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1.  Polysomnography in Patients With Obstructive Sleep Apnea 
Executive Summary
The objective of this health technology policy assessment was to evaluate the clinical utility and cost-effectiveness of sleep studies in Ontario.
Clinical Need: Target Population and Condition
Sleep disorders are common and obstructive sleep apnea (OSA) is the predominant type. Obstructive sleep apnea is the repetitive complete obstruction (apnea) or partial obstruction (hypopnea) of the collapsible part of the upper airway during sleep. The syndrome is associated with excessive daytime sleepiness or chronic fatigue. Several studies have shown that OSA is associated with hypertension, stroke, and other cardiovascular disorders; many researchers believe that these cardiovascular disorders are consequences of OSA. This has generated increasing interest in recent years in sleep studies.
The Technology Being Reviewed
There is no ‘gold standard’ for the diagnosis of OSA, which makes it difficult to calibrate any test for diagnosis. Traditionally, polysomnography (PSG) in an attended setting (sleep laboratory) has been used as a reference standard for the diagnosis of OSA. Polysomnography measures several sleep variables, one of which is the apnea-hypopnea index (AHI) or respiratory disturbance index (RDI). The AHI is defined as the sum of apneas and hypopneas per hour of sleep; apnea is defined as the absence of airflow for ≥ 10 seconds; and hypopnea is defined as reduction in respiratory effort with ≥ 4% oxygen desaturation. The RDI is defined as the sum of apneas, hypopneas, and abnormal respiratory events per hour of sleep. Often the two terms are used interchangeably. The AHI has been widely used to diagnose OSA, although with different cut-off levels, the basis for which are often unclear or arbitrarily determined. Generally, an AHI of more than five events per hour of sleep is considered abnormal and the patient is considered to have a sleep disorder. An abnormal AHI accompanied by excessive daytime sleepiness is the hallmark for OSA diagnosis. For patients diagnosed with OSA, continuous positive airway pressure (CPAP) therapy is the treatment of choice. Polysomnography may also used for titrating CPAP to individual needs.
In January 2005, the College of Physicians and Surgeons of Ontario published the second edition of Independent Health Facilities: Clinical Practice Parameters and Facility Standards: Sleep Medicine, commonly known as “The Sleep Book.” The Sleep Book states that OSA is the most common primary respiratory sleep disorder and a full overnight sleep study is considered the current standard test for individuals in whom OSA is suspected (based on clinical signs and symptoms), particularly if CPAP or surgical therapy is being considered.
Polysomnography in a sleep laboratory is time-consuming and expensive. With the evolution of technology, portable devices have emerged that measure more or less the same sleep variables in sleep laboratories as in the home. Newer CPAP devices also have auto-titration features and can record sleep variables including AHI. These devices, if equally accurate, may reduce the dependency on sleep laboratories for the diagnosis of OSA and the titration of CPAP, and thus may be more cost-effective.
Difficulties arise, however, when trying to assess and compare the diagnostic efficacy of in-home PSG versus in-lab. The AHI measured from portable devices in-home is the sum of apneas and hypopneas per hour of time in bed, rather than of sleep, and the absolute diagnostic efficacy of in-lab PSG is unknown. To compare in-home PSG with in-lab PSG, several researchers have used correlation coefficients or sensitivity and specificity, while others have used Bland-Altman plots or receiver operating characteristics (ROC) curves. All these approaches, however, have potential pitfalls. Correlation coefficients do not measure agreement; sensitivity and specificity are not helpful when the true disease status is unknown; and Bland-Altman plots measure agreement (but are helpful when the range of clinical equivalence is known). Lastly, receiver operating characteristics curves are generated using logistic regression with the true disease status as the dependent variable and test values as the independent variable. Thus, each value of the test is used as a cut-point to measure sensitivity and specificity, which are then plotted on an x-y plane. The cut-point that maximizes both sensitivity and specificity is chosen as the cut-off level to discriminate between disease and no-disease states. In the absence of a gold standard to determine the true disease status, ROC curves are of minimal value.
At the request of the Ontario Health Technology Advisory Committee (OHTAC), MAS has thus reviewed the literature on PSG published over the last two years to examine new developments.
Review Strategy
There is a large body of literature on sleep studies and several reviews have been conducted. Two large cohort studies, the Sleep Heart Health Study and the Wisconsin Sleep Cohort Study, are the main sources of evidence on sleep literature.
To examine new developments on PSG published in the past two years, MEDLINE, EMBASE, MEDLINE In-Process & Other Non-Indexed Citations, the Cochrane Database of Systematic Reviews and Cochrane CENTRAL, INAHTA, and websites of other health technology assessment agencies were searched. Any study that reported results of in-home or in-lab PSG was included. All articles that reported findings from the Sleep Heart Health Study and the Wisconsin Sleep Cohort Study were also reviewed.
Diffusion of Sleep Laboratories
To estimate the diffusion of sleep laboratories, a list of sleep laboratories licensed under the Independent Health Facility Act was obtained. The annual number of sleep studies per 100,000 individuals in Ontario from 2000 to 2004 was also estimated using administrative databases.
Summary of Findings
Literature Review
A total of 315 articles were identified that were published in the past two years; 227 were excluded after reviewing titles and abstracts. A total of 59 articles were identified that reported findings of the Sleep Heart Health Study and the Wisconsin Sleep Cohort Study.
Based on cross-sectional data from the Wisconsin Sleep Cohort Study of 602 men and women aged 30 to 60 years, it is estimated that the prevalence of sleep-disordered breathing is 9% in women and 24% in men, on the basis of more than five AHI events per hour of sleep. Among the women with sleep disorder breathing, 22.6% had daytime sleepiness and among the men, 15.5% had daytime sleepiness. Based on this, the prevalence of OSA in the middle-aged adult population is estimated to be 2% in women and 4% in men.
Snoring is present in 94% of OSA patients, but not all snorers have OSA. Women report daytime sleepiness less often compared with their male counterparts (of similar age, body mass index [BMI], and AHI). Prevalence of OSA tends to be higher in older age groups compared with younger age groups.
Diagnostic Value of Polysomnography
It is believed that PSG in the sleep laboratory is more accurate than in-home PSG. In the absence of a gold standard, however, claims of accuracy cannot be substantiated. In general, there is poor correlation between PSG variables and clinical variables. A variety of cut-off points of AHI (> 5, > 10, and > 15) are arbitrarily used to diagnose and categorize severity of OSA, though the clinical importance of these cut-off points has not been determined.
Recently, a study of the use of a therapeutic trial of CPAP to diagnose OSA was reported. The authors studied habitual snorers with daytime sleepiness in the absence of other medical or psychiatric disorders. Using PSG as the reference standard, the authors calculated the sensitivity of this test to be 80% and its specificity to be 97%. Further, they concluded that PSG could be avoided in 46% of this population.
Obstructive Sleep Apnea and Obesity
Obstructive sleep apnea is strongly associated with obesity. Obese individuals (BMI >30 kg/m2) are at higher risk for OSA compared with non-obese individuals and up to 75% of OSA patients are obese. It is hypothesized that obese individuals have large deposits of fat in the neck that cause the upper airway to collapse in the supine position during sleep. The observations reported from several studies support the hypothesis that AHIs (or RDIs) are significantly reduced with weight loss in obese individuals.
Obstructive Sleep Apnea and Cardiovascular Diseases
Associations have been shown between OSA and comorbidities such as diabetes mellitus and hypertension, which are known risk factors for myocardial infarction and stroke. Patients with more severe forms of OSA (based on AHI) report poorer quality of life and increased health care utilization compared with patients with milder forms of OSA. From animal models, it is hypothesized that sleep fragmentation results in glucose intolerance and hypertension. There is, however, no evidence from prospective studies in humans to establish a causal link between OSA and hypertension or diabetes mellitus. It is also not clear that the associations between OSA and other diseases are independent of obesity; in most of these studies, patients with higher values of AHI had higher values of BMI compared with patients with lower AHI values.
A recent meta-analysis of bariatric surgery has shown that weight loss in obese individuals (mean BMI = 46.8 kg/m2; range = 32.30–68.80) significantly improved their health profile. Diabetes was resolved in 76.8% of patients, hypertension was resolved in 61.7% of patients, hyperlipidemia improved in 70% of patients, and OSA resolved in 85.7% of patients. This suggests that obesity leads to OSA, diabetes, and hypertension, rather than OSA independently causing diabetes and hypertension.
Health Technology Assessments, Guidelines, and Recommendations
In April 2005, the Centers for Medicare and Medicaid Services (CMS) in the United States published its decision and review regarding in-home and in-lab sleep studies for the diagnosis and treatment of OSA with CPAP. In order to cover CPAP, CMS requires that a diagnosis of OSA be established using PSG in a sleep laboratory. After reviewing the literature, CMS concluded that the evidence was not adequate to determine that unattended portable sleep study was reasonable and necessary in the diagnosis of OSA.
In May 2005, the Canadian Coordinating Office of Health Technology Assessment (CCOHTA) published a review of guidelines for referral of patients to sleep laboratories. The review included 37 guidelines and associated reviews that covered 18 applications of sleep laboratory studies. The CCOHTA reported that the level of evidence for many applications was of limited quality, that some cited studies were not relevant to the recommendations made, that many recommendations reflect consensus positions only, and that there was a need for more good quality studies of many sleep laboratory applications.
As of the time of writing, there are 97 licensed sleep laboratories in Ontario. In 2000, the number of sleep studies performed in Ontario was 376/100,000 people. There was a steady rise in sleep studies in the following years such that in 2004, 769 sleep studies per 100,000 people were performed, for a total of 96,134 sleep studies. Based on prevalence estimates of the Wisconsin Sleep Cohort Study, it was estimated that 927,105 people aged 30 to 60 years have sleep-disordered breathing. Thus, there may be a 10-fold rise in the rate of sleep tests in the next few years.
Economic Analysis
In 2004, approximately 96,000 sleep studies were conducted in Ontario at a total cost of ~$47 million (Cdn). Since obesity is associated with sleep disordered breathing, MAS compared the costs of sleep studies to the cost of bariatric surgery. The cost of bariatric surgery is $17,350 per patient. In 2004, Ontario spent $4.7 million per year for 270 patients to undergo bariatric surgery in the province, and $8.2 million for 225 patients to seek out-of-country treatment. Using a Markov model, it was concluded that shifting costs from sleep studies to bariatric surgery would benefit more patients with OSA and may also prevent health consequences related to diabetes, hypertension, and hyperlipidemia. It is estimated that the annual cost of treating comorbid conditions in morbidly obese patients often exceeds $10,000 per patient. Thus, the downstream cost savings could be substantial.
Considerations for Policy Development
Weight loss is associated with a decrease in OSA severity. Treating and preventing obesity would also substantially reduce the economic burden associated with diabetes, hypertension, hyperlipidemia, and OSA. Promotion of healthy weights may be achieved by a multisectorial approach as recommended by the Chief Medical Officer of Health for Ontario. Bariatric surgery has the potential to help morbidly obese individuals (BMI > 35 kg/m2 with an accompanying comorbid condition, or BMI > 40 kg/m2) lose weight. In January 2005, MAS completed an assessment of bariatric surgery, based on which OHTAC recommended an improvement in access to these surgeries for morbidly obese patients in Ontario.
Habitual snorers with excessive daytime sleepiness have a high pretest probability of having OSA. These patients could be offered a therapeutic trial of CPAP to diagnose OSA, rather than a PSG. A majority of these patients are also obese and may benefit from weight loss. Individualized weight loss programs should, therefore, be offered and patients who are morbidly obese should be offered bariatric surgery.
That said, and in view of the still evolving understanding of the causes, consequences and optimal treatment of OSA, further research is warranted to identify which patients should be screened for OSA.
PMCID: PMC3379160  PMID: 23074483
2.  DQB1*0602 predicts interindividual differences in physiologic sleep, sleepiness, and fatigue 
Neurology  2010;75(17):1509-1519.
The human leukocyte antigen (HLA) DQB1*0602 allele is closely associated with narcolepsy, a neurologic disorder characterized by excessive daytime sleepiness, fragmented sleep, and shortened REM sleep latency. We evaluated whether DQB1*0602 was a novel marker of interindividual differences by determining its relationship to sleep homeostatic, sleepiness, and cognitive responses to baseline and chronic partial sleep deprivation (PSD) conditions.
Ninety-two DQB1*0602-negative and 37 DQB1*0602-positive healthy adults participated in a protocol of 2 baseline 10 hours time in bed (TIB) nights followed by 5 consecutive 4 hours TIB nights. DQB1*0602 allelic frequencies did not differ significantly between Caucasians and African Americans.
During baseline, although DQB1*0602-positive subjects were subjectively sleepier and more fatigued, they showed greater sleep fragmentation, and decreased sleep homeostatic pressure and differentially sharper declines during the night (measured by non-REM EEG slow-wave energy [SWE]). During PSD, DQB1*0602-positive subjects were sleepier and showed more fragmented sleep, despite SWE elevation comparable to negative subjects. Moreover, they showed differentially greater REM sleep latency reductions and smaller stage 2 reductions, along with differentially greater increases in fatigue. Both groups demonstrated comparable cumulative decreases in cognitive performance.
DQB1*0602 positivity in a healthy population may represent a continuum of some sleep–wake features of narcolepsy. DQB1*0602 was associated with interindividual differences in sleep homeostasis, physiologic sleep, sleepiness, and fatigue—but not in cognitive measures—during baseline and chronic PSD. Thus, DQB1*0602 may represent a genetic biomarker for predicting such individual differences in basal and sleep loss conditions.
= analysis of variance;
= Controlled Oral Word Association Test;
= Digit Span;
= Digit Symbol Substitution Task;
= human leukocyte antigen;
= Karolinska Sleepiness Scale;
= Maintenance of Wakefulness Test;
= Profile of Mood States;
= partial sleep deprivation;
= polysomnography;
= Psychomotor Vigilance Task;
= sleep onset latency;
= sleep deprivation/restriction;
= slow-wave activity;
= slow-wave energy;
= time in bed;
= Tower of London;
= total sleep deprivation;
= visual analog scale;
= wake after sleep onset.
PMCID: PMC2974463  PMID: 20975052
3.  Sleep Problems among Pre-School Children in Qazvin, Iran 
Background: Sleep problems are one of the main health issues raised by families. Therefore, we aimed to evaluate the sleep problems of pre-school children in Iran.
Methods: Five hundred and seventy-nine children aged 3–6 years were randomly recruited from 15 kindergartens in the city of Qazvin in Iran. The Iranian version of BEARS (Bedtime problems, Excessive daytime sleepiness, Awakenings during the night, Regularity and duration of sleep and Snoring) and the Children’s Sleep Habits questionnaire (CSHQ) were completed by interviewers. Data analysis was performed using SPSS version 19. The data were analysed with a Student’s t-test, chi-square and Fisher’s exact tests. A P value < 0.05 was considered significant.
Results: The study population consisted of 299 boys (51.6%) and 280 (48.3%) girls with a mean age of 4.1 years (SD 0.8). The mean body mass index (BMI) of the children was 15 (SD 2.1). The average sleep duration among the children was 10:54 h/day (SD 00:48). They went to bed late (23:18 h SD 00:48) and woke early (09:26 h; SD 01:00). Daytime sleepiness was reported by 6.9% of the participants. The incidence of awakening during the night, sleep-disordered breathing and snoring was 13.9%, 1.2% and 2.7%, respectively. Most of the children shared a room with their parents (87%) (P > 0.05).
Conclusion: The children had sleep-related problems, including a late bedtime, delayed sleep onset, daytime sleepiness, midnight awakening, sleep-disordered breathing, and snoring. Sharing a room was very common among the Iranian children.
PMCID: PMC4391455  PMID: 25897283
sleep; habits; child; pre-school; questionnaires
4.  Effects of Filtering Visual Short Wavelengths During Nocturnal Shiftwork on Sleep and Performance 
Chronobiology International  2013;30(8):951-962.
Circadian phase resetting is sensitive to visual short wavelengths (450–480 nm). Selectively filtering this range of wavelengths may reduce circadian misalignment and sleep impairment during irregular light-dark schedules associated with shiftwork. We examined the effects of filtering short wavelengths (<480 nm) during night shifts on sleep and performance in nine nurses (five females and four males; mean age ± SD: 31.3 ± 4.6 yrs). Participants were randomized to receive filtered light (intervention) or standard indoor light (baseline) on night shifts. Nighttime sleep after two night shifts and daytime sleep in between two night shifts was assessed by polysomnography (PSG). In addition, salivary melatonin levels and alertness were assessed every 2 h on the first night shift of each study period and on the middle night of a run of three night shifts in each study period. Sleep and performance under baseline and intervention conditions were compared with daytime performance on the seventh day shift, and nighttime sleep following the seventh daytime shift (comparator). On the baseline night PSG, total sleep time (TST) (p < 0.01) and sleep efficiency (p = 0.01) were significantly decreased and intervening wake times (wake after sleep onset [WASO]) (p = 0.04) were significantly increased in relation to the comparator night sleep. In contrast, under intervention, TST was increased by a mean of 40 min compared with baseline, WASO was reduced and sleep efficiency was increased to levels similar to the comparator night. Daytime sleep was significantly impaired under both baseline and intervention conditions. Salivary melatonin levels were significantly higher on the first (p < 0.05) and middle (p < 0.01) night shifts under intervention compared with baseline. Subjective sleepiness increased throughout the night under both conditions (p < 0.01). However, reaction time and throughput on vigilance tests were similar to daytime performance under intervention but impaired under baseline on the first night shift. By the middle night shift, the difference in performance was no longer significant between day shift and either of the two night shift conditions, suggesting some adaptation to the night shift had occurred under baseline conditions. These results suggest that both daytime and nighttime sleep are adversely affected in rotating-shift workers and that filtering short wavelengths may be an approach to reduce sleep disruption and improve performance in rotating-shift workers. (Author correspondence:
PMCID: PMC3786545  PMID: 23834705
Melatonin; shiftwork; short-wavelength light; sleep efficiency; total sleep time; wake after sleep onset
5.  Sleep patterns and habits in high school students in Iran 
Sleep patterns and habits in high school students in Iran have not been well studied to date. This paper aims to re-address this balance and analyse sleep patterns and habits in Iranian children of high school age.
The subjects were 1,420 high school students randomly selected by stratified cluster sampling. This was a self-report study using a questionnaire which included items about usual sleep/wake behaviours over the previous month, such as sleep schedule, falling asleep in class, difficulty falling asleep, tiredness or sleepiness during the day, difficulty getting up in the morning, nightmares, and taking sleeping pills.
The mean duration of night sleep was 7.7 h, with no difference between girls, boys, and school year (grade). The mean time of waking in the morning was not different between genders. About 9.9% of the girls and 4.6% of the boys perceived their quality of sleep as being bad, and 58% of them reported sleepiness during the day. About 4.2% of the subjects had used medication to enhance sleep. The time of going to bed was associated with grade level and gender. Sleep latency was not associated with gender and grade leve, l and 1.4% experienced bruxism more than four times a week.
Our results are in contrast with that of previous studies that concluded sleep duration is shorter in Asia than in Europe, that boys woke-up significantly later than girls, and that the frequency of sleep latency category was associated with gender and grade level. The magnitude of the daytime sleepiness, daytime sleepiness during classes, sleep latency, and incidences of waking up at night represent major public health concerns for Iran.
PMCID: PMC2292723  PMID: 18339201
6.  Alcohol disrupts sleep homeostasis 
Alcohol (Fayetteville, N.Y.)  2014;49(4):299-310.
Alcohol is a potent somnogen and one of the most commonly used “over the counter” sleep aids. In healthy non-alcoholics, acute alcohol decreases sleep latency, consolidates and increases the quality (delta power) and quantity of NREM sleep during the first half of the night. However, sleep is disrupted during the second half. Alcoholics, both during drinking periods and during abstinences, suffer from a multitude of sleep disruptions manifested by profound insomnia, excessive daytime sleepiness, and altered sleep architecture. Furthermore, subjective and objective indicators of sleep disturbances are predictors of relapse. Finally, within the USA, it is estimated that societal costs of alcohol-related sleep disorders exceeds $18 billion. Thus, although alcohol-associated sleep problems have significant economic and clinical consequences, very little is known about how and where alcohol acts to affect sleep.
In this review, we have described our attempts to understand how and where alcohol acts to affect sleep. We have conducted a series of experiments using two different species, rats and mice, as animal models, and a combination of multi-disciplinary experimental methodologies to examine and understand anatomical and cellular substrates mediating the effects of acute and chronic alcohol exposure on sleep-wakefulness.
The results of our studies suggest that the sleep-promoting effects of alcohol may be mediated via alcohol’s action on the mediators of sleep homeostasis: adenosine (AD) and the wake-promoting cholinergic neurons of the basal forebrain (BF). Alcohol, via its action on AD uptake, increases extracellular AD resulting in the inhibition of BF wake-promoting neurons. Lesions of the BF cholinergic neurons or blockade of AD A1 receptors results in attenuation of alcohol-induced sleep promotion, suggesting that AD and BF cholinergic neurons are critical for sleep-promoting effects of alcohol.
Since binge alcohol consumption is a highly prevalent pattern of alcohol consumption and disrupts sleep, we examined the effects of binge drinking on sleep-wakefulness. Our results suggest that disrupted sleep homeostasis may be the primary cause of sleep disruption observed following binge drinking. Finally, we have also shown that insomnia and associated sleep disruptions, observed during acute withdrawal, are caused due to impaired sleep homeostasis.
Based on our findings, we suggest that alcohol may disrupt sleep homeostasis to cause sleep disruptions.
PMCID: PMC4427543  PMID: 25499829
alcohol dependence; adenosine; basal forebrain; binge drinking; cholinergic; sleep deprivation; theta; delta; electroencephalogram
7.  Association between delayed bedtime and sleep-related problems among community-dwelling 2-year-old children in Japan 
Although delayed sleep timing causes many socio-psycho-biological problems such as sleep loss, excessive daytime sleepiness, obesity, and impaired daytime neurocognitive performance in adults, there are insufficient data showing the clinical significance of a ‘night owl lifestyle’ in early life. This study examined the association between habitual delayed bedtime and sleep-related problems among community-dwelling 2-year-old children in Japan.
Parents/caregivers of 708 community-dwelling 2-year-old children in Nishitokyo City, Tokyo, participated in the study. The participants answered a questionnaire to evaluate their child’s sleep habits and sleep-related problems for the past 1 month.
Of the 425 children for whom complete data were collected, 90 (21.2%) went to bed at 22:00 or later. Children with delayed bedtime showed significantly more irregular bedtime, delayed wake time, shorter total sleep time, and difficulty in initiating and terminating sleep. Although this relationship indicated the presence of sleep debt in children with delayed bedtime, sleep onset latency did not differ between children with earlier bedtime and those with delayed bedtime. Rather, delayed bedtime was significantly associated with bedtime resistance and problems in the morning even when adjusting for nighttime and daytime sleep time.
Even in 2-year-old children, delayed bedtime was associated with various sleep-related problems. The causal factors may include diminished homeostatic sleep drive due to prolonged daytime nap as well as diurnal preference (morning or night type) regulated by the biological clock.
PMCID: PMC4364649  PMID: 25858638
Sleep habits; Sleep problems; Toddlers; Prevalence; Cross-sectional study
8.  Obstructive Sleep Apnea and Risk of Cardiovascular Events and All-Cause Mortality: A Decade-Long Historical Cohort Study 
PLoS Medicine  2014;11(2):e1001599.
Tetyana Kendzerska and colleagues explore the association between physiological measures of obstructive sleep apnea other than the apnea-hypopnea index and the risk of cardiovascular events.
Please see later in the article for the Editors' Summary
Obstructive sleep apnea (OSA) has been reported to be a risk factor for cardiovascular (CV) disease. Although the apnea-hypopnea index (AHI) is the most commonly used measure of OSA, other less well studied OSA-related variables may be more pathophysiologically relevant and offer better prediction. The objective of this study was to evaluate the relationship between OSA-related variables and risk of CV events.
Methods and Findings
A historical cohort study was conducted using clinical database and health administrative data. Adults referred for suspected OSA who underwent diagnostic polysomnography at the sleep laboratory at St Michael's Hospital (Toronto, Canada) between 1994 and 2010 were followed through provincial health administrative data (Ontario, Canada) until May 2011 to examine the occurrence of a composite outcome (myocardial infarction, stroke, congestive heart failure, revascularization procedures, or death from any cause). Cox regression models were used to investigate the association between baseline OSA-related variables and composite outcome controlling for traditional risk factors. The results were expressed as hazard ratios (HRs) and 95% CIs; for continuous variables, HRs compare the 75th and 25th percentiles. Over a median follow-up of 68 months, 1,172 (11.5%) of 10,149 participants experienced our composite outcome. In a fully adjusted model, other than AHI OSA-related variables were significant independent predictors: time spent with oxygen saturation <90% (9 minutes versus 0; HR = 1.50, 95% CI 1.25–1.79), sleep time (4.9 versus 6.4 hours; HR = 1.20, 95% CI 1.12–1.27), awakenings (35 versus 18; HR = 1.06, 95% CI 1.02–1.10), periodic leg movements (13 versus 0/hour; HR = 1.05, 95% CI 1.03–1.07), heart rate (70 versus 56 beats per minute [bpm]; HR = 1.28, 95% CI 1.19–1.37), and daytime sleepiness (HR = 1.13, 95% CI 1.01–1.28).The main study limitation was lack of information about continuous positive airway pressure (CPAP) adherence.
OSA-related factors other than AHI were shown as important predictors of composite CV outcome and should be considered in future studies and clinical practice.
Please see later in the article for the Editors' Summary
Editors' Summary
Obstructive sleep apnea (OSA) is a common sleep-related breathing disorder, particularly among middle-aged and elderly people. It is characterized by apnea—a brief interruption in breathing that lasts at least 10 seconds—and hypopnea—a decrease of more than 50% in the amplitude of breathing that lasts at least 10 seconds or clear but smaller decrease in amplitude associated with either oxygen desaturation or an arousal. Patients with OSA experience numerous episodes of apnea and hypopnea during the night; severe OSA is defined as having 30 or more episodes per hour (an apnea-hypopnea index [AHI] of >30). These breathing interruptions occur when relaxation of the upper airway muscles decreases the airflow, which lowers the amount of oxygen in the blood. As a result, affected individuals frequently wake from deep sleep as they struggle to breathe. Symptoms of OSA include loud snoring and daytime sleepiness. Treatments include lifestyle changes such as losing weight (excess fat around the neck increases airway collapse) and smoking cessation. For severe OSA, doctors recommend continuous positive airway pressure (CPAP), in which a machine blows pressurized air through a face mask into the airway to keep it open.
Why Was This Study Done?
OSA can be life-threatening. Most directly, daytime sleepiness can cause accidents, but OSA is also associated with an increased risk of developing cardiovascular disease (CVD, disease that affects the heart and the circulation). To date, studies that have investigated the association between OSA and the risk of myocardial infarction (heart attack), congestive heart failure, stroke, and other CVDs have used the AHI to diagnose and categorize the severity of OSA. However, by focussing on AHI, clinicians and researchers may be missing opportunities to improve their ability to predict which patients are at the highest risk of CVD. In this historical cohort study, the researchers investigate the association between other OSA-related variables (for example, blood oxygen saturation and sleep fragmentation) and the risk of cardiovascular events and all-cause mortality (death). A historical cohort study examines the medical records of groups of individuals who have different characteristics at baseline for the subsequent occurrence of specific outcomes.
What Did the Researchers Do and Find?
The researchers used administrative data (including hospitalization records and physicians' claims for services supplied to patients) to follow up adults referred for suspected OSA who underwent diagnostic polysomnography (a sleep study) at a single Canadian hospital between 1994 and 2010. A database of the polysomnography results provided information on OSA-related variables for all the study participants. Over an average follow-up of about 6 years, 11.5% of the 10,149 participants were hospitalized for a myocardial infarction, stroke, or congestive heart failure, underwent a revascularization procedure (an intervention that restores the blood supply to an organ or tissue after CVD has blocked a blood vessel), or had died from any cause. After adjusting for multiple established risk factors for CVD such as smoking and age in Cox regression models (a statistical approach that examines associations between patient variables and outcomes), several OSA-related variables (but not AHI) were significant predictors of CVD. The strongest OSA-related predictor of cardiovascular events or all-cause mortality was total sleep time spent with oxygen saturation below 90%, which increased the risk of a cardiovascular event or death by 50%. Other statistically significant OSA-related predictors (predictors that were unlikely to be associated with the outcome through chance) of cardiovascular events or death included total sleep time, number of awakenings, frequency of periodic leg movements, heart rate, and daytime sleepiness.
What Do These Findings Mean?
These findings indicate that OSA-related factors other than AHI are important predictors of the composite outcome of a cardiovascular event or all-cause mortality. Indeed, although AHI was significantly associated with the researchers' composite outcome in an analysis that did not consider other established risk factors for CVD (“confounders”), the association became non-significant after controlling for potential confounders. The accuracy of these findings, which need to be confirmed in other settings, is likely to be limited by the lack of information available about the use of CPAP by study participants and by the lack of adjustment for some important confounders. Importantly, however, these findings suggest that OSA-related factors other than AHI should be considered as predictors of CVD in future studies and in clinical practice.
Additional Information
Please access these websites via the online version of this summary at
The US National Heart Lung and Blood Institute has information (including several videos) about obstructive sleep apnea (in English and Spanish), sleep studies, heart disease, and other cardiovascular diseases (some information in English and Spanish)
The UK National Health Service Choices website provides information (including personal stories) about sleep apnea and about cardiovascular disease
The not-for-profit American Sleep Apnea Association provides detailed information about sleep apnea for patients and health-care professionals, including personal stories about the condition
The MedlinePlus encyclopedia has pages on obstructive sleep apnea and on polysomnography; MedlinePlus provides links to further information and advice about obstructive sleep apnea, heart diseases, and vascular diseases (in English and Spanish)
PMCID: PMC3913558  PMID: 24503600
9.  Response Surface Mapping of Neurobehavioral Performance: Testing the Feasibility of Split Sleep Schedules for Space Operations 
Acta astronautica  2008;63(7-10):833-840.
The demands of sustaining high levels of neurobehavioral performance during space operations necessitate precise scheduling of sleep opportunities in order to best preserve optimal performance. We report here the results of the first split-sleep, dose-response experiment involving a range of sleep/wake scenarios with chronically reduced nocturnal sleep, augmented with a diurnal nap. To characterize performance over all combinations of split sleep in the range studied, we used response surface mapping methodology. Waking neurobehavioral performance was studied in N=90 subjects each assigned to one of 18 sleep regimens consisting of a restricted nocturnal anchor sleep period and a diurnal nap. Psychomotor vigilance task performance and subjective assessments of sleepiness were found to be primarily a function of total time in bed per 24 h regardless of how sleep was divided among nocturnal anchor sleep and diurnal nap periods. Digit symbol substitution task performance was also found to be primarily a function of total time in bed per 24 h; however, accounting for nocturnal sleep duration and nap duration separately provided a small but significant enhancement in the variance explained. The results suggest that reductions in total daily sleep result in a near-linear accumulation of impairment regardless of whether sleep is scheduled as a consolidated nocturnal sleep period or split into a nocturnal anchor sleep period and a diurnal nap. Thus, split sleep schedules are feasible and can be used to enhance the flexibility of sleep/work schedules for space operations involving restricted nocturnal sleep due to mission-critical task scheduling. These results are generally applicable to any continuous industrial operation that involves sleep restriction, night operations, and shift work.
PMCID: PMC2633932  PMID: 19194521
chronic sleep restriction; split sleep schedules; space flight; anchor sleep; napping; sleep physiology; neurobehavioral performance; subjective sleepiness; psychomotor vigilance task; response surface mapping; mixed-effects regression
10.  Sleep Disturbances and Frailty Status in Older Community-Dwelling Men 
Test the hypothesis that sleep disturbances are independently associated with greater evidence of frailty in older men.
Cross-sectional analysis of prospective cohort study
Six U.S. centers
3133 men ≥67 years
Self reported sleep parameters (questionnaire); objective parameters of sleep wake patterns (actigraphy data collected for an average of 5.2 nights); and objective parameters of sleep disordered breathing, nocturnal hypoxemia, and periodic leg movements with arousals (PLMA) (in-home overnight polysomnography). Frailty status classified as robust, intermediate stage or frail using criteria similar to those used in the Cardiovascular Health Study frailty index.
The prevalence of sleep disturbances including poor sleep quality, excessive daytime sleepiness, short sleep duration, reduced sleep efficiency, prolonged sleep latency, sleep fragmentation (greater nighttime wakefulness and frequent long wake episodes), sleep disordered breathing, nocturnal hypoxemia and frequent PLMA was lowest among robust men, intermediate among men in the intermediate stage group, and highest among frail men (p-for-trend ≤0.002 for all sleep parameters). After adjusting for multiple potential confounders, self-reported poor sleep quality (Pittsburgh Sleep Quality Index <5, multivariable odds ratio (MOR) 1.28, 95%CI 1.09–1.50), sleep efficiency <70% (MOR 1.37, 95% CI 1.12–1.67), sleep latency ≥60 minutes (MOR 1.42, 95% CI 1.10–1.82), and sleep disordered breathing (respiratory disturbance index ≥15, MOR 1.38, 95% CI 1.15–1.65) were each independently associated with an increased odds of greater frailty status.
Sleep disturbances including poor self-reported sleep quality, reduced sleep efficiency, prolonged sleep latency and sleep disordered breathing are independently associated with greater evidence of frailty.
PMCID: PMC3024909  PMID: 19793160
sleep disturbances; frailty; aging
11.  Obstructive sleep apnea and pulmonary function in patients with severe obesity before and after bariatric surgery: a randomized clinical trial 
The increasing prevalence of obesity in both developed and developing countries is one of the most serious public health problems and has led to a global epidemic. Obesity is one of the greatest risk factors of obstructive sleep apnea (OSA), which is found in 60 to 70% of obese patients mainly due to the buildup of fat tissue in the upper portion of the thorax and neck. The aim of the present randomized clinical trial is to assess daytime sleepiness, sleep architecture and pulmonary function in patients with severe obesity before and after bariatric surgery.
This randomized, controlled trial, was designed, conducted, and reported in accordance with the standards of The CONSORT (Consolidated Standards of Reporting Trials) Statement. Patients were divided into a bariatric surgery group and control group. The clinical evaluation was performed at the Sleep Laboratory of the Nove de JulhoUniversity (Sao Paulo, Brazil) and consisted of the collection of clinical data, weight, height, body mass index (BMI), measurements of neck and abdomen circumferences, spirometry, maximum ventilatory pressure measurements, standard overnight polysomnography (PSG) and the administration of the Berlin Questionnaire and Epworth Sleepiness Scale.
Fifty-two patients participated in the present study and performed PSG. Out of these, 16 underwent bariatric surgery. After surgery, mean BMI decreased from 48.15 ± 8.58 to 36.91 ± 6.67 Kg/m2. Significant differences were found between the preoperative and postoperative periods regarding neck (p < 0.001) and waist circumference (p < 0.001), maximum inspiratory pressure (p = 0.002 and p = 0.004) and maximum expiratory pressure (p = 0.001 and p = 0.002) for women and men, respectively, as well as sleep stage N3 (p < 0.001), REM sleep (p = 0.049) and the apnea-hypopnea index (p = 0.008).
Bariatric surgery effectively reduces neck and waist circumference, increases maximum ventilatory pressures, enhances sleep architecture and reduces respiratory sleep disorders, specifically obstructive sleep apnea, in patients with severe obesity.
Trial registration
The protocol for this study was registered with the World Health Organization (Universal Trial Number: U1111-1121-8873) and Brazilian Registry of Clinical Trials – ReBEC (RBR-9k9hhv).
PMCID: PMC4135715  PMID: 25136444
Bariatric surgery; Pulmonary function; Severe obesity; Sleep disorders; Ventilatory muscles
12.  Identification of Redeye, a new sleep-regulating protein whose expression is modulated by sleep amount 
eLife  2014;3:e01473.
In this study, we report a new protein involved in the homeostatic regulation of sleep in Drosophila. We conducted a forward genetic screen of chemically mutagenized flies to identify short-sleeping mutants and found one, redeye (rye) that shows a severe reduction of sleep length. Cloning of rye reveals that it encodes a nicotinic acetylcholine receptor α subunit required for Drosophila sleep. Levels of RYE oscillate in light–dark cycles and peak at times of daily sleep. Cycling of RYE is independent of a functional circadian clock, but rather depends upon the sleep homeostat, as protein levels are up-regulated in short-sleeping mutants and also in wild type animals following sleep deprivation. We propose that the homeostatic drive to sleep increases levels of RYE, which responds to this drive by promoting sleep.
eLife digest
Almost all animals need to sleep, including most insects. In experiments in the 1980s, a group of rats that were completely deprived of sleep died within only a few weeks. Sleep has been implicated in processes including tissue repair, memory consolidation and, more recently, the removal of waste materials from the brain. However, a full understanding of why we sleep is still lacking.
As anyone who has experienced jetlag can testify, the timing of the sleep/wake cycle is governed by the circadian clock, which leads us to feel sleepy at certain points of the day–night cycle and alert at others. The duration of sleep is regulated by a second process called sleep/wake homeostasis. The longer we remain awake, the more the body’s need for sleep—or ‘sleep drive’—increases, until it becomes almost impossible to stay awake any longer. Whereas many components of the circadian clock have been identified, relatively little is known about the molecular basis of this second process.
Now, Shi et al. have identified a key component of the sleep/wake homeostatic system using the fruit fly and genetic model organism, Drosophila. Flies with a mutation in one particular gene, subsequently named redeye, were found to sleep only half as long as normal flies. While the insects were able to fall asleep, they would wake again only a few minutes later.
Redeye encodes a subunit of a receptor that has previously been implicated in the control of wakefulness, known as the nicotinic acetylcholine receptor. Mutant flies had normal circadian rhythms, suggesting that their sleep problems were the result of disrupted sleep/wake homeostasis. Consistent with this, levels of redeye showed two daily peaks, one corresponding to night-time sleep and the second to the time at which flies would normally take an afternoon siesta. This suggests that redeye signals an acute need for sleep, and then helps to maintain sleep once it is underway.
While redeye is not thought to be the factor that triggers sleep per se, it is directly under control of the sleep homeostat, and may be a useful biomarker for sleep deprivation. The fact that redeye was identified in fruit flies, a species whose genome has been fully sequenced, opens up the possibility of further studies to identify the genetic basis of sleep regulation.
PMCID: PMC3912633  PMID: 24497543
sleep; acetylcholine signaling; cycling; Sleepless/Lynx-1; D. melanogaster
13.  Sleep-Disordered Breathing and Mortality: A Prospective Cohort Study 
PLoS Medicine  2009;6(8):e1000132.
In a cohort of 6,441 volunteers followed over an average of 8.2 years, Naresh Punjabi and colleagues find sleep-disordered breathing to be independently associated with mortality and identify predictive characteristics.
Sleep-disordered breathing is a common condition associated with adverse health outcomes including hypertension and cardiovascular disease. The overall objective of this study was to determine whether sleep-disordered breathing and its sequelae of intermittent hypoxemia and recurrent arousals are associated with mortality in a community sample of adults aged 40 years or older.
Methods and Findings
We prospectively examined whether sleep-disordered breathing was associated with an increased risk of death from any cause in 6,441 men and women participating in the Sleep Heart Health Study. Sleep-disordered breathing was assessed with the apnea–hypopnea index (AHI) based on an in-home polysomnogram. Survival analysis and proportional hazards regression models were used to calculate hazard ratios for mortality after adjusting for age, sex, race, smoking status, body mass index, and prevalent medical conditions. The average follow-up period for the cohort was 8.2 y during which 1,047 participants (587 men and 460 women) died. Compared to those without sleep-disordered breathing (AHI: <5 events/h), the fully adjusted hazard ratios for all-cause mortality in those with mild (AHI: 5.0–14.9 events/h), moderate (AHI: 15.0–29.9 events/h), and severe (AHI: ≥30.0 events/h) sleep-disordered breathing were 0.93 (95% CI: 0.80–1.08), 1.17 (95% CI: 0.97–1.42), and 1.46 (95% CI: 1.14–1.86), respectively. Stratified analyses by sex and age showed that the increased risk of death associated with severe sleep-disordered breathing was statistically significant in men aged 40–70 y (hazard ratio: 2.09; 95% CI: 1.31–3.33). Measures of sleep-related intermittent hypoxemia, but not sleep fragmentation, were independently associated with all-cause mortality. Coronary artery disease–related mortality associated with sleep-disordered breathing showed a pattern of association similar to all-cause mortality.
Sleep-disordered breathing is associated with all-cause mortality and specifically that due to coronary artery disease, particularly in men aged 40–70 y with severe sleep-disordered breathing.
Please see later in the article for the Editors' Summary
Editors' Summary
About 1 in 10 women and 1 in 4 men have a chronic condition called sleep-disordered breathing although most are unaware of their problem. Sleep-disordered breathing, which is commonest in middle-aged and elderly people, is characterized by numerous, brief (10 second or so) interruptions of breathing during sleep. These interruptions, which usually occur when relaxation of the upper airway muscles decreases airflow, lower the level of oxygen in the blood and, as a result, affected individuals are frequently aroused from deep sleep as they struggle to breathe. Symptoms of sleep-disordered breathing include loud snoring and daytime sleepiness. Treatments include lifestyle changes such as losing weight (excess fat around the neck increases airway collapse) and smoking cessation. Affected people can also use special devices to prevent them sleeping on their backs, but for severe sleep-disordered breathing, doctors often recommend continuous positive airway pressure (CPAP), a machine that pressurizes the upper airway through a face mask to keep it open.
Why Was This Study Done?
Sleep-disordered breathing is a serious condition. It is associated with several adverse health conditions including coronary artery disease (narrowing of the blood vessels that supply the heart, a condition that can cause a heart attack) and daytime sleepiness that can affect an individual's driving ability. In addition, several clinic- and community-based studies suggest that sleep-disordered sleeping may increase a person's risk of dying. However, because these studies have been small and have often failed to allow for other conditions and characteristics that affect an individual's risk of dying (“confounding factors”), they provide inconsistent or incomplete information about the potential association between sleep-disordered breathing and the risk of death. In this prospective cohort study (part of the Sleep Heart Health Study, which is researching the effects of sleep-disordered breathing on cardiovascular health), the researchers examine whether sleep-disordered breathing is associated with all-cause mortality (death from any cause) in a large community sample of adults. A prospective cohort study is one in which a group of participants is enrolled and then followed forward in time (in this case for several years) to see what happens to them.
What Did the Researchers Do and Find?
At enrollment, the study participants—more than 6,000 people aged 40 years or older, none of whom were being treated for sleep-disordered breathing—had a health examination. Their night-time breathing, sleep patterns, and blood oxygen levels were also assessed and these data used to calculate each participant's apnea-hypopnea index (AHI)—the number of apneas and hypopneas per hour. During the study follow-up period, 1,047 participants died. Compared to participants without sleep-disordered sleeping, participants with severe sleep-disordered breathing (an AHI of ≥30) were about one and a half times as likely to die from any cause after adjustment for potential confounding factors. People with milder sleep-disordered breathing did not have a statistically significant increased risk of dying. After dividing the participants into subgroups according to their age and sex, men aged 40–70 years with severe sleep-disordered breathing had a statistically increased risk of dying from any cause (twice the risk of men of a similar age without sleep-disordered breathing). Finally, death from coronary artery disease was also associated with sleep-disordered breathing in men but not in women.
What Do These Findings Mean?
These findings indicate that sleep-disordered breathing is associated with an increased risk of all-cause mortality, particularly in men aged 40–70 years, even after allowing for known confounding factors. They also suggest that the increased risk of death is specifically associated with coronary artery disease although further studies are needed to confirm this finding because it was based on the analysis of a small subgroup of study participants. Although this study is much larger than previous investigations into the association between sleep-disordered breathing and all-cause mortality, it has several limitations including its reliance on a single night's measurements for the diagnosis of sleep-disordered breathing. Nevertheless, these findings suggest that clinical trials should now be started to assess whether treatment can reduce the increased risk of death that seems to be associated with this common disorder.
Additional Information
Please access these Web sites via the online version of this summary at
The US National Heart Lung and Blood Institute has information (including a video) about sleep-disordered breathing (sleep apnea) (in English and Spanish)
The UK National Heath Service also provides information for patients about sleep apnea
MedlinePlus provides links to further information and advice about sleep-disordered breathing (in English and Spanish)
More information on the Sleep Heart Health Study is available
PMCID: PMC2722083  PMID: 19688045
14.  Longitudinal Change in Sleep and Daytime Sleepiness in Postpartum Women 
PLoS ONE  2014;9(7):e103513.
Sleep disruption strongly influences daytime functioning; resultant sleepiness is recognised as a contributing risk-factor for individuals performing critical and dangerous tasks. While the relationship between sleep and sleepiness has been heavily investigated in the vulnerable sub-populations of shift workers and patients with sleep disorders, postpartum women have been comparatively overlooked. Thirty-three healthy, postpartum women recorded every episode of sleep and wake each day during postpartum weeks 6, 12 and 18. Although repeated measures analysis revealed there was no significant difference in the amount of nocturnal sleep and frequency of night-time wakings, there was a significant reduction in sleep disruption, due to fewer minutes of wake after sleep onset. Subjective sleepiness was measured each day using the Karolinska Sleepiness Scale; at the two earlier time points this was significantly correlated with sleep quality but not to sleep quantity. Epworth Sleepiness Scores significantly reduced over time; however, during week 18 over 50% of participants were still experiencing excessive daytime sleepiness (Epworth Sleepiness Score ≥12). Results have implications for health care providers and policy makers. Health care providers designing interventions to address sleepiness in new mothers should take into account the dynamic changes to sleep and sleepiness during this initial postpartum period. Policy makers developing regulations for parental leave entitlements should take into consideration the high prevalence of excessive daytime sleepiness experienced by new mothers, ensuring enough opportunity for daytime sleepiness to diminish to a manageable level prior to reengagement in the workforce.
PMCID: PMC4117520  PMID: 25078950
15.  Inter-Individual Differences in Neurobehavioural Impairment following Sleep Restriction Are Associated with Circadian Rhythm Phase 
PLoS ONE  2015;10(6):e0128273.
Although sleep restriction is associated with decrements in daytime alertness and neurobehavioural performance, there are considerable inter-individual differences in the degree of impairment. This study examined the effects of short-term sleep restriction on neurobehavioural performance and sleepiness, and the associations between individual differences in impairments and circadian rhythm phase. Healthy adults (n = 43; 22 M) aged 22.5 ± 3.1 (mean ± SD) years maintained a regular 8:16 h sleep:wake routine for at least three weeks prior to laboratory admission. Sleep opportunity was restricted to 5 hours time-in-bed at home the night before admission and 3 hours time-in-bed in the laboratory, aligned by wake time. Hourly saliva samples were collected from 5.5 h before until 5 h after the pre-laboratory scheduled bedtime to assess dim light melatonin onset (DLMO) as a marker of circadian phase. Participants completed a 10-min auditory Psychomotor Vigilance Task (PVT), the Karolinska Sleepiness Scale (KSS) and had slow eye movements (SEM) measured by electrooculography two hours after waking. We observed substantial inter-individual variability in neurobehavioural performance, particularly in the number of PVT lapses. Increased PVT lapses (r = -0.468, p < 0.01), greater sleepiness (r = 0.510, p < 0.0001), and more slow eye movements (r = 0.375, p = 0.022) were significantly associated with later DLMO, consistent with participants waking at an earlier circadian phase. When the difference between DLMO and sleep onset was less than 2 hours, individuals were significantly more likely to have at least three attentional lapses the following morning. This study demonstrates that the phase of an individual’s circadian system is an important variable in predicting the degree of neurobehavioural performance impairment in the hours after waking following sleep restriction, and confirms that other factors influencing performance decrements require further investigation.
PMCID: PMC4456409  PMID: 26043207
16.  A description of sleep behaviour in healthy late pregnancy, and the accuracy of self-reports 
The importance of maternal sleep and its contribution to maternal and fetal health during pregnancy is increasingly being recognised. However, the ability to accurately recall sleep practices during pregnancy has been questioned. The aim of this study is to test the accuracy of recall of normal sleep practices in late pregnancy.
Thirty healthy women between 35 and 38 weeks of gestation underwent level III respiratory polysomnography (PSG) with infrared digital video recordings in their own homes. Data regarding sleep positions, number of times getting out of bed during the night and respiratory measures were collected. A sleep questionnaire was administered the morning after the recorded sleep. Continuous data were assessed using Spearman’s Rho and Bland-Altman. Cohen’s Kappa was used to assess recall in the categorical variables.
Two-thirds of participants went to sleep on their left side. There was good agreement in sleep onset position between video and questionnaire data (Kappa 0.52), however the there was poor agreement on position on wakening (Kappa 0.24). The number of times getting out of bed during the night was accurately recalled (Kappa 0.65). Twenty five out of 30 participants snored as recorded by PSG. Questionnaire data was inaccurate for this measure. Bland-Altman plots demonstrated acceptable agreement between video and questionnaire data for estimated sleep duration, but not the time taken to fall asleep (sleep latency). One participant had mild obstructive sleep apnoea and another probable high upper airways resistance.
Sleep onset position, sleep duration and the number of times getting out of bed during the night were accurately recalled, but sleep latency and sleep position on waking were not. This study identifies the sleep variables that can be accurately obtained by questionnaire and those that cannot.
Electronic supplementary material
The online version of this article (doi:10.1186/s12884-016-0905-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4870756  PMID: 27194093
Pregnancy; Self-report; Questionnaire; Sleep study; Polysomnography
17.  Association between maternal sleep practices and risk of late stillbirth: a case-control study 
Objectives To determine whether snoring, sleep position, and other sleep practices in pregnant women are associated with risk of late stillbirth.
Design Prospective population based case-control study.
Setting Auckland, New Zealand
Participants Cases: 155 women with a singleton late stillbirth (≥28 weeks’ gestation) without congenital abnormality born between July 2006 and June 2009 and booked to deliver in Auckland. Controls: 310 women with single ongoing pregnancies and gestation matched to that at which the stillbirth occurred. Multivariable logistic regression adjusted for known confounding factors.
Main outcome measure Maternal snoring, daytime sleepiness (measured with the Epworth sleepiness scale), and sleep position at the time of going to sleep and on waking (left side, right side, back, and other).
Results The prevalence of late stillbirth in this study was 3.09/1000 births. No relation was found between snoring or daytime sleepiness and risk of late stillbirth. However, women who slept on their back or on their right side on the previous night (before stillbirth or interview) were more likely to experience a late stillbirth compared with women who slept on their left side (adjusted odds ratio for back sleeping 2.54 (95% CI 1.04 to 6.18), and for right side sleeping 1.74 (0.98 to 3.01)). The absolute risk of late stillbirth for women who went to sleep on their left was 1.96/1000 and was 3.93/1000 for women who did not go to sleep on their left. Women who got up to go to the toilet once or less on the last night were more likely to experience a late stillbirth compared with women who got up more frequently (adjusted odds ratio 2.28 (1.40 to 3.71)). Women who regularly slept during the day in the previous month were also more likely to experience a late stillbirth than those who did not (2.04 (1.26 to 3.27)).
Conclusions This is the first study to report maternal sleep related practices as risk factors for stillbirth, and these findings require urgent confirmation in further studies.
PMCID: PMC3114953  PMID: 21673002
18.  Association between maternal sleep practices and risk of late stillbirth: a case-control study 
The BMJ  2011;342:d3403.
Objectives To determine whether snoring, sleep position, and other sleep practices in pregnant women are associated with risk of late stillbirth.
Design Prospective population based case-control study.
Setting Auckland, New Zealand
Participants Cases: 155 women with a singleton late stillbirth (≥28 weeks’ gestation) without congenital abnormality born between July 2006 and June 2009 and booked to deliver in Auckland. Controls: 310 women with single ongoing pregnancies and gestation matched to that at which the stillbirth occurred. Multivariable logistic regression adjusted for known confounding factors.
Main outcome measure Maternal snoring, daytime sleepiness (measured with the Epworth sleepiness scale), and sleep position at the time of going to sleep and on waking (left side, right side, back, and other).
Results The prevalence of late stillbirth in this study was 3.09/1000 births. No relation was found between snoring or daytime sleepiness and risk of late stillbirth. However, women who slept on their back or on their right side on the previous night (before stillbirth or interview) were more likely to experience a late stillbirth compared with women who slept on their left side (adjusted odds ratio for back sleeping 2.54 (95% CI 1.04 to 6.18), and for right side sleeping 1.74 (0.98 to 3.01)). The absolute risk of late stillbirth for women who went to sleep on their left was 1.96/1000 and was 3.93/1000 for women who did not go to sleep on their left. Women who got up to go to the toilet once or less on the last night were more likely to experience a late stillbirth compared with women who got up more frequently (adjusted odds ratio 2.28 (1.40 to 3.71)). Women who regularly slept during the day in the previous month were also more likely to experience a late stillbirth than those who did not (2.04 (1.26 to 3.27)).
Conclusions This is the first study to report maternal sleep related practices as risk factors for stillbirth, and these findings require urgent confirmation in further studies.
PMCID: PMC3114953  PMID: 21673002
19.  Nocturia, Sleep and Daytime Function in Stable Heart Failure 
Journal of Cardiac Failure  2012;18(7):569-575.
To evaluate nocturia severity and nocturia-related differences in sleep, daytime symptoms and functional performance among patients with stable heart failure (HF).
Method & Results
In this cross-sectional observational study we recruited 173 patients [M age = 60.3 ±16.8 years; n = 60 (35%) female; left ventricular ejection fraction M = 32 ±14.6] with stable chronic HF from HF disease management programs in the Northeastern United States. Participants reported nocturia and completed a Six Minute Walk test (6 MWT), one night of ambulatory polysomnography (PSG), and the Medical Outcomes Study SF 36, Epworth Sleepiness, Pittsburgh Sleep Quality Index, Multi-Dimensional Assessment of Fatigue, and the Centers for the Epidemiological Studies of Depression scales. Participants reported no (n = 30/17.3%), one or more (n = 87/50.2%), and three or more (n = 56/32.4%) nightly episodes of nocturia. There were decreases in sleep duration and efficiency, stages REM and 3–4 sleep, physical function, and 6 MWT distance; and increases in the percent wake after sleep onset, insomnia symptoms, fatigue and sleepiness across levels of nocturia severity.
Nocturia is common, severe, and closely associated with decrements in sleep and functional performance and increases in fatigue and sleepiness in patients with stable HF.
PMCID: PMC3389347  PMID: 22748491
heart failure; insomnia; nocturia; sleep; fatigue; physical function; quality of life
20.  Energy expenditure during sleep, sleep deprivation and sleep following sleep deprivation in adult humans 
The Journal of Physiology  2010;589(1):235-244.
Non-technical summary One of the proposed functions of sleep is to conserve energy. We determined the amount of energy conserved by sleep in humans, how much more energy is expended when missing a night of sleep, and how much energy is conserved during recovery sleep. Findings support the hypothesis that a function of sleep is to conserve energy in humans. Sleep deprivation increased energy expenditure indicating that maintaining wakefulness under bed-rest conditions is energetically costly. Recovery sleep after sleep deprivation reduced energy use compared to baseline sleep suggesting that human metabolic physiology has the capacity to make adjustments to respond to the energetic cost of sleep deprivation. The finding that sleep deprivation increases energy expenditure should not be interpreted that sleep deprivation is a safe or effective strategy for weight loss as other studies have shown that chronic sleep deprivation is associated with impaired cognition and weight gain.
Sleep has been proposed to be a physiological adaptation to conserve energy, but little research has examined this proposed function of sleep in humans. We quantified effects of sleep, sleep deprivation and recovery sleep on whole-body total daily energy expenditure (EE) and on EE during the habitual day and nighttime. We also determined effects of sleep stage during baseline and recovery sleep on EE. Seven healthy participants aged 22 ± 5 years (mean ±s.d.) maintained ∼8 h per night sleep schedules for 1 week before the study and consumed a weight-maintenance diet for 3 days prior to and during the laboratory protocol. Following a habituation night, subjects lived in a whole-room indirect calorimeter for 3 days. The first 24 h served as baseline – 16 h wakefulness, 8 h scheduled sleep – and this was followed by 40 h sleep deprivation and 8 h scheduled recovery sleep. Findings show that, compared to baseline, 24 h EE was significantly increased by ∼7% during the first 24 h of sleep deprivation and was significantly decreased by ∼5% during recovery, which included hours awake 25–40 and 8 h recovery sleep. During the night time, EE was significantly increased by ∼32% on the sleep deprivation night and significantly decreased by ∼4% during recovery sleep compared to baseline. Small differences in EE were observed among sleep stages, but wakefulness during the sleep episode was associated with increased energy expenditure. These findings provide support for the hypothesis that sleep conserves energy and that sleep deprivation increases total daily EE in humans.
PMCID: PMC3039272  PMID: 21059762
21.  Healthy Older Adults Better Tolerate Sleep Deprivation Than Young Adults 
To determine whether healthy aging is associated with increased sleepiness, and whether healthy older adults experience more sleepiness when acutely sleep deprived.
A 5-day inpatient circadian rhythm-sleep study consisting of 3 baseline nights, followed by an extended 26-hour wake episode in constant conditions.
Intensive Physiological Monitoring Unit, General Clinical Research Center, Brigham and Women’s Hospital.
37 healthy participants without medical, psychological, and sleep disorders: 26 young (7 women, 19 men; mean age 21.9 ± 3.3 years, range 18–29) and 11 “young-old” adults (3 women, 8 men; mean age 68.1 ± 3.6 years, range 65–76).
An extended 26-hour wake episode in constant conditions.
Electro-encephalographic-verified wakefulness, slow eye movements, sustained attention, subjective sleepiness.
Across the first 16 hours corresponding to the usual waking day, both groups rated themselves as alert, had similar levels of vigilance, and little evidence of sleepiness. As the wake episode continued, the older subjects were less impaired, showing faster reaction times, fewer performance lapses and attentional failures, and less frequent unintentional sleep episodes.
This small study suggests that excessive sleepiness is not normal in healthy “young-old” adults. Symptoms of excessive sleepiness in this population, including reliance on caffeine to maintain alertness, should be evaluated and treated. Further study is needed to determine whether increased daytime sleepiness in middle-old (75–84 years) and old-old (85+) adults is normal, or is instead associated with sleep restriction, undiagnosed sleep disorders, medication side effects, mood disorders, and/or other medical disorders that disrupt sleep.
PMCID: PMC3122254  PMID: 19460089
vigilance; circadian rhythm; neurobehavioral performance
22.  Perception versus polysomnographic assessment of sleep in CFS and non-fatigued control subjects: results from a population-based study 
BMC Neurology  2007;7:40.
Complaints of unrefreshing sleep are a prominent component of chronic fatigue syndrome (CFS); yet, polysomnographic studies have not consistently documented sleep abnormalities in CFS patients. We conducted this study to determine whether alterations in objective sleep characteristics are associated with subjective measures of poor sleep quality in persons with CFS.
We examined the relationship between perceived sleep quality and polysomnographic measures of nighttime and daytime sleep in 35 people with CFS and 40 non-fatigued control subjects, identified from the general population of Wichita, Kansas and defined by empiric criteria. Perceived sleep quality and daytime sleepiness were assessed using clinical sleep questionnaires. Objective sleep characteristics were assessed by nocturnal polysomnography and daytime multiple sleep latency testing.
Participants with CFS reported unrefreshing sleep and problems sleeping during the preceding month significantly more often than did non-fatigued controls. Participants with CFS also rated their quality of sleep during the overnight sleep study as significantly worse than did control subjects. Control subjects reported significantly longer sleep onset latency than latency to fall asleep as measured by PSG and MSLT. There were no significant differences in sleep pathology or architecture between subjects with CFS and control subjects.
People with CFS reported sleep problems significantly more often than control subjects. Yet, when measured these parameters and sleep architecture did not differ between the two subject groups. A unique finding requiring further study is that control, but not CFS subjects, significantly over reported sleep latency suggesting CFS subjects may have an increased appreciation of sleep behaviour that may contribute to their perception of sleep problems.
PMCID: PMC2231384  PMID: 18053240
23.  Unfair Treatment is associated with Poor Sleep in African American and Caucasian Adults: Pittsburgh SleepSCORE Project 
To test the association between self-reported unfair treatment and objective and self-reported sleep characteristics in African American and Caucasian adults.
Cross-sectional study of 97 African American and 113 Caucasian middle-aged adults.
Main Outcome Measures
Participants completed: a) two night in-home, polysomnography (PSG) sleep study, b) sleep diaries and actigraph assessments across nine days and nights, and c) self-report measures of sleep quality in the past month, and daytime sleepiness in the past two weeks.
Greater unfair treatment was associated with reports of poorer self-reported sleep quality and greater daytime sleepiness, shorter sleep duration and lower sleep efficiency as measured by actigraphy and PSG, and a smaller proportion of rapid eye movement (REM) sleep. Racial/ethnic differences were few. Exploratory analyses showed that nightly worry partially mediated the associations of unfair treatment with sleep quality, daytime sleepiness, sleep efficiency (actigraphy), and proportion of REM sleep.
Perceptions of unfair treatment are associated with sleep disturbances in both African American and Caucasian adults. Future studies are needed to identify the pathways that account for the association between unfair treatment and sleep.
PMCID: PMC3131074  PMID: 21553979
unfair treatment; discrimination; sleep disturbance; worry; race/ethnicity
24.  Increased sleep need and daytime sleepiness 6 months after traumatic brain injury: a prospective controlled clinical trial 
Brain  2015;138(3):726-735.
In a controlled, prospective, electrophysiological study, Imbach et al. demonstrate increased sleep need and excessive daytime sleepiness 6 months after traumatic brain injury. Sleep is more consolidated after brain trauma, and an increase in sleep need is associated with intracranial haemorrhage. Trauma patients underestimate their increased sleep need and sleepiness.
Post-traumatic sleep-wake disturbances are common after acute traumatic brain injury. Increased sleep need per 24 h and excessive daytime sleepiness are among the most prevalent post-traumatic sleep disorders and impair quality of life of trauma patients. Nevertheless, the relation between traumatic brain injury and sleep outcome, but also the link between post-traumatic sleep problems and clinical measures in the acute phase after traumatic brain injury has so far not been addressed in a controlled and prospective approach. We therefore performed a prospective controlled clinical study to examine (i) sleep-wake outcome after traumatic brain injury; and (ii) to screen for clinical and laboratory predictors of poor sleep-wake outcome after acute traumatic brain injury. Forty-two of 60 included patients with first-ever traumatic brain injury were available for follow-up examinations. Six months after trauma, the average sleep need per 24 h as assessed by actigraphy was markedly increased in patients as compared to controls (8.3 ± 1.1 h versus 7.1 ± 0.8 h, P < 0.0001). Objective daytime sleepiness was found in 57% of trauma patients and 19% of healthy subjects, and the average sleep latency in patients was reduced to 8.7 ± 4.6 min (12.1 ± 4.7 min in controls, P = 0.0009). Patients, but not controls, markedly underestimated both excessive sleep need and excessive daytime sleepiness when assessed only by subjective means, emphasizing the unreliability of self-assessment of increased sleep propensity in traumatic brain injury patients. At polysomnography, slow wave sleep after traumatic brain injury was more consolidated. The most important risk factor for developing increased sleep need after traumatic brain injury was the presence of an intracranial haemorrhage. In conclusion, we provide controlled and objective evidence for a direct relation between sleep-wake disturbances and traumatic brain injury, and for clinically significant underestimation of post-traumatic sleep-wake disturbances by trauma patients.
PMCID: PMC4408434  PMID: 25595147
traumatic brain injury; sleep; post-traumatic pleiosomnia; post-traumatic daytime sleepiness
25.  Comparison of Subjective and Objective Assessments of Sleep in Healthy Older Subjects Without Sleep Complaints 
Journal of sleep research  2009;18(2):254-263.
Older adults have reduced sleep quality compared to younger adults when sleeping at habitual times, and greater sleep disruption when their sleep is at adverse times. The purpose of this analysis was to investigate how subjective measures of sleep relate to objectively-recorded sleep in older subjects scheduled to sleep at all times of day. We analyzed data from 24 healthy older (55–74 years) subjects who took part in a 32-day inpatient study where polysomnography (PSG) was recorded each night and subjective sleep was assessed after each scheduled wake time. The study included baseline nights and a forced desynchrony (FD) protocol when the subjects lived on a 20-hr rest-activity schedule. Our post-sleep questionnaire both included quantitative and qualitative questions about the prior sleep. Under baseline and FD conditions, objective and subjective sleep latency were correlated, subjective sleep duration was related to slow wave sleep and wake after sleep onset, subjective sleep quality was related to Stage 1 and 2 sleep, and sleepiness and refreshment at wake time were related to duration of premature awakening. During FD, most measures of objective and subjective sleep varied with circadian phase, and many additional correlations between objective and subjective sleep were present. Our findings show that when sleeping at habitual times, these healthy older subjects did not perceive their generally poor sleep quality, but under FD conditions where sleep quality changed from day-to-day their subjective sleep ratings were more associated with their objective sleep.
PMCID: PMC2975570  PMID: 19645969
subjective sleep quality; PSG; aging; forced desynchrony; circadian rhythm

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