Deep learning-based image quality assessment for optical coherence tomography macular scans: a multicentre study.

AIMS: To develop and externally test deep learning (DL) models for assessing the image quality of three-dimensional (3D) macular scans from Cirrus and Spectralis optical coherence tomography devices. METHODS: We retrospectively collected two data sets including 2277 Cirrus 3D scans and 1557 Spectralis 3D scans, respectively, for training (70%), fine-tuning (10%) and internal validation (20%) from electronic medical and research records at The Chinese University of Hong Kong Eye Centre and the Hong Kong Eye Hospital. Scans with various eye diseases (eg, diabetic macular oedema, age-related macular degeneration, polypoidal choroidal vasculopathy and pathological myopia), and scans of normal eyes from adults and children were included. Two graders labelled each 3D scan as gradable or ungradable, according to standardised criteria. We used a 3D version of the residual network (ResNet)-18 for Cirrus 3D scans and a multiple-instance learning pipline with ResNet-18 for Spectralis 3D scans. Two deep learning (DL) models were further tested via three unseen Cirrus data sets from Singapore and five unseen Spectralis data sets from India, Australia and Hong Kong, respectively. RESULTS: In the internal validation, the models achieved the area under curves (AUCs) of 0.930 (0.885-0.976) and 0.906 (0.863-0.948) for assessing the Cirrus 3D scans and Spectralis 3D scans, respectively. In the external testing, the models showed robust performance with AUCs ranging from 0.832 (0.730-0.934) to 0.930 (0.906-0.953) and 0.891 (0.836-0.945) to 0.962 (0.918-1.000), respectively. CONCLUSIONS: Our models could be used for filtering out ungradable 3D scans and further incorporated with a disease-detection DL model, allowing a fully automated eye disease detection workflow.

Prevalence, associated risk factors; and patient and economic impact of multiple sensory impairment in a multi-ethnic elderly population in Singapore: the PIONEER study.

BACKGROUND: To determine the prevalence, risk factors; and impact on patient health and economic outcomes across the laterality spectrum of multiple sensory impairment (MSI) in a multi-ethnic older Asian population. METHODS: In this population-based study of Singaporeans aged ≥ 60 years, MSI was defined as concomitant vision (visual acuity > 0.3 logMAR), hearing (pure-tone air conduction average > 25 dB), and olfactory (score < 12 on the Sniffin' Sticks test) impairments across the spectrum of laterality (any, unilateral, combination [of unilateral and bilateral], and bilateral). RESULTS: Among 2,057 participants (mean ± SD 72.2 ± 0.2 years; 53.1% female), the national census-adjusted prevalence rates of any, unilateral, combination, and bilateral MSI were 20.6%, 1.2%, 12.2%, and 7.2%, respectively. Older age, male gender, low socioeconomic status (SES), and smoking (all p < 0.05) were independently associated with higher likelihood of any MSI. Compared to those with no sensory loss, those with MSI had significantly decreased mobility (range 5.4%-9.2%), had poor functioning (OR range 3.25-3.45) and increased healthcare costs (range 4-6 folds) across the laterality spectrum. Additionally, bilateral MSI had a significant decrease in HRQoL (5.5%, p = 0.012). CONCLUSIONS: MSI is a highly prevalent medical condition, with 1 in 5; and almost 1 in 10 community-dwelling older Asians having any and bilateral MSI, respectively, with a higher likelihood in men, smokers, and those with low SES. Critically, MSI has a substantial negative impact on patient health and economic outcomes across the laterality spectrum. Sensory testing is critical to detect and refer individuals with MSI for management to improve their functional independence and QoL.

Blood biomarkers improve the prediction of prevalent and incident severe chronic kidney disease.

BACKGROUND: The prevalence of chronic kidney disease (CKD) is high. Identification of cases with CKD or at high risk of developing it is important to tailor early interventions. The objective of this study was to identify blood metabolites associated with prevalent and incident severe CKD, and to quantify the corresponding improvement in CKD detection and prediction. METHODS: Data from four cohorts were analyzed: Singapore Epidemiology of Eye Diseases (SEED) (n = 8802), Copenhagen Chronic Kidney Disease (CPH) (n = 916), Singapore Diabetic Nephropathy (n = 714), and UK Biobank (UKBB) (n = 103,051). Prevalent CKD (stages 3-5) was defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2; incident severe CKD as CKD-related mortality or kidney failure occurring within 10 years. We used multivariable regressions to identify, among 146 blood metabolites, those associated with CKD, and quantify the corresponding increase in performance. RESULTS: Chronic kidney disease prevalence (stages 3-5) and severe incidence were 11.4% and 2.2% in SEED, and 2.3% and 0.2% in UKBB. Firstly, phenylalanine (Odds Ratio [OR] 1-SD increase = 1.83 [1.73, 1.93]), tyrosine (OR = 0.75 [0.71, 0.79]), docosahexaenoic acid (OR = 0.90 [0.85, 0.95]), citrate (OR = 1.41 [1.34, 1.47]) and triglycerides in medium high density lipoprotein (OR = 1.07 [1.02, 1.13]) were associated with prevalent stages 3-5 CKD. Mendelian randomization analyses suggested causal relationships. Adding these metabolites beyond traditional risk factors increased the area under the curve (AUC) by 3% and the sensitivity by 7%. Secondly, lactate (HR = 1.33 [1.08, 1.64]) and tyrosine (HR = 0.74 [0.58, 0.95]) were associated with incident severe CKD among individuals with eGFR < 90 mL/min/1.73 m2 at baseline. These metabolites increased the c-index by 2% and sensitivity by 5% when added to traditional risk factors. CONCLUSION: The performance improvements of CKD detection and prediction achieved by adding metabolites to traditional risk factors are modest and further research is necessary to fully understand the clinical implications of these findings.

Impact of Age on the Characteristics of Corneal Nerves and Corneal Epithelial Cells in Healthy Adults.

PURPOSE: The aim of this study was to investigate age-related changes in corneal nerves and corneal epithelial cell parameters and to establish age-adjusted reference values. METHODS: A total of 7025 corneal nerve images and 4215 corneal epithelial images obtained using in vivo confocal microscopy from 281 eyes of 143 healthy participants were included. Seven corneal nerve parameters and 3 corneal epithelial cell parameters were quantified using 2 automatic analytic software and analyzed across 6 age groups ranging from 21 to 80 years. RESULTS: There was a declining trend in all 7 nerve parameters with advancing age. In particular, corneal nerve fiber length and corneal nerve fiber density demonstrated a significant decrease in subjects aged 65 years or older compared with subjects younger than 65 years (10.8 ± 2.6 mm/mm 2 vs. 9.9 ± 2.0 mm/mm 2 , P = 0.011 in corneal nerve fiber length; 15.8 ± 5.2 fibers/mm 2 vs. 14.4 ± 4.3 fibers/mm 2 , P = 0.046 in corneal nerve fiber density), whereas corneal nerve fractal dimension demonstrated a borderline significant decrease ( P = 0.057). Similarly, there was a general declining trend in all epithelial cell parameters with advancing age. Corneal epithelial cell circularity was significantly lower in subjects aged 65 years and older as compared to subjects younger than 65 years (0.722 ± 0.021 µm 2 vs. 0.714 ± 0.021 µm 2 ; P = 0.011). CONCLUSIONS: Advancing age results in reduced corneal nerve metrics and alteration of corneal cell morphology. Aging effects should be considered when evaluating patients with corneal neuropathy.

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.

A deep learning system for retinal vessel calibre improves cardiovascular risk prediction in Asians with chronic kidney disease.

Backgraund: Cardiovascular disease (CVD) and mortality is elevated in chronic kidney disease (CKD). Retinal vessel calibre in retinal photographs is associated with cardiovascular risk and automated measurements may aid CVD risk prediction. Methods: Retrospective cohort study of 860 Chinese, Malay and Indian participants aged 40-80 years with CKD [estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2] who attended the baseline visit (2004-2011) of the Singapore Epidemiology of Eye Diseases Study. Retinal vessel calibre measurements were obtained by a deep learning system (DLS). Incident CVD [non-fatal acute myocardial infarction (MI) and stroke, and death due to MI, stroke and other CVD] in those who were free of CVD at baseline was ascertained until 31 December 2019. Risk factors (established, kidney, and retinal features) were examined using Cox proportional hazards regression models. Model performance was assessed for discrimination, fit, and net reclassification improvement (NRI). Results: Incident CVD occurred in 289 (33.6%) over mean follow-up of 9.3 (4.3) years. After adjusting for established cardiovascular risk factors, eGFR [adjusted HR 0.98 (95% CI: 0.97-0.99)] and retinal arteriolar narrowing [adjusted HR 1.40 (95% CI: 1.17-1.68)], but not venular dilation, were independent predictors for CVD in CKD. The addition of eGFR and retinal features to established cardiovascular risk factors improved model discrimination with significantly better fit and better risk prediction according to the low (<15%), intermediate (15-29.9%), and high (30% or more) risk categories (NRI 5.8%), and with higher risk thresholds (NRI 12.7%). Conclusions: Retinal vessel calibre measurements by DLS were significantly associated with incident CVD independent of established CVD risk factors. Addition of kidney function and retinal vessel calibre parameters may improve CVD risk prediction among Asians with CKD.

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.

Large language models and their impact in ophthalmology.

The advent of generative artificial intelligence and large language models has ushered in transformative applications within medicine. Specifically in ophthalmology, large language models offer unique opportunities to revolutionise digital eye care, address clinical workflow inefficiencies, and enhance patient experiences across diverse global eye care landscapes. Yet alongside these prospects lie tangible and ethical challenges, encompassing data privacy, security, and the intricacies of embedding large language models into clinical routines. This Viewpoint highlights the promising applications of large language models in ophthalmology, while weighing up the practical and ethical barriers towards their real-world implementation. This Viewpoint seeks to stimulate broader discourse on the potential of large language models in ophthalmology and to galvanise both clinicians and researchers into tackling the prevailing challenges and optimising the benefits of large language models while curtailing the associated risks.

Gene-educational attainment interactions in a multi-population genome-wide meta-analysis identify novel lipid loci.

Introduction: Educational attainment, widely used in epidemiologic studies as a surrogate for socioeconomic status, is a predictor of cardiovascular health outcomes. Methods: A two-stage genome-wide meta-analysis of low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglyceride (TG) levels was performed while accounting for gene-educational attainment interactions in up to 226,315 individuals from five population groups. We considered two educational attainment variables: "Some College" (yes/no, for any education beyond high school) and "Graduated College" (yes/no, for completing a 4-year college degree). Genome-wide significant (p < 5 × 10-8) and suggestive (p < 1 × 10-6) variants were identified in Stage 1 (in up to 108,784 individuals) through genome-wide analysis, and those variants were followed up in Stage 2 studies (in up to 117,531 individuals). Results: In combined analysis of Stages 1 and 2, we identified 18 novel lipid loci (nine for LDL, seven for HDL, and two for TG) by two degree-of-freedom (2 DF) joint tests of main and interaction effects. Four loci showed significant interaction with educational attainment. Two loci were significant only in cross-population analyses. Several loci include genes with known or suggested roles in adipose (FOXP1, MBOAT4, SKP2, STIM1, STX4), brain (BRI3, FILIP1, FOXP1, LINC00290, LMTK2, MBOAT4, MYO6, SENP6, SRGAP3, STIM1, TMEM167A, TMEM30A), and liver (BRI3, FOXP1) biology, highlighting the potential importance of brain-adipose-liver communication in the regulation of lipid metabolism. An investigation of the potential druggability of genes in identified loci resulted in five gene targets shown to interact with drugs approved by the Food and Drug Administration, including genes with roles in adipose and brain tissue. Discussion: Genome-wide interaction analysis of educational attainment identified novel lipid loci not previously detected by analyses limited to main genetic effects.

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.

Genome-Wide Association Analysis of Protein-Coding Variants in IgA Nephropathy.

SIGNIFICANCE STATEMENT: Genome-wide association studies have identified nearly 20 IgA nephropathy susceptibility loci. However, most nonsynonymous coding variants, particularly ones that occur rarely or at a low frequency, have not been well investigated. The authors performed a chip-based association study of IgA nephropathy in 8529 patients with the disorder and 23,224 controls. They identified a rare variant in the gene encoding vascular endothelial growth factor A (VEGFA) that was significantly associated with a two-fold increased risk of IgA nephropathy, which was further confirmed by sequencing analysis. They also identified a novel common variant in PKD1L3 that was significantly associated with lower haptoglobin protein levels. This study, which was well-powered to detect low-frequency variants with moderate to large effect sizes, helps expand our understanding of the genetic basis of IgA nephropathy susceptibility. BACKGROUND: Genome-wide association studies have identified nearly 20 susceptibility loci for IgA nephropathy. However, most nonsynonymous coding variants, particularly those occurring rarely or at a low frequency, have not been well investigated. METHODS: We performed a three-stage exome chip-based association study of coding variants in 8529 patients with IgA nephropathy and 23,224 controls, all of Han Chinese ancestry. Sequencing analysis was conducted to investigate rare coding variants that were not covered by the exome chip. We used molecular dynamic simulation to characterize the effects of mutations of VEGFA on the protein's structure and function. We also explored the relationship between the identified variants and the risk of disease progression. RESULTS: We discovered a novel rare nonsynonymous risk variant in VEGFA (odds ratio, 1.97; 95% confidence interval [95% CI], 1.61 to 2.41; P = 3.61×10 -11 ). Further sequencing of VEGFA revealed twice as many carriers of other rare variants in 2148 cases compared with 2732 controls. We also identified a common nonsynonymous risk variant in PKD1L3 (odds ratio, 1.16; 95% CI, 1.11 to 1.21; P = 1.43×10 -11 ), which was associated with lower haptoglobin protein levels. The rare VEGFA mutation could cause a conformational change and increase the binding affinity of VEGFA to its receptors. Furthermore, this variant was associated with the increased risk of kidney disease progression in IgA nephropathy (hazard ratio, 2.99; 95% CI, 1.09 to 8.21; P = 0.03). CONCLUSIONS: Our study identified two novel risk variants for IgA nephropathy in VEGFA and PKD1L3 and helps expand our understanding of the genetic basis of IgA nephropathy susceptibility.

Contribution of common and rare variants to Asian neovascular age-related macular degeneration subtypes.

Neovascular age-related macular degeneration (nAMD), along with its clinical subtype known as polypoidal choroidal vasculopathy (PCV), are among the leading causes of vision loss in elderly Asians. In a genome-wide association study (GWAS) comprising 3,128 nAMD (1,555 PCV and 1,573 typical nAMD), and 5,493 controls of East Asian ancestry, we identify twelve loci, of which four are novel ([Formula: see text]). Substantial genetic sharing between PCV and typical nAMD is noted (rg = 0.666), whereas collagen extracellular matrix and fibrosis-related pathways are more pronounced for PCV. Whole-exome sequencing in 259 PCV patients revealed functional rare variants burden in collagen type I alpha 1 chain gene (COL1A1; [Formula: see text]) and potential enrichment of functional rare mutations at AMD-associated loci. At the GATA binding protein 5 (GATA5) locus, the most significant GWAS novel loci, the expressions of genes including laminin subunit alpha 5 (Lama5), mitochondrial ribosome associated GTPase 2 (Mtg2), and collagen type IX alpha 3 chain (Col9A3), are significantly induced during retinal angiogenesis and subretinal fibrosis in murine models. Furthermore, retinoic acid increased the expression of LAMA5 and MTG2 in vitro. Taken together, our data provide insights into the genetic basis of AMD pathogenesis in the Asian population.

Eyes as the windows into cardiovascular disease in the era of big data.

Cardiovascular disease (CVD) is a major cause of mortality and morbidity worldwide and imposes significant socioeconomic burdens, especially with late diagnoses. There is growing evidence of strong correlations between ocular images, which are information-dense, and CVD progression. The accelerating development of deep learning algorithms (DLAs) is a promising avenue for research into CVD biomarker discovery, early CVD diagnosis, and CVD prognostication. We review a selection of 17 recent DLAs on the less-explored realm of DL as applied to ocular images to produce CVD outcomes, potential challenges in their clinical deployment, and the path forward. The evidence for CVD manifestations in ocular images is well documented. Most of the reviewed DLAs analyze retinal fundus photographs to predict CV risk factors, in particular hypertension. DLAs can predict age, sex, smoking status, alcohol status, body mass index, mortality, myocardial infarction, stroke, chronic kidney disease, and hematological disease with significant accuracy. While the cardio-oculomics intersection is now burgeoning, very much remain to be explored. The increasing availability of big data, computational power, technological literacy, and acceptance all prime this subfield for rapid growth. We pinpoint the specific areas of improvement toward ubiquitous clinical deployment: increased generalizability, external validation, and universal benchmarking. DLAs capable of predicting CVD outcomes from ocular inputs are of great interest and promise to individualized precision medicine and efficiency in the provision of health care with yet undetermined real-world efficacy with impactful initial results.

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.

Angle closure extent, anterior segment dimensions and intraocular pressure.

AIM: To investigate the association between the extent of iridotrabecular contact and other quantitative anterior segment dimensions measured by swept-source optical coherence tomography (SS-OCT; CASIA SS-1000, Tomey, Nagoya, Japan) with intraocular pressure (IOP). METHODS: Cross-sectional study. All subjects who were ≥50 years with no history of glaucoma, ocular surgery or trauma, underwent SS-OCT imaging (eight equally spaced radial scans), Goldman applanation tonometry and gonioscopy on the same day. We measured iridotrabecular contact (ITC) index and area, total volume of trabeculo-iris space area and angle opening distance at 500 and 750 from the scleral spur (TISA 500 and 750, AOD 500 and 750, respectively), anterior chamber depth (ACD), volume, area and width, pupil diameter, lens vault and iris volume.Their relationship with IOP (dependent variable) was assessed by locally weighted scatterplot smoothing (Lowess) regression with change-point analysis and generalised additive models adjusted for confounders. RESULTS: 2027 right eyes of mostly Chinese Singaporeans (90%) were analysed. ITC index above a threshold of ~60% (95% CI 34% to 92%) was significantly associated with higher IOP. Independent of the extent of ITC, ACD was also significantly associated with higher IOP below a threshold of 2.5 mm (95% CI 2.33 mm to 2.71 mm). Greater ITC index and shallower ACD had a joint association with IOP. A model including ACD and ITC index was more predictive of IOP than a model considering these variables separately, particularly for women with gonioscopically closed angles (R2 52.7%, p<0.05). CONCLUSIONS: The extent of angle closure and the ACD below a certain threshold had a significant joint association with IOP. These parameters, as biometrical surrogates of mechanical obstruction of the aqueous outflow, may jointly contribute to elevated IOP, particularly in women with gonioscopic angle closure.

Outcome and prognostic factors of unexpected ovarian carcinomas.

BACKGROUND: We investigated risk factors influencing the outcome of unexpected ovarian carcinomas. METHODS: We reviewed the ovarian carcinoma patients treated at atertiary medical institution between 2000 and 2017 and analyze the clinico-pathological characteristics, treatment strategies, recurrence status, and outcome. RESULTS: A total of 112 women (65 primary laparoscopic surgery [LSC] and 47 laparotomic surgery [LAPA]) were included in the analysis. The LSC group had smaller ovarian tumors (10.5 ± 7.3 cm vs. 16.6 ± 8.7 cm, p = 0.031) and higher incidence of subsequent staging surgery (56.9% vs. 25.5%, p = 0.0001) compared to the LAPA group. There were 98/112 (86.6%) of early stages (I/II) diseases. The difference between the recurrent rate (27.7% vs. 31.9%), disease-free survival (DFS), and overall survival (OS) were not significant among surgical groups. In the multivariate analysis, FIGO stage (stage II hazard ratio [HR] 6.61, p = 0.007; stage III HR 8.40, p = 0.002) was the only prognostic factor for DFS. FIGO stage (stage II HR 20.78, p = 0.0001; stage III HR 7.99, p = 0.017), histological type (mucinous HR 12.49, p = 0.036), and tumor grade (grade 3 HR 35.01, p = 0.003) were independent prognostic factors for OS, while women with latency >28 days from primary to staging surgery had significantly poorer OS (p = 0.008). Women with latency >28 days between primary surgery and adjuvant chemotherapy had similar DFS (p = 0.31) and a trend of poorer OS (p = 0.064). CONCLUSIONS: The prognosis of unexpected ovarian cancer is independent from the primary surgical procedure and comprehensive staging surgery should be performed at close proximity after the diagnosis of unexpected ovarian malignancy.

Serum Cholesterol Efflux Capacity in Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy.

Purpose: To investigate serum cholesterol efflux capacity (the ability of the serum to accept cholesterol) and factors that regulate it using nuclear magnetic resonance-quantified measures of lipoprotein particle composition and size and apolipoproteins metrics in patients with age-related macular degeneration (AMD). Design: Case-control study. Participants: Four hundred two serum samples from 80 patients with early AMD (eAMD), and 212 patients with neovascular AMD (nAMD), including 80 with typical nAMD (tAMD) and 132 with polypoidal choroidal vasculopathy (PCV), and 110 age- and gender matched control participants. Methods: Serum from participants showed cholesterol efflux capacity measured using in vitro cell assays and lipoprotein subfractions measured using nuclear magnetic resonance (Nightingale, Ltd). Associations between cholesterol efflux capacity (measured in percentage) and lipid subfractions were investigated in the patients and control participants. Main Outcome Measures: Cholesterol efflux capacity and lipid subfractions in control, eAMD, and nAMD. Associations between HDL subfractions and cholesterol efflux capacity. Results: Cholesterol efflux capacity was higher in patients with eAMD (68.0 ± 11.3% [mean ± standard deviation]) and nAMD (75.9 ± 27.7%) than in the control participants (56.9 ± 16.7%) after adjusting for age, gender, and use of lipid-lowering drug (P < 0.0001). Nuclear magnetic resonance lipidomics demonstrated that the mean diameter of HDL was larger both in eAMD (9.96 ± 0.27 mm [mean ± standard deviation]) and PCV (9.97 ± 0.23 mm) compared with that of the control participants (9.84 ± 0.24 mm; P = 0.0001 for both). Among the 28 HDL subfractions, most of the small, medium, and large HDLs, but none of the 7 extra large HDLs fractions, were associated moderately with cholesterol efflux capacity in eAMD and PCV (R = 0.149-0.277). Conclusions: Serum cholesterol efflux capacity was increased in eAMD and PCV, but not tAMD, possibly reflecting differential underlying pathophysiologic features of lipid dysregulation in tAMD and PCV. Further studies should be directed toward investigating the diverse biological activities of HDL in AMD, including macular pigment transport, regulation of inflammation, and local cholesterol transport system.

Impact of Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) GFR Estimating Equations on CKD Prevalence and Classification Among Asians.

Background: In 2021, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) validated a new equation for estimated glomerular filtration rate (eGFR). However, this new equation is not ethnic-specific, and prevalence of CKD in Asians is known to differ from other ethnicities. This study evaluates the impact of the 2009 and 2021 creatinine-based eGFR equations on the prevalence of CKD in multiple Asian cohorts. Methods: Eight population-based studies from China, India, Russia (Asian), Singapore and South Korea provided individual-level data (n = 67,233). GFR was estimated using both the 2009 CKD-EPI equation developed using creatinine, age, sex, and race (eGFRcr [2009, ASR]) and the 2021 CKD-EPI equation developed without race (eGFRcr [2021, AS]). CKD was defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m2 (G3-G5). Prevalence of eGFR categories was compared within each study and within subgroups of age, sex, body mass index (BMI), diabetes, and hypertension status. The extent of reclassification was examined using net reclassification improvement (NRI). Findings: Of 67,233 adults, CKD prevalence was 8.6% (n = 5800/67,233) using eGFRcr (2009, ASR) and 6.4% (n = 4307/67,233) using eGFRcr (2021, AS). With the latter, CKD prevalence was reduced across all eight studies, ranging from -7.0% (95% CI -8.5% to -5.4%) to -0.4% (-1.3% to 0.5%), and across all subgroups except those in the BMI < 18.5% subgroup. Net reclassification index (NRI) was significant at -2.33% (p < 0.001). No individuals were reclassified as a higher (more severe) eGFR category, while 1.7%-4.2% of individuals with CKD were reclassified as one eGFR category lower when eGFRcr (2021, AS) rather than eGFRcr (2009, ASR) was used. Interpretation: eGFRcr (2021, AS) consistently provided reduced CKD prevalence and higher estimation of GFR among Asian cohorts than eGFRcr (2009, ASR). Based on current risk-stratified approaches to CKD management, more patients reclassified to lower-risk GFR categories could help reduce inappropriate care and its associated adverse effects among Asian renal patients. Comparison of both equations to predict progression to renal failure or adverse outcomes using prospective studies are warranted. Funding: National Medical Research Council, Singapore.

Smartphone-Acquired Anterior Segment Images for Deep Learning Prediction of Anterior Chamber Depth: A Proof-of-Concept Study.

Purpose: To develop a deep learning (DL) algorithm for predicting anterior chamber depth (ACD) from smartphone-acquired anterior segment photographs. Methods: For algorithm development, we included 4,157 eyes from 2,084 Chinese primary school students (aged 11-15 years) from Mojiang Myopia Progression Study (MMPS). All participants had with ACD measurement measured with Lenstar (LS 900) and anterior segment photographs acquired from a smartphone (iPhone Xs), which was mounted on slit lamp and under diffuses lighting. The anterior segment photographs were randomly selected by person into training (80%, no. of eyes = 3,326) and testing (20%, no. of eyes = 831) dataset. We excluded participants with intraocular surgery history or pronounced corneal haze. A convolutional neural network was developed to predict ACD based on these anterior segment photographs. To determine the accuracy of our algorithm, we measured the mean absolute error (MAE) and coefficient of determination (R 2) were evaluated. Bland Altman plot was used to illustrate the agreement between DL-predicted and measured ACD values. Results: In the test set of 831 eyes, the mean measured ACD was 3.06 ± 0.25 mm, and the mean DL-predicted ACD was 3.10 ± 0.20 mm. The MAE was 0.16 ± 0.13 mm, and R 2 was 0.40 between the predicted and measured ACD. The overall mean difference was -0.04 ± 0.20 mm, with 95% limits of agreement ranging between -0.43 and 0.34 mm. The generated saliency maps showed that the algorithm mainly utilized central corneal region (i.e., the site where ACD is clinically measured typically) in making its prediction, providing further plausibility to the algorithm's prediction. Conclusions: We developed a DL algorithm to estimate ACD based on smartphone-acquired anterior segment photographs. Upon further validation, our algorithm may be further refined for use as a ACD screening tool in rural localities where means of assessing ocular biometry is not readily available. This is particularly important in China where the risk of primary angle closure disease is high and often undetected.

Retinal vascular profile in predicting incident cardiometabolic diseases among individuals with diabetes.

OBJECTIVE: To determine the longitudinal associations between retinal vascular profile (RVP) and four major cardiometabolic diseases; and to quantify the predictive improvements when adding RVP beyond traditional risk factors in individuals with diabetes. METHODS: Subjects were enrolled from the Singapore Epidemiology of Eye Disease (SEED) study, a multi-ethnic population-based cohort. Four incident cardiometabolic diseases, calculated over a ~ 6-year period, were considered: cardiovascular disease (CVD), hypertension (HTN), diabetic kidney disease (DKD), and hyperlipidemia (HLD). The RVP-vessel tortuosity, branching angle, branching coefficient, fractal dimension, vessel caliber, and DR status-was characterized at baseline using a computer-assisted program. Traditional risk factors at baseline included age, gender, ethnicity, smoking, blood pressure (BP), HbA1c, estimated glomerular filtration rate (eGFR), or cholesterol. The improvements in predictive performance when adding RVP (compared with only traditional risk factors) was calculated using several metrics including area under the receiver operating characteristics curve (AUC) and net reclassification improvement (NRI). RESULTS: Among 1770 individuals with diabetes, incidences were 6.3% (n = 79/1259) for CVD, 48.7% (n = 166/341) for HTN, 14.6% (n = 175/1199) for DKD, and 59.4% (n = 336/566) for HLD. DR preceded the onset of CVD (RR 1.85[1.14;3.00]) and DKD (1.44 [1.06;1.96]). Narrower arteriolar caliber preceding the onset of HTN (0.84 [0.72;0.99]), and changes in arteriolar branching angle preceded the onset of CVD (0.78 [0.62;0.98]) and HTN (1.15 [1.03;1.29]). The largest predictive improvement was found for HTN with AUC increment of 3.4% (p = .027) and better reclassification of 11.4% of the cases and 4.6% of the controls (p = .008). CONCLUSION: We found that RVPs improved the prediction of HTN in individuals with diabetes, but add limited information for CVD, DKD, and HLD predictions.