Facial features analyzed from 3D photographs could predict the likelihood of having obstructive sleep apnea


Facial features analyzed from 3D photographs could predict the likelihood of having obstructive sleep apnea, according to a study published in the April issue of the Journal of Clinical Sleep Medicine.

Using 3D photography, the study found that geodesic measurements – the shortest distance between two points on a curved surface – predicted with 89 percent accuracy which patients had sleep apnea.

Using traditional 2D linear measurements alone, the algorithm’s accuracy was 86 percent.

“This application of the technique used predetermined landmarks on the face and neck,” said principle investigator Peter Eastwood, who holds a doctorate in respiratory and sleep physiology and is the director of the Centre for Sleep Science at the University of Western Australia (UWA).

“Geodesic and linear distances between these landmarks were determined, and a linear discriminant algorithm was trained, tested and used to classify an individual as being at high or low risk of having obstructive sleep apnea.”

The study involved 300 individuals with varying severity levels of sleep apnea and 100 people without sleep apnea.

These individuals came from a local hospital and from the Raine Study, a longitudinal cohort study in Western Australia.

All underwent overnight sleep studies and took 3D photos with a craniofacial scanner system. Data were used to build a predictive algorithm that was tested on another patient set.

Eastwood worked with Syed Zulqarnain Gilani, a computer scientist at UWA to identify the facial features most commonly associated with sleep apnea as neck width and degree of retrusion of the lower jaw (retrognathia), but the study also uncovered other possible indicators.

“The data obtained from the present study indicate that other measurements such as width and length of the lower jaw, width of the face, and distance between the eyes also contribute to distinguishing individuals with and without OSA,” he said.

In a related commentary, also published in the April issue of JCSM, Drs. Ofer Jacobowitz and Stuart MacKay indicated that they see a bright future for 3D photography as a screening tool, potentially combined with data from a patient’s digital health tracker and health history.

“Certain wearable devices are already capable of measuring pulse oximetry and some provide oximetry variability analysis,” they wrote.

“Likewise, the home of tomorrow will likely incorporate sensors in the bedroom which may gather physiological sleep data using optical, acoustic, infrared, ultrasonographic or other means.”

According to Eastwood, existing studies show a genetic predisposition to sleep apnea, and facial structure is a significant component of such predisposition, leading researchers to seek an accessible, affordable method of screening based on facial characteristics.

Eastwood believes that 3D facial photography could represent the first, inexpensive, widely available screening tool for sleep apnea.

“OSA is a huge public health problem, and despite effective treatments being available, many with OSA are currently undiagnosed,” said Eastwood. “Therefore, simple, accurate screening tools are needed to predict those who have OSA.”

Epidemiology of obstructive sleep apnoea

The most prevalent form of sleep disordered breathing in industrialised societies is obstructive sleep apnoea (OSA) [1]. OSA is characterised by repetitive collapses (apnoeas) or near collapses (hypopnoeas) of the upper airway during sleep, resulting in intermittent hypoxaemia and increased sympathetic arousal.

When symptoms of daytime dysfunction and other neurological impairment are directly attributed to the apnoeas and hypopnoeas in sleep, the disorder is known as obstructive sleep apnoea/hypopnoea syndrome (OSAHS) [1–3]. The apnoea–hypopnoea index (AHI) can be used to assess severity of the sleep disorder when an electroencephalographic measure of sleep is available.

Daytime sleepiness is usually recorded by a thorough clinical history, but is also frequently recorded in both practice and in research studies using the Epworth Sleepiness Scale (ESS) [4]; a score of ≥11 out of 24 is considered consistent with excessive daytime sleepiness. Unfortunately, the ESS does not correlate well with objective measures of daytime sleepiness [5].

Thus, the epidemiology of OSA and OSAHS can vary significantly in the population depending on definitions used for the nocturnal breathing pauses and any resulting daytime sleepiness/impairment. Additionally, the prevalence of sleep disordered breathing will vary according to age and sex [1–3].

The most frequently cited study in respect of OSA and OSAHS prevalence in a mostly white, mid-American cohort of people demonstrated that 24% of males (n=325) and 9% of females (n=250) had an AHI ≥5 events·h−1 of sleep [6].

However, when sleepiness was factored in as causally related to the AHI, the prevalence fell to 4% in males and 2% in females. Several population prevalence studies since then have quoted mean prevalences of OSA of 27.3% in males (range 9–86%) and 22.5% in females (3.7–63.7%) and mean (range) prevalence of OSAHS of 6% (3–18%) in males and 4% (1–17%) in females [7, 8].

Consequently, and unsurprisingly, OSA/OSAHS has thus been considered a male disease, with male:female ratios ranging from 3:1 to 5:1 in the general population and from 8:1 to 10:1 in selected clinical populations [9]. Despite this, females now represent up to 40–50% of presentations at sleep clinics [10].

Clinical presentation
Failure to recognise the distinct clinical presentation and sex-specific differences in sleep studies may lead to underdiagnosis or misdiagnosis of OSA/OSAHS in females [11, 12].

Females are less likely to report snoring (males have higher snoring intensity by comparison [13]) or witnessed apnoeas. Females are more likely to complain of daytime fatigue, lack of energy, insomnia symptoms, morning headaches, mood disturbances and nightmares compared to males [11, 12].

This “atypical” clinical presentation at least partly explains the fact that female patients are diagnosed with OSA/OSAHS at older ages and with higher body mass index (BMI) than males [11, 12].

Females seem to have greater impairment of quality of life and higher healthcare expenditure compared to males with similar AHI levels [14–19]. In addition, females with OSA report a higher rate of impaired work performance, sick leave and divorce compared to females without OSA, identical in age and visceral fat mass; this kind of association has not been found among males [14–19].

OSA in females is associated with an increased risk of sickness absence compared to males with OSA, even 5 years versus 1 year prior to diagnosing OSA [20]. A prospective study of 74 543 cases of OSA from the Swedish Patient Register matched with 371 592 non-cases, demonstrated during a 5-year follow-up period a higher risk for disability pension among females with OSA compared to males with OSA [19].

Compared to males, OSA/OSAHS typically manifests in females as a lower AHI, shorter apnoeic episodes, lower proportion of supine OSA and clustering of apnoea during rapid eye movement (REM) sleep [11]. However, in females, the longest apnoeas are associated with a more severe oxygen desaturation [21].

Respiratory events during sleep are less frequently associated with complete upper airway collapse in females than in males [11]. However, despite less-severe OSA in terms of AHI, females are not less symptomatic compared to males, but report sleepiness at relatively low levels of AHI [22].

Therefore, especially in females, AHI alone is not a sufficient criterion for clinical severity of OSA. The severity should be specified with objective polysomnography (or cardiorespiratory polygraphy) findings (AHI/respiratory effort index plus flow-limitation) and subjective daytime sleepiness with functional disability. In females with low AHI, a continuous positive airway pressure (CPAP) trial should be symptom-driven [23, 24].

What might explain this apparent discrepancy between AHI and symptoms in females particularly? In females, upper airway obstruction often manifests as subcriterion events (snoring, flow limitation or prolonged partial upper airway obstruction) [25–28].

Arousals induce less ventilatory instability in females, thereby protecting them from OSA. Prolonged episodes of partial upper airway obstruction [25–28] typically appear in slow-wave sleep and are associated with increased carbon dioxide (CO2) levels [29–31]. Importantly, prolonged partial upper airway obstruction is far more common than “conventional” sleep apnoea in females [32]. Furthermore, hypothyroidism is more prevalent in females than in males, which per se may induce OSA.

Prolonged partial upper airway obstruction is related to increased respiratory resistance [33], which is characterised by increase in end-tidal CO2 [34] and transcutaneous CO2 [29, 30]. Prolonged partial obstruction with increased CO2 during sleep may contribute to a different symptom profile in females.

This is supported by the finding that in females, excessive daytime sleepiness and daytime fatigue associate with habitual snoring independent of AHI, age, obesity, smoking or sleep parameters [26]. Correction of prolonged flow limitation with CPAP treatment is associated with a higher attentiveness and a higher efficiency in normalising daytime vigilance than when eliminating only apnoea, hypopnoea and snoring [35].

Hypercapnia is associated with electroencephalogram (EEG) slowing and daytime sleepiness in OSA [36], and CPAP treatment corrects the EEG slowing and alleviates daytime sleepiness [37].

Pathophysiology of OSA in females

The different OSA prevalence between males and females has generated interest in sex-related aspects of OSA pathophysiology. The topic is complex, encompassing anatomical and physiological features of the upper airways, the modulating effects of sex hormones on control of breathing, and sex-dependent features of fat distribution in obesity [66].

Animal models have been developed, allowing to assess sex-related differences in sleep structure [67] and acquisition of phenotypes during early development. Moreover, recent work in animal models focused on the complex action of sex steroids, not only in control of breathing, but also regarding the protective action of oestrogen against oxidative stress [68].

Anatomy of the upper airways

Upper airway dimensions are normally larger in males than in females, but similar when normalised for body size [69]. Smaller dimensions should promote collapsibility of the airways in females compared to males, but this is not the case [70].

Upper airway length was found to be higher in males than in females, and associated with higher airway collapsibility [70]. Differences between sexes in airway length are not present in the prepubertal period, but become evident in post-pubertal girls and boys, suggesting a major effect of sex hormones [71]. Upper airway length correlates with OSA severity assessed as AHI [72], and is modified by ageing, with lengthening of upper airways especially in females [73], possibly secondary to increased laxity of soft tissues [74].

Physiology of the upper airways

In OSA patients, upper airway collapsibility under passive conditions (critical closing pressure, Pcrit) was consistently shown to be lower in females than in males [75, 76], while no sex-related difference was found in respiratory stability during sleep, evaluated as loop gain [75].

However, data on the relationship between adiposity, assessed as BMI (kg·m−2), and Pcrit differed between studies, since the slope of the relationship was similar in males and females in one study [75], and was markedly lower in females compared to males in another study of a larger sample [76].

The higher Pcrit in males is believed to be secondary to anatomical factors, i.e. longer upper airways as previously discussed, and differences in fat distribution, since females, especially in the pre-menopausal phase, show a peripheral rather than the central pattern distribution typical of males, with lower fat deposition around the upper airways and a smaller neck circumference for a similar BMI [77].

Ventilation during sleep is similarly regulated in healthy males and females [78, 79]. However, ventilation and upper airway function in females are physiologically modulated by sex hormones. Progesterone stimulates ventilation especially when associated with oestrogen [80].

Upper airway dilator muscle function at baseline and during application of an inspiratory load during wakefulness increased in normal females during the luteal compared to the follicular phase [81].

In females without OSA, upper airway resistance during sleep was lower in the luteal compared to the follicular phase, in agreement with a “protective” effect of progesterone [82]. However, the response to inspiratory muscle loading during sleep was not accompanied by increased upper airway dilator muscle activity in normal females compared to normal males [83].

More recent data showed that compensatory responses to prolonged upper airway obstruction during non-REM sleep were more effective in obese females than in obese males [84].

Several factors may account for such differences, including a lower airflow demand secondary to lower metabolic rate in females, differences in ventilatory timing responses to obstructed upper airways [85], lower chemoresponsiveness [86] or ventilatory response to arousal [87, 88].

In addition, experimental studies in rodents suggest that females are more resistant to the detrimental effects of chronic intermittent hypoxia, an effect possibly mediated by oestrogens [89, 90]. Although some controversies still exist due to species-dependent differences [91], recent human studies suggested a role of leptin in the modulation of neural compensatory mechanisms at the upper airway level [92].

Since plasma levels of leptin are higher in females, leptin represents a potential protective factor in obese females against upper airway obstruction, possibly acting at multiple levels. The therapeutic use of intranasal leptin has been successfully tested in obese animals [93].

Recent data indicate that expression of oestrogen receptor-α is decreased in the upper airway muscles of males with OSA compared to controls, possibly contributing to changes in muscle fibre types in OSA. However, no similar data in females have been collected thus far [94].

In summary, upper airways in females are less collapsible and more stable during sleep than in males, through a variety of mechanisms which involve sex hormones but are not limited to them. More efficient active responses of upper airways during respiratory events, different body fat distribution and lower instability of respiratory drive after arousals probably contribute to the lower susceptibility to respiratory events during non-REM sleep in females.

Currently, there are large efforts to physiologically phenotype OSA patients in order to personalise treatment [95]. To date, the question whether specific physiological phenotypes occur in females with OSA remains unanswered, and deserves further study.

The role of hormone replacement therapy

Approximately 25 years ago, sex steroid-based hormone replacement therapy (HRT) was no longer prescribed worldwide because of the negative results of randomised controlled trials showing that oestrogen did not confer protection against cardiovascular disease and might increase the risk of breast cancer [96].

More recently, a protective effect of oestrogen-based HRT has emerged, especially in females starting treatment early in the perimenopausal period, whereas treatment initiation at a later time did not confer any benefit [96].

As far as sleep disordered breathing is concerned, the possible protective role of HRT in post-menopausal females with OSA was assessed in studies involving small numbers of subjects.

In females without symptoms of sleep disordered breathing, respiratory events during sleep were few and unaffected by oestrogen replacement therapy [97], while treatment with medroxyprogesterone acetate (MPA) improved the inspiratory flow pattern in females with airflow limitation during sleep [49, 98].

In females with OSA, the effects of HRT have been controversial. One study found no effect of MPA 30 mg·day−1 [99]. Another study reported improved breathing during sleep after progestin and oestrogen HRT in females with mild OSAS in post-surgical menopause [100]. Cistulli et al. [101] found a decrease in AHI in REM sleep after HRT, while another study reported decreased AHI after treatment with oestrogens in post-menopausal females with moderate OSAS [102].

More recently, a randomised controlled trial in post-menopausal females with OSA treated with MPA after discontinuing CPAP for a few weeks showed no protective effects of MPA against respiratory events during sleep [103].

Metabolic changes

Females have a different fat distribution pattern compared to males [104]. Adipose tissue tends to be peripherally distributed in females, and centrally distributed in males, with a higher percentage of visceral fat in males compared to females with a similar BMI.

Such differences reflect a role of sex hormones during the fertile age [105], tending to disappear after the menopause, and may influence the prevalence and severity of OSA in females. It has long been known that females are usually more obese than males for a similar level of OSA severity and OSA can be predicted by visceral abdominal fat in males, and by peripheral and total fat in females [106–109].

The metabolic syndrome (MetS), a cluster of risk factors for visceral obesity and insulin resistance, is often associated with OSA in both sexes [110]. In patients with MetS and OSA, the anthropometric markers of obesity appear to be similar in males and females [111].

Finally, a recent study in young morbidly obese females awaiting bariatric surgery found that the waist-to-hip ratio was the best single predictor of AHI, even though it accounted for only 20% of total variance [112]. Therefore, menopausal status and degree of obesity interact variably in determining adipose tissue distribution and metabolic variables in females, and probably affect OSA prevalence.

The literature on OSA-associated metabolic changes does not provide satisfactory data to explore whether females show particular metabolic changes compared to males. This reflects the predominance of males in patient cohorts, and the fact that data analysis is usually adjusted for age, sex and BMI, which are the variables of interest in studies on OSA according to sex.

Conversely, studies in females indicate a similar relationship between altered glucose metabolism and OSA severity as in males [113]. Females show a high frequency of respiratory events exclusively in REM sleep [114].

In diabetic patients, derangement in glycaemic control was associated only with AHI in REM, possibly due to the increased sympathetic activity typical of this sleep phase [115].

According to these data, females may be at relatively higher risk of OSA-associated glucose disturbances compared to males, despite an overall AHI which is lower than in males. To date, no study has tested such a hypothesis. In relatively young (mean age 37 years), overweight/obese subjects without comorbidities other than well-controlled hypertension or hypothyroidism, insulin resistance was documented in males, but not in females with OSA [44], in agreement with the more favourable metabolic pattern associated with peripheral distribution of adipose tissue.

In summary, knowledge on whether metabolic aspects of OSA show differences between males and females is still rather limited. Sex-related differences in adipose tissue distribution are well known, and are probably involved in both upper airway function and metabolism. Such differences tend to disappear after menopause.



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