[Show abstract][Hide abstract] ABSTRACT: Obstructive sleep apnea is associated with high cardiovascular morbidity and mortality. Intermittent hypoxia of obstructive sleep apnea is implicated in the development and progression of insulin resistance and atherosclerosis, which have been attributed to systemic inflammation. Intermittent hypoxia leads to pro-inflammatory gene up-regulation in cell culture, but the effects of intermittent hypoxia on gene expression in humans have not been elucidated. A cross-over study was performed exposing eight healthy men to intermittent hypoxia or control conditions for five hours with peripheral blood mononuclear cell isolation before and after exposures. Total RNA was isolated followed by gene microarrays and confirmatory real time reverse transcriptase PCR. Intermittent hypoxia led to greater than two fold up-regulation of the pro-inflammatory gene toll receptor 2 (TLR2), which was not increased in the control exposure. We hypothesize that up-regulation of TLR2 by intermittent hypoxia may lead to systemic inflammation, insulin resistance and atherosclerosis in patients with obstructive sleep apnea.
[Show abstract][Hide abstract] ABSTRACT: Study objective:
To characterize the association among apnea-hypopnea indices (AHIs) determined using three common metrics for defining hypopnea, and to develop a model to calibrate between these AHIs.
Cross-sectional analysis of Sleep Heart Health Study Data.
There were 6,441 men and women age 40 y or older.
Measurement and results:
Three separate AHIs have been calculated, using all apneas (defined as a decrease in airflow greater than 90% from baseline for ≥ 10 sec) plus hypopneas (defined as a decrease in airflow or chest wall or abdominal excursion greater than 30% from baseline, but not meeting apnea definitions) associated with either: (1) a 4% or greater fall in oxyhemoglobin saturation - AHI4; (2) a 3% or greater fall in oxyhemoglobin saturation - AHI3; or (3) a 3% or greater fall in oxyhemoglobin saturation or an event-related arousal - AHI3a. Median values were 5.4, 9.7, and 13.4 for AHI4, AHI3, and AHI3a, respectively (P < 0.0001). Penalized spline regression models were used to compare AHI values across the three metrics and to calculate prediction intervals. Comparison of regression models demonstrates divergence in AHI scores among the three methods at low AHI values and gradual convergence at higher levels of AHI.
The three methods of scoring hypopneas yielded significantly different estimates of AHI, although the relative difference is reduced in severe disease. The regression models presented will enable clinicians and researchers to more appropriately compare AHI values obtained using differing metrics for hypopnea.
[Show abstract][Hide abstract] ABSTRACT: A workshop was held at the National Institute for Diabetes and Digestive and Kidney Diseases with a focus on the impact of sleep and circadian disruption on energy balance and diabetes. The workshop identified a number of key principles for research in this area and a number of specific opportunities. Studies in this area would be facilitated by active collaboration between investigators in sleep/circadian research and investigators in metabolism/diabetes. There is a need to translate the elegant findings from basic research into improving the metabolic health of the American public. There is also a need for investigators studying the impact of sleep/circadian disruption in humans to move beyond measurements of insulin and glucose and conduct more in-depth phenotyping. There is also a need for the assessments of sleep and circadian rhythms as well as assessments for sleep-disordered breathing to be incorporated into all ongoing cohort studies related to diabetes risk. Studies in humans need to complement the elegant short-term laboratory-based human studies of simulated short sleep and shift work etc. with studies in subjects in the general population with these disorders. It is conceivable that chronic adaptations occur, and if so, the mechanisms by which they occur needs to be identified and understood. Particular areas of opportunity that are ready for translation are studies to address whether CPAP treatment of patients with pre-diabetes and obstructive sleep apnea (OSA) prevents or delays the onset of diabetes and whether temporal restricted feeding has the same impact on obesity rates in humans as it does in mice.
[Show abstract][Hide abstract] ABSTRACT: 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
Full-text · Article · Oct 2015 · Human Molecular Genetics
[Show abstract][Hide abstract] ABSTRACT: Study objectives:
Prospective data evaluating abnormal sleep quality and quantity with cognitive decline are limited because most studies used subjective data and/or had short follow-up. We hypothesized that, over 15 y of follow-up, participants with objectively measured obstructive sleep apnea (OSA) and other indices of poor sleep quantity and quality would experience greater decline in cognitive functioning than participants with normal sleep patterns.
Prospective observational cohort.
Atherosclerosis Risk in Communities (ARIC) participants (N = 966; mean age 61 y, 55% women) with in-home polysomnography (1996-1998) and repeated cognitive testing.
Three cognitive tests (Delayed Word Recall, Word Fluency, and Digit Symbol Substitution) were administered at two time points (1996-1998 and 2011-2013). Ten additional cognitive tests were administered at the 2011-2013 neurocognitive examination. OSA was modeled using established clinical OSA severity categories. Multivariable linear regression was used to explore associations of OSA and other sleep indices with change in cognitive tests between the two assessments.
A median of 14.9 y (max: 17.3) passed between the two cognitive assessments. OSA category and additional indices of sleep (other measures of hypoxemia and disordered breathing, sleep fragmentation, sleep duration) were not associated with change in any cognitive test. Analyses of OSA severity categories and 10 cognitive tests administered only in 2011-2013 also showed little evidence of an association.
Overall, abnormal sleep quality and quantity at midlife was not related to cognitive decline and later-life cognition. The effect of adverse sleep quality and quantity on cognitive decline among the elderly remains to be determined.
[Show abstract][Hide abstract] ABSTRACT: Methods are introduced for the analysis of large sets of sleep study data (hypnograms) using a 5-state 20-transition-type structure defined by the American Academy of Sleep Medicine. Application of these methods to the hypnograms of 5598 subjects from the Sleep Heart Health Study provide: the first analysis of sleep hypnogram data of such size and complexity in a community cohort with a range of sleep-disordered breathing severity; introduce a novel approach to compare 5-state (20-transition-type) to 3-state (6-transition-type) sleep structures to assess information loss from combining sleep state categories; extend current approaches of multivariate survival data analysis to clustered, recurrent event discrete-state discrete-time processes; and provide scalable solutions for data analyses required by the case study. The analysis provides detailed new insights into the association between sleep-disordered breathing and sleep architecture. The example data and both R and SAS code are included in online supplementary materials.
No preview · Article · Sep 2015 · Computational Statistics & Data Analysis
[Show abstract][Hide abstract] ABSTRACT: Sleep-disordered breathing (SDB) has been associated with impaired glucose metabolism. It is possible that the association between SDB and glucose metabolism is distinct for NREM vs. REM sleep because of differences in sleep-state dependent sympathetic activation and/or degree of hypoxemia.
Thus, the primary objective of the current study was to characterize the association between REM-related SDB, glucose intolerance, and insulin resistance in a community-based sample.
A cross-sectional analysis that included 3,310 participants from the Sleep Heart Health Study was undertaken (53% women, mean age 66.1years). Full montage home-polysomnography and fasting glucose were available on all participants. SDB severity during REM and NREM sleep was quantified using the apnea-hypopnea index in REM (AHIREM) and NREM sleep (AHINREM), respectively. Fasting and 2-hour post-challenge glucose levels were assessed during a glucose tolerance test (N=2264). The homeostatic model assessment index for insulin resistance (HOMA-IR) was calculated (N=1543). Linear regression was used to assess the associations of AHIREM and AHINREM with fasting and post-prandial glucose levels and HOMA-IR.
AHIREM and AHINREM were associated with fasting glycemia, post-prandial glucose levels and HOMA-IR in models that adjusted for age, sex, race, and site. However, with additional adjustment for BMI, waist circumference and sleep duration, AHIREM was only associated with HOMA-IR (β=0.04, 95%CI:[0.1-0.07] p=0.01), while AHINREM was only associated with fasting (β=0.93, 95%CI:[0.14-1.72] p=0.02) and post-prandial glucose levels (β=3.0, 95%CI:[0.5-5.5] p=0.02).
AHIREM is associated with insulin resistance but not with fasting glycemia or glucose intolerance.
No preview · Article · Jul 2015 · American Journal of Respiratory and Critical Care Medicine
[Show abstract][Hide abstract] ABSTRACT: It is quite reasonable to advocate that the apnea-hypopnea index (AHI) is a clinically valuable metric for obstructive sleep apnea (OSA) on the basis that patients with a high AHI have a higher prevalence of excessive sleepiness, hypertension, and cardiovascular disease compared to those with a lower AHI. Moreover, the contention that the AHI is a "marker of disease" is also sound given that clinical symptoms improve or resolve when the AHI decreases with treatment. However, these arguments only suggest that the AHI is, at best, a crude metric for OSA. Indeed, Dr. Rappaport's conclusion that the AHI is useful in "defining the presence of obstructive sleep apnea if severely elevated and … the risk of obstructive sleep apnea is moderately increased" indicates that the AHI is not a metric with high fidelity. A high fidelity index of disease can identify the presence of that disease and also exhibit a dose-response association with relevant health outcomes. The lack of a strong association between increasing AHI and clinical consequences, such as daytime sleepiness and hypertension, points to its relative crude nature and rigorous consideration is thus required of alternative or complementary measures that can correlate with endpoints more precisely than the AHI.
[Show abstract][Hide abstract] ABSTRACT: Since the early clinical descriptions of obstructive sleep apnea in the 1970s, our understanding of the pathogenesis and adverse consequences of this chronic disease has advanced substantially. Initially, the primary focus was the recognition of sleep-related apneic events which were observed to severely fragment sleep, induce cardiovascular instability, and lead to excessive sleepiness during the day. Given the significant hemodynamic and sleep-related effects of obstructive apneas during sleep, it comes as no surprise that the "apnea index", which tallies the number of apneas per hour of sleep, became the primary disease defining metric for obstructive sleep apnea. However, over time as the full spectrum of upper airway collapse during sleep became more apparent, the simple concept of only quantifying apneas quickly evolved into something more complex. It is now obvious that obstructive apneas, the original sine qua non for the disease, are not the only events of interest as obstructive hypopneas have similar effects (e.g., arousals, blood pressure swings). As the clinical impact of hypopneas became widely recognized, these events were incorporated in quantifying disease activity and the original "apnea-index" gave way to the now commonly used "apnea-hypopneas index" (AHI). Although defining hypopneas continues to be plagued with many challenges, the AHI has become a ubiquitous measure in sleep and respiratory medicine. In fact, the AHI is used not only to diagnose obstructive sleep apnea but also is central in assessing disease severity.
[Show abstract][Hide abstract] ABSTRACT: Objectives:
The objective of this study was to evaluate associations between obesity measures and sleep-disordered breathing severity among White, Black, Hispanic, and Chinese Americans.
The method used in this study was a community-based cross-sectional study of 2053 racially/ethnically diverse adults in the Multi-Ethnic Study of Atherosclerosis. Anthropometry and polysomnography were used to measure obesity and apnea-hypopnea index (AHI). Linear regression models were fitted to investigate associations of body mass index (BMI) and waist circumference with AHI (log transformed) with adjustment for sociodemographics, lifestyle factors, and comorbidities.
The mean participant age was 68.4 (range: 54-93) years; 53.6% of participants were women. The median AHI was 9.1 events/h. There were significant associations of BMI and waist circumference with AHI in the overall cohort and within each racial/ethnic group. A significant interaction was observed between race/ethnicity and BMI (Pinteraction = 0.017). Models predicted that for each unit increase in BMI (kg/m(2)), the mean AHI increased by 19.7% for Chinese, 11.6% for Whites and Blacks, and 10.5% for Hispanics. Similarly, incremental changes in waist circumference were associated with larger increases in AHI among Chinese than among other groups.
Associations of BMI and waist circumference with AHI were stronger among Chinese than among other racial/ethnic groups. These findings highlight a potential emergence of elevated sleep-disordered breathing prevalence occurring in association with increasing obesity in Asian populations.
[Show abstract][Hide abstract] ABSTRACT: No data exist as to the role of ethnicity in the associations between obstructive sleep apnea (OSA), sleep duration, and metabolic dysfunction.
To examine links between OSA, objectively-measured habitual sleep duration, and fasting glucose in United States ethnic groups.
The Multi-Ethnic Study of Atherosclerosis is a multi-site community-based study which 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 /hour), mild (5-14.9 /hour), or moderate-to-severe (≥15 /hour). Actigraphic sleep duration was classified as short (≤5 hours/night), intermediate (>5, <8 hours/night), or long (≥8 hours/night). Subjects were classified as having normal fasting glucose (<100mg/dL and no hypoglycemic medication use) or abnormal fasting glucose (≥100mg/dL and/or hypoglycemic medication use). Measurements & Main Results: The sample was 45.8% male, age 68.5±9.2 (mean±SD) years, and 27.3% African-American, 37.2% Caucasian, 11.8% Chinese, 23.8% Hispanic. The prevalence of abnormal fasting glucose was 40.2%. Relative to non-apneics, moderate-to-severe OSA was significantly associated with abnormal fasting glucose in African-Americans (odds ratio [OR] 2.14, 95% CI 1.12 - 4.08) and Caucasians (OR 2.85, 95% CI 1.20-6.75), but not among Chinese or Hispanic subjects, after adjusting for site, age, gender, 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.
This large multi-ethnic study confirmed previous reports of an independent association between OSA and metabolic dysfunction, and suggested that this association may vary by ethnicity.
No preview · Article · Jun 2015 · American Journal of Respiratory and Critical Care Medicine
[Show abstract][Hide abstract] ABSTRACT: Usual sleep duration is a heritable trait correlated with psychiatric morbidity, cardiometabolic disease and mortality, although little is known about the genetic variants influencing this trait. A genome-wide association study (GWAS) of usual sleep duration was conducted using 18 population-based cohorts totaling 47 180 individuals of European ancestry. Genome-wide significant association was identified at two loci. The strongest is located on chromosome 2, in an intergenic region 35- to 80-kb upstream from the thyroid-specific transcription factor PAX8 (lowest P=1.1 × 10(-9)). This finding was replicated in an African-American sample of 4771 individuals (lowest P=9.3 × 10(-4)). The strongest combined association was at rs1823125 (P=1.5 × 10(-10), minor allele frequency 0.26 in the discovery sample, 0.12 in the replication sample), with each copy of the minor allele associated with a sleep duration 3.1 min longer per night. The alleles associated with longer sleep duration were associated in previous GWAS with a more favorable metabolic profile and a lower risk of attention deficit hyperactivity disorder. Understanding the mechanisms underlying these associations may help elucidate biological mechanisms influencing sleep duration and its association with psychiatric, metabolic and cardiovascular disease.Molecular Psychiatry advance online publication, 2 December 2014; doi:10.1038/mp.2014.133.
Full-text · Article · Dec 2014 · Molecular Psychiatry
[Show abstract][Hide abstract] ABSTRACT: Background:The advent of home sleep testing has allowed for the development of an ambulatory care model for obstructive sleep apnea (OSA) that is easily deployed by most healthcare providers. While automated algorithms that accompany home sleep monitors can identify and classify disordered breathing events, it is unclear if manual scoring followed by expert review of home sleep recordings is of any value. Thus, the current study examined the agreement between automated and manual scoring of home sleep recordings. Methods:Two type III monitors (ApneaLink Plus and Embletta) with distinct study samples were used. Data from manual and automated scoring were available for 200 subjects. Two thresholds for oxygen desaturation (≥3% and ≥4%) were used to define disordered breathing events. Agreement between manual and automated scoring was examined using Pearson's correlation coefficients and Bland-Altman analyses. Results:Automated scoring consistently underscored disordered breathing events compared with manual scoring for both sleep monitors irrespective of whether a ≥3% or ≥4% oxygen desaturation threshold was used to define the apnea-hypopnea index (AHI). Bland-Altman analyses revealed that for the ApneaLink Plus, the average AHI difference between the manual and automated scoring was 6.1 events/hr (95% CI: 4.9-7.3) and 4.6 events/hr (95% CI: 3.5-5.6) for the ≥3% and ≥4% oxygen desaturation threshold, respectively. Similarly, for the Embletta, the average difference between the manual and automated scoring was 5.3 events/hr (95% CI: 3.2-7.3) and 8.4 events/hr (95% CI: 7.2-9.6), respectively. Conclusions:While agreement between automated and manual scoring of home sleep recordings varies based on the device used, modest agreement was observed between the two approaches. However, manual review of HST recordings can decrease the misclassification of OSA severity, particularly for those with mild disease. Study Registration:http://www.clinicaltrials.gov (NCT01503164).
The advent of home sleep testing has allowed for the development of an ambulatory care model for obstructive sleep apnea (OSA) that is easily deployed by most healthcare providers. While automated algorithms that accompany home sleep monitors can identify and classify disordered breathing events, it is unclear if manual scoring followed by expert review of home sleep recordings is of any value. Thus, the current study examined the agreement between automated and manual scoring of home sleep recordings.
Two type III monitors (ApneaLink Plus and Embletta) with distinct study samples were used. Data from manual and automated scoring were available for 200 subjects. Two thresholds for oxygen desaturation (≥3% and ≥4%) were used to define disordered breathing events. Agreement between manual and automated scoring was examined using Pearson's correlation coefficients and Bland-Altman analyses.
Automated scoring consistently underscored disordered breathing events compared with manual scoring for both sleep monitors irrespective of whether a ≥3% or ≥4% oxygen desaturation threshold was used to define the apnea-hypopnea index (AHI). Bland-Altman analyses revealed that for the ApneaLink Plus, the average AHI difference between the manual and automated scoring was 6.1 events/hr (95% CI: 4.9-7.3) and 4.6 events/hr (95% CI: 3.5-5.6) for the ≥3% and ≥4% oxygen desaturation threshold, respectively. Similarly, for the Embletta, the average difference between the manual and automated scoring was 5.3 events/hr (95% CI: 3.2-7.3) and 8.4 events/hr (95% CI: 7.2-9.6), respectively.
While agreement between automated and manual scoring of home sleep recordings varies based on the device used, modest agreement was observed between the two approaches. However, manual review of HST recordings can decrease the misclassification of OSA severity, particularly for those with mild disease.
[Show abstract][Hide abstract] ABSTRACT: Objectives
To determine the association between sleep-disordered breathing (SDB) and decline in instrumental activities of daily living (IADLs) and mobility in older women.DesignProspective cohort.SettingMinneapolis and Pittsburgh sites of the Study of Osteoporotic Fractures, participants' homes.ParticipantsWomen with a mean age ± standard deviation of 82.3 ± 3.2 (N = 302).MeasurementsParticipants completed a single night of unattended polysomnography and provided data regarding difficulty with IADLs and mobility. They repeated IADL and mobility measures 5.0 ± 0.7 years later.ResultsAfter adjustment for age, obesity, Mini-Mental State Examination score, depressive symptoms, history of hypertension and chronic obstructive pulmonary disease, and number of IADL impairments at baseline, women with an apnea-hypopnea index (AHI) of 15 or greater at baseline had more than twice the odds of an increase in number of IADL difficulties (adjusted odds ratio (aOR) = 2.22, 95% confidence interval (CI) = 1.09-4.53) and of incident IADL difficulty (aOR = 2.43, 95% CI = 1.00-5.92), of women with an AHI less than 5. There was no association between AHI and mobility difficulty. Women in the middle and highest tertiles of oxygen desaturation index had more than double the odds as those in the lowest tertile of an increase in number of IADL difficulties (middle tertile aOR = 2.64, 95% CI = 1.38-5.04, highest tertile aOR = 2.17, 95% CI = 1.13-4.17) and approximately three times the odds of incident IADL difficulty (middle tertile aOR = 2.84, 95% CI = 1.27-6.36, highest tertile aOR = 3.07, 95% CI = 1.31-7.18). Neither sleep fragmentation nor sleep duration was associated with IADL outcomes.ConclusionSDB and associated hypoxemia are risk factors for functional decline in older women. Research is needed to determine whether treatment of SDB prevents functional decline.
No preview · Article · Nov 2014 · Journal of the American Geriatrics Society
[Show abstract][Hide abstract] ABSTRACT: Study objective:
Blood pressure (BP) may be adversely affected by a variety of sleep disturbances, including sleep fragmentation, hypoxemia, respiratory disturbances, and periodic limb movements. We aim to identify which polysomnography indices are most strongly and consistently associated with systolic and diastolic blood pressure (SBP, DBP) levels in a population-based sample.
Cross-sectional analysis of data from 2,040 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) who underwent polysomnography at MESA Exam 5 in 2011-2013.
Multisite cohort study.
Participants were mean age 68 y (54% females; 28% African American, 24% Hispanic, 11% Chinese).
Thirty-two candidate polysomnography predictors were identified representing the domains of breathing disturbance frequency, hypoxemia, sleep architecture, and periodic limb movements. Cluster analysis was used for variable reduction. Statistical models, adjusted for potential confounders, were derived using stepwise regression. Final models were selected using cross-validation techniques.
The apnea-hypopnea index (AHI) defined using a 4% desaturation hypopnea criterion (AHI4P) was most consistently associated with SBP level. The AHI and periodic limb movement index (associated with arousals; PLMIA) were significantly associated with DBP. Estimated adjusted differences in SBP and DBP levels between an individual with no sleep apnea (AHI4P = 0) and one with moderately severe sleep apnea (AHI4P = 30) were 2.2 mm Hg and 1.1 mm Hg, respectively. Each 10-unit increase in the PLMIA was associated with an increase in DBP of 1.2 mm Hg.
Our results support the use of a currently recommended apnea-hypopnea index definition as a marker of blood pressure risk and indicate that measurement of limb movements with arousals is also independently associated with diastolic blood pressure.