Obstructive sleep apnea heterogeneity and autonomic function: a role for heart rate variability in therapy selection and efficacy monitoring.

Obstructive sleep apnea is a highly prevalent sleep-related breathing disorder, resulting in a disturbed breathing pattern, changes in blood gases, abnormal autonomic regulation, metabolic fluctuation, poor neurocognitive performance, and increased cardiovascular risk. With broad inter-individual differences recognised in risk factors, clinical symptoms, gene expression, physiological characteristics, and health outcomes, various obstructive sleep apnea subtypes have been identified. Therapeutic efficacy and its impact on outcomes, particularly for cardiovascular consequences, may also vary depending on these features in obstructive sleep apnea. A number of interventions such as positive airway pressure therapies, oral appliance, surgical treatment, and pharmaceutical options are available in clinical practice. Selecting an effective obstructive sleep apnea treatment and therapy is a challenging medical decision due to obstructive sleep apnea heterogeneity and numerous treatment modalities. Thus, an objective marker for clinical evaluation is warranted to estimate the treatment response in patients with obstructive sleep apnea. Currently, while the Apnea-Hypopnea Index is used for severity assessment of obstructive sleep apnea and still considered a major guide to diagnosis and managements of obstructive sleep apnea, the Apnea-Hypopnea Index is not a robust marker of symptoms, function, or outcome improvement. Abnormal cardiac autonomic modulation can provide additional insight to better understand obstructive sleep apnea phenotyping. Heart rate variability is a reliable neurocardiac tool to assess altered autonomic function and can also provide cardiovascular information in obstructive sleep apnea. Beyond the Apnea-Hypopnea Index, this review aims to discuss the role of heart rate variability as an indicator and predictor of therapeutic efficacy to different modalities in order to optimise tailored treatment for obstructive sleep apnea.

Implementing a home-based virtual hypertension programme-a pilot feasibility study.

INTRODUCTION: Implementing a health system-based hypertension programme may lower blood pressure (BP). METHODS: We performed a randomized, controlled pilot study to assess feasibility, acceptability, and safety of a home-based virtual hypertension programme integrating evidence-based strategies to overcome current barriers to BP control. Trained clinical pharmacists staffed the virtual collaborative care clinic (vCCC) to remotely manage hypertension using a BP dashboard and phone "visits" to monitor BP, adherence, side effects of medications, and prescribe anti-hypertensives. Patients with uncontrolled hypertension were identified via electronic health records. Enrolled patients were randomized to either vCCC or usual care for 3 months. We assessed patients' home BP monitoring behaviour, and patients', physicians', and pharmacists' perspectives on feasibility and acceptability of individual programme components. RESULTS: Thirty-one patients (vCCC = 17, usual care = 14) from six physician clinics completed the pilot study. After 3 months, average BP decreased in the vCCC arm (P = 0.01), but not in the control arm (P = 0.45). The vCCC participants measured BP more (9.9 vs. 1.2 per week, P < 0.001). There were no intervention-related adverse events. Participating physicians (n = 6), pharmacists (n = 5), and patients (n = 31) rated all programme components with average scores of >4.0, a pre-specified benchmark. Nine adaptations in vCCC design and delivery were made based on potential barriers to implementing the programme and suggestions. CONCLUSION: A home-based virtual hypertension programme using team-based care, technology, and a logical integration of evidence-based strategies is safe, acceptable, and feasible to intended users. These pilot data support studies to assess the effectiveness of this programme at a larger scale.

Diabetes and cardiovascular diseases are associated with the worsening of intermittent hypoxaemia.

Intermittent hypoxaemia is a risk factor for numerous diseases. However, the reverse pathway remains unclear. Therefore, we investigated whether pre-existing hypertension, diabetes or cardiovascular diseases are associated with the worsening of intermittent hypoxaemia. Among the included 2,535 Sleep Heart Health Study participants, hypertension (n = 1,164), diabetes (n = 170) and cardiovascular diseases (n = 265) were frequently present at baseline. All participants had undergone two polysomnographic recordings approximately 5.2 years apart. Covariate-adjusted linear regression analyses were utilized to investigate the difference in the severity of intermittent hypoxaemia at baseline between each comorbidity group and the group of participants free from all comorbidities (n = 1,264). Similarly, we investigated whether the pre-existing comorbidities are associated with the progression of intermittent hypoxaemia. Significantly higher oxygen desaturation index (ß = 1.77 [95% confidence interval: 0.41-3.13], p = 0.011), desaturation severity (ß = 0.07 [95% confidence interval: 0.00-0.14], p = 0.048) and desaturation duration (ß = 1.50 [95% confidence interval: 0.31-2.69], p = 0.013) were observed in participants with pre-existing cardiovascular diseases at baseline. Furthermore, the increase in oxygen desaturation index (ß = 3.59 [95% confidence interval: 1.78-5.39], p < 0.001), desaturation severity (ß = 0.08 [95% confidence interval: 0.02-0.14], p = 0.015) and desaturation duration (ß = 2.60 [95% confidence interval: 1.22-3.98], p < 0.001) during the follow-up were higher among participants with diabetes. Similarly, the increase in oxygen desaturation index (ß = 2.73 [95% confidence interval: 1.15-4.32], p = 0.001) and desaturation duration (ß = 1.85 [95% confidence interval: 0.62-3.08], p = 0.003) were higher among participants with cardiovascular diseases. These results suggest that patients with pre-existing diabetes or cardiovascular diseases are at increased risk for an expedited worsening of intermittent hypoxaemia. As intermittent hypoxaemia is an essential feature of sleep apnea, these patients could benefit from the screening and follow-up monitoring of sleep apnea.

Symptom Subtypes of Obstructive Sleep Apnea Predict Incidence of Cardiovascular Outcomes.

Rationale: Symptom subtypes have been described in clinical and population samples of patients with obstructive sleep apnea (OSA). It is unclear whether these subtypes have different cardiovascular consequences.Objectives: To characterize OSA symptom subtypes and assess their association with prevalent and incident cardiovascular disease in the Sleep Heart Health Study.Methods: Data from 1,207 patients with OSA (apnea-hypopnea index ≥ 15 events/h) were used to evaluate the existence of symptom subtypes using latent class analysis. Associations between subtypes and prevalence of overall cardiovascular disease and its components (coronary heart disease, heart failure, and stroke) were assessed using logistic regression. Kaplan-Meier survival analysis and Cox proportional hazards models were used to evaluate whether subtypes were associated with incident events, including cardiovascular mortality.Measurements and Main Results: Four symptom subtypes were identified (disturbed sleep [12.2%], minimally symptomatic [32.6%], excessively sleepy [16.7%], and moderately sleepy [38.5%]), similar to prior studies. In adjusted models, although no significant associations with prevalent cardiovascular disease were found, the excessively sleepy subtype was associated with more than threefold increased risk of prevalent heart failure compared with each of the other subtypes. Symptom subtype was also associated with incident cardiovascular disease (P < 0.001), coronary heart disease (P = 0.015), and heart failure (P = 0.018), with the excessively sleepy again demonstrating increased risk (hazard ratios, 1.7-2.4) compared with other subtypes. When compared with individuals without OSA (apnea-hypopnea index < 5), significantly increased risk for prevalent and incident cardiovascular events was observed mostly for patients in the excessively sleepy subtype.Conclusions: OSA symptom subtypes are reproducible and associated with cardiovascular risk, providing important evidence of their clinical relevance.

Whole genome and exome sequencing realignment supports the assignment of KCNJ12, KCNJ17, and KCNJ18 paralogous genes in thyrotoxic periodic paralysis locus: functional characterization of two polymorphic Kir2.6 isoforms.

Next-generation sequencing (NGS) has enriched the understanding of the human genome. However, homologous or repetitive sequences shared among genes frequently produce dubious alignments and can puzzle NGS mutation analysis, especially for paralogous potassium channels. Potassium inward rectifier (Kir) channels are important to establish the resting membrane potential and regulating the muscle excitability. Mutations in Kir channels cause disorders affecting the heart and skeletal muscle, such as arrhythmia and periodic paralysis. Recently, a susceptibility muscle channelopathy-thyrotoxic periodic paralysis (TPP)-has been related to Kir2.6 channel (KCNJ18 gene). Due to their high nucleotide sequence homology, variants found in the potassium channels Kir2.6 and Kir2.5 have been mistakenly attributable to Kir2.2 polymorphisms or mutations. We aimed at elucidating nucleotide misalignments by performing realignment of whole exome sequencing (WES) and whole genome sequencing (WGS) reads to specific Kir2.2, Kir2.5, and Kir2.6 cDNA sequences using BWA-MEM/GATK pipeline. WES/WGS reads correctly aligned 26.9/43.2, 37.6/31.0, and 35.4/25.8 % to Kir2.2, Kir2.5, and Kir2.6, respectively. Realignment was able to reduce over 94 % of misalignments. No putative mutations of Kir2.6 were identified for the three TPP patients included in the cohort of 36 healthy controls using either WES or WGS. We also distinguished sequences for a single Kir2.2, a single Kir2.5 sequence, and two Kir2.6 isoforms, which haplotypes were named RRAI and QHEV, based on changes at 39, 40, 56, and 249 residues. Electrophysiology records on both Kir2.6_RRAI and _QHEV showed typical rectifying currents. In our study, the reduction of misalignments allowed the elucidation of paralogous gene sequences and two distinct Kir2.6 haplotypes, and pointed the need for checking the frequency of these polymorphisms in other populations with different genetic background.

The role inflammatory response genes in obstructive sleep apnea syndrome: a review.

BACKGROUND: Obstructive sleep apnea syndrome (OSAS) has a negative impact on health and behavior of millions of individuals worldwide. The pathogenesis of this disorder is a multifactorial process related to a variety of mechanisms, including selective activation of inflammatory response pathways. A number of inflammatory factors, such as IL-6, IL-8, and TNF-α, can be found in high concentrations in subjects with OSAS and may serve as biological markers of this disease. The concentration of these cytokines contributes to weight gain in patients with OSAS and can also modify the risk of obesity-related metabolic disorders, especially insulin resistance. Nevertheless, the mechanisms by which specific genes are associated with these processes are still poorly known. In addition to gene expression studies, investigations aiming at the identification of epigenetic factors associated with OSAS are still scarce in the literature. The documented data support the hypothesis that the molecular changes that mediate inflammatory response are important mechanisms in the pathogenesis of OSAS, sleepiness, insulin resistance, visceral obesity, and cardiovascular disease, perhaps by leading to a more severe OSAS. Often, systemic changes may not be detected in mild OSA; however, molecular changes, which are much more sensitive to the mechanisms of intermittent hypoxia and oxidative stress, may be present. PURPOSE: This review aimed to show an updated view on the studies evaluating the genetic basis of inflammatory response in many aspects of OSAS and to highlight potential research areas not fully explored to date in this field.

Brain-derived neurotrophic factor gene polymorphism predicts interindividual variation in the sleep electroencephalogram.

Previous studies have suggested that brain-derived neurotrophic factor (BDNF) participates in the homeostatic regulation of sleep. The objective of this study was to investigate the influence of the Val66Met functional polymorphism of the BDNF gene on sleep and sleep EEG parameters in a large population-based sample. In total 337 individuals participating in the São Paulo Epidemiologic Sleep Study were selected for analysis. None of the participants had indications of a sleep disorder, as measured by full-night polysomnography and questionnaire. Spectral analysis of the EEG was carried out in all individuals using fast Fourier transformation of the oscillatory signals for each EEG electrode. Sleep and sleep EEG parameters in individuals with the Val/Val genotype were compared with those in Met carriers (Val/Met and Met/Met genotypes). After correction for multiple comparisons and for potential confounding factors, Met carriers showed decreased spectral power in the alpha band in stage one and decreased theta power in stages two and three of nonrapid-eye-movement sleep, at the central recording electrode. No significant influence on sleep macrostructure was observed among the genotype groups. Thus, the Val66Met polymorphism seems to modulate the electrical activity of the brain, predicting interindividual variation of sleep EEG parameters. Further studies of this and other polymorphic variants in potential candidate genes will help the characterization of the molecular basis of sleep.

Sex Differences in the Role of Sleep on Cognition in Older Adults.

Study Objectives: The study aimed to investigate sex differences in the relationship between sleep quality (self-report and objective) and cognitive function across three domains (executive function, verbal memory, and attention) in older adults. Methods: We analyzed cross-sectional data from 207 participants with normal cognition or mild cognitive impairment (89 males and 118 females) aged over 60. The relationship between sleep quality and cognitive performance was estimated using generalized additive models. Objective sleep was measured with the GT9X Link Actigraph, and self-reported sleep was measured with the Pittsburgh Sleep Quality Index. Results: We found that females exhibited stable performance of executive function with up to about 400 minutes of total sleep time, with significant declines in performance (p = 0.02) when total sleep time was longer. Additionally, a longer total sleep time contributed to lower verbal memory in a slightly non-linear manner (p = 0.03). Higher self-reported sleep complaints were associated with poorer executive function in females with normal cognition (p = 0.02). In males, a positive linear relationship emerged between sleep efficiency and executive function (p = 0.04), while self-reported sleep was not associated with cognitive performance in males with normal cognition. Conclusions: Our findings suggest that the relationships between sleep quality and cognition differ between older males and females, with executive function being the most influenced by objective and self-reported sleep. Interventions targeting sleep quality to mitigate cognitive decline in older adults may need to be tailored according to sex, with distinct approaches for males and females.

Positive Airway Pressure Therapy Predicts Lower Mortality and Major Adverse Cardiovascular Events Incidence in Medicare Beneficiaries with Obstructive Sleep Apnea.

Background: Obesity is associated with obstructive sleep apnea (OSA) and cardiovascular risk. Positive airway pressure (PAP) is the first line treatment for OSA, but evidence on its beneficial effect on major adverse cardiovascular events (MACE) prevention is limited. Using claims data, the effects of PAP on mortality and incidence of MACE among Medicare beneficiaries with OSA were examined. Methods: A cohort of Medicare beneficiaries with ≥2 distinct OSA claims was defined from multi-state, state-wide, multi-year (2011-2020) Medicare fee-for-service claims data. Evidence of PAP initiation and utilization was based on PAP claims after OSA diagnosis. MACE was defined as a composite of myocardial infarction, heart failure, stroke, or coronary revascularization. Doubly robust Cox proportional hazards models with inverse probability of treatment weights estimated treatment effects controlling for sociodemographic and clinical factors. Results: Among 888,835 beneficiaries with OSA (median age 73 years; 43.9% women; median follow-up 1,141 days), those with evidence of PAP initiation (32.6%) had significantly lower all-cause mortality (HR [95%CI]: 0.53 [0.52-0.54]) and MACE incidence risk (0.90 [0.89-0.91]). Higher quartiles of annual PAP claims were progressively associated with lower mortality (Q2: 0.84 [0.81-0.87], Q3: 0.76 [0.74-0.79], Q4: 0.74 [0.72-0.77]) and MACE incidence risk (Q2: 0.92 [0.89-0.95], Q3: 0.89 [0.86-0.91], Q4: 0.87 [0.85-0.90]). Conclusion: PAP utilization was associated with lower all-cause mortality and MACE incidence among Medicare beneficiaries with OSA. Results might inform trials assessing the importance of OSA therapy towards minimizing cardiovascular risk and mortality in older adults.

Symptom subtype progression in obstructive sleep apnea over 5 years.

STUDY OBJECTIVES: There is limited knowledge regarding the progression or consistency of symptoms in OSA over time. Our objective was to examine the changes in symptom subtypes and identify predictors over a span of 5 years. METHODS: Data of 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; transitions to moderately sleepy were the most common (77% of all transitions). A five-year older age was associated with a 50% increase in odds to transit from excessively sleepy to moderately sleepy [OR (95% CI: 1.52 (1.17, 1.97)]. Women had 1.97 times higher odds (95% CI: 1.21, 3.18) to transition from moderately sleepy to minimal symptoms. A 5-unit increase in BMI was associated with 2.39 greater odds (95% CI: 1.30, 4.40) to transition from minimal symptoms to excessively sleepy. Changes in AHI did not significantly predict any transitions. CONCLUSIONS: The symptoms of OSA may fluctuate or remain stable over time. Knowledge of symptom progression in OSA may support clinicians with treatment decisions.

Loop Gain as a Predictor of Blood Pressure Response in Patients Treated for Obstructive Sleep Apnea: Secondary Analysis of a Clinical Trial.

Rationale: Randomized trials have shown inconsistent cardiovascular benefits from obstructive sleep apnea (OSA) therapy. Intermittent hypoxemia can increase both sympathetic nerve activity and loop gain ("ventilatory instability"), which may thus herald cardiovascular treatment benefit. Objectives: To test the hypothesis that loop gain predicts changes in 24-hour mean blood pressure (MBP) in response to OSA therapy and compare its predictive value against that of other novel biomarkers. Methods: The HeartBEAT (Heart Biomarker Evaluation in Apnea Treatment) trial assessed the effect of 12 weeks of continuous positive airway pressure (CPAP) versus oxygen versus control on 24-hour MBP. We measured loop gain and hypoxic burden from sleep tests and identified subjects with a sleepy phenotype using cluster analysis. Associations between biomarkers and 24-h MBP were assessed in the CPAP/oxygen arms using linear regression models adjusting for various covariates. Secondary outcomes and predictors were analyzed similarly. Results: We included 93 and 94 participants in the CPAP and oxygen arms, respectively. Overall, changes in 24-hour MBP were small, but interindividual variability was substantial (mean [standard deviation], -2 [8] and 1 [8] mm Hg in the CPAP and oxygen arms, respectively). Higher loop gain was significantly associated with greater reductions in 24-hour MBP independent of covariates in the CPAP arm (-1.5 to -1.9 mm Hg per 1-standard-deviation increase in loop gain; P ⩽ 0.03) but not in the oxygen arm. Other biomarkers were not associated with improved cardiovascular outcomes. Conclusions: To our knowledge, this is the first study suggesting that loop gain predicts blood pressure response to CPAP therapy. Eventually, loop gain estimates may facilitate patient selection for research and clinical practice. Clinical trial registered with www.clinicaltrials.gov (NCT01086800).

Incident Coronary Calcium Score in Patients With OSA With and Without Excessive Sleepiness: Brazilian Longitudinal Study of Adult Health.

BACKGROUND: Uncertainty exists about the impact of OSA and its phenotypes on cardiovascular disease. RESEARCH QUESTION: Are OSA and clinical features such as daytime sleepiness associated with incident subclinical coronary atherosclerosis? STUDY DESIGN AND METHODS: In this prospective community-based cohort study, we administered a sleepiness questionnaire, actigraphy, and home sleep studies at baseline. Coronary artery calcium (CAC; 64-slice multidetector CT scan imaging) was measured at two different time points throughout the study (baseline, between 2010 and 2014, and follow-up, between 2016 and 2018). Incidence of subclinical atherosclerosis was defined as baseline CAC of 0 followed by CAC of > 0 at a 5-year follow-up visit. The association of incident CAC outcome was assessed using logistic regression. Stratified analyses based on excessive daytime sleepiness (EDS) were performed. RESULTS: We analyzed 1,956 participants with available CAC scores at baseline (mean age, 49 ± 8 years; 57.9% female; 32.4% with OSA). In covariate-adjusted analyses (n = 1,247; mean follow-up, 5.1 ± 0.9 years), we found a significant association between OSA and incidence of subclinical atherosclerosis (OR, 1.26; 95% CI, 1.06-1.48), with stronger effects among those reporting EDS (OR, 1.66; 95% CI, 1.30-2.12; P = .028 for interaction). Interestingly, EDS per se was not associated with any CAC outcome. An exploratory analysis of the square root of CAC progression (baseline CAC > 0 followed by a numerical increase in scores at follow-up; n = 319) showed a positive association for both OSA (ß = 1.084; 95% CI, 0.032-2.136; P = .043) and OSA with EDS (ß = 1.651; 95% CI, 0.208-3.094; P = .025). INTERPRETATION: OSA, particularly with EDS, predicts the incidence and progression of CAC. These results support biological plausibility for the increased cardiovascular risk observed among patients with OSA with excessive sleepiness.

Design of a pragmatic randomized implementation effectiveness trial testing a health system wide hypertension program for older adults.

Hypertension control remains poor. Multiple barriers at the level of patients, providers, and health systems interfere with implementation of hypertension guidelines and effective lowering of BP. Some strategies such as self-measured blood pressure (SMBP) and remote management by pharmacists are safe and effectively lower BP but have not been effectively implemented. In this study, we combine such evidence-based strategies to build a remote hypertension program and test its effectiveness and implementation in large health systems. This randomized, controlled, pragmatic type I hybrid implementation effectiveness trial will examine the virtual collaborative care clinic (vCCC), a hypertension program that integrates automated patient identification, SMBP, remote BP monitoring by trained health system pharmacists, and frequent patient-provider communication. We will randomize 1000 patients with uncontrolled hypertension from two large health systems in a 1:1 ratio to either vCCC or control (usual care with education) groups for a 2-year intervention. Outcome measures including BP measurements, cognitive function, and a symptom checklist will be completed during study visits. Other outcome measures of cardiovascular events, mortality, and health care utilization will be assessed using Medicare data. For the primary outcome of proportion achieving BP control (defined as systolic BP < 130 mmHg) in the two groups, we will use a generalized linear mixed model analysis. Implementation outcomes include acceptability and feasibility of the program. This study will guide implementation of a hypertension program within large health systems to effectively lower BP.

The human leucocyte antigen DQB1*0602 allele is associated with electroencephelograph differences in individuals with obstructive sleep apnoea syndrome.

Human leucocyte antigen (HLA) DQB1*0602 allele, a well-known genetic risk factor for narcolepsy, has been associated with sleep parameters in healthy subjects. We aimed to assess the association of this allele with daytime sleepiness and altered sleep electroencephalogram characteristics in the general population and in patients with obstructive sleep apnoea syndrome (OSAS). Eight hundred and ninety-four individuals from the Epidemiologic Study of Sleep were genotyped for the HLA DQB1*0602 allele. Full-night polysomnography was performed, and daytime sleepiness was analysed according to the Epworth Sleepiness Scale. HLA-DQB1*0602 allele-positive and -negative subjects in the general population, as well as in patients with OSAS, exhibited similar sleep parameters and levels of daytime sleepiness. However, spectral analysis showed that allele-positive individuals with OSAS exhibited higher theta power during sleep Stage 1 (P < 0.05) in occipital derivations, and lower delta power during sleep Stages 1 and 2 (P < 0.01) compared with individuals negative for the allele, even after correction for potential confounders as age, sex, body mass index and European ancestry. No significant differences in the electroencephalogram variables were found in individuals without OSAS. The data highlight the HLA-DQB1*0602 as a potential genetic factor influencing sleep physiology in individuals diagnosed with OSAS.

Estimating sleep duration: performance of open-source processing of actigraphy compared to in-laboratory polysomnography in the community.

Comparisons of actigraphy findings between studies are challenging given differences between brand-specific algorithms. This issue may be minimized by using open-source algorithms. However, the accuracy of actigraphy-derived sleep parameters processed in open-source software needs to be assessed against polysomnography (PSG). Middle-aged adults from the Raine Study (n = 835; F 58%; Age 56.7 ± 5.6 years) completed one night of in-laboratory PSG and concurrent actigraphy (GT3X+ ActiGraph). Actigraphic measures of total sleep time (TST) were analyzed and processed using the open-source R-package GENEActiv and GENEA data in R (GGIR) with and without a sleep diary and additionally processed using proprietary software, ActiLife, for comparison. Bias and agreement (intraclass correlation coefficient) between actigraphy and PSG were examined. Common PSG and sleep health variables associated with the discrepancy between actigraphy, and PSG TST were examined using linear regression. Actigraphy, assessed in GGIR, with and without a sleep diary overestimated PSG TST by (mean ± SD) 31.0 ± 50.0 and 26.4 ± 69.0 minutes, respectively. This overestimation was greater (46.8 ± 50.4 minutes) when actigraphy was analyzed in ActiLife. Agreement between actigraphy and PSG TST was poor (ICC = 0.27-0.44) across all three methods of actigraphy analysis. Longer sleep onset latency and longer wakefulness after sleep onset were associated with overestimation of PSG TST. Open-source processing of actigraphy in a middle-aged community population, agreed poorly with PSG and, on average, overestimated TST. TST overestimation increased with increasing wakefulness overnight. Processing of actigraphy without a diary in GGIR was comparable to when a sleep diary was used and comparable to actigraphy processed with proprietary algorithms in ActiLife.

The relationship between alcohol- and sleep-related traits: Results from polygenic risk score and Mendelian randomization analyses.

STUDY OBJECTIVES: We investigated whether genetic risk for insomnia and sleep duration abnormalities are associated with AUD and alcohol consumption. We also evaluated the causal relationships between sleep- and alcohol-related traits. METHODS: Individual-level phenotype and genotype data from the Million Veteran Program were used. Polygenic risk scores (PRS) were computed using summary statistics from two recent discovery GWAS of insomnia (N= 453,379 European-ancestry (EA) individuals) and sleep duration (N= 446,118 EAs) and tested for association with lifetime AUD diagnosis (N= 34,658 EA cases) and past-year Alcohol Use Disorders Identification Test-Consumption scale scores (AUDIT-C, N= 200,680 EAs). Bi-directional two-sample Mendelian Randomization (MR) analyses assessed causal associations between the two sleep traits and the two alcohol-related traits. RESULTS: The insomnia PRS was positively associated with AUD at 2/9 PRS thresholds, with p<0.01 being the most significant (OR = 1.02, p = 3.48 × 10-5). Conversely, insomnia PRS was negatively associated with AUDIT-C at 6/9 PRS thresholds (most significant threshold being p = 0.001 (ß = -0.02, p = 5.6 × 10-8). Sleep duration PRS was positively associated with AUDIT-C at 2/9 PRS thresholds, with the most significant threshold being p = 1 × 10-6 (ß = 0.01, p = 0.0009). MR analyses supported a significant positive causal effect of insomnia on AUD (14 SNPs; ß = 104.14; SE = 16.19; p = 2.22 × 10-5), although with significant heterogeneity. MR analyses also showed that shorter sleep duration had a causal effect on the risk of AUD (27 SNPs; ß = -63.05; SE = 3.54; p = 4.55 × 10-16), which was robust to sensitivity analyses. CONCLUSION: The genetic risk for insomnia shows pleiotropy with AUD, and sleep continuity abnormalities have a causal influence on the development of AUD.

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.