Jia Weng

Association of Genetic Loci with Sleep Apnea in European Americans and African-Americans: The Candidate Gene Association Resource (CARe)

Although obstructive sleep apnea (OSA) is known to have a strong familial basis, no genetic polymorphisms influencing apnea risk have been identified in cross-cohort analyses. We utilized the National Heart, Lung, and Blood Institute (NHLBI) Candidate Gene Association Resource (CARe) to identify sleep apnea susceptibility loci. Using a panel of 46,449 polymorphisms from roughly 2,100 candidate genes on a customized Illumina iSelect chip, we tested for association with the apnea hypopnea index (AHI) as well as moderate to severe OSA (AHI≥15) in 3,551 participants of the Cleveland Family Study and two cohorts participating in the Sleep Heart Health Study. Among 647 African-Americans, rs11126184 in the pleckstrin (PLEK) gene was associated with OSA while rs7030789 in the lysophosphatidic acid receptor 1 (LPAR1) gene was associated with AHI using a chip-wide significance threshold of p-value<2×10−6. Among 2,904 individuals of European ancestry, rs1409986 in the prostaglandin E2 receptor (PTGER3) gene was significantly associated with OSA. Consistency of effects between rs7030789 and rs1409986 in LPAR1 and PTGER3 and apnea phenotypes were observed in independent clinic-based cohorts. Novel genetic loci for apnea phenotypes were identified through the use of customized gene chips and meta-analyses of cohort data with replication in clinic-based samples. The identified SNPs all lie in genes associated with inflammation suggesting inflammation may play a role in OSA pathogenesis.

Predictors of obstructive sleep apnea severity in adenotonsillectomy candidates

STUDY OBJECTIVES There is uncertainty over which characteristics increase obstructive sleep apnea syndrome (OSAS) severity in children. In candidates for adenotonsillectomy (AT), we evaluated the relationship of OSAS severity and age, sex, race, body mass index (BMI), environmental tobacco smoke (ETS), prematurity, socioeconomic variables, and comorbidities. DESIGN Cross-sectional screening and baseline data were analyzed from the Childhood Adenotonsillectomy Trial, a randomized, controlled, multicenter study evaluating AT versus medical management. Regression analysis assessed the relationship between the apnea hypopnea index (AHI) and risk factors obtained by direct measurement or questionnaire. SETTING Clinical referral setting. PARTICIPANTS Children, ages 5 to 9.9 y with OSAS. MEASUREMENTS AND RESULTS Of the 1,244 children undergoing screening polysomnography, 464 (37%) were eligible (2 ≤ AHI < 30 or 1 ≤ obstructive apnea index [OAI] < 20 and without severe oxygen desaturation) and randomized; 129 (10%) were eligible but were not randomized; 608 (49%) had AHI/OAI levels below entry criteria; and 43 (3%) had levels of OSAS that exceeded entry criteria. Among the randomized children, univariate analyses showed significant associations of AHI with race, BMI z score, environmental tobacco smoke (ETS), family income, and referral source, but not with other variables. After adjusting for potential confounders, African American race (P = 0.003) and ETS (P = 0.026) were each associated with an approximately 20% increase in AHI. After adjusting for these factors, obesity and other factors were not significant. CONCLUSIONS Apnea hypopnea index level was significantly associated with race and environmental tobacco smoke, highlighting the potential effect of environmental factors, and possibly genetic factors, on pediatric obstructive sleep apnea syndrome severity. Efforts to reduce environmental tobacco smoke exposure may help reduce obstructive sleep apnea syndrome severity. CLINICAL TRIAL REGISTRATION Clinicaltrials.gov (#NCT00560859).

The Effect of Adenotonsillectomy for Childhood Sleep Apnea on Cardiometabolic Measures.

STUDY OBJECTIVES Obstructive sleep apnea syndrome (OSAS) has been associated with cardiometabolic disease in adults. In children, this association is unclear. We evaluated the effect of early adenotonsillectomy (eAT) for treatment of OSAS on blood pressure, heart rate, lipids, glucose, insulin, and C-reactive protein. We also analyzed whether these parameters at baseline and changes at follow-up correlated with polysomnographic indices. DESIGN Data collected at baseline and 7-mo follow-up were analyzed from a randomized controlled trial, the Childhood Adenotonsillectomy Trial (CHAT). SETTING Clinical referral setting from multiple centers. PARTICIPANTS There were 464 children, ages 5 to 9.9 y with OSAS without severe hypoxemia. INTERVENTIONS Randomization to eAT or Watchful Waiting with Supportive Care (WWSC). MEASUREMENTS AND RESULTS There was no significant change of cardiometabolic parameters over the 7-mo interval in the eAT group compared to WWSC group. However, overnight heart rate was incrementally higher in association with baseline OSAS severity (average heart rate increase of 3 beats per minute [bpm] for apnea-hypopnea index [AHI] of 2 versus 10; [standard error = 0.60]). Each 5-unit improvement in AHI and 5 mmHg improvement in peak end-tidal CO2 were estimated to reduce heart rate by 1 and 1.5 bpm, respectively. An increase in N3 sleep also was associated with small reductions in systolic blood pressure percentile. CONCLUSIONS There is little variation in standard cardiometabolic parameters in children with obstructive sleep apnea syndrome (OSAS) but without severe hypoxemia at baseline or after intervention. Of all measures, overnight heart rate emerged as the most sensitive parameter of pediatric OSAS severity. CLINICAL TRIAL REGISTRATION Clinicaltrials.gov (#NCT00560859).

Utility of symptoms to predict treatment outcomes in obstructive sleep apnea syndrome

BACKGROUND AND OBJECTIVES: Polysomnography defines the pathophysiology of obstructive sleep apnea syndrome (OSAS) but does not predict some important comorbidities or their response to adenotonsillectomy. We assessed whether OSAS symptoms, as reflected on the Sleep-Related Breathing Disorders Scale of the Pediatric Sleep Questionnaire (PSQ), may offer clinical predictive value. METHODS: Baseline and 7-month follow-up data were analyzed from 185 participants (aged 5–9 years with polysomnographically confirmed OSAS) in the surgical treatment arm of the multicenter Childhood Adenotonsillectomy Trial. Associations were assessed between baseline PSQ or polysomnographic data and baseline morbidity (executive dysfunction, behavior, quality of life, sleepiness) or postsurgical improvement. RESULTS: At baseline, each 1-SD increase in baseline PSQ score was associated with an adjusted odds ratio that was ∼3 to 4 times higher for behavioral morbidity, 2 times higher for reduced global quality of life, 6 times higher for reduced disease-specific quality of life, and 2 times higher for sleepiness. Higher baseline PSQ scores (greater symptom burden) also predicted postsurgical improvement in parent ratings of executive functioning, behavior, quality of life, and sleepiness. In contrast, baseline polysomnographic data did not independently predict these morbidities or their postsurgical improvement. Neither PSQ nor polysomnographic data were associated with objectively assessed executive dysfunction or improvement at follow-up. CONCLUSIONS: PSQ symptom items, in contrast to polysomnographic results, reflect subjective measures of OSAS-related impairment of behavior, quality of life, and sleepiness and predict their improvement after adenotonsillectomy. Although objective polysomnography is needed to diagnose OSAS, the symptoms obtained during an office visit can offer adjunctive insight into important comorbidities and likely surgical responses.

Associations between obstructive sleep apnea, sleep duration, and abnormal fasting glucose the multi-ethnic study of atherosclerosis

RATIONALE No data exist as to the role of ethnicity in the associations between obstructive sleep apnea (OSA), sleep duration, and metabolic dysfunction. OBJECTIVES To examine links between OSA, objectively measured habitual sleep duration, and fasting glucose in U.S. ethnic groups. METHODS The Multi-Ethnic Study of Atherosclerosis is a multisite community-based study that conducted polysomnography and wrist actigraphy. In 2,151 subjects (1,839 in fully adjusted models), the apnea-hypopnea index was used to classify OSA as none (0-4.9/h), mild (5-14.9/h), or moderate to severe (≥15/h). Actigraphic sleep duration was classified as short (≤5 h/night), intermediate (>5 and <8 h/night), or long (≥8 h/night). Subjects were classified as having normal fasting glucose (<100 mg/dl and no hypoglycemic medication use) or abnormal fasting glucose (≥100 mg/dl and/or hypoglycemic medication use). MEASUREMENTS AND MAIN RESULTS The sample was 45.8% male, age 68.5 ± 9.2 (mean ± SD) years, and 27.3% African American, 37.2% white, 11.8% Chinese, and 23.8% Hispanic. The prevalence of abnormal fasting glucose was 40.2%. Relative to subjects without apnea, moderate-to-severe OSA was significantly associated with abnormal fasting glucose in African Americans (odds ratio, 2.14; 95% confidence interval, 1.12-4.08) and white participants (odds ratio, 2.85; 95% confidence interval, 1.20-6.75), but not among Chinese or Hispanic subjects, after adjusting for site, age, sex, waist circumference, and sleep duration (P = 0.06 for ethnicity-by-OSA severity interaction). In contrast, sleep duration was not significantly associated with abnormal fasting glucose after considering the influence of OSA. CONCLUSIONS This large multiethnic study confirmed previous reports of an independent association between OSA and metabolic dysfunction, and suggested that this association may vary by ethnicity.

Common variants in DRD2 are associated with sleep duration: the CARe consortium

Sleep duration is implicated in the etiologies of chronic diseases and premature mortality. However, the genetic basis for sleep duration is poorly defined. We sought to identify novel genetic components influencing sleep duration in a multi-ethnic sample. Meta-analyses were conducted of genetic associations with self-reported, habitual sleep duration from seven Candidate Gene Association Resource (CARe) cohorts of over 25 000 individuals of African, Asian, European and Hispanic American ancestry. All individuals were genotyped for ∼50 000 SNPs from 2000 candidate heart, lung, blood and sleep genes. African-Americans had additional genome-wide genotypes. Four cohorts provided replication. A SNP (rs17601612) in the dopamine D2 receptor gene (DRD2) was significantly associated with sleep duration (P = 9.8 × 10(-7)). Conditional analysis identified a second DRD2 signal with opposite effects on sleep duration. In exploratory analysis, suggestive association was observed for rs17601612 with polysomnographically determined sleep latency (P = 0.002). The lead DRD2 signal was recently identified in a schizophrenia GWAS, and a genetic risk score of 11 additional schizophrenia GWAS loci genotyped on the IBC array was also associated with longer sleep duration (P = 0.03). These findings support a role for DRD2 in influencing sleep duration. Our work motivates future pharmocogenetics research on alerting agents such as caffeine and modafinil that interact with the dopaminergic pathway and further investigation of genetic overlap between sleep and neuro-psychiatric traits.

Reproducibility of a Standardized Actigraphy Scoring Algorithm for Sleep in a US Hispanic/Latino Population.

STUDY OBJECTIVES While actigraphy is considered objective, the process of setting rest intervals to calculate sleep variables is subjective. We sought to evaluate the reproducibility of actigraphy-derived measures of sleep using a standardized algorithm for setting rest intervals. DESIGN Observational study. SETTING Community-based. PARTICIPANTS A random sample of 50 adults aged 18-64 years free of severe sleep apnea participating in the Sueño sleep ancillary study to the Hispanic Community Health Study/Study of Latinos. INTERVENTIONS N/A. MEASUREMENTS AND RESULTS Participants underwent 7 days of continuous wrist actigraphy and completed daily sleep diaries. Studies were scored twice by each of two scorers. Rest intervals were set using a standardized hierarchical approach based on event marker, diary, light, and activity data. Sleep/wake status was then determined for each 30-sec epoch using a validated algorithm, and this was used to generate 11 variables: mean nightly sleep duration, nap duration, 24-h sleep duration, sleep latency, sleep maintenance efficiency, sleep fragmentation index, sleep onset time, sleep offset time, sleep midpoint time, standard deviation of sleep duration, and standard deviation of sleep midpoint. Intra-scorer intraclass correlation coefficients (ICCs) were high, ranging from 0.911 to 0.995 across all 11 variables. Similarly, inter-scorer ICCs were high, also ranging from 0.911 to 0.995, and mean inter-scorer differences were small. Bland-Altman plots did not reveal any systematic disagreement in scoring. CONCLUSIONS With use of a standardized algorithm to set rest intervals, scoring of actigraphy for the purpose of generating a wide array of sleep variables is highly reproducible.

Entropy-Based Measures for Quantifying Sleep-Stage Transition Dynamics: Relationship to Sleep Fragmentation and Daytime Sleepiness

We present two novel entropy-based measures that quantify sleep-stage transition dynamics (sleep structure) from polysomnogram derived hypnograms: Walsh spectral entropy (WSE) and Haar spectral entropy (HSE). These measures quantify patterns of temporal regularity of a categorical time series without requiring numerical encoding (scaling) of the (categorical) sleep stages. Additionally, we show that conditional entropy (CE) is well suited for quantifying predictability of the hypnogram. The relationship of those measures with traditional sleep fragmentation indices (arousal index, total sleep time, and sleep efficiency) is explored for a 394 participant sample of the Cleveland Family Study, an epidemiologic study in which standardized single-night polysomnogram data were collected. The new entropy-based sleep structure measures (WSE, HSE, and CE) are positively correlated (moderate to weak) with the traditional sleep fragmentation indices. Because the sleep structure measures developed in this paper provide direct information related to temporal patterns of sleep that is not contained in traditional sleep fragmentation measures, the correlation between these new alternative sleep structure measures and the traditional sleep fragmentation measures is less important. Our goal is not to develop alternative measures that correlate highly with traditional measures of sleep fragmentation, but rather to provide methods to quantify sleep structure by examining other (e.g., dynamic sleep-stage transition) properties of the hypnogram. Additionally, the relationship of the new entropy-based and traditional measures with daytime sleepiness as quantified by the Epworth sleepiness scale (ESS) is investigated. Multiple linear regression analysis shows that WSE has a stronger relationship with ESS than the traditional measures, even after both are adjusted for common confounders (age, race, gender, and body mass index). This further suggests that the entropy-based measures, especially WSE, are capturing additional temporal patterns of sleep not captured in the traditional sleep fragmentation measures, and have a relationship with daytime sleepiness.

Obstructive and Central Sleep Apnea and the Risk of Incident Atrial Fibrillation in a Community Cohort of Men and Women

Background Previous studies have documented a high prevalence of atrial fibrillation (AF) in individuals with obstructive sleep apnea (OSA). Central sleep apnea (CSA) has been associated with AF in patients with heart failure. However, data from prospective cohorts are sparse and few studies have distinguished the associations of obstructive sleep apnea from CSA with AF in population studies. Methods and Results We assessed the association of obstructive sleep apnea and CSA with incident AF among 2912 individuals without a history of AF in the SHHS (Sleep Heart Health Study), a prospective, community‐based study of existing (“parent”) cohort studies designed to evaluate the cardiovascular consequences of sleep disordered breathing. Incident AF was documented by 12‐lead ECG or assessed by the parent cohort. obstructive sleep apnea was defined by the obstructive apnea‐hypopnea index (OAHI). CSA was defined by a central apnea index ≥5 or the presence of Cheyne Stokes Respiration. Logistic regression was used to assess the association between sleep disordered breathing and incident AF. Over a mean of 5.3 years of follow‐up, 338 cases of incident AF were observed. CSA was a predictor of incident AF in all adjusted models and was associated with 2‐ to 3‐fold increased odds of developing AF (central apnea index ≥5 odds ratio [OR], 3.00, 1.40–6.44; Cheyne–Stokes respiration OR, 1.83, 0.95–3.54; CSA or Cheyne–Stokes respiration OR, 2.00, 1.16–3.44). In contrast, OAHI was not associated with incident AF (OAHI per 5 unit increase OR, 0.97, 0.91–1.03; OAHI 5 to <15 OR, 0.84, 0.59–1.17; OAHI 15 to <30 OR, 0.93, 0.60–1.45; OAHI ≥30 OR, 0.76, 0.42–1.36). Conclusions In a prospective, community‐based cohort, CSA was associated with incident AF, even after adjustment for cardiovascular risk factors.

Validity of a commercial wearable sleep tracker in adult insomnia disorder patients and good sleepers

OBJECTIVES To compare the accuracy of the commercial Fitbit Flex device (FF) with polysomnography (PSG; the gold-standard method) in insomnia disorder patients and good sleepers. METHODS Participants wore an FF and actigraph while undergoing overnight PSG. Primary outcomes were intraclass correlation coefficients (ICCs) of the total sleep time (TST) and sleep efficiency (SE), and the frequency of clinically acceptable agreement between the FF in normal mode (FFN) and PSG. The sensitivity, specificity, and accuracy of detecting sleep epochs were compared among FFN, actigraphy, and PSG. RESULTS The ICCs of the TST between FFN and PSG in the insomnia (ICC=0.886) and good-sleepers (ICC=0.974) groups were excellent, but the ICC of SE was only fair in both groups. The TST and SE were overestimated for FFN by 6.5min and 1.75%, respectively, in good sleepers, and by 32.9min and 7.9% in the insomnia group with respect to PSG. The frequency of acceptable agreement of FFN and PSG was significantly lower (p=0.006) for the insomnia group (39.4%) than for the good-sleepers group (82.4%). The sensitivity and accuracy of FFN in an epoch-by-epoch comparison with PSG was good and comparable to those of actigraphy, but the specificity was poor in both groups. CONCLUSIONS The ICC of TST in the FFN-PSG comparison was excellent in both groups, and the frequency of agreement was high in good sleepers but significantly lower in insomnia patients. These limitations need to be considered when applying commercial sleep trackers for clinical and research purposes in insomnia.