X-chromosome and kidney function: evidence from a multi-trait genetic analysis of 908,697 individuals reveals sex-specific and sex-differential findings in genes regulated by androgen response elements.

X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits (n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 for uric acid and 16 for estimated glomerular filtration rate (eGFR), including four novel eGFR loci containing the functionally plausible prioritized genes ACSL4, CLDN2, TSPAN6 and the female-specific DRP2. Further, we identified five novel sex-interactions, comprising male-specific effects at FAM9B and AR/EDA2R, and three sex-differential findings with larger genetic effect sizes in males at DCAF12L1 and MST4 and larger effect sizes in females at HPRT1. All prioritized genes in loci showing significant sex-interactions were located next to androgen response elements (ARE). Five ARE genes showed sex-differential expressions. This study contributes new insights into sex-dimorphisms of kidney traits along with new prioritized gene targets for further molecular research.

Is Kidney Function Associated with Age-Related Macular Degeneration?: Findings from the Asian Eye Epidemiology Consortium.

PURPOSE: Chronic kidney disease (CKD) may elevate susceptibility to age-related macular degeneration (AMD) because of shared risk factors, pathogenic mechanisms, and genetic polymorphisms. Given the inconclusive findings in prior studies, we investigated this association using extensive datasets in the Asian Eye Epidemiology Consortium. DESIGN: Cross-sectional study. PARTICIPANTS: Fifty-one thousand two hundred fifty-three participants from 10 distinct population-based Asian studies. METHODS: Age-related macular degeneration was defined using the Wisconsin Age-Related Maculopathy Grading System, the International Age-Related Maculopathy Epidemiological Study Group Classification, or the Beckman Clinical Classification. Chronic kidney disease was defined as estimated glomerular filtration rate (eGFR) of less than 60 ml/min per 1.73 m2. A pooled analysis using individual-level participant data was performed to examine the associations between CKD and eGFR with AMD (early and late), adjusting for age, sex, hypertension, diabetes, body mass index, smoking status, total cholesterol, and study groups. MAIN OUTCOME MEASURES: Odds ratio (OR) of early and late AMD. RESULTS: Among 51 253 participants (mean age, 54.1 ± 14.5 years), 5079 had CKD (9.9%). The prevalence of early AMD was 9.0%, and that of late AMD was 0.71%. After adjusting for confounders, individuals with CKD were associated with higher odds of late AMD (OR, 1.46; 95% confidence interval [CI], 1.11-1.93; P = 0.008). Similarly, poorer kidney function (per 10-unit eGFR decrease) was associated with late AMD (OR, 1.12; 95% CI, 1.05-1.19; P = 0.001). Nevertheless, CKD and eGFR were not associated significantly with early AMD (all P ≥ 0.149). CONCLUSIONS: Pooled analysis from 10 distinct Asian population-based studies revealed that CKD and compromised kidney function are associated significantly with late AMD. This finding further underscores the importance of ocular examinations in patients with CKD. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

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.

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.

International incidence and temporal trends for rhegmatogenous retinal detachment: A systematic review and meta-analysis.

We set out to estimate the international incidence of rhegmatogenous retinal detachment (RRD) and to evaluate its temporal trend over time. There is a lack of robust estimates on the worldwide incidence and trend for RRD, a major cause of acute vision loss. We conducted a systematic review of RRD incidence. The electronic databases PubMed, Scopus, and Thomson Reuters' Web of Science were searched from inception through 2nd June 2022. Random-effects meta-analysis model with logit transformation was performed to obtain pooled annual incidence estimates of RRD. Pooled analysis was performed to evaluate the temporal trend of RRD incidence of the 20,958 records identified from the database searches; 33 studies from 21 countries were included for analysis (274,836 cases of RRD in 273,977 persons). Three of the 6 global regions as defined by WHO had studies that met the inclusion and exclusion criteria of the study. The annual international incidence of RRD was estimated to be 12.17 (95% confidence interval [CI] 10.51-14.09) per 100,000 population; with an increasing temporal trend of RRD at 5.4 per 100,000 per decade (p 0.001) from 1997 to 2019. Amongst world regions, the RRD incidence was highest in Europe (14.52 [95% CI 11.79 - 17.88] per 100,000 population), followed by Western Pacific (10.55 [95% CI 8.71-12.75] per 100,000 population) and Regions of Americas (8.95 [95% CI 6.73-11.92] per 100,000 population). About one in 10,000 persons develop RRD each year. There is evidence of increasing trend for RRD incidence over time, with possibly doubling of the current incidence rate within the next 2 decades.

PATTERN AND CHARACTERISTICS OF DRUSEN SUBTYPES IN CHINESE AND INDIAN POPULATIONS IN SINGAPORE.

PURPOSE: To report the pattern and characteristics of drusen subtypes in Asian populations and the association with choroidal thickness. METHODS: This is the cross-sectional analysis of the population-based cohort study. Two thousand three hundred and fifty-three eyes of 1,336 Chinese and Indian participants aged older than 50 years, eyes with best-corrected visual acuity better than 20/60, and without other retinal diseases were recruited. Pachydrusen, reticular pseudodrusen, soft and hard drusen were graded on both color fundus photographs, and optical coherence tomography imaging with automated segmentation yielding and measurements of choroidal thickness. RESULTS: Nine hundred and fifty-five Chinese and 381 Indians were included in the final analysis. The pattern of pachydrusen, soft drusen, hard drusen, and reticular pseudodrusen was 14.0%, 3.7%, 12.5%, and 0.2%, respectively. Mean choroidal thickness was the thickest in eyes with pachydrusen (298.3 µm; 95% confidence interval: 290.5-306.1), then eyes with hard (298.1 µm; 95% confidence interval: 290.6-305.5) and soft drusen (293.7 µm; 95% confidence interval: 281.9-305.4) and thinnest in eyes without drusen (284.6 µm; 95% confidence interval: 280.5-288.7). Systemic associations of the various drusen subtypes also differed. CONCLUSION: Patterns, characterization and choroidal thickness of drusen subtypes, and their associations provide insights into the Asian phenotypic spectrum of age-related macular degeneration and the underlying pathogenesis.

Six-year incidence of age-related macular degeneration and correlation to OCT-derived drusen volume measurements in a Chinese population.

AIMS: To report the 6-year incidence of optical coherence tomography (OCT)-derived age-related changes in drusen volume and related systemic and ocular associations. METHODS: Chinese adults aged 40 years and older were assessed at baseline and 6 years with colour fundus photography (CFP) and spectral domain (SD) OCT. CFPs were graded for age-related macular degeneration (AMD) features and drusen volume was generated using commercially available automated software. RESULTS: A total of 4172 eyes of 2580 participants (mean age 58.12±9.03 years; 51.12% women) had baseline and 6-year follow-up CFP for grading, of these, 2130 eyes of 1305 participants had gradable SD-OCT images, available for analysis. Based on CFP grading, 136 (3.39%) participants developed incident early AMD and 10 (0.25%) late AMD. Concurrently, retinal pigment epithelial-Bruch's membrane (RPE-BrC) volumes decreased, remained stable and increased in 6.8%, 78.5% and 14.7%, respectively, over 6 years. In eyes where RPE-BrC volumes were >0 mm3 at baseline, this was associated with two-fold higher prevalence rate of any AMD at baseline (p<0.001). Multivariable analysis showed that when compared with eyes where RPE-BrC volume was unchanged, volume decrease was significantly associated with older age (OR=1.30; p<0.001), smoking (OR=2.21; p=0.001) and chronic kidney disease (OR=3.4, p=0.008), while increase was associated with older age (OR=1.36; p<0.001) and hypertension (OR=1.43; p=0.016). CONCLUSION: AMD incidence detected at 6 years on CFP and correlated OCT-derived drusen volume measurement change is low. Older age and some systemic risk factors are associated with drusen volume change, and our data provide new insights into relationship between systemic risk factors and outer retinal morphology in Asian eyes.

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.

Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies.

Estimated glomerular filtration rate (eGFR) reflects kidney function. Progressive eGFR-decline can lead to kidney failure, necessitating dialysis or transplantation. Hundreds of loci from genome-wide association studies (GWAS) for eGFR help explain population cross section variability. Since the contribution of these or other loci to eGFR-decline remains largely unknown, we derived GWAS for annual eGFR-decline and meta-analyzed 62 longitudinal studies with eGFR assessed twice over time in all 343,339 individuals and in high-risk groups. We also explored different covariate adjustment. Twelve genome-wide significant independent variants for eGFR-decline unadjusted or adjusted for eGFR-baseline (11 novel, one known for this phenotype), including nine variants robustly associated across models were identified. All loci for eGFR-decline were known for cross-sectional eGFR and thus distinguished a subgroup of eGFR loci. Seven of the nine variants showed variant-by-age interaction on eGFR cross section (further about 350,000 individuals), which linked genetic associations for eGFR-decline with age-dependency of genetic cross-section associations. Clinically important were two to four-fold greater genetic effects on eGFR-decline in high-risk subgroups. Five variants associated also with chronic kidney disease progression mapped to genes with functional in-silico evidence (UMOD, SPATA7, GALNTL5, TPPP). An unfavorable versus favorable nine-variant genetic profile showed increased risk odds ratios of 1.35 for kidney failure (95% confidence intervals 1.03-1.77) and 1.27 for acute kidney injury (95% confidence intervals 1.08-1.50) in over 2000 cases each, with matched controls). Thus, we provide a large data resource, genetic loci, and prioritized genes for kidney function decline, which help inform drug development pipelines revealing important insights into the age-dependency of kidney function genetics.

Six-Year Incidence and Risk Factors for Primary Angle-Closure Disease: The Singapore Epidemiology of Eye Diseases Study.

PURPOSE: To determine the incidence and risk factors of primary angle-closure disease (PACD) over 6 years in a multi-ethnic Asian population. DESIGN: Population-based, longitudinal study. PARTICIPANTS: The Singapore Epidemiology of Eye Diseases study is a population-based cohort study conducted among adults aged 40 years or more. The baseline examination was conducted between 2004 and 2010, and the 6-year follow-up visit was conducted between 2011 and 2017. Of 6762 participants who attended the follow-up examination, 5298 at risk for primary angle-closure glaucoma (PACG) and 5060 at risk for PACD were included for analyses. METHODS: Standardized examinations including slit-lamp biomicroscopy, indentation gonioscopy, intraocular pressure (IOP) measurement, and static automated perimetry were performed. In this study, PACD includes primary angle-closure suspect (PACS), primary angle-closure (PAC), and PACG. MAIN OUTCOME MEASURES: The 6-year PACD incidence was evaluated among an at-risk population excluding adults with baseline glaucoma, PACS, PAC, pseudophakia at baseline or follow-up, or laser peripheral iridotomy or iridectomy at baseline visit. Logistic regression analysis adjusting for age, gender, and ethnicity was performed to evaluate associations between PACD development and demographic or ocular characteristics. Forward selection based on the Quasi-likelihood Information Criterion was used in multivariable analysis to reduce potential multicollinearity. RESULTS: The 6-year age-adjusted PACD incidence was 3.50% (95% confidence interval [CI], 2.94-4.16). In multivariable analysis, increasing age per decade (odds ratio [OR], 1.35; 95% CI, 1.15-1.59), higher IOP (OR, 1.04; 95% CI, 1.00-1.08), and shallower anterior chamber depth (OR, 1.11; 95% CI, 1.08-1.14) at baseline were associated with higher odds of PACD, whereas late posterior subcapsular cataract (PSC) (OR, 0.60; 95% CI, 0.48-0.76) was associated with lower odds of PACD. The 6-year age-adjusted incidences of PACG, PAC, and PACS were 0.29% (95% CI, 0.14-0.55), 0.46% (95% CI, 0.29-0.75), and 2.54% (95% CI, 2.07-3.12), respectively. CONCLUSIONS: Our study showed that the 6-year incidence of PACD was 3.50%. Increasing age, higher IOP, and shallower anterior chamber were associated with a higher risk of incident PACD, whereas late PSC was associated with a lower odds of PACD. These findings can aid in future projections and formulation of health care policies for screening of at-risk individuals for timely intervention.

Incidence and progression of diabetic retinopathy in a multi-ethnic US cohort: the Multi-Ethnic Study of Atherosclerosis.

AIM: To provide contemporary longitudinal data on the incidence and progression of diabetic retinopathy (DR) in a multi-ethnic population of whites, African Americans, Chinese and Hispanics in the United States. METHODS: A prospective, multi-region, multi-ethnic population-based cohort study that included 498 participants with diabetes, aged 45-84 years at baseline, from the Multi-Ethnic Study of Atherosclerosis with retinal images obtained twice, on average 8 years apart. Presence and severity of DR were graded from these retinal images according to the modified Airlie House classification system. Main outcome measures were 8-year incidence, progression and improvement of DR, and their associated risk factors. RESULTS: Over the 8 years, the cumulative rates were 19.2% for incident DR, 17.3% for DR progression, 23.3% for DR improvement, 2.7% for incident vision-threatening DR, 1.8% for incident proliferative DR and 2.2% for incident macular oedema. In multivariate analysis, significant risk factors associated with incident DR were higher glycosylated haemoglobin (relative risk (RR) 1.28; 95% CI: 1.16 to 1.41) and higher systolic blood pressure (RR 1.14; 95% CI: 1.04 to 1.25). Significant factors associated with DR progression were higher glycosylated haemoglobin (RR 1.20; 95% CI: 1.00 to 1.43) and higher low-density lipoprotein cholesterol (RR 1.01; 95% CI: 1.00 to 1.03). CONCLUSION: Over an 8-year period, approximately one in five participants with diabetes developed DR, while almost a quarter of those with DR at baseline showed improvement, possibly reflecting the positive impact of clinical and public health efforts in improving diabetes care in the United States over the last two decades.

Deep learning algorithms for automatic detection of pterygium using anterior segment photographs from slit-lamp and hand-held cameras.

BACKGROUND/AIMS: To evaluate the performances of deep learning (DL) algorithms for detection of presence and extent pterygium, based on colour anterior segment photographs (ASPs) taken from slit-lamp and hand-held cameras. METHODS: Referable pterygium was defined as having extension towards the cornea from the limbus of >2.50 mm or base width at the limbus of >5.00 mm. 2503 images from the Singapore Epidemiology of Eye Diseases (SEED) study were used as the development set. Algorithms were validated on an internal set from the SEED cohort (629 images (55.3% pterygium, 8.4% referable pterygium)), and tested on two external clinic-based sets (set 1 with 2610 images (2.8% pterygium, 0.7% referable pterygium, from slit-lamp ASP); and set 2 with 3701 images, 2.5% pterygium, 0.9% referable pterygium, from hand-held ASP). RESULTS: The algorithm's area under the receiver operating characteristic curve (AUROC) for detection of any pterygium was 99.5%(sensitivity=98.6%; specificity=99.0%) in internal test set, 99.1% (sensitivity=95.9%, specificity=98.5%) in external test set 1 and 99.7% (sensitivity=100.0%; specificity=88.3%) in external test set 2. For referable pterygium, the algorithm's AUROC was 98.5% (sensitivity=94.0%; specificity=95.3%) in internal test set, 99.7% (sensitivity=87.2%; specificity=99.4%) in external set 1 and 99.0% (sensitivity=94.3%; specificity=98.0%) in external set 2. CONCLUSION: DL algorithms based on ASPs can detect presence of and referable-level pterygium with optimal sensitivity and specificity. These algorithms, particularly if used with a handheld camera, may potentially be used as a simple screening tool for detection of referable pterygium. Further validation in community setting is warranted. SYNOPSIS/PRECIS: DL algorithms based on ASPs can detect presence of and referable-level pterygium optimally, and may be used as a simple screening tool for the detection of referable pterygium in community screenings.

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.

Association between body mass index and diabetic retinopathy in Asians: the Asian Eye Epidemiology Consortium (AEEC) study.

BACKGROUND/AIMS: Obesity is a well-known risk factor for diabetes, but its association with diabetic retinopathy (DR) is inconclusive, in particular in Asians. We aimed to assess whether body mass index (BMI) is associated with the presence and severity of DR in Asian populations with diabetes. METHODS: Pooled analysis of individual-level cross-sectional data from 10 010 adults with diabetes who participated in 12 population-based studies conducted in China, India, Japan, Russia (Asian), Singapore and South Korea that were part of the Asian Eye Epidemiology Consortium (AEEC). BMI was calculated as weight in kilograms divided by height in square metres and categorised into normal (<25 kg/m2, reference), overweight (25-29.9 kg/m2) and obese (≥30 kg/m2). Any-DR (n=1669) and vision-threatening DR (VTDR, n=489) were assessed from digital retinal photographs and graded according to standard protocols. Each study was analysed separately using multivariable logistic regression models adjusted for age, sex, haemoglobin A1c%, systolic blood pressure and diabetes duration, and the estimated odds ratios (ORs) and 95% confidence interval (CIs) from all studies were then combined using random-effects models. RESULTS: In multivariable models, obesity showed a significant inverse association with any-DR (pooled OR (95% CI) =0.74 (0.59 to 0.91)) and VTDR (0.75 (0.60 to 0.93)). Similarly, in continuous analysis, BMI showed a significant inverse association with both any-DR (0.93 (0.87 to 0.99)) and VTDR (0.79 (0.68 to 0.92) per SD increase). Overweight did not show a significant association with any-DR. CONCLUSIONS: Among Asian adults with diabetes, both BMI and obesity showed an inverse association with DR. These findings warrant confirmation in further longitudinal studies.

Detecting visually significant cataract using retinal photograph-based deep learning.

Age-related cataracts are the leading cause of visual impairment among older adults. Many significant cases remain undiagnosed or neglected in communities, due to limited availability or accessibility to cataract screening. In the present study, we report the development and validation of a retinal photograph-based, deep-learning algorithm for automated detection of visually significant cataracts, using more than 25,000 images from population-based studies. In the internal test set, the area under the receiver operating characteristic curve (AUROC) was 96.6%. External testing performed across three studies showed AUROCs of 91.6-96.5%. In a separate test set of 186 eyes, we further compared the algorithm's performance with 4 ophthalmologists' evaluations. The algorithm performed comparably, if not being slightly more superior (sensitivity of 93.3% versus 51.7-96.6% by ophthalmologists and specificity of 99.0% versus 90.7-97.9% by ophthalmologists). Our findings show the potential of a retinal photograph-based screening tool for visually significant cataracts among older adults, providing more appropriate referrals to tertiary eye centers.

Novel Serum and Urinary Metabolites Associated with Diabetic Retinopathy in Three Asian Cohorts.

Diabetic retinopathy (DR) is a microvascular complication of diabetes mellitus, a metabolic disorder, but understanding of its pathophysiology remains incomplete. Meta-analysis of three population-based cross-sectional studies (2004-11) representing three major Asian ethnic groups (aged 40-80 years: Chinese, 592; Malays, 1052; Indians, 1320) was performed. A panel of 228 serum/plasma metabolites and 54 urinary metabolites were quantified using nuclear magnetic resonance (NMR) spectroscopy. Main outcomes were defined as any DR, moderate/above DR, and vision-threatening DR assessed from retinal photographs. The relationship between metabolites and DR outcomes was assessed using multivariate logistic regression models, and metabolites significant after Bonferroni correction were meta-analyzed. Among serum/plasma metabolites, lower levels of tyrosine and cholesterol esters to total lipids ratio in IDL and higher levels of creatinine were positively associated with all three outcomes of DR (all p < 0.005). Among urinary metabolites, lower levels of citrate, ethanolamine, formate, and hypoxanthine were positively associated with all three DR outcomes (all p < 0.005). Higher levels of serum/plasma 3-hydroxybutyrate and lower levels of urinary 3-hydroxyisobutyrate were associated with VTDR. Comprehensive metabolic profiling in three large Asian cohorts with DR demonstrated alterations in serum/plasma and urinary metabolites mostly related to amino acids, lipoprotein subclasses, kidney function, and glycolysis.

COVID-19 awareness, knowledge and perception towards digital health in an urban multi-ethnic Asian population.

This study aimed to determine COVID-19-related awareness, knowledge, impact and preparedness among elderly Asians; and to evaluate their acceptance towards digital health services amidst the pandemic. 523 participants (177 Malays, 171 Indians, 175 Chinese) were recruited and underwent standardised phone interview during Singapore's lockdown period (07 April till 01 June 2020). Multivariable logistic regression models were performed to evaluate the associations between demographic, socio-economic, lifestyle, and systemic factors, with COVID-19 awareness, knowledge, preparedness, well-being and digital health service acceptance. The average perception score on the seriousness of COVID-19 was 7.6 ± 2.4 (out of 10). 75.5% of participants were aware that COVID-19 carriers can be asymptomatic. Nearly all (≥ 90%) were aware of major prevention methods for COVID-19 (i.e. wearing of mask, social distancing). 66.2% felt prepared for the pandemic, and 86.8% felt confident with government's handling and measures. 78.4% felt their daily routine was impacted. 98.1% reported no prior experience in using digital health services, but 52.2% felt these services would be helpful to reduce non-essential contact. 77.8% were uncomfortable with artificial intelligence software interpreting their medical results. In multivariable analyses, Chinese participants felt less prepared, and more likely felt impacted by COVID-19. Older and lower income participants were less likely to use digital health services. In conclusion, we observed a high level of awareness and knowledge on COVID-19. However, acceptance towards digital health service was low. These findings are valuable for examining the effectiveness of COVID-19 communication in Singapore, and the remaining gaps in digital health adoption among elderly.

Visual Impairment, Major Eye Diseases, and Mortality in a Multi-Ethnic Asian Population and a Meta-analysis of Prospective Studies.

PURPOSE: Vision impairment (VI) is associated with poor quality of life and increased risk of falls. Few prospective data are available on Asians. This study investigates the longitudinal impact of VI and the major eye diseases on mortality risk in Asians. DESIGN: Prospective cohort study with meta-analysis. METHODS: We conducted a multi-ethnic prospective study of adults (40-80 years old) in the Singapore Epidemiology of Eye Diseases Study (baseline: 2004-2011). All-cause mortality was obtained from the National Death Registry until May 2017. VI was defined by best-corrected visual acuity (BCVA) <20/40 in the better eye. Major eye diseases were assessed using standard protocols. We examined associations using multivariate-adjusted Cox proportional hazards regression models. Finally, we conducted a meta-analysis of the associations between VI and mortality. RESULTS: Of 9,986 participants, 1,210 deaths occurred (12.1%) over a median follow-up of 8.8 years. Compared to participants with normal vision, persons with VI had increased risk of mortality (hazards ratio [HR]: 1.53; 95% confidence interval [CI:] 1.30-1.81) in multivariate models. In ethnicity-specific analyses, this association was significant across Chinese (HR: 1.63; 95% CI: 1.08-2.48); Malays (HR: 1.31; 95% CI: 1.06-1.62); and Indians (HR: 2.25; 95% CI: 1.61-3.15). Cataract, under-corrected refractive errors (URE), and diabetic retinopathy (DR) were significantly associated with mortality (HRs: 1.30, 1.22, and 1.54, respectively). In a meta-analysis of 12 studies including 58,034 persons, VI was associated with 30% increased risk of mortality (HR: 1.3; 95% CI: 1.2-1.5). CONCLUSIONS: In this multi-ethnic Asian population, VI and preventable eye conditions (cataract, URE, and DR) were associated with mortality, emphasizing the need for early detection and intervention to prevent and treat VI and major eye diseases.