAP adherence was associated with significantly lower health care costs over 3 years. Findings support the importance of strategies to enhance long-term PAP adherence.