Retinal Nerve Fiber Layer Thickness and Rim Area Profiles in Asians: Pooled Analysis from the Asian Eye Epidemiology Consortium.

PURPOSE: To evaluate ethnic variations, ocular and systemic determinants of retinal nerve fiber layer (RNFL) thickness, and neuroretinal rim area among Asians using a large consortium of population-based eye studies. DESIGN: Cross-sectional pooled analysis. PARTICIPANTS: Twenty-two thousand four hundred thirty-six participants (22 436 eyes) from 10 population-based studies (in China, Hong Kong, India, Japan, Russia, and Singapore) of the Asian Eye Epidemiology Consortium. METHODS: Participants 40 years of age or older without glaucoma were included. All participants underwent spectral-domain OCT imaging and systemic and ocular examinations. Data were pooled from each study. Multivariable regression was performed to evaluate interethnic differences, intermachine variations, and ocular and systemic factors associated with RNFL thickness and rim area, adjusting for age, gender, diabetes, intraocular pressure (IOP), spherical equivalent (SE), ethnicity, OCT model, and study group. When evaluating body mass index, smoking, and hypertension as exposures, these factors were additionally adjusted for in the model. MAIN OUTCOME MEASURES: Average RNFL thickness (in micrometers) and rim area (in square millimeters). RESULTS: Indian and Japanese eyes have thinner RNFLs than those of other Asian ethnicities (ß values range, 7.31-12.76 µm; P < 0.001 for all pairwise comparisons). Compared with measurements by Cirrus HD-OCT (Carl Zeiss Meditec, Inc), RNFL on average was 7.29 µm thicker when measured by Spectralis (Heidelberg Engineering), 12.85 µm thicker when measured by RS-3000 (NIDEK Co, Ltd), and 17.48 µm thicker when measured by iVue/RTVue (Optovue, Inc) devices (all P < 0.001). Additionally, older age (per decade, ß = -2.70), diabetes (ß = -0.72), higher IOP (per 1 mmHg, ß = -0.07), more myopic SE (per diopter, ß = -1.13), cardiovascular disease (ß = -0.94), and hypertension (ß = -0.68) were associated with thinner RNFL (all P ≤ 0.003). Similarly, older age (ß = -0.019), higher IOP (ß = -0.010), and more myopic SE (ß = -0.025) were associated with smaller rim area (all P < 0.001). CONCLUSIONS: In this large pooled analysis of Asian population studies, Indian and Japanese eyes were observed to have thinner RNFL profiles. These findings suggest the need for an ethnic-specific normative database to improve glaucoma detection.

The Global Extent of Undetected Glaucoma in Adults: A Systematic Review and Meta-analysis.

TOPIC: Glaucoma is the leading cause of irreversible blindness, despite having good prognosis with early treatment. We evaluated the global extent of undetected glaucoma and the factors associated with it in this systematic review and meta-analysis. CLINICAL RELEVANCE: Undetected glaucoma increases the risk of vision impairment, which leads to detrimental effects on the quality-of-life and socioeconomic well-being of those affected. Detailed information on the extent and factors associated with undetected glaucoma aid in the development of public health interventions. METHODS: We conducted a systematic review and meta-analysis of population-based studies published between January 1, 1990, and June 1, 2020. Article search was conducted in online databases (PubMED, Web-of-Science), grey literatures (OpenGrey), and nongovernment organization reports. Our outcome measure was the proportion of glaucoma cases that were undetected previously. Manifest glaucoma included any form of glaucoma reported in the original studies and may include primary open-angle glaucoma (POAG), primary angle-closure-glaucoma, secondary glaucoma, or a combination thereof. Undetected glaucoma was defined as glaucoma cases that were undetected prior to diagnosis in the respective study. Random-effect meta-analysis was used to estimate the pooled proportion of undetected glaucoma. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and the Meta-analysis of Observational Studies in Epidemiology guidelines in our study. RESULTS: We identified 61 articles from 55 population-based studies (n = 189 359 participants; n = 6949 manifest glaucoma). Globally, more than half of all glaucoma cases were undetected previously on average in each geographical region. Africa (odds ratio [OR], 12.70; 95% confidence interval [CI], 4.91-32.86) and Asia (OR, 3.41; 95% CI, 1.63-7.16) showed higher odds of undetected glaucoma as compared with Europe. Countries with low Human Development Index (HDI; <0.55) showed a higher proportion of undetected manifest glaucoma as compared with countries of medium to very high HDI (≥0.55; all P < 0.001). In 2020, 43.78 million POAG cases were projected to be undetected, of which 76.7% were in Africa and Asia. DISCUSSION: Undetected glaucoma is highly prevalent across diverse communities worldwide and more common in Africa and Asia. Strategies to improve detection are needed to prevent excess visual disability and blindness resulting from glaucoma.

Association of Antihypertensive Medication with Retinal Nerve Fiber Layer and Ganglion Cell-Inner Plexiform Layer Thickness.

PURPOSE: To evaluate the association between different classes of antihypertensive medication with retinal nerve fiber layer (RNFL) and ganglion cell-inner plexiform layer (GC-IPL) thickness in a nonglaucomatous multiethnic Asian population. DESIGN: Population-based, cross-sectional study. PARTICIPANTS: A total of 9144 eyes for RNFL analysis (2668 Malays, 3554 Indians, and 2922 Chinese) and 8549 eyes for GC-IPL analysis (2460 Malays, 3230 Indians, and 2859 Chinese) aged 44 to 86 years. METHODS: Participants underwent standardized systemic and ocular examinations and interviewer-administered questionnaires for collection of data on medication and other variables. Intraocular pressure (IOP) readings were obtained by Goldmann applanation tonometry before pupil dilation for fundoscopy and OCT imaging. Blood pressure (BP) was measured with an automatic BP monitor. Mean arterial pressure (MAP) was defined as diastolic BP plus 1/3 (systolic BP - diastolic BP). Regression models were used to investigate the association of antihypertensive medication with OCT measurements of RNFL and GC-IPL. MAIN OUTCOME MEASURES: Average and sectoral RNFL and GC-IPL thickness. RESULTS: After adjusting for age, gender, ethnicity, MAP, IOP, body mass index (BMI), and presence of diabetes, we found that participants taking any type of antihypertensive medication (ß = -0.83; 95% confidence interval [CI], -1.46 to -0.02; P = 0.01), specifically angiotensin-converting enzyme inhibitors (ACEIs) (ß = -1.66; 95% CI, -2.57 to -0.75; P < 0.001) or diuretics (ß = -1.38; 95% CI, -2.59 to -0.17; P < 0.05), had thinner average RNFL in comparison with participants who were not receiving antihypertensive treatment. Use of a greater number of antihypertensive medications was significantly associated with thinner average RNFL (P for trend = 0.001). This association was most evident in the inferior RNFL quadrant in participants using ACEIs (ß = -2.44; 95% CI, -3.99 to -0.89; P = 0.002) or diuretics (ß = -2.76; 95% CI, -4.76 to -0.76; P = 0.007). A similar trend was noted in our analysis of macular GC-IPL thickness. CONCLUSIONS: Use of 2 or more antihypertensive medications, ACEI, and diuretics were associated with a loss of structural markers of retinal ganglion cell health in a multiethnic Asian population.

Profiles of Ganglion Cell-Inner Plexiform Layer Thickness in a Multi-Ethnic Asian Population: The Singapore Epidemiology of Eye Diseases Study.

PURPOSE: To examine the normative profile and determinants of macular ganglion cell-inner plexiform layer (GCIPL) thickness based on spectral-domain OCT (SD-OCT) in a nonglaucoma, multi-ethnic Asian population. DESIGN: Population-based, cross-sectional study. PARTICIPANTS: Ethnic Chinese, Malay, and Indian adults aged ≥40 years recruited from the Singapore Epidemiology of Eye Diseases Study. METHODS: All participants underwent standardized examinations. The GCIPL thickness was measured using Cirrus HD-OCT (Carl Zeiss Meditec, Dublin, CA). Participants with glaucoma or poor-quality scans were excluded. Eye-specific data were used. Associations of ocular and systemic factors with GCIPL thickness parameters were investigated using multivariable linear regression with generalized estimating equation models to account for correlation between both eyes. MAIN OUTCOME MEASURES: GCIPL thickness. RESULTS: A total of 4464 participants (7520 eyes) consisting of 1625 Chinese, 1212 Malay, and 1627 Indian adults contributed to this analysis. Average GCIPL thickness was 82.6±6.1 µm in Chinese, 81.5±6.8 µm in Malays, and 78.0±6.9 µm in Indians (P < 0.001 by analysis of variance). The 5th percentile limit of average GCIPL thickness was 72 µm in Chinese, 70 µm in Malays, and 67 µm in Indians. In multivariable analysis adjusting for age, gender, axial length, presence of cataract, OCT signal strength, disc area, hypertension, diabetes, and hyperlipidemia, eyes of Indians were observed to have 3.43 µm thinner GCIPL on average compared with Chinese (P < 0.001) and 3.36 µm thinner GCIPL compared with Malays (P < 0.001). In addition, older age (per decade; ß = -2.51), female (ß = -1.57), longer axial length (per mm; ß = -1.54), and presence of chronic kidney disease (ß = -1.49) were significantly associated with thinner average GCIPL (all P ≤ 0.008). Larger optic disc area (per mm2; ß = 0.78; P < 0.001) was associated with thicker GCIPL. These factors were consistently observed to be significant for superior and inferior hemisphere GCIPL thickness. CONCLUSIONS: GCIPL thickness profiles were significantly thinner in Indians compared with Chinese and Malays. Our findings further highlight the need of a more refined, ethnic-specific normative database for GCIPL thickness, which in turn may improve the detection and diagnosis of glaucoma in Asians.

Retinal Nerve Fiber Layer Thickness in a Multiethnic Normal Asian Population: The Singapore Epidemiology of Eye Diseases Study.

PURPOSE: To describe variations in retinal nerve fiber layer (RNFL) thickness based on spectral-domain (SD) OCT in a multiethnic Asian population. DESIGN: Population-based, cross-sectional study. PARTICIPANTS: Ethnic Chinese, Malay, and Indian adults older than 48 years without glaucoma who were recruited from the Singapore Epidemiology of Eye Diseases Study. METHODS: All participants underwent standardized systemic and ocular examinations. Retinal nerve fiber layer thickness was measured using SD OCT. Participants with poor-quality scans were excluded. Linear regression models were used to investigate the associations of ocular and systemic factors with average RNFL thickness. Generalized estimating equation models were used to account for correlation between both eyes. MAIN OUTCOME MEASURE: Average RNFL thickness. RESULTS: Four thousand four hundred seventy-five participants (8178 eyes) consisting of 1371 Chinese, 1303 Malay, and 1801 Indian adults contributed to this analysis. Average RNFL thickness measured was 95.7±9.6 µm in Chinese participants, 94.9±10.6 µm in Malay participants, and 87.3±10.6 µm in Indian participants (P < 0.001). Multivariate analysis adjusted for age, gender, and ethnicity revealed a reduction in RNFL thickness with increased intraocular pressure and axial length (P < 0.001 for both), as well as a diagnosis of diabetes (P = 0.04); greater RNFL thickness was associated with increased disc area (P < 0.001), signal strength (P < 0.001), and low-density lipoprotein cholesterol (P = 0.02). When these significant variables were taken into account, the average RNFL thickness of Indian participants was significantly thinner compared with Chinese participants (7.45 µm thinner on average [95% confidence interval, 6.75-8.15 µm; P < 0.001]), whereas there was no significant difference in average RNFL thickness between Malay and Chinese participants (P = 0.15). CONCLUSIONS: Average and regional RNFL thicknesses were significantly thinner in Indian eyes compared with Chinese and Malay eyes. Results of the study highlight the need to acquire more refined normative data for the comparison of individual patients with others of similar ethnic background while accounting for ocular factors that could influence RNFL thickness. This in turn may improve the sensitivity and specificity of glaucoma detection.

Six-Year Incidence and Risk Factors for Primary Open-Angle Glaucoma and Ocular Hypertension: The Singapore Epidemiology of Eye Diseases Study.

OBJECTIVE: To determine the incidence and risk factors for primary open-angle glaucoma (POAG) and ocular hypertension (OHT) in a multiethnic Asian population. DESIGN: Population-based cohort study. PARTICIPANTS: The Singapore Epidemiology of Eye Diseases study included 10 033 participants in the baseline examination between 2004 and 2011. Of those, 6762 (response rate = 78.8%) participated in the 6-year follow-up visit between 2011 and 2017. METHODS: Standardized examination and investigations were performed, including slit lamp biomicroscopy, intraocular pressure (IOP) measurement, pachymetry, gonioscopy, optic disc examination and static automated perimetry. Glaucoma was defined according to a combination of clinical evaluation, ocular imaging (fundus photo, visual field, and OCT) and criteria given by International Society of Geographical and Epidemiological Ophthalmology. OHT was defined on the basis of elevated IOP over the upper limit of normal; i.e., 20.4 mmHg, 21.5 mmHg, and 22.6 mmHg for the Chinese, Indian, and Malay cohort respectively, without glaucomatous optic disc change. MAIN OUTCOME MEASURES: Incidence of POAG, OHT, and OHT progression. RESULTS: The overall 6-year age-adjusted incidences of POAG and OHT were 1.31% (95% confidence interval [CI], 1.04-1.62) and 0.47% (95% CI, 0.30-0.70). The rate of progression of baseline OHT to POAG at 6 years was 5.32%. Primary open-angle glaucoma incidence was similar (1.37%) in Chinese and Indians and lower (0.80%) in Malays. Malays had higher incidence (0.79%) of OHT than Indians (0.38%) and Chinese (0.37%). Baseline parameters associated with higher risk of POAG were older age (per decade: odds ratio [OR], 1.90; 95% CI, 1.54-2.35; P < 0.001), higher baseline IOP (per mmHg: OR, 1.20; 95% CI, 1.12-1.29; P < 0.001) and longer axial length (per mm: OR, 1.22; 95% CI, 1.07-1.40, P = 0.004). CONCLUSION: Six-year incidence of POAG was 1.31% in a multiethnic Asian population. Older age, higher IOP, and longer axial length were associated with higher risk of POAG. These findings can help in future projections and guide public healthcare policy decisions for screening at-risk individuals. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any materials discussed in this article.

Machine learning identifying peripheral circulating metabolites associated with intraocular pressure alterations.

AIMS: To identify blood metabolite markers associated with intraocular pressure (IOP) in a population-based cross-sectional study. METHODS: This study was conducted in a multiethnic Asian population (Chinese, n=2805; Indians, n=3045; Malays, n=3041 aged 40-80 years) in Singapore. All subjects underwent standardised systemic and ocular examinations, and biosamples were collected. Selected metabolites (n=228) in either serum or plasma were analysed and quantified using nuclear magnetic resonance spectroscopy. Least absolute shrinkage and selection operator regression was used for metabolites selection. Multivariable linear regression was used to evaluate the relationship between metabolites and IOP in each of the three ethnic groups, followed by a meta-analysis combining the three cohorts. RESULTS: Six metabolites, including albumin, glucose, lactate, glutamine, ratio of saturated fatty acids to total fatty acids (SFAFA) and cholesterol esters in very large high-density lipoprotein (HDL), were significantly associated with IOP in all three cohorts. Higher levels of albumin (per SD, beta=0.24, p=0.002), lactate (per SD, beta=0.27, p=0.008), glucose (per SD, beta=0.11, p=0.010) and cholesterol esters in very large HDL (per SD, beta=0.47, p=0.006), along with lower levels of glutamine (per SD, beta=0.17, p<0.001) and SFAFA (per SD, beta=0.21, p=0.008) were associated with higher IOP levels. CONCLUSION: We identify several novel blood metabolites associated with IOP. These findings may provide insight into the physiological and pathological processes underlying IOP control.

Associations between visual impairment, incident falls and fall frequency among older asians: longitudinal findings from the Singapore Epidemiology of Eye Diseases study.

BACKGROUND: Association between baseline visual impairment (VI) bilaterality and severity, and associated causes; and incident and frequent falls at 6 years in a multiethnic Asian population aged ≥60 years. METHODS: It is a population-based prospective cohort study. Visual acuity was clinically measured at both visits. Self-reported incidence and frequency of falls were defined as having no fall at baseline but having one fall and ≥2 incident falls in the 12 months prior to the follow-up visit, respectively. RESULTS: Of the 1972 older participants (mean age (SD): 67.37 (5.4) years), 253 (12.8%) and 69 (3.5%) reported at least one fall and ≥2 falls, respectively, at a 6-year follow-up. After multivariable adjustments, baseline bilateral VI, but not unilateral, was associated with higher odds of any incident falls (mild bilateral VI: OR=1.79, 95% CI 1.07 to 2.98; moderate-severe VI in one eye and mild VI in the other eye: OR=1.58, 95% CI 1.01 to 2.47). However, having any form of bilateral VI (OR ranging between 2.46 and 4.32; all p<0.05) and even unilateral mild VI (OR=2.34, 95% CI 1.09 to 5.03) significantly increased the odds of incident frequent falls, compared with bilateral normal vision. VI caused by correctable (OR=2.02, 95% CI 1.19 to 3.44) and uncorrectable (OR=3.09, 95% CI 1.08 to 8.80) eye conditions were both associated with greater odds of incident frequent falls, compared with no VI. CONCLUSIONS: Baseline bilateral but not unilateral VI conferred nearly two-fold higher odds of incident fall. Importantly, even mild unilateral VI conferred a substantially greater likelihood of frequent falls from correctable and uncorrectable conditions.

Correction: From 2 dimensions to 3rd dimension: Quantitative prediction of anterior chamber depth from anterior segment photographs via deep-learning.

[This corrects the article DOI: 10.1371/journal.pdig.0000193.].

Cardiovascular disease and thinning of retinal nerve fiber layer in a multi-ethnic Asian population: the Singapore epidemiology of eye diseases study.

Introduction: Our study aimed to examine the relationship between cardiovascular diseases (CVD) with peripapillary retinal fiber layer (RNFL) and macular ganglion cell-inner plexiform layer (GCIPL) thickness profiles in a large multi-ethnic Asian population study. Methods: 6,024 Asian subjects were analyzed in this study. All participants underwent standardized examinations, including spectral domain OCT imaging (Cirrus HD-OCT; Carl Zeiss Meditec). In total, 9,188 eyes were included for peripapillary RNFL analysis (2,417 Malays; 3,240 Indians; 3,531 Chinese), and 9,270 eyes (2,449 Malays, 3,271 Indians, 3,550 Chinese) for GCIPL analysis. History of CVD was defined as a self-reported clinical history of stroke, myocardial infarction, or angina. Multivariable linear regression models with generalized estimating equations were performed, adjusting for age, gender, ethnicity, diabetes, hypertension, hyperlipidaemia, chronic kidney disease, body mass index, current smoking status, and intraocular pressure. Results: We observed a significant association between CVD history and thinner average RNFL (ß = -1.63; 95% CI, -2.70 to -0.56; p = 0.003). This association was consistent for superior (ß = -1.79, 95% CI, -3.48 to -0.10; p = 0.038) and inferior RNFL quadrant (ß = -2.14, 95% CI, -3.96 to -0.32; p = 0.021). Of the CVD types, myocardial infarction particularly showed significant association with average (ß = -1.75, 95% CI, -3.08 to -0.42; p = 0.010), superior (ß = -2.22, 95% CI, -4.36 to -0.09; p = 0.041) and inferior (ß = -2.42, 95% CI, -4.64 to -0.20; p = 0.033) RNFL thinning. Among ethnic groups, the association between CVD and average RNFL was particularly prominent in Indian eyes (ß = -1.92, 95% CI, -3.52 to -0.33; p = 0.018). CVD was not significantly associated with average GCIPL thickness, albeit a consistent negative direction of association was observed (ß = -0.22, 95% CI, -1.15 to 0.71; p = 0.641). Discussion: In this large multi-ethnic Asian population study, we observed significant association between CVD history and RNFL thinning. This finding further validates the impact of impaired systemic circulation on RNFL thickness.

Six-Year Incidence of Visual Impairment in a Multiethnic Asian Population: The Singapore Epidemiology of Eye Diseases Study.

Purpose: To examine the 6-year incidence of visual impairment (VI) and identify risk factors associated with VI in a multiethnic Asian population. Design: Prospective, population-based, cohort study. Participants: Adults aged ≥ 40 years were recruited from the Singapore Epidemiology of Eye Diseases cohort study at baseline. Eligible subjects were re-examined after 6 years. Subjects included in the final analysis had a mean age of 56.1 ± 8.9 years, and 2801 (50.5%) were female. Methods: All participants underwent standardized examination and interviewer-administered questionnaire at baseline. Incidences were standardized to the Singapore Population Census 2010. A Poisson binomial regression model was used to evaluate the associations between baseline factors and incident presenting VI. Main Outcome Measures: Incident presenting VI was assessed at the 6-year follow-up visit. Visual impairment (presenting visual acuity < 20/40), low vision (presenting visual acuity < 20/40 but ≥ 20/200), and blindness (presenting visual acuity < 20/200) were defined based on United States definition. Results: A total of 5551 subjects (2188 Chinese, 1837 Indians, and 1526 Malays) were evaluated, of whom 514 developed incident presenting VI over 6 years. Malays had a higher incidence of low vision and blindness (13.0%; 0.6%) than Indians (7.0%; 0.1%) and Chinese (7.7%; 0.2%). Among Malay individuals with VI at baseline, 52.8% remained visually impaired after 6 years, which was considerably higher than Chinese (32.4%) and Indians (37.2%). Older age (per decade; relative risk [RR] = 1.59), a history of cardiovascular disease (RR = 1.38), current smoking (RR = 1.31), smaller housing type (1- to 2-room public flat; RR = 2.01), and no formal education (RR = 1.63) at baseline were associated with a higher risk of incident VI (all P ≤ 0.027). Older age (> 60 years) contributed the highest population attributable risk to incident VI (27.1%), followed by lower monthly income (Singapore dollar < $2000; 26.4%) and smaller housing type (24.7%). Overall, undercorrected refractive error (49.1%) and cataract (82.6%) were leading causes for low vision and blindness, respectively. This was consistently observed across the 3 ethnicities. Conclusions: In this multiethnic Asian population, Malays had a higher VI incidence compared to Indians and Chinese. Leading causes of VI are mostly treatable, suggesting that more efforts are needed to further mitigate preventable visual loss. Financial Disclosures: The authors have no proprietary or commercial interest in any materials discussed in this article.

From 2 dimensions to 3rd dimension: Quantitative prediction of anterior chamber depth from anterior segment photographs via deep-learning.

Anterior chamber depth (ACD) is a major risk factor of angle closure disease, and has been used in angle closure screening in various populations. However, ACD is measured from ocular biometer or anterior segment optical coherence tomography (AS-OCT), which are costly and may not be readily available in primary care and community settings. Thus, this proof-of-concept study aims to predict ACD from low-cost anterior segment photographs (ASPs) using deep-learning (DL). We included 2,311 pairs of ASPs and ACD measurements for algorithm development and validation, and 380 pairs for algorithm testing. We captured ASPs with a digital camera mounted on a slit-lamp biomicroscope. Anterior chamber depth was measured with ocular biometer (IOLMaster700 or Lenstar LS9000) in data used for algorithm development and validation, and with AS-OCT (Visante) in data used for testing. The DL algorithm was modified from the ResNet-50 architecture, and assessed using mean absolute error (MAE), coefficient-of-determination (R2), Bland-Altman plot and intraclass correlation coefficients (ICC). In validation, our algorithm predicted ACD with a MAE (standard deviation) of 0.18 (0.14) mm; R2 = 0.63. The MAE of predicted ACD was 0.18 (0.14) mm in eyes with open angles and 0.19 (0.14) mm in eyes with angle closure. The ICC between actual and predicted ACD measurements was 0.81 (95% CI 0.77, 0.84). In testing, our algorithm predicted ACD with a MAE of 0.23 (0.18) mm; R2 = 0.37. Saliency maps highlighted the pupil and its margin as the main structures used in ACD prediction. This study demonstrates the possibility of predicting ACD from ASPs via DL. This algorithm mimics an ocular biometer in making its prediction, and provides a foundation to predict other quantitative measurements that are relevant to angle closure screening.

Assessing the external validity of machine learning-based detection of glaucoma.

Studies using machine learning (ML) approaches have reported high diagnostic accuracies for glaucoma detection. However, none assessed model performance across ethnicities. The aim of the study is to externally validate ML models for glaucoma detection from optical coherence tomography (OCT) data. We performed a prospective, cross-sectional study, where 514 Asians (257 glaucoma/257 controls) were enrolled to construct ML models for glaucoma detection, which was then tested on 356 Asians (183 glaucoma/173 controls) and 138 Caucasians (57 glaucoma/81 controls). We used the retinal nerve fibre layer (RNFL) thickness values produced by the compensation model, which is a multiple regression model fitted on healthy subjects that corrects the RNFL profile for anatomical factors and the original OCT data (measured) to build two classifiers, respectively. Both the ML models (area under the receiver operating [AUC] = 0.96 and accuracy = 92%) outperformed the measured data (AUC = 0.93; P < 0.001) for glaucoma detection in the Asian dataset. However, in the Caucasian dataset, the ML model trained with compensated data (AUC = 0.93 and accuracy = 84%) outperformed the ML model trained with original data (AUC = 0.83 and accuracy = 79%; P < 0.001) and measured data (AUC = 0.82; P < 0.001) for glaucoma detection. The performance with the ML model trained on measured data showed poor reproducibility across different datasets, whereas the performance of the compensated data was maintained. Care must be taken when ML models are applied to patient cohorts of different ethnicities.

Machine learning to determine relative contribution of modifiable and non-modifiable risk factors of major eye diseases.

AIMS: To use machine learning (ML) to determine the relative contributions of modifiable and non-modifiable clinical, metabolic, genetic, lifestyle and socioeconomic factors on the risk of major eye diseases. METHODS: We conducted analyses in a cross-sectional multi-ethnic population-based study (n=10 033 participants) and determined a range of modifiable and non-modifiable risk factors of common eye diseases, including diabetic retinopathy (DR), non-diabetic-related retinopathy (NDR); early and late age-related macular degeneration (AMD); nuclear, cortical and posterior subcapsular (PSC) cataract; and primary open-angle (POAG) and primary angle-closure glaucoma (PACG). Risk factors included individual characteristics, metabolic profiles, genetic background, lifestyle patterns and socioeconomic status (n~100 risk factors). We used gradient boosting machine to estimate the relative influence (RI) of each risk factor. RESULTS: Among the range of risk factors studied, the highest contributions were duration of diabetes for DR (RI=22.1%), and alcohol consumption for NDR (RI=6.4%). For early and late AMD, genetic background (RI~20%) and age (RI~15%) contributed the most. Axial length was the main risk factor of PSC (RI=30.8%). For PACG, socioeconomic factor (mainly educational level) had the highest influence (20%). POAG was the disease with the highest contribution of modifiable risk factors (cumulative RI~35%), followed by PACG (cumulative RI ~30%), retinopathy (cumulative RI between 20% and 30%) and late AMD (cumulative RI ~20%). CONCLUSION: This study illustrates the utility of ML in identifying factors with the highest contributions. Risk factors possibly amenable to interventions were intraocular pressure (IOP) and Body Mass Index (BMI) for glaucoma, alcohol consumption for NDR and levels of HbA1c for DR.

Three-dimensional modelling of the choroidal angioarchitecture in a multi-ethnic Asian population.

This study aimed to describe the topographic variation of the macula's choroidal angioarchitecture using three-dimensional (3D) choroidal vascularity index (CVI) of healthy eyes from an Asian population and to investigate the associations of CVI. 50 participants were recruited via stratified randomisation based on subfoveal choroidal thickness from the Singapore Epidemiology of Eye Diseases Study. Macular volume scans were acquired using spectral-domain optical coherence tomography with enhanced depth imaging. CVI was assessed based on B-scan binarisation and choroid segmentation. The 3D CVI of the whole, superior, central, and inferior macula were 62.92 ± 1.57%, 62.75 ± 1.93%, 63.35 ± 1.72%, and 62.66 ± 1.70%, respectively, pairwise comparisons P all > 0.05). 3D CVI (Whole Macula) and 2D CVI (Subfoveal) were associated only with each other and not with other ocular and systemic factors. 2D CVI (Subfoveal) had a moderate agreement with 3D CVI (Central Macula) [intraclass corelation coefficient (ICC) = 0.719], and had poorer agreement with 3D CVI of the whole macula, superior, and inferior macula (ICC = 0.591, 0.483, and 0.394, respectively). Scanning volume did not influence 3D CVI measurements. In conclusion, 3D CVI demonstrated no significant topographic variation. CVI was not correlated with demographic or ocular structural features. 2D CVI of the fovea is partially representative of 3D CVI of the macula.

Normative profiles of neuroretinal rim area in a multiethnic Asian population: the Singapore Epidemiology of Eye Diseases study.

AIMS: To evaluate the normative profiles for neuroretinal rim area (RA) in a multiethnic Asian population. METHODS: Subjects were recruited from the Singapore Epidemiology of Eye Diseases (2009-2015) study and underwent standardised examinations. RA measurements were performed using Cirrus high-definition optical coherence tomography (Carl Zeiss Meditec). Multivariable linear regression with generalised estimating equation model was used to evaluate the associations between demographic, systemic and ocular factors with RA. RESULTS: A total of 9394 eyes from 5116 subjects (1724 Chinese, 1463 Malay, 1929 Indian) were included in the final analysis. The mean (±SD) of RA was 1.28 (±0.23) mm2 for Chinese, 1.33 (±0.26) mm2 for Malays, and 1.23 (±0.23) mm2 for Indians. The 5th percentile value for RA was 0.94 mm2 for Chinese, 0.96 mm2 for Malay, and 0.89 mm2 for Indian. In multivariable analysis, following adjustment for age, gender, body mass index, diabetes mellitus, hyperlipidaemia, history of cataract surgery, axial length, intraocular pressure (IOP) and disc area, Indian eyes have smaller RA when compared with Malays (ß=-0.074; 95% CI -0.090 to -0.058; p<0.001) and Chinese (ß=-0.035; 95% CI -0.051 to -0.019; p<0.001), respectively. Additionally, older age (per decade, ß=-0.022), male gender (ß=-0.031), longer axial length (per mm, ß=-0.025), spherical equivalent (per negative dioptre, ß=-0.005), higher IOP (per mm Hg, ß=-0.009) were associated with smaller RA (all p≤0.004). CONCLUSION: In this multiethnic population-based study, we observed significantly smaller RA in Indian eyes, compared with Chinese and Malays. This indicates the need of a more refined ethnic-specific RA normative databases among Asians.

Utilisation of poor-quality optical coherence tomography scans: adjustment algorithm from the Singapore Epidemiology of Eye Diseases (SEED) study.

PURPOSE: To evaluate the effect of signal strength (SS) on optical coherence tomography (OCT) parameters, and devise an algorithm to adjust the effect, when acceptable SS cannot be obtained. METHODS: 5085 individuals (9582 eyes), aged ≥40 years from the Singapore Epidemiology of Eye Diseases population-based study were included. Everyone underwent a standardised ocular examination and imaging with Cirrus HD-OCT. Effect of SS was evaluated using multiple structural breaks linear mixed-effect models. Expected change for increment in SS between 4 and 10 for individual parameter was calculated. Subsequently we devised and evaluated an algorithm to adjust OCT parameters to higher SS. RESULTS: Average retinal nerve fibre layer (RNFL) thickness showed shift of 4.11 µm from SS of 5 to 6. Above 6, it increased by 1.72 and 3.35 µm to 7 and 8; and by 1.09 µm (per unit increase) above 8 SS. Average ganglion cell-inner plexiform layer (GCIPL) thickness shifted 5.15 µm from SS of 5 to 6. Above 6, increased by 0.94 µm from 7 to 8; and by 0.16 µm (per unit increase) above 8 SS. When compared with reference in an independent test set, the algorithm produced less systemic bias. Algorithm-adjusted average RNFL was 0.549 µm thinner than the reference, while the unadjusted one was 2.841 µm thinner (p<0.001). Algorithm-adjusted and unadjusted average GCIPL was 1.102 µm and 2.228 µm thinner (p<0.001). CONCLUSIONS: OCT parameters can be adjusted for poor SS using an algorithm. This can potentially assist in diagnosis and monitoring of glaucoma when scans with acceptable SS cannot be acquired from patients in clinics.

Normative Data and Associations of OCT Angiography Measurements of the Macula: The Singapore Malay Eye Study.

OBJECTIVE: To describe the normative quantitative parameters of the macular retinal vasculature, as well as their systemic and ocular associations using OCT angiography (OCTA). DESIGN: Population-based, cross-sectional study. SUBJECTS: Adults aged > 50 years were recruited from the third examination of the population-based Singapore Malay Eye Study. METHODS: All participants underwent a standardized comprehensive examination and spectral-domain OCTA (Optovue) of the macula. OCT angiography scans that revealed pre-existing retinal disease, revealed macular pathology, and had poor quality were excluded. MAIN OUTCOME MEASURES: The normative quantitative vessel densities of the superficial layer, deep layer, and foveal avascular zone (FAZ) were evaluated. Ocular and systemic associations with macular retinal vasculature parameters were also evaluated in a multivariable analysis using linear regression models with generalized estimating equation models. RESULTS: We included 1184 scans (1184 eyes) of 749 participants. The mean macular superficial vessel density (SVD) and deep vessel density (DVD) were 45.1 ± 4.2% (95% confidence interval [CI], 37.8%-51.4%) and 44.4 ± 5.2% (95% CI, 36.9%-53.2%), respectively. The mean SVD and DVD were highest in the superior quadrant (48.7 ± 5.9%) and nasal quadrant (52.7 ± 4.6%), respectively. The mean FAZ area and perimeter were 0.32 ± 0.11 mm2 (95% CI, 0.17-0.51 mm) and 2.14 ± 0.38 mm (95% CI, 1.54-2.75 mm), respectively. In the multivariable regression analysis, female sex was associated with higher SVD (ß = 1.25, P ≤ 0.001) and DVD (ß = 0.75, P = 0.021). Older age (ß = -0.67, P < 0.001) was associated with lower SVD, whereas longer axial length (ß = -0.42, P = 0.003) was associated with lower DVD. Female sex, shorter axial length, and worse best-corrected distance visual acuity were associated with a larger FAZ area. No association of a range of systemic parameters with vessel density was found. CONCLUSIONS: This study provided normative macular vasculature parameters in an adult Asian population, which may serve as reference values for quantitative interpretation of OCTA data in normal and disease states.

Multivariate Normative Comparison, a Novel Method for Improved Use of Retinal Nerve Fiber Layer Thickness to Detect Early Glaucoma.

PURPOSE: Detection of early glaucoma remains limited with the conventional analysis of the retinal nerve fiber layer (RNFL). This study assessed whether compensating the RNFL thickness for multiple demographic and anatomic factors improves the detection of glaucoma. DESIGN: Cross-sectional study. PARTICIPANTS: Three hundred eighty-seven patients with glaucoma and 2699 healthy participants. METHODS: Two thousand six hundred ninety-nine healthy participants were enrolled to construct and test a multivariate compensation model, which then was applied in 387 healthy participants and 387 patients with glaucoma (early glaucoma, n = 219; moderate glaucoma, n = 97; and advanced glaucoma, n = 71). Participants underwent Cirrus spectral-domain OCT (Carl Zeiss Meditec) imaging of the optic disc and macular cubes. Compensated RNFL thickness was generated based on ethnicity, age, refractive error, optic disc (ratio, orientation, and area), fovea (distance and angle), and retinal vessel density. The RNFL thickness measurements and their corresponding areas under the receiver operating characteristic curve (AUCs) were obtained. MAIN OUTCOME AND MEASURES: Measured and compensated RNFL thickness measurements. RESULTS: After applying the Asian-specific compensation model, the standard deviation of RNFL thickness reduced, where the effect was greatest for Chinese participants (16.9%), followed by Malay participants (13.9%), and Indian participants (12.1%). Multivariate normative comparison outperformed measured RNFL for discrimination of early glaucoma (AUC, 0.90 vs. 0.85; P < 0.001), moderate glaucoma (AUC, 0.94 vs. 0.91; P < 0.001), and advanced glaucoma (AUC, 0.98 vs. 0.96; P < 0.001). CONCLUSIONS: The multivariate normative database of RNFL showed better glaucoma discrimination capability than conventional age-matched comparisons, suggesting that accounting for demographic and anatomic variance in RNFL thickness may have usefulness in improving glaucoma detection.

Iris and its relevance to angle closure disease: a review.

Glaucoma is a leading cause of irreversible visual impairment, and primary angle closure glaucoma (PACG) affects Asians disproportionately. Whereas advances in ocular imaging have identified several anatomical risk factors, our ability to predict PACG still requires considerable improvement. The iris plays a crucial role in the pathophysiology of angle closure disease, either through a mechanical or vascular mechanism. Irises of closed-angle eyes inhibit vastly different structural constituents as compared with those of open-angle eyes, thereby effecting variations in biomechanical properties and iris fluid conductivity. The clinical consequences include a smaller change in iris volume on pupil dilation in closed-angle eyes, thereby bringing the iris and trabecular meshwork closer in apposition. In this review, we summarise the potential role of the iris in the pathogenesis of angle closure disease.