Ethnicity and obstructive sleep apnoea

Sleep Medicine Reviews (2005) 9, 419–436

www.elsevier.com/locate/smrv

CLINICAL REVIEW

Ethnicity and obstructive sleep apnoea Anna Tessa C. Villaneuvaa,b, Peter R. Buchanana,c,*, Brendon J. Yeea, Ronald R. Grunsteina a

Sleep Research Group, Woolcock Institute of Medical Research, University of Sydney, and Centre for Respiratory Failure and Sleep Disorders, Royal Prince Alfred Hospital, Sydney, Australia b Centre for Snoring and Sleep Disorders, The Medical City, Manila, Philippines c Queensland Sleep Disorders Unit, Mater Misericordiae Hospital Townsville, Australia

KEYWORDS Obstructive sleep apnoea; Ethnicity; Prevalence; Obesity; Cephalometry; Craniofacial structure; Genetics; Phenotypes; Ventilatory control

Summary There is a scarcity of adult prevalence studies of OSA outside the Caucasian populations of North America, Europe and Australia, and comparisons have been complicated by methodological differences in sleep study settings, respiratory events definition, measured risk factors and clinical outcomes, and the lack of objective parameters for the measurement of ethnicity itself. Comparing studies with the same methodological design and respiratory events definition, recent largescale prevalence studies from Hong Kong, Korea and India show similar OSA rates to populations of mainly Caucasian composition. OSA is a very complex disorder determined by several phenotypes such as obesity, craniofacial structure and abnormalities in neuromuscular and ventilatory control. Genetics may partially explain some of the ethnic clustering of these phenotypes, modulated by cultural and environmental factors. The exact contribution of these component phenotypes to overall OSA risk will be determined by their varying prevalence and relative risk conferred across ethnic groups. For lesser degrees of obesity, Asians are at risk for a more severe degree of illness compared with Caucasians. Inter-ethnic studies suggests that African–American ethnicity may also be a significant risk factor for OSA. The increased prevalences of OSA among American Indians and Hispanic adults, and increased severity among Pacific Islanders and Maoris, were mainly explained by increased obesity parameters. Most cephalometric studies have largely been conducted without specific regard to ethnicity and comparisons of findings across studies have been mainly limited by differences in sampling methods and the varying selection and definition of measured cephalometric variables. The limited number of studies with inter-ethnic comparative data suggest cephalometric variables and their degree of contribution to OSA vary across ethnic groups. Q 2005 Elsevier Ltd. All rights reserved.

* Corresponding author. Address: Department of Respiratory & Sleep Medicine, Level 11, Royal Prince Alfred Hospital, Missenden Road, Camperdown, Sydney, NSW 2050, Australia. Tel.: C61 295156324; fax: C61 295158196. E-mail address: [email protected] (P.R. Buchanan).

Introduction Obstructive sleep apnoea (OSA) is a disorder characterized by repetitive episodes of complete or partial upper airway obstruction during sleep,

1087-0792/$ - see front matter Q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.smrv.2005.04.005

420 often associated with hypoxemia, increased breathing effort and arousals. OSA has a range of deleterious consequences that include unrefreshing sleep and excessive daytime sleepiness, neurocognitive impairment, and cardiovascular morbidity.1–7 OSA has been increasingly recognized over many years as an important health issue with major clinical and public health implications.8,9 The clinical syndrome is typically referred to as OSAS (OSA plus daytime sleepiness) or more recently modified to OSAHS, where H introduces hypopnoea into the acronym.10 The most commonly quoted estimate of prevalence of OSAS derives from a study of middle-aged public servants from Wisconsin, USA: 4% in males, 2% in females.11 The ethnicity of the Wisconsin Sleep Cohort was overwhelmingly Caucasian. This prevalence gives an indication of the minimal size of the health problem associated with sleep apnoea. Documented risk factors for OSA include increasing age, male gender, obesity, craniofacial structure, ventilatory control dysfunction, and there is also some evidence for other risk factors including alcohol and other drugs, and both active and passive smoking. Ethnicity is also suggested as an important associated indicator of OSA risk and/or severity.12–16 The major purpose of this review will be to consider the ethnic aspects of obstructive sleep apnoea.

Ethnicity and health The definition of ethnicity or of an ethnic group in medical literature is not always clear, but would generally pertain to a group of individuals sharing a common racial and/or cultural background.17 A very broad connotation of race separates just three categories, i.e. African, Caucasian and Mongoloid (sic), but this limited classification can be criticised on numerous grounds. Mixing of the human genetic pool has long occurred in developed countries, and in previously colonized regions of the world particularly, blurring assumed ethnic/racial separations. In USA the contemporary national classification of ethnic groups includes Hispanics, Blacks not Hispanic (African–Americans), Whites not Hispanic (European–Americans), Asian/Pacific Islanders and American Indian/Alaska Natives. A national descriptor is not necessarily an ethnic one, at least not uniformly so, e.g. an Australian could have any number of ethnic qualifiers, i.e. Aboriginal Australian, Anglo-Celt, Italian, Turkish, Lebanese, Chinese, etc. Furthermore such national descriptors themselves may well hide a variance of ethnic

A.T.C. Villaneuva et al. content, even in the country/nation of origin of migrating populations. There may be more genetic variation among individuals within a so defined ethnic group than can be found between ethnic groups.18 Systematic attempts to define ethnicity in any individual or group, based for example on sophisticated genetic techniques such as whole genomic analysis, would be problematic, and the fact is most reports of ethnic groups in medical and epidemiological studies published to date rely on the assumptions of subjects themselves, or the observations and assumptions of the author(s) of the study. In one study dealing with ethnic aspects of OSA the ethnic classification of subjects was a two-stage process, with self-reporting followed by three-member majority panel classification.19 The assumptions entailed in ethnic classification are likely to be generally valid, but remain assumptions nonetheless, and are likely to have greater validity when applied in more isolated (geographically, culturally, etc.) living regions, than in obviously multiracial or multiethnic societies such as exist in many developed and developing countries. Despite the above and other reservations, ethnicity and racial classification systems, imperfect though they may be, continue to be widely employed by governments and other bodies for statistical analyses of populations. Importantly, ethnicity is used by medical and epidemiological researchers for the purpose of learning about disease distributions, etc. and by those administering health care systems for planning of health funding.

Prevalence of OSA worldwide Adult prevalence Previously published reviews of OSA epidemiology have largely described prevalences from studies in predominantly Caucasian populations. A 1996 review20 included 12 prevalence studies, which varied considerably in the methods used, particularly systematic use or not of polysomnography (PSG) as the arbiter of OSA, the definitional criteria for OSA, geographical location and gender inclusiveness. Estimated whole population prevalences varied between 0.3 and 15%, although the authors went on to reanalyse some studies and argued therefrom that the wide variation of reported prevalences in this review paper were in fact more apparent than real. They concluded that in males the most likely correct figure for OSAS prevalence lay between 1 and 5%. All these studies

Ethnicity and obstructive sleep apnoea

421

were looking at populations in Europe (including the United Kingdom and Scandinavia), North America and Australia, and one study from Israel. Most likely the very great majority of study subjects were Caucasian, though that assumption may be less soundly based in study populations from multiracial societies like those in USA. A further review looked at 10 two-staged prevalence studies, each having a screening procedure usually but not exclusively questionnaire-based, followed by selective PSG and measurements of AHI (apnoea hypopnoea index) or AI (apnoea index) and using for its purposes a cut-off abnormal AHI/AI of O5/h, or O10/h.21 Again, the balance of these studies was of Caucasian populations in Europe or North America. Reported OSAS prevalences ranged from 0.3 to 4.7%. In a select comparison of a further three studies which had used similar design and methodology, but in this case compared OSA prevalence (rather than prevalence of OSAS), and for an AHI cut-off of R5/h, OSA prevalence ranged from 17 to 26% in men, and 9 to 28% in women.9 These authors concluded from reviewing these and other studies that in the populations studied the likely burden of OSAS was about 5%

of the adult population and furthermore that a larger proportion, perhaps 7–20%, had mild– moderate OSA. Within the last few years some large-scale prevalence studies from Asia have become available. These studies were from Hong Kong, India and Korea and also used a two-stage design method with complete PSG done either in the subject’s home or in-lab. When compared with Caucasian studies11,22–27 with similar methodological designs and using similar definitions and cut-offs for sleep disordered breathing, these studies showed rates which were comparable to Caucasian prevalences (see Table 1). Conservative estimates from middleaged Hong Kong residents showed an OSAS prevalence of 4.1% in males and 2.1% in females.28,29 From Mumbai, there is a reported prevalence of OSA of 19.5%, and OSAS prevalence of 7.5%, using AHI cut-off of R5/h, in a study involving middleaged Indian males.30 Other researchers have described OSAS prevalences of 4.2% (males) and 3.5% (females) in a Korean population31 using the same methodology. From population-based cohort and family studies, the OSA prevalence of African–Americans in north America does not differ substantially in

Table 1 Selected adult OSAS prevalences measured by PSG across 4 continents (respiratory disturbance index, RDIZAHI, unless otherwise indicated). Selected OSAS prevalences worldwide Settting

Males RDI O5/h CEDS (%)

Females RDI O5/h CEDS (%)

602

Lab

4

2

40–65

294

Home

3a

n/a

Caucasian

30–69

61

Lab

1.3

n/a

Caucasian

40–59

35

Lab

n/a

2.5

Caucasian

30–70

555

Lab

?O3.4b

?O3.0b

USA/ Pennsylvania

?Caucasian

20–100 1741

Lab

?O3.9b

?O1.2b

Hong Kong

Asian Chinese Asian Indian Asian Korean

30–60

259

Lab

4.1

2.1

35–65

250

Home

7.5

n/a

40–69

457

Lab (320) Home (137)

4.5

3.2

Author, year

Country/region

Ethnic group

Age range (yrs)

Young et al. (1993)11 Bearpark et al. (1993)22 Gislason et al. (1988)23 Gislason et al. (1993)24 Duran et al. (2001)27 Bixler et al. (1998, 2001)25,

USA/Wisconcin

Caucasian

30–60

Australia/Western Australia Sweden/Uppsala

Caucasian

Iceland/ Reykjavik Spain/Basque

Number (PSG)

26

Ip et al. (2001, 2004)28,29 Udawaida et al. (2004)30 Kim et al. (2004)31

a a

India/Mumbai Korea/Ansan

RDI in this study was ODI4, oxygen desaturation index 4%; RDI of O10 prevalence figures, assuming greater prevalence if RDI O5 had been used.

422 the middle-aged from that in Caucasian North Americans,15,32 though some studies suggest that in elderly African–Americans OSA may be more severe14 and that in younger African–Americans (! 25 years of age) it is more prevalent, in addition to being more severe.15 Other studies12,33 have used questionnaires eliciting key OSA symptoms, anthropometrics and measures of co-morbidity (e.g. systemic hypertension), but importantly without objective measure such as PSG. These findings defined a prevalence of 2.1–4.9% of sleep breathing-related disorder (sic) in a mixed-race Singaporean population, and with increased odds ratio in Indian versus Chinese subjects. Hong Kong Chinese university students have been shown to have PSG-defined OSAS prevalence of 2.3%.34 In summary, in well designed studies in Europe, North America, Asia and Australia adult prevalence figures for OSAS have been remarkably consistent with a range of 3–7.5% in males and 2–3% in females. This near-uniformity of prevalences across various ethnic groups belies a non-uniformity of relative importance of attributable risk factors.

Prevalence in children The selected prevalence studies in Table 1 apply to mainly middle-aged, and some to older, subjects and do not address prevalence levels in children, though it is clinically recognized that OSA can affect those in the youngest age ranges. As in adults, studies of OSA in children have also varied widely in patient age inclusion, methods of measurement and on required symptoms and objective criteria for OSA(S) definition. The limited normative data on children and the resulting lack of consensus and standard criteria for the diagnosis of OSAS have made prevalence estimates in children more problematic.9,35 Of those studies in North America and Europe which have reported on objectively measured OSAS prevalence, rates ranged from 0.77 to 2.9% among children less than 12 years of age.36–39 Thai children aged 6–13 years have an estimated OSAS prevalence of 0.69% which is comparable to these western figures.40 Subjective reports on habitual snoring from this cohort and from 2 other Asian studies done in Hong Kong and Korea were higher and ranged from 8.5 to 14.5% in older children (O6 years old) and adolescents.40–42 Habitual snoring data from studies of children O5 years of age in western countries have varied similarly across studies from 5.6 to 14.8%.43–46 For comparison, studies of children !6 years of age in Europe

A.T.C. Villaneuva et al. and North America have documented an even wider range of frequent snoring at 3–38%.36,37,47–49 As stated earlier there is some evidence for a greater prevalence of OSA in younger African– Americans 15,50 compared to Caucasians. This increased predisposition to sleep disordered breathing among African–American children was also shown in a follow-up study of the same cohort focusing on subjects 2–18 years of age and in another study of children 8–11 years of age.39,50 As with their elders,14 there are findings to suggest that African–American children (!18 years of age) are susceptible to more severe OSA-related desaturation than their Caucasian or Hispanic counterparts51 and that these differences persist when controlled for body mass index (BMI).

Ethnicity as an OSA risk factor Genetics, culture, environment (incorporating socioeconomic status) and development may all influence separately or in various combinations some of the recognized OSA risk factors. In addition, these components to a greater or lesser degree inform the construct of ethnicity which itself has been identified as a separate OSA risk factor. This complex amalgam of influences makes analysis of the contribution of ethnicity to OSA problematic (Fig. 1).

Cultural and environmental influence Symptom reporting and perception: ethnic implications Inter-ethnic difference in reporting of OSA-related symptoms may be a complicating factor in many epidemiologic studies. In 1118 older residents of

Genetics/Race ETHNICITY

Environment/Development

Culture

Figure 1 Venn diagram of important components related to ethnicity.

Ethnicity and obstructive sleep apnoea New York stratified according to ethnic grouping, the strongest ethnic predictor of reported sleep disturbance was with immigrant European–Americans.52 In another study of 3976 elderly adults, Caucasian grouping was similarly associated with more sleep complaints relating to insomnia compared with African–Americans even after adjustments for depression and associated comorbidities.53 In a population-based study from New Zealand using stratified random sampling, daytime sleepiness in 5441 participants as measured by mean Epworth Sleepiness Scale (ESS) score was notably higher among Maori participants compared to non-Maori, with the former also more likely to have an ESS score O10.54 Minority ethnic status was also a significant risk factor for sleep disturbance in a survey of multi-ethnic Texan adolescents although the parameters studied, insomnia and hypersomnia, are uncertain surrogates for OSA.55 Since these studies however provided no objective measure of sleep quality, it is unclear how much of these findings are reflective of an existing sleep disturbance, including OSA, and how much is attributable to culturally influenced differences in perception, acceptance and threshold for reporting of sleep concerns within these groups. Patients perceptions and ways of reporting sleep symptoms may be affected by the culture and level of education prevalent in these ethnic groups. Comparisons of questionnaire-based subjective symptoms across groups may not be reflective of the actual variation in sleep disturbance when measured objectively. Among Asian and Caucasian adult patients matched for age, sex and BMI there was no significant difference in the severity of reported OSA symptoms, yet the Asian patients were found to have more severe OSA as measured by a higher respiratory disturbance index and lower minimum oxygen saturation.16 In such studies which use clinical populations, referral bias would always be a consideration. It may be that through cultural influence or because of the limitations set by the economic conditions in a particular area, Asians tolerate a more severe degree of symptoms and for a longer duration of time before seeking medical consultation. In the Sleep Heart Health Study, American Indian women were also more likely to report breathing pauses in sleep than their white counterparts, but PSG data in a subset of subjects suggested that the association between this questionnaire-reported symptom and objective documentation of OSA was relatively weak.56 This differences between objective and subjective measures of sleep is even more complicated in children. Prevalence in young children is usually

423 from parental report. This adds another layer of complication which may increase interpretational bias. In a study of 5-year old children to assess the prevalence of OSA symptoms and their relation to sleepiness and problem behaviour, there were ethnic differences in labelling sleep-related noises.57 In this study Caucasian parents were less likely to report that their children snore and more likely to report loud noisy breathing compared to parents of African–American, Hispanic, or Asian children. In the TUCASA study, Hispanic children aged 4–11 years were described by parental report as having more snoring, excessive daytime sleepiness, witnessed apnoeas and learning problems than their white counterparts.58 Culturally and perhaps economically influenced sleeping arrangements, such as room and bed sharing, which were found to be more prevalent in Asian and African– American families,59–61 may also contribute to the inter-ethnic variability of parental awareness and frequency of reporting of sleep disturbance in children. If progression to objective measurement of sleep disturbance, such as by PSG, is based on responses to key indicator questionnaire-based inquiry, e.g. ‘do you/does your child snore’, whether for epidemiological, other research or clinical reasons, then account needs to be taken of such inter-ethnic symptom reporting discrimination. Findings such as from the Sleep Heart Health Study that frequent snoring was reported more in Hispanic men and women and black women, than in their white counterparts, after adjustment for BMI and other factors56 might need to be interpreted in light of such ethnic differences in symptom reporting. Socioeconomic status The complex interaction between race and socioeconomic status may also confound the analysis of the relationship of OSA and ethnicity. One study used school performance in children as a health outcome measure of OSA and demonstrated that any association between African–American ethnicity or OSA with poor performance measures was rendered non-significant after adjustments for socioeconomic status. The authors conjectured that this effect was probably mediated through obesity, and that in turn dietary differences, different activity levels, differing access to health care and levels of health awareness contribute to these variations.62 In contrast, another study on socioeconomically disadvantaged preschool children of both ethnic groups showed there were significantly more African–Americans at risk for sleep disordered breathing as measured by snoring,

424 and that this difference was unexplained after controlling for socioeconomic status.63 Site of testing effects and sleep architecture Environmental effects on sleep physiology is demonstrated in ‘site of testing effects’ as measured by PSG. In a study among 24 black and 27 white healthy subjects polysomnography was monitored in a laboratory environment followed a few weeks later by a sleep study in the patients’ homes.64 After adjustments for RDI, blacks were found to have less slow wave sleep in both sleep study locations. Interestingly, whites had significantly more slow wave sleep in the hospital than they did at home and the reverse was true for blacks. Data from this study suggests that under conditions of measurement ethnic groups may have varying reactions to different sleeping environments. It is unclear whether these site-testing effects may ameliorate with a larger sample size or repeat testing, though in this study the method did incorporate one in-hospital acclimatization night. The magnitude and directions of these variations in sleep physiology due to site location may thus be influenced by ethnicity. This may have implications for the interpretation of both laboratory polysomnography and home sleep study results comparing different ethnic groups. Inter-ethnic differences in objectively measured sleep architecture were seen in a relatively small study of African–Americans, Caucasians, Hispanics and Asians.65 There was less deep (stage 4) and more light (stage 2) sleep in the African–Americans compared to other ethnic groups. Others have also reported that blacks had less time in deep sleep than their white study counterparts in laboratorybased PSG studies, as well as showing some other sleep architectural differences.66 Using home PSG, American Indians and African–Americans have also been reported to have less deep sleep stages relative to other ethnic groups. These differences are however small relative to other gender and agerelated sleep architecture differences; furthermore this study concluded that only a minor proportion of the observed variance in sleep architecture variables could be explained by the measured covariates.67 Home PSG monitoring in 6–11 year-old children from the TUCASA study also showed inter-ethnic differences in sleep architecture: Hispanic children had less deep (stages 3 and 4) and more stage 2 sleep than the Caucasian subjects.68 The possibility that increased prevalence of underlying co-morbidites in certain racial groups may explain these variations in sleep pattern was addressed in many of these studies. Isolation of

A.T.C. Villaneuva et al. effects of ethnicity on sleep patterns was done by inclusion only of healthy subjects with no significant medical history and with no symptoms of sleep disordered breathing in some studies.64,68 In the largest study, analysis of effects of ethnicity was done with adjustment for age, sex, BMI, RDI and comorbid medical conditions that may likely affect sleep architecture.67 It is unclear whether these documented interethnic sleep architectural differences represent further site of testing effects, as described above, or true ethnobiological variation. In any event, if such differences are confirmed by further study, such findings have potential implications for stageinfluenced sleep pathophysiology in both epidemiological and clinical research into OSA.

Genetic influence A useful conceptual approach to the study of the genetics of a disorder of complex aetiology such as OSA involves the recognition of levels of phenotypes.69–71 OSA is recognized as a complex disorder with genetic, environmental, developmental and other factors influencing its presentation. Thus OSA is said to be a high-level phenotype, determined by a number of intermediate-level phenotypes such as obesity, craniofacial structural dysmorphisms, abnormalities of neuromuscular control of the upper airway, and disorders of ventilatory control and sleep regulation. In turn low-level phenotypes, which are more directly influenced by specific genes, are regarded as respectively influencing particular intermediate phenotypes or combinations thereof. Examples of low-level phenotypes include hormones such as leptin and insulin growth factor, the orexins, tumour necrosis factor-a, and a number of receptor subtypes. The cogent rationale for this multi-level phenotype approach is that it may make the study of the genetics of a complex disorder such as OSA more productive by promoting the pursuit of the genetics of the individual lowlevel targets. Examining genetic/racial/inherited influences on the multi-level phenotypes may illuminate more of the nexus between OSA and ethnicity. When looking into the anatomic intermediate phenotypes, it could be argued that the genetic/ racial component of OSA predisposition might impact most on the hard as opposed to soft anatomical factors of the upper airway, as particularly expressed in craniofacial structure, and that contribute to the expression of OSA in any ethnic group. There is also the likelihood that genetics may impact other aspects, such as obesity,

Ethnicity and obstructive sleep apnoea neuromuscular control of upper airway, and overall sleep-wake ventilatory control, and even to predisposition to substance dependencies (nicotine, alcohol) that may contribute to OSA risk. Genetics/race can be viewed as separately influencing elements at all levels of OSA phenotypes in an overall contribution to OSA. Recent heritability estimates using variance component analysis underscore the strong familial and probably genetic basis for not just obesity but also for other OSA-related phenotypes such as neck circumference, waist/hip ratio, high density lipoprotein cholesterol, intermaxillary cranial length and posterior airway space.71 There is also evidence which demonstrates a role played by genetics in the risk for nicotine and alcohol dependence which would partially explain the varying prevalence of smoking and alcohol use within a certain ethnic population.72 Although still unproven, inherited or genetically determined differences in sensitivity to the effects of these factors may also exist and contribute to the varying OSA risk conferred across ethnic groups.

425 an integrated anatomical configuration which is disadvantageous or not, vis a vis maintenance of upper airway patency in sleep. This may be an intra- and/or inter-ethnic predisposing factor to, or protector from, OSA that is independent of or at least precedes any putative contribution of generalized and/or regional obesity. Aside from cephalometry, other imaging methods are currently available for defining the upper airway structures and the surrounding tissues. These include fluoroscopy, acoustic reflectance, computed tomography (CT) and magnetic resonance imaging (MRI). There have been recent comprehensive reviews outlining the details, advantages and disadvantages of these modalities.73,74 Perhaps the most informative method to date involves the use of sophisticated analytical techniques applied to volumetric MRI.74,75 This technique has had limited clinical application to date, though in areas where it is available it has the potential to be a powerful research tool for accurate measurement of the upper airway (Fig. 2).

Intra-ethnic studies

Specific OSA risk factors: role of ethnicity Craniofacial structure and upper airway Craniofacial structure has both a bony component and a soft tissue component. The former would be expressed in adults in the relatively fixed elements of the skull, facial bones and cervical spinal skeleton, which in concert provide the bony framework and support of the upper airway. Those fixed elements can be identified on lateral cephalograms and are usually expressed as indicative angles and linear distances, and two-dimensional areas. It is then possible to establish norms for those bony fixed elements within any defined ethnic group, and the range of normality as there always pertains to any biological variable, as a basis for comparison to sub-groups from the same ethnicity who have an associated and adverse adaptation of interest, i.e. OSA. The hypothesis might be that within any ethnic group, those with OSA and taking into account other confounding factors will display variation from the norm that is reliably measurable and provides biological plausibility for the more likely development of OSA. A similar inter-ethnic comparison might be utilized to explain, at least in part, any documented ethnic differences in OSA prevalence and/or clinical manifestation. Furthermore a certain bony framework of the upper airway leads on to a particular layering of soft tissue onto that framework, which in turn provides

Caucasian cephalometry studies Cephalometric abnormalities described across a range of studies in Caucasian OSA subjects include reduced dimensions of the anterior cranial base (NS, NSBa8), reduced posterior and superior airway spaces (II), inferiorly displaced hyoid (increased MP-H), increased soft palate dimension, and other soft tissue enlargements and changes of lower facial height.76–80 Some have also placed emphasis on brachycephalic head shape, its association with OSA in Caucasians but not in African– Americans,15,77 and its frequent occurrence in the Asian population though whether in Asians this is an important pre-disposing factor to OSA is unknown.69 In more recent studies looking at anatomic determinants of OSA, it was the reduced horizontal measurement of the maxilla (PV-A) which was found to be the single most important cephalometric variable in predicting AHI severity. Reductions of another maxillary projection measurement (PNS-SO), and of 2 angular mandibular measurements (SNB, Go-SE-PNS) were also found to be also significantly correlated with AHI. Like the earlier studies the reduced superior posterior airway space (PAS) and more inferior hyoid position were also likewise significantly correlated with AHI.81 A recent study of Caucasian subjects with OSAHS and their siblings without demonstrated an increased MP-H distance in the subjects independent of any influence of

426

A.T.C. Villaneuva et al.

Figure 2

Cephalometry landmarks. See Appendices for details.

generalized obesity.82 Some studies have documented decreased cranial base dimensions83–85 and bony nasopharyngeal measurements among OSA patients compared to controls.84 In addition to these craniofacial abnormalities, CT and MRI imaging have also demonstrated an increase in the cross-sectional area and volume of the soft palate, tongue, parapharyngeal fat pads and lateral pharyngeal walls in patients with sleep apnoea.74 A large part of these cephalometric data were however generated from studies of subjects without regard to ethnicity. Although there were several that have specifically stated the ethnic composition of their study group,75,83,86,87 the majority of the studies did not, and it can only be assumed that they were mainly of Caucasian composition based on geography. Asian cephalometry studies There has been a range of cephalometry findings in studies of Chinese OSA subjects. A more consistent finding has been increased MP-H compared with controls.88–91 SNA has been reported narrower in some88 and SNB in others,90 or no bony measurement differences at all in another study.91 In one of these studies non-obese OSA patients had a longer anterior lower facial height compared to controls.88

Soft tissue measurements are usually larger and associated with reduced retro-palatal airway dimensions particularly in the more severe OSA cases.89–92 Findings in studies of Japanese OSA subjects have also shown inconsistent bony cephalometry results with diametrically opposite findings in some instances. Angular metrics (SNA, SNB, SNBa) were different between patients and controls in only some of these studies. Increased MP-H hyoid displacement was a consistent result in many studies and there were also soft tissue enlargements and airway dimension reductions in OSA patients.93–98 Summary of intra-ethnic studies Most of these studies have been derived from Caucasian, Japanese and Chinese populations and are inaccurate for use in other ethnic groups. The patient inclusion criteria have been based on selfreports of race or because of assumed membership based on geography. Comparisons of the intraethnic studies have been limited not only by this inherent difficulty in the sampling selection, but also because of the varying OSA definitions and cephalometric variables measured. This is reflected in the inconsistencies in the significant findings

Ethnicity and obstructive sleep apnoea found in these intra-ethnic studies. In 1996 an attempted qualitative and meta-analysis of the available literature examined the possible causal relationship between craniofacial structure and OSAS and found a marked paucity of adequate studies to include because of the these methodological shortcomings.99 The authors only guardedly described mandibular body length (Go-Gn) as having a potentially significant association with OSA. With the influx of recent intra-ethnic studies, a new meta-analysis is clearly warranted and may be most helpful in addressing this issue.

Inter-ethnic studies Perhaps the more informative studies are those that span different ethnicities. This approach has the critical advantage of using the same methodological design and would also facilitate comparison of similar cephalometric variable across ethnic groups. Currently there are only a limited number of studies in the literature which have directly investigated and compared racial variations in craniofacial forms as they relate to OSA. One of the largest of these cohorts involved 95 Caucasians and 41 African–American subjects. The most consistent craniofacial findings among the OSA subjects were brachycephaly, decreased dimensions of the middle cranial fossa and maxilla, and increased soft tissue measurements of the tongue and soft palate among Caucasians. The predictive cephalometric variables in African– American were mostly limited to the soft tissue contributions.15 A follow-up study on the same cohort but limiting the analysis to those O25 years of age and with a BMI !32 (to minimize contributions of growth and extreme obesity) also confirmed the previous findings of a propensity among the Caucasian OSA subjects towards brachycephaly.77 Another study compared cephalometric variables among a clinical population of Caucasian, African–American and Hispanic subjects with at least moderate-severe OSA (RDIO20). Their results showed significant bimaxillary prognathism among African–Americans and bimaxillary retropositioning among Hispanics relative to the other ethnic groups. There was a positive correlation between the degree of inferior displacement of the hyoid and RDI in all groups.100 This study is limited though by the small sample size and the absence of any adjustments for age and BMI. Another inter-ethnic comparative study investigated male Polynesians versus Caucasian patients with moderate OSA in New Zealand.19 Although

427 both groups were markedly obese, the weight, BMI and neck circumference between the two groups were significantly different and this is consistent with previous findings of increased obesity rates among Polynesians and other Pacific Islanders.101–103 When controlled for BMI, analysis showed that among Polynesians, skeletal structures such as bony nasal aperture and mandibular retrognathism were factors significantly correlated with disease severity while in Caucasians, it was the increased neck circumference and diminished retro-palatal airway dimensions that so correlated (Table 2). A prospective study compared 50 male Far East Asians (72% Chinese) to Caucasian men with OSA.104 There were two control groups (50 each) of white males controlled, respectively, for AHI and nadir of oxygen saturation during PSG in the one control group, and for BMI in the other. In this study although the posterior airway space and hyoid position were less abnormal compared to Caucasians, the Far East Asian men were noted to have a significantly shorter cranial base and a smaller anterior cranial base angle. The results of the study also showed that Asian men were more likely to have severe OSA at a non-obese level of BMI when using Caucasian standards for obesity, and that the mentioned craniofacial factors may be contributing to that notable tendency. In another inter-ethnic comparison, Caucasian (nZ43) and Chinese (nZ30) men with OSA well matched for age, BMI, RDI and overall craniofacial skeletal pattern were studied.13 Compared to Caucasians, the Chinese group showed a number of craniofacial skeletal differences including the same findings of shorter and steeper anterior cranial base. Other findings were a smaller midface, a smaller and more posteriorly positioned mandible and larger total and upper facial height. There were minimal soft tissue differences (higher tongue in Caucasians) and only a few airway dimension differences (larger naso- and oropharynx cross-sectional areas, and a larger superior posterior airway space dimension in the Chinese). Analysis of these results suggested to the authors that cephalometry offered potential as a method aiding treatment choices in OSA. The findings from these intra-ethnic and interethnic cephalometric studies do provide evidence of ethnic differences in the range of specific cephalometric measures that may be predictive of OSA and their conferred attributable risk Obesity and body fat distribution Obesity increases risk for sleep apnoea in adults of both sexes.9,105 Weight loss eliminates or reduces

428 Table 2

A.T.C. Villaneuva et al. Inter-ethnic cephalometric differences in studies of OSA (cf, compared to).

Notable inter-ethnic caphalometric findings in OSA Caucasians cf blacks

Adults

Adults cf blacks and Hispanics

Adults

cf Polynesians

Adults

cf Chinese

Adults

Brachycephaly, decreased middle cranial fossa and intermaxillary length, smaller airway in Caucasians; increased tongue area and soft palate length in African–Americans Brachycephaly in Caucasians Bimaxillary prognathism among blacks and maxillary and mandibular repositioning among hispanics; MP-H was positively correlated to RDI across all ethnic groups Among polynesians, skeletal structures such as bony nasal aperture and mandibular retrognathism were the factors significantly correlated with disease severity and explained 35% of AHI variance; inreased neck circumference and diminished retropalatal airway in caucasians accounted for 65% AHI variance SNA and SNB were significantly narrower in both white control groups cf Asians, and there was greater anterior cranial flexure in the Asians. The depth of the anterior cranial base was greater in both the white controls groups cf the Asians, and the linear distance MP-H was greater in the whites

OSA though the amount of weight loss required to do this is variable; !10% weight loss often ameliorates OSA.105–108 Obesity does not contribute to this increased risk for OSA by just one mechanism. In studies which have used CT and MRI, increased fat deposition mainly in the lateral pharyngeal walls and tongue area has been demonstrated in sleep apneic patients, and may be the main areas that increase with weight gain.74,75 There has been recent focus on preferential upper body regional fat distribution in OSA, with some evidence for such deposition in relatively non-obese individuals with OSA, particularly in the anterolateral upper airway.109 Increase in the quantity of the non-adipose muscular component, alterations in dynamic compliance of these soft tissue structures, reduction in residual lung volume and increase in whole body oxygen demand that comes with weight gain are other mechanisms that may also be contributory to this overall effect.9,74 Because a large part of the structural and functional respiratory variability associated with OSA may be explained by obesity, aside from genetics, the cultural and environmental influences informing obesity as reflected in the diet, standard of living, etc. that differ across ethnic groups will likely have a significant role. Currently, the ‘metabolically’ acceptable BMI range for Asian populations has been redefined as co-morbidities such as cardiovascular disease,

Redline et al. (1997)15

Cakirer et al. (2001)77 Will et al. (1995)100

Coltman et al. (2000)19

Li et al. (2000)104

hypertension and metabolic syndrome has been shown to occur at lower levels of BMI in these ethnic groups.103 This may also be true for sleep disordered breathing in some Asian ethnic groups. There was a weaker association with BMI in the Hong Kong Chinese OSAS prevalence studies28,29 despite a similar prevalence to that seen in the Caucasian-based studies; the highest OSAS prevalence of 7.5% seen in Indian men was recorded in a population with mean BMI !25 kg/m2.30 In another study comparing a clinical population of Far East Asian men (of mainly Chinese composition) and Caucasians with OSA, Asian men were found to be less obese for the same severity of OSA.104 These inter-ethnic findings are consistent with the notion that in these ethnic groups the predominantly operative risk factors for OSAS differ, at least in relative terms, from those seen in Caucasian populations, where obesity is seen as the major risk factor. The likely candidate risk factors that so displace obesity as the predominant risk factor in these racial groups include inherited and perhaps developmental differences in craniofacial structure, and neural and ventilatory control. Alternatively, the central fat distribution that predisposes to OSA may occur at a lower level of BMI in these ethnic groups. The role of obesity as an OSA risk factor is clearly not totally diminished in these ethnic groups as the odds ratio for any OSA (AHIR 5/h) per one standard deviation increase of BMI was

Ethnicity and obstructive sleep apnoea Table 3

429

Comparative odds ratios for OSA (SD, standard deviation; CI, confidence interval).

Correlates and odds ratios of obstructive sleep apnoea and measures of body habitus OR for a 1-SD increment in the covariate 95% CI Hong Kong29 2.96 BMI (kg/m2) Girth Neck 4.43 Waist 2.73 Hip 2.14 Waist/Hip 1.26 Skin fold thickness Biceps 1.99 Triceps 1.52 Suprailiac 1.48 Subscapular 1.77

USA11

India30

Hong Kong

USA

India

4.17

5.7

2.00–4.38

2.89–6.04

2.86–11.4

5 4.12 3.86 3.41

5.34 6.24 5.58 1.52

2.57–7.61 1.79–4.16 1.48–3.09 0.87–1.83

3.29–7.61 2.91–5.83 2.71–5.53 2.27–5.13

2.01–14.2 2.94–13.2 2.67–11.6 0.68–3.39

1.32–3.02 1.09–2.12 1.07–2.05 1.27–2.47

2.03–3.77 1.85–3.34 1.77–2.95 1.53–2.48

2.76 2.49 2.29 1.87

Hong Kong data, pooled data of men and women; United States data, includes data from men and women of the Wisconsin Cohort; India, data on Indian men.

greater in the Mumbai study compared with odds ratios from, respectively, the Wisconsin Caucasian and Hong Kong Chinese populations: 5.7 vs 4.17 vs 2.96 (see Table 3). In other studies which have comparative data, increased prevalence among American Indians and increased severity of disease among Pacific Islanders and Maori in New Zealand relative to Caucasians were found to be mainly due to the increased measures of obesity.32,110,111 Among middle-aged adult subjects in San Diego, ethnicity was also found to be a risk factor for OSA. Compared with nonHispanic whites, the prevalence of objectively measured OSA based on desaturation was noted to be threefold higher (16.3% vs 4.9) in a combined racial minority group with 65% Hispanic composition. In this study obesity was likewise found to be the most important anthropometric predictor. Hispanic ethnicity in isolation however was not quite significantly correlated with OSA after controlling for BMI, gender and age.112 It is apparent from these studies that although obesity is still a common significant risk factor for sleep disordered breathing across ethnic groups, the magnitude of risk conferred by obesity as well as the impact of regional fat distribution differs between racial groups. In assessing this complex association, the underlying contribution of the differences in socioeconomic status and culture in these ethnic groups will likely affect obesity rates and eventual OSA risk. This is likely mediated through the influence of differences in dietary patterns, physical activity, level of education and public health awareness for this issue, and body image perceptions across ethnic groups. It is interesting to note that migrants

to the United States from South and East Asia and from Polynesia have a significantly higher BMI compared to their counterparts of the same ethnicity living in their country of origin. The increased susceptibility may be explained by the acculturation process which relates to westernization of the diet and the accompanying lifestyle changes.101 Thus although metabolic rate, thermic response to food, levels of spontaneous physical activity and even the intersubject variability in regional fat distribution are to some extent heritable,113–115 undoubtedly a large part of interindividual and inter-ethnic variability is culturally and environmentally influenced and will always have to be taken into consideration. Segregation analysis and whole genome analysis approach: AHI and obesity Studies of twins, adoptees, and families all suggest the existence of genetic factors in human obesity.116–118 Segregation analysis techniques have been used to define the genetic contribution to AHI in Caucasian and African–American family sample groups, and described in the latter group a codominant gene allele that accounted for some 35% of AHI variance and was consistent with a genetic basis to the OSA phenotype independent of BMI.119 Perhaps the most promising examination to date of the genetic contribution to OSA mediated by obesity has been the approach of whole-genome scanning.120,121 This group have evaluated whole genome analyses of two cohorts from the Cleveland Family Study, looking at European–Americans and at African–Americans, using the same study design, analytic techniques, etc. A multipoint model-free variance component linkage analysis technique was

430 employed. They examined the inheritance of the high-level phenotype OSA as indicated by its definitional surrogate the PSG-measured AHI, as well as the intermediate-level phenotype general obesity as indicated by BMI, and their interacting effects The results indicated that there are both shared and unshared genetic determinants of AHI and BMI in both ethnic groups, but it is particularly noteworthy that the specific locations of these linkages differ between those identified in the European–American and in the African–American cohorts, suggesting that the important low-level phenotypes, and their associated single-gene products (biochemical markers, receptor types, etc.) may differ among racial/ethnic groups. Ventilatory control patterns Dysfunction of sleep-related upper airway neuromuscular control has obvious implications for the generation and perpetuation of apneic episodes. Central ventilatory control may well also be impaired in OSA patients.122 An inherited basis to ventilatory responsiveness to hypoxemia or hypercapnea has been suggested by twin and family studies.123–125 Heritability estimates for oxygen saturation or chemoresponsiveness to hypoxia ranges from 30 to 75%, suggesting a substantial contribution of inheritance to this trait.125,126 Alterations at the genetic and post-translational levels of S-nitrosylated proteins have been found to be of importance to this ventilatory response to hypoxia.127 The potential role for these inherited impairments of ventilatory control in influencing susceptibility to OSA is suggested by several studies showing familial aggregation of both OSA and ventilatory control dysfunction128 and inter-family studies showing blunted hypoxic responses and impairment of load compensation among relatives of probands compared with relatives of control.129,130 This supportive evidence for a familial and in some cases a genetic basis for ventilatory responsiveness dysfunction may partially explain some of the variations in OSA expressions across ethnic groups, but comparative studies of ventilatory control across ethnic groups is lacking. Studies looking into the association of ventilatory control and OSA have involved a limited number of subjects and would preclude any attempts to compare across ethnic groups. Smoking and alcohol: ethnic implications Several studies have suggested that smoking may be a possible risk factor for sleep disordered breathing. Epidemiologic studies from Europe, North America and Australia, all with a presumably mainly

A.T.C. Villaneuva et al. Caucasian population, have found a positive correlation between smoking and either snoring or more overt sleep disordered breathing.22,131–133 This association to snoring has also been found in several studies investigating other ethnic populations, for example in a Hispanic population from New Mexico.134 In another study of a multi-ethnic population composed of Chinese, Malays and Indians in Singapore, current smoking was likewise found to be associated with both snoring and sleep disordered breathing.12 In a northern European study it was demonstrated that even in a uniformly Caucasian study population, from different regions in five countries, the prevalence of present, past and passive smoking history varied and may have conferred different attributable risk for habitual snoring.135 This study illustrates the impact of variation in smoking habits, an environmental risk factor, in partially explaining OSA symptoms prevalence independent of ethnicity. Furthermore, the fact that geographic differences in snoring prevalence persist after adjustments for BMI and smoking, together with age, ethnicity and gender, also suggests that these variations may need further explanation by other environmental factors that were not investigated in this study. Though several epidemiologic studies have investigated the correlation between alcohol use and sleep disordered breathing, the results have been inconsistent. This discrepancy may be a reflection of the difficulties and differences in methods of quantification of self-reported alcohol consumption across these studies.9,21 A positive association was seen between snoring and sleep disordered breathing, from mainly Caucasian study populations, in epidemiologic studies from Denmark, United Kingdom and a study in the United States with 95% Caucasian composition.131,133,136 A similar association between alcohol use and apneic snoring was likewise found in the multi-ethnic epidemiologic study from Singapore12 but no association to OSA was found in other Asian studies on Chinese and Indian males.28,30 Clearly cultural variation in smoking and alcohol use has the potential to influence any impact on sleep disordered breathing in a differential way across ethnic groups.

Phenotypic interactions The racial variations in the prevalence and expression of these phenotypes may be related to ethnic differences in risks for obesity, craniofacial morphology and ventilatory control. Directly, these factors which are to some extent heritable, in various combinations and modulated by cultural

Ethnicity and obstructive sleep apnoea and environmental influence, will determine the overall susceptibility for collapse of the upper airways.69 The interaction of these factors with each other may also serve to modify the contribution required from each of these factors to produce OSA. As an example of the interactive influence of middle-level phenotypes on OSA, a study showed that obesity and craniofacial abnormalities contributed almost equally to the overall variance in PSG-measured AHI in a spectrum of nonclinical and clinical subjects.81 Their interactive effects accounted for an additional 15%, to account for a total of 65% of the AHI variance. The relative contributions of these risk factors were modified depending on the level of obesity and the horizontal maxillary bony dimensions of the subjects. In subjects with smaller maxillary dimensions, a greater part of the variance can be attributed to both BMI and cephalometry. In contrast, in patients with larger horizontal maxillary dimensions, cephalometry variability becomes relatively insignificant (contributes only 5% of the variance) and BMI becomes a more important predictor of AHI. In fact in this latter sub-group, obesity and cephalometry combined accounted for only 36% of the variance, and it was therefrom speculated that these types of subjects are less constrained by anatomic factors and that neural and ventilatory control may take on more significance in the genesis of sleep-state upper airway obstruction. Other studies have also shown this varying correlation between craniofacial measurements and OSA depending on the degree of obesity.86,137 Changes in upper airway soft tissue dimensions which are more vulnerable to the effects of weight gain have been more marked in obese OSA subjects compared to those who are non-obese. Comparing the independent cephalometric determinants for AHI, there is more marked bony dimensional influence by the middle cranial fossa in non-obese subjects. The largest predictor of AHI in the obese group involved soft tissue dimensions such as tongue length and MP-H. Variations in soft tissue dimensions such as increased thickness of the soft palate and the posterior pharyngeal wall and reduction in the transverse diameter of the velopharynx with increasing BMI have been observed in a spectrum of snoring subjects with varying degrees of OSA.84. This relationship paralleled the correlation between BMI and increased severity of OSA. In a morphometric model taking into consideration BMI, neck circumference and oral cavity, the contributions of the craniofacial component was emphasized especially in non-obese OSA patients.138 The exact contribution of these phenotypes to overall OSA risk will thus be determined by

431 the varying prevalence of each component, the relative risk conferred across ethnic groups and their interactive effects.

Practice points 1. The lower risk attributable to obesity among Asians supports the likely greater contribution of craniofacial risk factors and other unmeasured variables in the pathogenesis of OSA in this group. 2. There are ethnic differences in symptom perception and reporting of sleep disturbances which are influenced by the culture and level of education of the studied population. This is a possible explanation for the higher severity of disease found in Asian clinical subjects. In this ethnic group, more specific questioning regarding sleep disturbance even in the absence of obesity will help identify those in need of further diagnostic work-up and will prevent underdiagnosis of this condition. 3. There is some evidence to suggest that there is an increased severity of OSA among elderly African–Americans compared to their Caucasian counterparts. In younger African–American adults (!25 years old) and in children it is more severe in addition to being more prevalent. 4. Compared with Caucasians, the increased prevalences of OSA among American Indians and Hispanic adults and increased prevalence and severity among Pacific Islanders and Maoris in New Zealand were mainly explained by increased obesity parameters. 5. Cephalometric normative values and cephalometric measurements predictive of OSA derived from a specific population should not be generalized to other ethnic groups.

Research agenda 1. There is a need to identify the best technique and to develop an international standard for measuring ethnicity, possibly incorporating genomic analysis methods. 2. A relative dearth of prevalence studies of OSA outside the Caucasian populations of North America and western Europe

432

A.T.C. Villaneuva et al.

indicates a need for more prevalence studies around the world as it is most likely that there is an unmet burden of OSA in many unstudied regions. While it is clear that reliance on in-laboratory PSG may not be a realistic proposition in some areas of the world, home PSG is a credible alternative method of measurement that may be feasible and that has been reliably validated. There should be emphasis on inter-ethnic comparative data collection and analysis. 3. There is a need to develop low-technology culturally attuned and validated questionnaire-led methods for identifying the prevalence of OSA in developing countries which lack access to the standards of medical care available in the developed world. There is also a need for further studies to determine the appropriateness of the subjective terms used in questionnaire surveys. Appropriate labelling of sleep complaints in questionnaires surveys may have to be tailored across ethnic groups. 4. There should be an attempt to develop validated normative cephalometric values in each ethnic group and to compare these with cephalometric values of OSA patients

of the same ethnicity to elucidate which intra-ethnic craniofacial factors are operative and predicitive of OSA. Migrant population studies may also play a role in this regard. 5. There should also be more inter-ethnic studies comparing the independent and inter-dependent effects of obesity, ventilatory control and craniofacial structure on sleep disordered breathing and the varying attributable risk conferred by these factors across the different ethnic groups. 6. There should be more studies looking into the inheritance patterns of low and intermediate level phenotypes in the different ethnic groups. This would provide more insights into the pathophysiology of OSA across ethnic groups and help in the prioritization of treatment options.

Acknowledgements The authors are grateful for the assistance provided by Dr Louis Wong during the initial draft of the paper. We would also like to thank Maria Vanessa V Alvarez for her invaluable help in the creation of the graphics used for the cephalometric figures.

Appendix A. Cephalometric landmarks, reference lines and interpretation Reference lines

Landmarks

Measurement plane

Interpretation

Type of measurement

SN

Sella to Nasion

Horizontal

Bony

PNS-SO

Posterior Nasal Spine to Sphenooccipital point; parallel to Frankfurt line Porion vertical to supradentale; parallel to Frankfurt line

Horizontal

Cranial base length measurement Measure of mid-facial dimension

Bony

Anterior Nasal Spine to posterior Nasal Spine Gonion to Gnathion Gonion to Menton Mandibular plane to Hyoid bone

Horizontal

Measure of maxillary sufficiency/projection of maxilla from the skull base Maxillary length measurement Mandibular body length Mandibular body length A measure of the inferior displacement of the hyoid A measure of the inferior displacement of the hyoid Superior posterior airway space

Bony Bony Bony/soft tissue

Soft palate length

Soft tissue

PVA

ANS-PNS Go-Gn Go-Me MP-H PNS-H II

PNS-P

Posterior Nasal Spine to the Hyoid bone Distance from behind the soft palate and the nearest point in the posterior pharyngeal wall Distance from the posterior nasal spine to the tip of the soft palate

Horizontal

Horizontal Horizontal Vertical Vertical Horizontal

Vertical

Bony

Bony

Bony/soft tissue Soft tissue

Ethnicity and obstructive sleep apnoea

Appendix B. Cephalometric angles Reference angles

Interpretation

NSBa8 SNA8

Cranial base angle measurement Measure of maxillary prognathism; degree of maxillary protrusion Measure of mandibular prognathism; degree of mandibular protrusion A measure of the posterior displacement of the mandible relative to the maxilla A measure of mandibular sufficiency

SNB8

ANB8

Go-SE-PNS8

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