Publications by authors named "Susan Redline"

650 Publications

Physical activity, sedentary behavior, and incidence of obstructive sleep apnea in three prospective US cohorts.

Eur Respir J 2021 Jul 21. Epub 2021 Jul 21.

Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

Reduced physical activity and increased sedentary behavior may independently contribute to development of obstructive sleep apnea (OSA) through increased adiposity, inflammation, insulin resistance and body fluid retention. However, epidemiologic evidence remains sparse, and is primarily limited to cross-sectional studies.We prospectively followed 50 332 women from the Nurses' Health Study (2002-2012), 68 265 women from the Nurses' Health Study II (1995-2013), and 19 320 men from the Health Professionals Follow-up Study (1996-2012). Recreational physical activity (quantified by metabolic equivalent of task [MET]-hours/week) and sitting time spent watching TV and at work/away from home were assessed by questionnaires every 2-4 years. Physician-diagnosed OSA was identified by validated self-report. Cox models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for OSA incidence associated with physical activity and sedentary behavior.During 2 004 663 person-years of follow-up, we documented 8733 incident OSA cases. After adjusting for potential confounders, the pooled HR for OSA comparing participants with ≥36.0 <6.0 MET-hours/week of physical activity was 0.46 (95% CI: 0.43, 0.50; p<0.001). Compared with participants spending <4.0 h/week sitting watching TV, the multivariable-adjusted HR (95% CI) was 1.78 (1.60, 1.98) for participants spending ≥28.0 h/week (p<0.001). The comparable HR (95% CI) was 1.49 (1.38, 1.62) for sitting hours at work/away from home (p<0.001). With additional adjustment for several metabolic factors including BMI and waist circumference, the associations with physical activity and sitting hours at work/away from home were attenuated but remained significant (p<0.001), whereas the association with sitting hours watching TV was no longer statistically significant (p=0.18).Higher levels of physical activity and fewer sedentary hours were associated with lower OSA incidence. The potential mediating role of metabolic factors in the association between sedentary behavior and OSA incidence may depend on type of sedentary behavior. Our results suggest that promoting an active lifestyle may reduce OSA incidence.
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http://dx.doi.org/10.1183/13993003.00606-2021DOI Listing
July 2021

Perceived Home Sleep Environment: Associations of Household-level Factors and In-bed Behaviors with Actigraphy-based Sleep Duration and Continuity in the Jackson Heart Sleep Study.

Sleep 2021 Jul 20. Epub 2021 Jul 20.

Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston MA USA.

Study Objectives: In an older African-American sample (n=231) we tested associations of the household environment and in-bed behaviors with sleep duration, efficiency, and wakefulness after sleep onset (WASO).

Methods: Older adult participants completed a household-level sleep environment questionnaire, a sleep questionnaire, and underwent 7-day wrist actigraphy for objective measures of sleep. Perceived household environment (self-reported) was evaluated using questions regarding safety, physical comfort, temperature, noise, and light disturbances. In-bed behaviors included: watching television, listening to radio/music, use of computer/tablet/phone, playing video games, reading books, and eating. To estimate the combined effect of the components in each domain (perceived household environment and in-bed behaviors), we calculated and standardized a weighted score per sleep outcome (e.g., duration, efficiency, WASO), with a higher score indicating worse conditions. The weights were derived from the coefficients of each component estimated from linear regression models predicting each sleep outcome while adjusting for covariates.

Results: A standard deviation increase in an adverse household environment score was associated with lower self-reported sleep duration (β=-13.9 minutes, 95% confidence interval: -21.6, -1.7) and actigraphy-based sleep efficiency (β=-0.7%, -1.4, 0.0). A standard deviation increase in the in-bed behaviors score was associated with lower actigraphy-based sleep duration (β=-9.7 minutes, -18.0, -1.3), sleep efficiency (β=-1.2%, -0.9, -0.6), and higher WASO (5.3 minutes, 2.1, 8.6).

Conclusion: Intervening on the sleep environment, including healthy sleep practices, may improve sleep duration and continuity among African-Americans.
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http://dx.doi.org/10.1093/sleep/zsab163DOI Listing
July 2021

Phenotypes of Obstructive Sleep Apnea in the Hispanic Community Health Study/Study of Latinos.

Sleep 2021 Jul 17. Epub 2021 Jul 17.

Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, United States.

Study Objectives: Recent work on US Whites from clinical samples used obstructive sleep apnea (OSA) symptoms to generate phenotypes for individuals with moderate-severe OSA which suggested 3 to 5 symptom classes. However, it is unknown whether similar classes generalize to diverse Hispanics/Latino adults. Therefore, we sought to fill this gap by empirically deriving sleep phenotypes among a large sample of diverse Hispanics/Latinos.

Methods: We used data from The Hispanic Community Health Study/Study of Latinos (HCHS/SOL; 2008-2011), a prospective cohort study designed using a multisite multistage probability sample of adults 18-74 years old. The subpopulation of interest included participants with moderate-severe OSA symptoms (≥15 respiratory event index (REI) events per hour; n=1,605). We performed latent class analysis for complex survey data using 15 common OSA symptoms (e.g. Epworth Sleepiness Scale) and four comorbidities to identify phenotype classes.

Results: Average age was 52.4 ± 13.9 years and 34.0% were female. Mean respiratory event index was 33.8 ± 22.5 events per hour. Fit statistics and clinical significance suggested that a three-class solution provided best fit to the data. The three phenotypes were: 1) Minimally Symptomatic (47.7%), 2) Excessive sleepiness (37.1%), and (3) Disturbed Sleep (15.2%). Sensitivity models were consistent with main proposed solution.

Conclusions: Derived sleep phenotypes among diverse Hispanic/Latinos were consistent with recent findings from the Sleep Apnea Global Interdisciplinary Consortium, but we found notable differences in class prevalence relative to Whites. Further research is needed to link derived sleep phenotypes to health comorbidities in diverse populations.
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http://dx.doi.org/10.1093/sleep/zsab181DOI Listing
July 2021

Frequency of flow limitation using airflow shape.

Sleep 2021 Jul 8. Epub 2021 Jul 8.

School of Information Technology and Electrical Engineering, The University of Queensland, Brisbane, Australia.

Study Objectives: The presence of flow limitation during sleep is associated with adverse health consequences independent of obstructive sleep apnea (OSA) severity (apnea-hypopnea index, AHI), but remains extremely challenging to quantify. Here we present a unique library and an accompanying automated method that we apply to investigate flow limitation during sleep.

Methods: A library of 117,871 breaths (N=40 participants) were visually classified (certain flow limitation, possible flow limitation, normal) using airflow shape and physiological signals (ventilatory drive per intra-esophageal diaphragm EMG). An ordinal regression model was developed to quantify flow limitation certainty using flow-shape features (e.g. flattening, scooping); breath-by-breath agreement (Cohen's ƙ) and overnight flow limitation frequency (R 2, %breaths in certain or possible categories during sleep) were compared against visual scoring. Subsequent application examined flow limitation frequency during arousals and stable breathing, and associations with ventilatory drive.

Results: The model (23 features) assessed flow limitation with good agreement (breath-by-breath ƙ=0.572, p<0.001) and minimal error (overnight flow limitation frequency R 2=0.86, error=7.2%). Flow limitation frequency was largely independent of AHI (R 2=0.16) and varied widely within individuals with OSA (74[32-95]%breaths, mean[range], AHI>15/hr, N=22). Flow limitation was unexpectedly frequent but variable during arousals (40[5-85]%breaths) and stable breathing (58[12-91]%breaths), and was associated with elevated ventilatory drive (R 2=0.26-0.29; R 2<0.01 AHI v. drive).

Conclusions: Our method enables quantification of flow limitation frequency, a key aspect of obstructive sleep-disordered breathing that is independent of the AHI and often unavailable. Flow limitation frequency varies widely between individuals, is prevalent during arousals and stable breathing, and reveals elevated ventilatory drive.
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http://dx.doi.org/10.1093/sleep/zsab170DOI Listing
July 2021

Associations between everyday discrimination and sleep quality and duration among African Americans over time in the Jackson Heart Study.

Sleep 2021 Jul 1. Epub 2021 Jul 1.

Division of Sleep and Circadian Disorders, Brigham and Women's Hospital.

Study Objectives: African-Americans have a high burden of poor sleep, yet, psychosocial determinants (e.g., discrimination) are understudied. We investigated longitudinal associations between everyday discrimination and sleep quality and duration among African-Americans (N=3404) in the Jackson Heart Study.

Methods: At Exam 1 (2000-2004) and Exam 3 (2008-2013), participants completed the Everyday Discrimination Scale, rated their sleep quality (1=poor to 5=excellent), and self-reported hours of sleep. A subset of participants (N=762) underwent 7-day actigraphy to objectively assess sleep duration (Sleep Exam 2012-2016). Changes in discrimination were defined as low stable (reference), increasing, decreasing, and stable high. Within-person changes in sleep from Exam 1-to-3 were regressed on change in discrimination from Exam 1-to-3 while adjusting for age, sex, education, income, employment, physical activity, smoking, body mass index, social support and stress.

Results: At Exam 1, the mean age was 54.1 (12.0) years; 64% were female, mean sleep quality was 3.0 (1.1) and 54% were short sleepers. The distribution of the discrimination change trajectories, were 54.1% low stable, 13.5% increasing, 14.6% decreasing, and 17.7% were high stable. Participants who were in the increasing (vs. stable low) discrimination group had greater decrease in sleep quality. There was no association between change in discrimination and change in sleep duration. Among Sleep Exam participants, higher discrimination was cross-sectionally associated with shorter self-reported sleep duration, independent of stress.

Conclusion: Discrimination is a unique stressor for African-Americans; thus, future research should identify interventions to reduce the burden of discrimination on sleep quality.
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http://dx.doi.org/10.1093/sleep/zsab162DOI Listing
July 2021

Prevalence of sleepiness and associations with quality of life in patients with sleep apnea in an online cohort.

J Clin Sleep Med 2021 Jun 21. Epub 2021 Jun 21.

Division of Sleep and Circadian Disorders, Brigham and Women's Hospital.

Study Objectives: Excessive daytime sleepiness (EDS) is a treatment target for many patients with obstructive sleep apnea (OSA). We aimed to understand the prevalence, risk factors and quality of life associated with EDS in a non-clinical, "real world" sample of patients with OSA.

Methods: Cross-sectional survey of patients with OSA participating in an online peer support community, assessing demographics, comorbidities, treatment, and quality of life. Differences in those with and without EDS (Epworth Sleepiness Scale [ESS] > and ≤ 10) were assessed.

Results: The sample (n=422) was 54.2% male, 65.9% were ≥ 55 years, and 43.3% reported sleeping ≤ 6 hours/night. EDS was identified among 31.0% of respondents and 51.7% reported sleepiness as a precipitating factor for seeking initial OSA treatment. EDS was more prevalent in individuals reporting asthma, insomnia symptoms, positive airway pressures (PAP) use less than 6 hours/night on ≥ 5 nights/week, or sleep duration < 6 hours/night. After adjusting for demographics and comorbidities, patients with EDS reported poorer mental and physical health and well-being, lower disease-specific functional status, more activity and work impairment, and more driving impairment (p values < 0.05). In the sub-sample (n=265) with high PAP adherence, 26.0% reported EDS, and similar associations between EDS and outcomes were observed.

Conclusions: These "real-world" data suggest that patients seeking online OSA support experience a high prevalence of EDS, which was associated with poorer quality of life and worse functional status. Associations persisted among respondents with high self-reported PAP-adherence, potentially driving these individuals to seek online support for sleepiness-related symptoms.
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http://dx.doi.org/10.5664/jcsm.9436DOI Listing
June 2021

Characteristics and Reproducibility of Novel Sleep EEG Biomarkers and their Variation with Sleep Apnea and Insomnia in a Large Community-Based Cohort.

Sleep 2021 Jun 22. Epub 2021 Jun 22.

Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.

Study Objectives: New EEG features became available for use in polysomnography and have shown promise in early studies. They include a continuous index of sleep depth (Odds-Ratio-Product; ORP), agreement between right and left sleep depth (R/L coefficient), dynamics of sleep recovery following arousals (ORP-9), general EEG amplification (EEG Power), alpha intrusion and arousal intensity. This study was undertaken to establish ranges and reproducibility of these features in subjects with different demographics and clinical status.

Methods: We utilized data from the two phases of the Sleep-Heart-Health-Study (SHHS1 and SHHS2). Polysomnograms of 5804 subjects from SHHS1 were scored to determine the above features. Feature values were segregated according to clinical status of Obstructive Sleep Apnea (OSA), insomnia, insomnia plus OSA, no clinical sleep disorder, and demographics (age, gender and race). Results from SHHS visit2 were compared with SHHS1 results.

Results: All features varied widely among clinical groups and demographics. Relative to participants with no sleep disorder, wake ORP was higher in participants reporting insomnia symptoms and lower in those with OSA (p<0.0001 for both), reflecting opposite changes in sleep pressure, while NREM ORP was higher in both insomnia and OSA (p<0.0001), reflecting lighter sleep in both groups. There were significant associations with age, gender, and race. EEG Power, and REM ORP were highly reproducible across the two studies (ICC>0.75).

Conclusions: The reported results serve as bases for interpreting studies that utilize novel sleep EEG biomarkers and identify characteristic EEG changes that vary with age, gender and may help distinguish insomnia from OSA.
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http://dx.doi.org/10.1093/sleep/zsab145DOI Listing
June 2021

Obstructive Sleep Apnea and Cardiovascular Disease: A Scientific Statement From the American Heart Association.

Circulation 2021 Jul 21;144(3):e56-e67. Epub 2021 Jun 21.

Obstructive sleep apnea (OSA) is characterized by recurrent complete and partial upper airway obstructive events, resulting in intermittent hypoxemia, autonomic fluctuation, and sleep fragmentation. Approximately 34% and 17% of middle-aged men and women, respectively, meet the diagnostic criteria for OSA. Sleep disturbances are common and underdiagnosed among middle-aged and older adults, and the prevalence varies by race/ethnicity, sex, and obesity status. OSA prevalence is as high as 40% to 80% in patients with hypertension, heart failure, coronary artery disease, pulmonary hypertension, atrial fibrillation, and stroke. Despite its high prevalence in patients with heart disease and the vulnerability of cardiac patients to OSA-related stressors and adverse cardiovascular outcomes, OSA is often underrecognized and undertreated in cardiovascular practice. We recommend screening for OSA in patients with resistant/poorly controlled hypertension, pulmonary hypertension, and recurrent atrial fibrillation after either cardioversion or ablation. In patients with New York Heart Association class II to IV heart failure and suspicion of sleep-disordered breathing or excessive daytime sleepiness, a formal sleep assessment is reasonable. In patients with tachy-brady syndrome or ventricular tachycardia or survivors of sudden cardiac death in whom sleep apnea is suspected after a comprehensive sleep assessment, evaluation for sleep apnea should be considered. After stroke, clinical equipoise exists with respect to screening and treatment. Patients with nocturnally occurring angina, myocardial infarction, arrhythmias, or appropriate shocks from implanted cardioverter-defibrillators may be especially likely to have comorbid sleep apnea. All patients with OSA should be considered for treatment, including behavioral modifications and weight loss as indicated. Continuous positive airway pressure should be offered to patients with severe OSA, whereas oral appliances can be considered for those with mild to moderate OSA or for continuous positive airway pressure-intolerant patients. Follow-up sleep testing should be performed to assess the effectiveness of treatment.
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http://dx.doi.org/10.1161/CIR.0000000000000988DOI Listing
July 2021

A composite sleep and pulmonary phenotype predicting hypertension.

EBioMedicine 2021 Jun 15;68:103433. Epub 2021 Jun 15.

Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 221 Longwood Ave, Boston MA 02115, room 225C, USA. Electronic address:

Background: Multiple aspects of sleep and Sleep Disordered Breathing (SDB) have been linked to hypertension. However, the standard measure of SDB, the Apnoea Hypopnea Index (AHI), has not identified patients likely to experience large improvements in blood pressure with SDB treatment.

Methods: To use machine learning to select sleep and pulmonary measures associated with hypertension development when considered jointly, we applied feature screening followed by Elastic Net penalized regression in association with incident hypertension using a wide array of polysomnography measures, and lung function, derived for the Sleep Heart Health Study (SHHS).

Findings: At baseline, n=860 SHHS individuals with complete data were age 61 years, on average. Of these, 291 developed hypertension ~5 years later. A combination of pulmonary function and 18 sleep phenotypes predicted incident hypertension (OR=1.43, 95% confidence interval [1.14, 1.80] per 1 standard deviation (SD) of the phenotype), while the apnoea-hypopnea index (AHI) had low evidence of association with incident hypertension (OR =1.13, 95% confidence interval [0.97, 1.33] per 1 SD). In a generalization analysis in 923 individuals from the Multi-Ethnic Study of Atherosclerosis, aged 65 on average with 615 individuals with hypertension, the new phenotype was cross-sectionally associated with hypertension (OR=1.26, 95% CI [1.10, 1.45]).

Interpretation: A unique combination of sleep and pulmonary function measures better predicts hypertension compared to the AHI. The composite measure included indices capturing apnoea and hypopnea event durations, with shorter event lengths associated with increased risk of hypertension.

Funding: This research was supported by National Heart, Lung, and Blood Institute (NHLBI) contracts HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, and N01-HC-95169 and by National Center for Advancing Translational Sciences grants UL1-TR- 000040, UL1-TR-001079, and UL1-TR-001420. The MESA Sleep ancillary study was supported by NHLBI grant HL-56984. Pulmonary phenotyping in MESA was funded by NHLBI grants R01-HL077612 and R01-HL093081. This work was supported by NHLBI grant R35HL135818 to Susan Redline.
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http://dx.doi.org/10.1016/j.ebiom.2021.103433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217680PMC
June 2021

Association of Delaying School Start Time With Sleep-Wake Behaviors Among Adolescents.

J Adolesc Health 2021 Jun 5. Epub 2021 Jun 5.

Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis, Minnesota.

Purpose: Few adolescents spend enough time asleep on school nights. This problem could be addressed by delaying high school start times, but does this translate to reduced prevalence of sleep-wake problems like awakening too early or feeling sleepy during the day?

Methods: The START study (n = 2,414) followed a cohort of students from five Minnesota high schools to evaluate impacts of school start time delays. Participants were enrolled in ninth grade (Baseline) when all schools started early (7:30 or 7:45 a.m.). At Follow-Up 1 (10th grade) and Follow-Up 2 (11th grade), two schools had delayed their start times by 50 and 65 minutes while three comparison schools started at 7:30 a.m. Six sleep-wake behaviors were assessed at all three time points via survey. Generalized estimating equation models were used to investigate changes in sleep-wake problems between policy change and comparison schools.

Results: The prevalence of sleep-wake problems at Baseline ranged from 11% for being late to class due to oversleeping to 48% for needing to be told to wake multiple times in the morning. Compared to students from comparison schools, students at policy change schools reported smaller increases in the prevalence of feeling sleepy daily and oversleeping and being late to class between 9th and 11th grade. After implementation of the delayed start, awakening too early was more common among students at policy change schools compared to the comparison schools.

Conclusions: This longitudinal study provides evidence that delaying high school start times reduces daytime sleepiness and school tardiness.
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http://dx.doi.org/10.1016/j.jadohealth.2021.04.030DOI Listing
June 2021

Response.

Chest 2021 Jun;159(6):2516-2517

Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Division of Sleep Medicine, Harvard Medical School, Boston, MA.

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http://dx.doi.org/10.1016/j.chest.2021.02.030DOI Listing
June 2021

Assessing Changes in Adolescents' Sleep Characteristics and Dietary Quality in the START Study, a Natural Experiment on Delayed School Start Time Policies.

J Nutr 2021 Jun 4. Epub 2021 Jun 4.

Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis, MN, USA.

Background: Sleep duration, quality, and timing may influence dietary quality. In adults, poor dietary quality is a risk factor for numerous chronic diseases. It is unclear how these various sleep domains influence adolescents' diets because prior population-based studies have not effectively manipulated sleep, did not include objective sleep measures, and had short follow-up times.

Objectives: The objectives of this study were to examine 1) how adolescent sleep characteristics relate to dietary quality; and 2) how delay in high school start times (which lengthened sleep duration) affects dietary quality over 2 y.

Methods: In the START study, adolescents (grades 9-11, n = 423) attending 5 high schools in the Minneapolis, Minnesota metropolitan area were annually assessed in 3 waves (2016-2018). At Baseline, all schools started "early" (07:30 or 07:45). From Follow-up 1 through Follow-up 2, 2 "policy change schools" shifted to later start times (to 08:20 and 08:50). Three "comparison schools" maintained their early start throughout. Sleep characteristics were measured with actigraphy. Mixed-effect regression models were used to examine cross-sectional and longitudinal associations of sleep characteristics with dietary quality, and school start time policy change with dietary quality change.

Results: Cross-sectionally, later sleep midpoint and onset were associated with dietary quality scores 1.6-1.7 lower (both P < 0.05). However, no prospective associations were observed between sleep characteristics and dietary quality in longitudinal models. Shifting to later school start time tended to be associated with a 2.4-point increase in dietary quality score (P = 0.09) at Follow-up 1, but was not associated with change in dietary quality scores at Follow-up 2 (P = 0.35).

Conclusions: High school students attending delayed-start schools maintained better dietary quality than students in comparison schools; however, differences were not statistically significant. Overall study findings highlight the complexity of the relation between sleep behavior and diet in adolescence.
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http://dx.doi.org/10.1093/jn/nxab169DOI Listing
June 2021

The trans-ancestral genomic architecture of glycemic traits.

Nat Genet 2021 06 31;53(6):840-860. Epub 2021 May 31.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.
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http://dx.doi.org/10.1038/s41588-021-00852-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610958PMC
June 2021

Modifying pathways by age and sex for the association between combined sleep disordered breathing and long sleep duration with neurocognitive decline in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).

Alzheimers Dement 2021 May 25. Epub 2021 May 25.

University of Miami Miller School of Medicine, Miami, Florida, USA.

Introduction: We aimed to determine whether obesity or metabolic syndrome (MetS) modify associations between sleep-disordered breathing (SDB), self-reported sleep duration (SD), and phenotypes of combined SDB/SD with 7-year neurocognitive decline (ND) in a community based-cohort of U.S. Hispanic/Latinos (N = 5500) in different age and sex groups.

Methods: The exposures were baseline SDB (respiratory event index ≥ 15), sleepiness (Epworth Sleepiness Scale ≥ 10), SD (< 6 hours, 6-9 hours, ≥ 9 hours). The outcome was 7-year ND.

Results: Mean age was 56.0 years, 54.8% were females. Obesity modified the association between SDB/SD and ND in memory (F = 21.49, P < 0.001) and global cognition (F = 9.14, P < 0.001) in the oldest age group. Women without MetS with combined long sleep/SDB exhibited most pronounced decline in global cognition (F = 3.07, P = 0.010).

Discussion: The association between combined SDB/long sleep and declines in memory and global cognition was most pronounced in obese older adults. Among women, MetS status modified the association between long sleep/SDB and decline in global cognition.
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http://dx.doi.org/10.1002/alz.12361DOI Listing
May 2021

Benchmarking association analyses of continuous exposures with RNA-seq in observational studies.

Brief Bioinform 2021 May 20. Epub 2021 May 20.

Harbor-UCLA Medical Center at the Lundquist Institute, USA.

Large datasets of hundreds to thousands of individuals measuring RNA-seq in observational studies are becoming available. Many popular software packages for analysis of RNA-seq data were constructed to study differences in expression signatures in an experimental design with well-defined conditions (exposures). In contrast, observational studies may have varying levels of confounding transcript-exposure associations; further, exposure measures may vary from discrete (exposed, yes/no) to continuous (levels of exposure), with non-normal distributions of exposure. We compare popular software for gene expression-DESeq2, edgeR and limma-as well as linear regression-based analyses for studying the association of continuous exposures with RNA-seq. We developed a computation pipeline that includes transformation, filtering and generation of empirical null distribution of association P-values, and we apply the pipeline to compute empirical P-values with multiple testing correction. We employ a resampling approach that allows for assessment of false positive detection across methods, power comparison and the computation of quantile empirical P-values. The results suggest that linear regression methods are substantially faster with better control of false detections than other methods, even with the resampling method to compute empirical P-values. We provide the proposed pipeline with fast algorithms in an R package Olivia, and implemented it to study the associations of measures of sleep disordered breathing with RNA-seq in peripheral blood mononuclear cells in participants from the Multi-Ethnic Study of Atherosclerosis.
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http://dx.doi.org/10.1093/bib/bbab194DOI Listing
May 2021

Longer sleep improves cardiovascular outcomes: time to make sleep a priority.

Eur Heart J 2021 May 16. Epub 2021 May 16.

Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

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http://dx.doi.org/10.1093/eurheartj/ehab248DOI Listing
May 2021

Physiological sleep measures predict time to 15-year mortality in community adults: Application of a novel machine learning framework.

J Sleep Res 2021 May 15:e13386. Epub 2021 May 15.

Department of Population Health Sciences, University of Wisconsin, Madison, WI, USA.

Clarifying whether physiological sleep measures predict mortality could inform risk screening; however, such investigations should account for complex and potentially non-linear relationships among health risk factors. We aimed to establish the predictive utility of polysomnography (PSG)-assessed sleep measures for mortality using a novel permutation random forest (PRF) machine learning framework. Data collected from the years 1995 to present are from the Sleep Heart Health Study (SHHS; n = 5,734) and the Wisconsin Sleep Cohort Study (WSCS; n = 1,015), and include initial assessments of sleep and health, and up to 15 years of follow-up for all-cause mortality. We applied PRF models to quantify the predictive abilities of 24 measures grouped into five domains: PSG-assessed sleep (four measures), self-reported sleep (three), health (eight), health behaviours (four), and sociodemographic factors (five). A 10-fold repeated internal validation (WSCS and SHHS combined) and external validation (training in SHHS; testing in WSCS) were used to compute unbiased variable importance metrics and associated p values. We observed that health, sociodemographic factors, and PSG-assessed sleep domains predicted mortality using both external validation and repeated internal validation. The PSG-assessed sleep efficiency and the percentage of sleep time with oxygen saturation <90% were among the most predictive individual measures. Multivariable Cox regression also revealed the PSG-assessed sleep domain to be predictive, with very low sleep efficiency and high hypoxaemia conferring the highest risk. These findings, coupled with the emergence of new low-burden technologies for objectively assessing sleep and overnight oxygen saturation, suggest that consideration of physiological sleep measures may improve risk screening.
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http://dx.doi.org/10.1111/jsr.13386DOI Listing
May 2021

Gender Differences in the Association of Insomnia Symptoms and Coronary Artery Calcification in the Multi-Ethnic Study of Atherosclerosis.

Sleep 2021 May 14. Epub 2021 May 14.

Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA.

Study Objectives: To quantify the gender-specific associations between insomnia symptoms and subclinical atherosclerosis, measured by coronary artery calcium (CAC) scores, which has strong predictive value for incident cardiovascular disease.

Methods: We analyzed data from 1,429 participants in the Multi-Ethnic Study of Atherosclerosis (MESA). Participants completed standardized questionnaires and underwent polysomnography (PSG) and 7-day actigraphy. Insomnia symptoms was defined as: self-reported trouble falling, staying or returning to sleep, early-morning awakenings, or hypnotic use, for ≥5 nights/week. MESA assessed CAC using computed tomography. We employed multivariable linear regression to model the probability of CAC>0 overall and to model the linear continuous effect among those with non-zero CAC.

Results: Our sample was a mean age of 68.1 ± 9.1yrs, 53.9% female, and 36.2% white, 28.0% Black, 24.2% Hispanic, and 11.5% Chinese-American. Insomnia symptoms was present in 49.7% of men and 47.2% of women. In multivariable-adjusted analyses, insomnia symptoms was associated with an 18% higher prevalence of CAC (PR 1.18, 95% CI 1.04, 1.33) among females, but no association was observed among males (PR 1.00, 95% CI 0.91, 1.08). There was no evidence that the association between insomnia symptoms and prevalence of CAC>0 differed by objective sleep duration status (by single-night PSG or multi-night actigraphy) in females or males.

Conclusions: We found that among women, insomnia symptoms was associated with an 18% higher prevalence of CAC compared to no insomnia. Insomnia symptoms was not associated with CAC prevalence in men. Additionally, there was no evidence that the association between insomnia symptoms and CAC score >0 differed by objective short sleep duration status.
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http://dx.doi.org/10.1093/sleep/zsab116DOI Listing
May 2021

Sleep apnea, coronary artery calcium density and cardiovascular events: results from the Multi-Ethnic Study of Atherosclerosis (MESA).

J Clin Sleep Med 2021 May 14. Epub 2021 May 14.

Icahn School of Medicine at Mount Sinai, New York, NY.

Study Objectives: Evaluate the association between obstructive sleep apnea (OSA), coronary artery calcium (CAC) density, and cardiovascular events in the Multi-Ethnic Study of Atherosclerosis (MESA).

Methods: We analyzed 1041 participants with non-zero CAC scores who had polysomnography and CAC density data from the fifth examination of MESA. OSA was defined as apnea-hypopnea index [AHI] ≥ 15 events/hour. Multivariable linear regression models were used to evaluate the independent association between OSA and CAC density. Additionally, we evaluated the impact of OSA on associations of CAC measures with incident CVD events by testing for interaction in Cox proportional hazard regression models.

Results: Our analytical sample was 45% female with a mean age of 70.6 +/- 9 years. Of this sample, 36.7% (n=383/1041) had OSA (AHI≥15). OSA was inversely and weakly associated with CAC density (β= -0.09, 95% CI -0.17 to -0.02, p=0.014) and remained significantly associated after controlling for traditional cardiovascular risk factors (β= -0.08, 95% CI -0.16 to 0, p=0.043). However, this inverse association was attenuated after controlling for BMI (β=-0.05, 95% CI -0.13 to 0.02, p=0.174). The mean follow-up period for CVD events was 13.3 +/- 2.8 years. Additionally, exploratory analysis demonstrated that CAC density was independently and inversely associated with CVD events only in the non-OSA subgroup (AHI≤15) (HR 0.509 [CI 0.323 - 0.801], p=0.0035).

Conclusions: OSA was associated with lower CAC density, but this association was attenuated by BMI. Further, increased CAC density was associated with a reduced risk of CVD events only in individuals within the non-OSA group in exploratory analysis.
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http://dx.doi.org/10.5664/jcsm.9356DOI Listing
May 2021

Sleep duration and vascular inflammation using hybrid positron emission tomography/magnetic resonance imaging: results from the Multi-Ethnic Study of Atherosclerosis (MESA).

J Clin Sleep Med 2021 May 10. Epub 2021 May 10.

Division of Pulmonary, Critical Care, and Sleep Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.

Study Objectives: Short sleep duration (SD) is associated with cardiovascular disease (CVD). We investigated the relationship between objective SD and subclinical atherosclerosis employing hybrid PET/MRI with F-FDG tracer in the MESA cohort.

Methods: We utilized data from MESA-SLEEP and MESA-PET ancillary studies. SD and sleep fragmentation index (SFI) were assessed using 7-day actigraphy. The primary and secondary outcomes were carotid inflammation, defined using target-to-background ratios (TBR), and measures of carotid wall remodeling (carotid wall thickness [CWT]), summarized by SD category. Multivariate linear regression was performed to assess the association between SD and SFI with the primary/secondary outcomes, adjusting for several covariates including apnea-hypopnea index (AHI), and CVD risk.

Results: Our analytical sample (n=58) was 62% female (mean age 68±8.4 years). Average SD was 5.1±0.9 hours in the short SD group (≤6 hours/night, 31%), and 7.1±0.8 hours in the normal SD group (69%). Prevalence of pathologic vascular inflammation (TBRmax>1.6) was higher in the short SD group (89% vs. 53%, p=0.009). Those with short SD had a higher TBRmax (1.77 vs 1.71), though this was not statistically significant (p=0.39). CWT was positively correlated with SFI even after adjusting for covariates (Beta [SE]=0.073±[0.032], p=0.025).

Conclusions: Prevalence of pathologic vascular inflammation was higher among those who slept ≤6 hours, and vascular inflammation was higher among those with a SD of ≤6 hours. Interestingly, SFI was positively correlated with CWT even after adjustment for covariates. Our results are hypothesis-generating but suggest that both habitual SD and SFI should be investigated in future studies as potential risk factors for subclinical atherosclerosis.
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http://dx.doi.org/10.5664/jcsm.9382DOI Listing
May 2021

Predicting incident dementia and mild cognitive impairment in older women with nonparametric analysis of circadian activity rhythms in the Study of Osteoporotic Fractures.

Sleep 2021 May 8. Epub 2021 May 8.

Research Institute, California Pacific Medical Center, San Francisco, CA.

Study Objectives: Disrupted daily rhythms are associated with mild cognitive impairment (MCI) and dementia. The specific nature of how rhythms and cognition are related, however, is unknown. We hypothesized characteristics from a nonparametric estimate of circadian rest-activity rhythm patterns would be associated to the development of MCI or dementia.

Methods: Wrist actigraphy from 1232 cognitively healthy, community-dwelling women (mean age 82.6 years) from the Study of Osteoporotic Fractures was used to estimate rest-activity patterns, including intradaily variability (IV), interdaily stability (IS), most active 10-hour period (M10), least active 5-hour period (L5), and relative amplitude (RA). Logistic regression examined associations of these predictors with 5-year incidence of MCI or dementia. Models were adjusted for potential confounders.

Results: Women with earlier sleep/wake times had higher risk of dementia, but not MCI, (early vs. average L5 midpoint: OR, 1.66; 95% CI, 1.08-2.55) as did women with smaller day/night activity differentials (low vs. high RA: OR, 1.96; 95% CI, 1.14-3.35). IV, IS, and M10 were not associated with MCI or dementia.

Conclusion: The timing and difference in day/night amplitude, but not variability of activity, may be useful as predictors of dementia.
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http://dx.doi.org/10.1093/sleep/zsab119DOI Listing
May 2021

Cutting the fat: advances and challenges in sleep apnoea genetics.

Eur Respir J 2021 05 6;57(5). Epub 2021 May 6.

Division of Sleep and Circadian Disorders, Dept of Medicine, Brigham and Women's Hospital, Boston, MA, USA.

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http://dx.doi.org/10.1183/13993003.04644-2020DOI Listing
May 2021

Reply to Sankari and to Kawada.

Am J Respir Crit Care Med 2021 Jul;204(2):240-241

Brigham and Women's Hospital and Harvard University Boston, Massachusetts.

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http://dx.doi.org/10.1164/rccm.202103-0690LEDOI Listing
July 2021

Genome-wide association study of neck circumference identifies sex-specific loci independent of generalized adiposity.

Int J Obes (Lond) 2021 Jul 27;45(7):1532-1541. Epub 2021 Apr 27.

Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Background/objectives: Neck circumference, an index of upper airway fat, has been suggested to be an important measure of body-fat distribution with unique associations with health outcomes such as obstructive sleep apnea and metabolic disease. This study aims to study the genetic bases of neck circumference.

Methods: We conducted a multi-ethnic genome-wide association study of neck circumference, adjusted and unadjusted for BMI, in up to 15,090 European Ancestry (EA) and African American (AA) individuals. Because sexually dimorphic associations have been observed for anthropometric traits, we conducted both sex-combined and sex-specific analysis.

Results: We identified rs227724 near the Noggin (NOG) gene as a possible quantitative locus for neck circumference in men (N = 8831, P = 1.74 × 10) but not in women (P = 0.08). The association was replicated in men (N = 1554, P = 0.045) in an independent dataset. This locus was previously reported to be associated with human height and with self-reported snoring. We also identified rs13087058 on chromosome 3 as a suggestive locus in sex-combined analysis (N = 15090, P = 2.94 × 10; replication P =0.049). This locus was also associated with electrocardiogram-assessed PR interval and is a cis-expression quantitative locus for the PDZ Domain-containing ring finger 2 (PDZRN3) gene. Both NOG and PDZRN3 interact with members of transforming growth factor-beta superfamily signaling proteins.

Conclusions: Our study suggests that neck circumference may have unique genetic basis independent of BMI.
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http://dx.doi.org/10.1038/s41366-021-00817-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8236408PMC
July 2021

Sleep and Big Data: harnessing data, technology, and analytics for monitoring sleep and improving diagnostics, prediction, and interventions-an era for Sleep-Omics?

Sleep 2021 06;44(6)

Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

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http://dx.doi.org/10.1093/sleep/zsab107DOI Listing
June 2021

Sleep arousal burden is associated with long-term all-cause and cardiovascular mortality in 8001 community-dwelling older men and women.

Eur Heart J 2021 06;42(21):2088-2099

School of Electrical and Electronic Engineering, The University of Adelaide, Adelaide, Australia.

Aims: To quantify the arousal burden (AB) across large cohort studies and determine its association with long-term cardiovascular (CV) and overall mortality in men and women.

Methods And Results: We measured the AB on overnight polysomnograms of 2782 men in the Osteoporotic Fractures in Men Study (MrOS) Sleep study, 424 women in the Study of Osteoporotic Fractures (SOF) and 2221 men and 2574 women in the Sleep Heart Health Study (SHHS). During 11.2 ± 2.1 years of follow-up in MrOS, 665 men died, including 236 CV deaths. During 6.4 ± 1.6 years of follow-up in SOF, 105 women died, including 47 CV deaths. During 10.7 ± 3.1 years of follow-up in SHHS, 987 participants died, including 344 CV deaths. In women, multivariable Cox proportional hazard analysis adjusted for common confounders demonstrated that AB is associated with all-cause mortality [SOF: hazard ratio (HR) 1.58 (1.01-2.42), P = 0.038; SHHS-women: HR 1.21 (1.06-1.42), P = 0.012] and CV mortality [SOF: HR 2.17 (1.04-4.50), P = 0.037; SHHS-women: HR 1.60 (1.12-2.28), P = 0.009]. In men, the association between AB and all-cause mortality [MrOS: HR 1.11 (0.94-1.32), P = 0.261; SHHS-men: HR 1.31 (1.06-1.62), P = 0.011] and CV mortality [MrOS: HR 1.35 (1.02-1.79), P = 0.034; SHHS-men: HR 1.24 (0.86-1.79), P = 0.271] was less clear.

Conclusions: Nocturnal AB is associated with long-term CV and all-cause mortality in women and to a lesser extent in men.
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http://dx.doi.org/10.1093/eurheartj/ehab151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197565PMC
June 2021

Pulse arrival time, a novel sleep cardiovascular marker: the multi-ethnic study of atherosclerosis.

Thorax 2021 Apr 16. Epub 2021 Apr 16.

Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.

Background: Pulse arrival time (PAT) is commonly used to estimate blood pressure response. We hypothesised that PAT response to obstructive respiratory events would be associated with increased cardiovascular risk in people with obstructive sleep apnoea.

Methods: PAT, defined as the time interval between electrocardiography R wave and pulse arrival by photoplethysmography, was measured in the Multi-Ethnic Study of Atherosclerosis Sleep study participants. The PAT response to apnoeas/hypopnoeas was defined as the area under the PAT waveform following respiratory events. Cardiovascular outcomes included markers of subclinical cardiovascular disease (CVD): left ventricular mass, carotid plaque burden score and coronary artery calcification (CAC) (cross-sectional) and incident composite CVD events (prospective). Multivariable logistic and Cox proportional hazard regressions were performed.

Results: A total of 1407 participants (mean age 68.4 years, female 47.5%) were included. Higher PAT response (per 1 SD increase) was associated with higher left ventricular mass (5.7 g/m higher in fourth vs first quartile, p<0.007), higher carotid plaque burden score (0.37 higher in fourth vs first quartile, p=0.02) and trended to greater odds of CAC (1.44, 95% CI 0.98 to 2.15, p=0.06). A total of 65 incident CVD events were observed over the mean of 4.1 (2.6) years follow-up period. Higher PAT response was associated with increased future CVD events (HR: 1.20, 95% CI 1.02 to 1.42, p=0.03).

Conclusion: PAT is independently associated with markers of subclinical CVD and incident CVD events. Respiratory-related PAT response is a novel and promising polysomnography metric with cardiovascular implications.
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http://dx.doi.org/10.1136/thoraxjnl-2020-216399DOI Listing
April 2021

Multi-ancestry genome-wide gene-sleep interactions identify novel loci for blood pressure.

Mol Psychiatry 2021 Apr 15. Epub 2021 Apr 15.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Long and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups in two stages using 2 degree of freedom (df) joint test followed by 1df test of interaction effects. Primary multi-ancestry analysis in 62,969 individuals in stage 1 identified three novel gene by sleep interactions that were replicated in an additional 59,296 individuals in stage 2 (stage 1 + 2 P < 5 × 10), including rs7955964 (FIGNL2/ANKRD33) that increases BP among long sleepers, and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) that increase BP among short sleepers (P < 5 × 10). Secondary ancestry-specific analysis identified another novel gene by long sleep interaction at rs111887471 (TRPC3/KIAA1109) in individuals of African ancestry (P = 2 × 10). Combined stage 1 and 2 analyses additionally identified significant gene by long sleep interactions at 10 loci including MKLN1 and RGL3/ELAVL3 previously associated with BP, and significant gene by short sleep interactions at 10 loci including C2orf43 previously associated with BP (P < 10). 2df test also identified novel loci for BP after modeling sleep that has known functions in sleep-wake regulation, nervous and cardiometabolic systems. This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation.
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http://dx.doi.org/10.1038/s41380-021-01087-0DOI Listing
April 2021

Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices.

Nat Commun 2021 04 12;12(1):2182. Epub 2021 Apr 12.

Division of Cardiology, George Washington University School of Medicine and Healthcare Sciences, Washington, DC, USA.

Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids.
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http://dx.doi.org/10.1038/s41467-021-22339-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042019PMC
April 2021

Machine and Deep Learning in Molecular and Genetic Aspects of Sleep Research.

Neurotherapeutics 2021 01 7;18(1):228-243. Epub 2021 Apr 7.

Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA, USA.

Epidemiological sleep research strives to identify the interactions and causal mechanisms by which sleep affects human health, and to design intervention strategies for improving sleep throughout the lifespan. These goals can be advanced by further focusing on the environmental and genetic etiology of sleep disorders, and by development of risk stratification algorithms, to identify people who are at risk or are affected by, sleep disorders. These studies rely on comprehensive sleep-related data which often contains complex multi-dimensional physiological and molecular measurements across multiple timepoints. Thus, sleep research is well-suited for the application of computational approaches that can handle high-dimensional data. Here, we survey recent advances in machine and deep learning together with the availability of large human cohort studies with sleep data that can jointly drive the next breakthroughs in the sleep-research field. We describe sleep-related data types and datasets, and present some of the tasks in the field that can be targets for algorithmic approaches, as well as the challenges and opportunities in pursuing them.
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http://dx.doi.org/10.1007/s13311-021-01014-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116376PMC
January 2021