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Abstract
Background/aims In order to address the eye care needs of the increasing numbers of elderly Chinese globally, there is a need for comprehensive understanding on the longitudinal trends of age-related eye diseases among Chinese. We herein report the key findings from the baseline Singapore Chinese Eye Study (SCES-1), and describe the rationale and methodology of the 6-year follow-up study (SCES-2).
Methods 3353 Chinese adults who participated in the baseline SCES-1 (2009–2011) were invited for the 6-year follow-up SCES-2 (2015–2017). Examination procedures for SCES-2 included standardised ocular, systemic examinations and questionnaires identical to SCES-1. SCES-2 further included new examinations such as optical coherence tomography angiography, and questionnaires to evaluate health impact and economic burden of eye diseases.
Results In SCES-1, the age-adjusted prevalence of best-corrected low vision (VA<6/12, better-seeing eye) and blindness (VA<6/60, better-seeing eye) were 3.4% and 0.2%, respectively. The prevalence rates for glaucoma, age related macular degeneration, and diabetic retinopathy (among diabetics) were 3.2%, 6.8%, 26.2%, respectively. Of the 3033 eligible individuals from SCES-1, 2661 participated in SCES-2 (response rate=87.7%). Comparing with those who did not attend SCES-2, those attended were younger, had higher SES (all p<0.001), but less likely to be a current smoker, to have diabetes, hypertension, hyperlipidaemia (all p≤0.025).
Conclusions Building on SCES-1, SCES-2 will be one of the few longitudinal population-based eye studies to report incidence, progression, and risk factors of major age-related eye diseases. Findings from this cohort may offer new insights, and provide useful reference information for other Chinese populations elsewhere.
- epidemiology
- eye (globe)
- vision
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Introduction
Chinese account for more than half of Asia’s population. Given the rapid ageing trend in Mainland China, Hong Kong, Taiwan and other countries with large Chinese migrant populations such as Singapore, Indonesia, Thailand and Malaysia, it is expected that the global number of elderly ethnic Chinese will further increase in the coming decades.1 2 A number of age-related eye diseases such as cataract, glaucoma, age-related macular degeneration (AMD) and diabetic retinopathy (DR) are expected to increase correspondingly and thus there will be a growing demand for eye care.2 In view of this, comprehensive understanding on the long-term trends of age-related eye diseases among Chinese is crucial.
The Singapore Chinese Eye Study (SCES) is a population-based cohort study with the baseline visit (SCES-1) conducted from 2009 to 2011. Based on preliminary findings from SCES-1, we observed that Chinese have higher AMD prevalence (8.0%), compared with Indians (6.1%) and Malays (5.9%) in Singapore.3 In addition, Chinese also have a higher rate of glaucoma4 (3.2%) than Indians5 (2.0%) and have the higher prevalence of primary angle-closure glaucoma (PACG, 1.2%) than Indians and Malays. This further highlights the need to evaluate trends of age-related eye diseases over time among Chinese, in order to provide better insights into the allocation of healthcare resources.
Importantly, there is currently limited longitudinal data in this aspect among the Chinese population. The Beijing Eye Study,6 Yunnan Eye Study7 8 and Shihpai Eye Study9 are the only Chinese longitudinal studies that had reported on incidence findings on age-related eye diseases or visual impairment (VI). In view of this, we initiated and conducted the SCES 6-year follow-up visit (SCES-2) to build on the baseline SCES-1. The overall objective of SCES-2 was to determine the incidence and progression of major age-related eye diseases and VI affecting adult Chinese in Singapore, determine their relationship to traditional risk factors and explore a range of novel disease biomarkers, and evaluate the health impact and economic burden associated with eye diseases.
Hence, the purpose of this report was twofold: first, we herein report the key findings from the baseline SCES-1, and second, to describe the rationale and methodology of the SCES-2 in detail.
Materials and methods
Study design
SCES-1 was conducted from 2009 to 2011 which involved 3353 Singaporean Chinese adults aged 40–80 years old, and SCES-2 was the 6-year follow-up study of SCES, conducted from 2015 to 2017. The study protocol of SCES-2 was similar to SCES-1.10
Study population and recruitment of SCES-1 and SCES-2
The recruitment details of SCES-1 had been described previously.10 Briefly, the sampling frame composed of Chinese adults aged 40–80 years living in south-western Singapore (online supplementary figure 1). An age-stratified random sampling design was used to select eligible individuals. Of the 4445 eligible individuals, 3353 took part in the baseline SCES-1 study (72.8% response rate).
Supplemental material
All 3353 individuals who attended SCES-1 were then re-invited for SCES-2 6 years later by a postal delivered letter detailing the eye study. Participants who did not reply to the invitation letter were contacted at least three times by telephone. A home visit was further made when participants could not be contacted. A person was further categorised as ‘ineligible’ if he or she was deceased, terminally ill (eg, late-stage cancer, significant cognitively impairment, bed ridden and psychiatric illness), in prison or had migrated. A person was considered ‘not contactable’ after six unsuccessful telephone calls and home visits. Of the 3353 individuals from SCES-1, 320 were ineligible to participate in SCES-2 due to the above mentioned reasons. Of the remaining 3033 eligible individuals, 2661 (87.71% response rate) attended SCES-2, well-exceeding the minimum target response rate of 75%. Recruitment details are shown in figure 1.
Singapore Chinese Eye Study (SCES-2) recruitment flow chart.
Informed consent was obtained from all participants.
Systemic, ophthalmic examinations and questionnaires in SCES-1 and SCES-2
Systolic, diastolic blood pressure (BP), pulse rate, height and weight were measured for each participant. Body mass index (BMI) of each participant was then calculated. Non-fasting blood (37.5 mL) samples were drawn for biochemical tests including Haemoglobin A1c (HbA1c), lipid profile, serum creatinine, full blood count and blood glucose. A 20 mL urine sample was collected for urine dipstick analysis. In the event that a subject refused blood sample extraction, buccal swab was offered as an alternative for genetic testing.
Presenting distance visual acuity (VA) with participant’s current optical correction was measured for each eye using the logarithm of the minimum angle of resolution (LogMAR) ETDRS numerical charts (Lighthouse International, New York, USA) at a distance of 4 m. Binocular near VA was performed using the logarithmic Near Visual Acuity Chart ‘2000’ at 40 cm. Subjective refraction and best corrected visual acuity (BCVA) was determined by a trained and certified study optometrist when presenting VA was worse than 0.3 LogMAR.
Predilation tests included iris photography, anterior segment optical coherence tomography (OCT), anterior segment slit lamp examination, intraocular pressure (IOP) assessment using the Goldmann Applanation Tonometer (Haag-Streit, Switzerland). Pachymetry was only indicated for subjects who underwent ocular surgery after SCES-1. In addition, known glaucoma cases and glaucoma suspects (definition detailed in online supplementary table 1) further underwent gonioscopy and a Humphrey visual field test prior to pupil dilation.
Supplemental material
Post-dilation tests included fundus biomicroscopy with slit lamp, retinal photography, and posterior segment OCT.
Standardised questionnaires encompassing socioeconomic characteristics, general quality of life, vision related quality of life and lifestyle questions. A full list of the questionnaires utilised and comparisons between examination components and questionnaires administered in SCES-1 and SCES-2 can be found in online supplementary table 3. Questionnaires were administered by trained interviewers fluent in Chinese.
Novel components/examinations in SCES-2
To the best of our knowledge, SCES-2 may well be the first population-based study which included OCT angiography (OCT-A) (RTVue XR 100 Avanti, Optovue, Fremont, California, USA). This novel ocular imaging technique was not available during SCES-1 and was introduced in SCES-2 to collect non-invasive data on retinal microcirculation. This state-of-the-art technology allows flow density to be measured for the macular and optic nerve head region (online supplementary figures 2 and 3). OCT-A image analyses could provide new information on the pathogenesis of major eye diseases. Furthermore, additional questionnaires were also added to the interview portion in SCES-2 to further evaluate the health and economic burden of eye diseases. All details of SCES-2 methodology are further described in online supplementary appendix A.
Supplemental material
Supplemental material
Grading and definitions of ocular diseases
Detailed definitions of VI, major eye diseases and conditions are described in online supplementary table 1. In brief, VI and blindness were defined according to USA and WHO definition. Glaucoma was defined based on the International Society for Geographical and Epidemiologic Ophthalmology criteria.11 AMD was graded based on a modification of the Wisconsin AMD classification described in more detail in SiMES-1 and elsewhere.12–14 DR was graded using a modified Airlie House classification system and a modified ETDRS system for DR,15 and cataract was graded using the Lens Opacities Classification System III (LOCS III).16
Detailed assessment and definitions of systemic conditions can be found in online supplementary table 2 and further details of the above mentioned methods and data quality control processes are described in online supplementary appendix A.
Supplemental material
Statistical analysis
In this report, crude and age-standardised prevalence of VI and eye diseases in SCES-1 were calculated and age-standardised to the Singapore Chinese Population Census 2010. We also compared the baseline characteristics of participants who attended SCES-2 (n=2661) compared with those who did not attend (n=692) using t test and χ2 test for continuous and categorical variables, respectively. These analyses were performed using Stata V.14.0.
Analytic plan for subsequent SCES-2 final report
Subsequent analysis for the final SCES-2 report will be conducted using standard statistical software (SPSS, STATA, R program). We will use a variety of statistical methods for analysis. Age-standardised 6-year cumulative incidence and progression of major eye disease such as DR, AMD, cataract, VI, and glaucoma will be calculated. The 2010 Singapore Chinese population will be used as the standard population for calculation of all age-standardised incidence rates.
For incidence and progression of eye diseases such as AMD, cataract, DR and glaucoma, comparison of participants with and without incidence eye disease will be done using different types of statistical test such as independent t test, χ2 or fisher exact test depending on the data distribution. We will construct multivariable binomial Poisson regression model with robust variance adjusted for age, gender and relevant covariates to examine the prospective association of various risk factors with incidence and progression of these eye diseases.
Comparison of differences between groups of interest for continuous ocular traits such as IOP, macular thickness, GCIPL choroidal thickness, and quality of life index will be done using student t test, analysis of variance and analysis of covariance as appropriate. We will construct multiple linear regression model to examine determinants and evaluate association of major eye diseases with the specified traits mentioned above. We will also assess the longitudinal impact of vision loss on QOL based on the 6 years change in VF-14 and EQ-5D scores. Economic burden associated with major blinding eye disease and VI will be also be evaluated in a separate model.
For eye-specific analysis, generalised estimating equation (GEE) models will be used to account for the correlation between the two eyes of an individual.
Results
Key findings from SCES-1
Of the 3353 participants in SCES-1, the mean age was 59.7±9.9 years and 1691 (50.4%) were females. Overall participant characteristics are shown in table 1; 2045 participants had hypertension (61.0%) and 592 participants had diabetes (17.7%).
Characteristics of participants who attended baseline SCES-1
Table 2 describes the crude and age-adjusted prevalence for VI major age-related eye diseases in baseline SCES-1, and table 3 summarises the observed factors associated with these eye conditions. Based on the better-seeing eye and US definition, the age-adjusted prevalence of best-corrected blindness (VA <6/60) and low vision (VA <6/12 to ≥6/60) was 0.2% (95% CI 0.1% to 0.4%), 3.4% (95% CI 2.8% to 4.4%), respectively.17 The age-adjusted prevalence of best-corrected VI according to the WHO criteria for blindness (VA <6/120) was 0.1% (95% CI 0.0% to 0.3%) and for low vision (VA <6/18) was 1.3% (95% CI 1.0% to 1.7%). Cataract was the main cause of best-corrected VI with an age-adjusted prevalence of 35.6% (95% CI 33.4% to 38.0%) and older age, female gender, current smoker, lower educational level and lower income were the associated factors for cataract.18 Factors associated with best-corrected VI include older age, diabetes and lower educational level (table 3).17
Prevalence of visual impairment and major age-related eye diseases from baseline SCES-1
Associated risk factors for visual impairment and major age-related eye diseases at baseline SCES-1
The age-adjusted prevalence rates for glaucoma was 3.2% (95% CI 2.7% to 3.9%), primary open angle glaucoma (POAG) was 1.4% (95% CI 1.1% to 1.9%), and PACG was 1.2% (95% CI 0.9% to 1.6%) (table 2).4 Older age (≤70 years old compared with 40–49 years), male gender and higher IOP were associated with POAG (table 3).4
On the other hand, 6.8% (95% CI 6.0% to 7.7%) of study participants were diagnosed with any type of AMD. The prevalence rates for early and late AMD were 5.7% (95% CI 5.0% to 7.8%) and 0.6% (95% CI 0.4% to 2.7%), respectively (table 2).3 Chinese ethnicity (compared with Malays), older age, male gender and shorter axial length were associated with early AMD (table 3).3
Separately, among the 581 diabetic participants in SCES-1, the age-adjusted prevalence for DR was 26.2% (95% CI 20.7% to 33.1%) (table 2).19 Longer duration of diabetes, higher HbA1c levels, lower educational level, CKD, and higher systolic BP were associated with DR (table 3).19
Prevalence of VI and major age-related eye diseases, stratified by age groups are further presented in online supplementary tables 45. It was consistently observed that the prevalence rates of VI and major age-related eye diseases increased with age, except for DR, where the rates were similar between younger and older age groups.
SCES-2 study population and recruitment
Among the original 3353 participants from the baseline SCES-1 examination, 320 were ineligible for SCES-2 due to death, severe cognitive impairment, severe mobility impairment, psychiatric illness, migrated/moved without traceable address or imprisonment. Of the remaining 3034 eligible individuals, 372 did not attend the follow-up exam, leaving a final 2661 individuals who completed the SCES-2 follow-up exam from year 2015 to 2017 (figure 1). Compared with individuals who did not return for SCES-2, participants who returned for the SCES-2 follow-up were more likely to be younger, female, have higher SES, and lower HbA1c level at baseline (all p≤0.05); less likely to be a current smoker, underweight, have diabetes, hypertension, hyperlipidaemia, history of cardiovascular disease and chronic kidney disease (all p≤0.031), (table 4). In addition, compared with eligible individuals who attended SCES-2, those eligible but did not return for follow-up exam were more likely to have hypertension and lower SES (all p≤0.005) (table 4).
Baseline characteristics of participants who attended SCES-2 compared with those who did not attend
Discussion
SCES is one of the few population-based cohort studies on ocular diseases in Asia. Key findings from SCES-1 complemented other population studies in Asia. For example, the prevalence of blindness and VI in SCES-1 was 0.1% and 1.3%, respectively (according to WHO definitions). These findings are similar to other major population-based Chinese studies such as the Beijing Eye Study20 (0.3%, 1.1%) and the Handan eye study21 (0.5%, 1.2%). Additionally, the prevalence reported for glaucoma was 3.25% similar to the glaucoma rate (3.7%) reported by the Beijing Eye Study.22 SCES-1 reported a prevalence of AMD of 8.0% which was higher than the prevalence reported by the Beijing Eye Study (1.6%)23 and the Handan Eye Study (3.1%).24 Furthermore, data from SCES-1 also provided better understanding on the correlation between automated OCT-derived drusen volume and colour fundus photographs-based AMD grading.25 Findings from SCES-1 also provided useful insights on the burden of eye diseases among Chinese adults in Singapore.26 Lastly, SCES-1 was one of the main datasets which contributed to the development of a new deep learning system in detecting referable DR among individuals with diabetes.27
To the best of our knowledge, SCES-2 is the first population-based study to include advanced ocular imaging technology such as OCT-A on all participants. This novel ocular imaging technique was introduced in SCES-2 to provide non-invasive data on microvasculature (online supplementary figures 2 and 3) in various retinal layers. Along with traditional methods such as fundus photography and Cirrus HD-OCT, this cutting-edge imaging technology has the potential to provide new information on the function and morphology of the retina for different eye diseases,28 which will hopefully provide practitioners with improved forms of early disease detection and disease progression techniques. OCT-A data collected in SCES-2 will to help provide normative data on microvasculature for Asian populations. Additionally, SCES-2 is one of the few studies evaluating the health impact and economic burden of age-related eye diseases in elderly Chinese. Therefore, SCES-2 will help provide new insights into the longitudinal impact of major age-related eye diseases, and their consequences on vision loss and quality of life.
The major strengths of SCES-2 include a well-established and characterised cohort at baseline, with high-quality ocular/systemic data, including high-resolution images of retina and optic nerve, and a rich collection of bio-samples. Since SCES-2 follows the standardised protocol as used in the Singapore Malay Eye Study-229 (SiMES-2), and the Singapore Indian Eye Study-230 (SINDI-2), this provides a unique opportunity to compare ethnic differences among Asians in disease incidence, progression and associated risk factors. These data will be critical for the planning of public health strategies to reduce visual loss in Singapore, and such information may also as useful reference for other Asian populations in the region.
Similar to other population cohorts, SCES-2 experienced data loss due to the demise of older participants and uncontactable participants.30 As a result, there were some differences between participants and non-participants of SCES-2 in a few baseline characteristics, such as SES, rate of diabetes and hypertension (table 4). Thus, bias due to loss of follow-up cannot be entirely ruled out. Nevertheless, the overall follow-up rate (87.7%) among eligible SCES-2 individuals was relatively higher, especially when comparing with other population cohorts in Asians,6 31 32 the effect of follow-up bias is likely to be mitigated and may not substantially impact our findings.
In conclusion, the eventual results from SCES-2 are expected to have an important, positive clinical impact. Given the inclusion of state-of-the-art technology and novel measurements, SCES-2 will assist in establishing Chinese normative datasets for these new technologies. Notably, SCES-2 will provide a large amount of longitudinal Chinese cohort data, offering insights into the pathogenesis and related risk factors of major eye diseases in Singaporean Chinese. Findings from our study may potentially provide useful reference information for other Chinese urban populations around the world.
Acknowledgments
The authors thank the ocular epidemiology research group and data science unit of the Singapore Epidemiology Research Institute for their invaluable contributions.
References
Footnotes
SM and YCT contributed equally.
Contributors TYW, C-YC, YCT, ELL and CS conceived and designed the study. SM, MLC, YCT, WD, M-LC and NK analysed and interpreted the data. SM, YCT, CLT, MLC wrote the manuscript.
Funding The study is funded by the National Medical Research Council (NMRC/CIRG/1417/2015).
Competing interests None declared.
Patient consent for publication Obtained.
Ethics approval Both SCES-1 and SCES-2 were conducted in accordance with the Declaration of Helsinki and were approved by the SingHealth Centralised Institutional Review Board.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement No data are available.