Search

Background In adult patients with high myopia (HM), progressive axial elongation poses a significant risk for the development of subsequent ocular complications that may lead to visual impairment. Effective strategies to reduce or prevent further axial elongation in highly myopic adult patients have not been available so far. Recent studies suggested that medically lowering intraocular pressure (IOP) may reduce axial elongation.Objective This clinical randomised controlled trial (RCT) aims to evaluate the efficacy of medical IOP reduction in adult patients with progressive HM (PHM).Trial design Single-centre, open-label, prospective RCT.Methods This RCT will recruit 152 participants with PHM at the Zhongshan Ophthalmic Center (ZOC). Randomised in a ratio of 1:1, participants will receive IOP-lowering eyedrops (intervention group) or will be followed without treatment (control group) for 12 months. Follow-up visits will be conducted at 1, 6 and 12 months after baseline. Only one eye per eligible participant will be included for analysis. The primary outcome is the change in axial length (AL) within the study period of 12 months. Secondary outcomes include the incidence and progression of visual field (VF) defects, changes in optic disc morphology and incidence and progression of myopic maculopathy. Difference in AL changes between the two groups will be analysed using linear regression analysis. For the secondary outcomes, a multifactor Poisson regression within a generalised linear model will be used to estimate the relative risk of progression in VF defects and myopic maculopathy, and the rate of thinning in retinal nerve fibre layer and ganglion cell-inner plexiform will be assessed through Kaplan-Meier curves and log-rank tests.Ethics and dissemination Full ethics approval for this trial has been obtained from the Ethics Committee of ZOC, Sun Yat-sen University, China (ID: 2023KYPJ110). Results of this trial will be disseminated through peer-reviewed journals and conference presentations.Trial registration number NCT05850936.

Abstract Background Cataract diagnosis typically requires in-person evaluation by an ophthalmologist. However, color fundus photography (CFP) is widely performed outside ophthalmology clinics, which could be exploited to increase the accessibility of cataract screening by automated detection. Methods DeepOpacityNet was developed to detect cataracts from CFP and highlight the most relevant CFP features associated with cataracts. We used 17,514 CFPs from 2573 AREDS2 participants curated from the Age-Related Eye Diseases Study 2 (AREDS2) dataset, of which 8681 CFPs were labeled with cataracts. The ground truth labels were transferred from slit-lamp examination of nuclear cataracts and reading center grading of anterior segment photographs for cortical and posterior subcapsular cataracts. DeepOpacityNet was internally validated on an independent test set (20%), compared to three ophthalmologists on a subset of the test set (100 CFPs), externally validated on three datasets obtained from the Singapore Epidemiology of Eye Diseases study (SEED), and visualized to highlight important features. Results Internally, DeepOpacityNet achieved a superior accuracy of 0.66 (95% confidence interval (CI): 0.64–0.68) and an area under the curve (AUC) of 0.72 (95% CI: 0.70–0.74), compared to that of other state-of-the-art methods. DeepOpacityNet achieved an accuracy of 0.75, compared to an accuracy of 0.67 for the ophthalmologist with the highest performance. Externally, DeepOpacityNet achieved AUC scores of 0.86, 0.88, and 0.89 on SEED datasets, demonstrating the generalizability of our proposed method. Visualizations show that the visibility of blood vessels could be characteristic of cataract absence while blurred regions could be characteristic of cataract presence. Conclusions DeepOpacityNet could detect cataracts from CFPs in AREDS2 with performance superior to that of ophthalmologists and generate interpretable results. The code and models are available at https://github.com/ncbi/DeepOpacityNet ( https://doi.org/10.5281/zenodo.10127002 ).

Abstract 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

Abstract Background Currently in the United Kingdom, cardiovascular disease (CVD) risk assessment is based on the QRISK3 score, in which 10% 10-year CVD risk indicates clinical intervention. However, this benchmark has limited efficacy in clinical practice and the need for a more simple, non-invasive risk stratification tool is necessary. Retinal photography is becoming increasingly acceptable as a non-invasive imaging tool for CVD. Previously, we developed a novel CVD risk stratification system based on retinal photographs predicting future CVD risk. This study aims to further validate our biomarker, Reti-CVD, (1) to detect risk group of ≥ 10% in 10-year CVD risk and (2) enhance risk assessment in individuals with QRISK3 of 7.5–10% (termed as borderline-QRISK3 group) using the UK Biobank. Methods Reti-CVD scores were calculated and stratified into three risk groups based on optimized cut-off values from the UK Biobank. We used Cox proportional-hazards models to evaluate the ability of Reti-CVD to predict CVD events in the general population. C-statistics was used to assess the prognostic value of adding Reti-CVD to QRISK3 in borderline-QRISK3 group and three vulnerable subgroups. Results Among 48,260 participants with no history of CVD, 6.3% had CVD events during the 11-year follow-up. Reti-CVD was associated with an increased risk of CVD (adjusted hazard ratio [HR] 1.41; 95% confidence interval [CI], 1.30–1.52) with a 13.1% (95% CI, 11.7–14.6%) 10-year CVD risk in Reti-CVD-high-risk group. The 10-year CVD risk of the borderline-QRISK3 group was greater than 10% in Reti-CVD-high-risk group (11.5% in non-statin cohort [n = 45,473], 11.5% in stage 1 hypertension cohort [n = 11,966], and 14.2% in middle-aged cohort [n = 38,941]). C statistics increased by 0.014 (0.010–0.017) in non-statin cohort, 0.013 (0.007–0.019) in stage 1 hypertension cohort, and 0.023 (0.018–0.029) in middle-aged cohort for CVD event prediction after adding Reti-CVD to QRISK3. Conclusions Reti-CVD has the potential to identify individuals with ≥ 10% 10-year CVD risk who are likely to benefit from earlier preventative CVD interventions. For borderline-QRISK3 individuals with 10-year CVD risk between 7.5 and 10%, Reti-CVD could be used as a risk enhancer tool to help improve discernment accuracy, especially in adult groups that may be pre-disposed to CVD.

Background Genome-wide association studies for glycemic traits have identified hundreds of loci associated with these biomarkers of glucose homeostasis. Despite this success, the challenge remains to link variant associations to genes, and underlying biological pathways. Methods To identify coding variant associations which may pinpoint effector genes at both novel and previously established genome-wide association loci, we performed meta-analyses of exome-array studies for four glycemic traits: glycated hemoglobin (HbA1c, up to 144,060 participants), fasting glucose (FG, up to 129,665 participants), fasting insulin (FI, up to 104,140) and 2hr glucose post-oral glucose challenge (2hGlu, up to 57,878). In addition, we performed network and pathway analyses. Results Single-variant and gene-based association analyses identified coding variant associations at more than 60 genes, which when combined with other datasets may be useful to nominate effector genes. Network and pathway analyses identified pathways related to insulin secretion, zinc transport and fatty acid metabolism. HbA1c associations were strongly enriched in pathways related to blood cell biology. Conclusions Our results provided novel glycemic trait associations and highlighted pathways implicated in glycemic regulation. Exome-array summary statistic results are being made available to the scientific community to enable further discoveries.

Summary: Background: Large language models (LLMs) are garnering wide interest due to their human-like and contextually relevant responses. However, LLMs’ accuracy across specific medical domains has yet been thoroughly evaluated. Myopia is a frequent topic which patients and parents commonly seek information online. Our study evaluated the performance of three LLMs namely ChatGPT-3.5, ChatGPT-4.0, and Google Bard, in delivering accurate responses to common myopia-related queries. Methods: We curated thirty-one commonly asked myopia care-related questions, which were categorised into six domains—pathogenesis, risk factors, clinical presentation, diagnosis, treatment and prevention, and prognosis. Each question was posed to the LLMs, and their responses were independently graded by three consultant-level paediatric ophthalmologists on a three-point accuracy scale (poor, borderline, good). A majority consensus approach was used to determine the final rating for each response. ‘Good’ rated responses were further evaluated for comprehensiveness on a five-point scale. Conversely, ‘poor’ rated responses were further prompted for self-correction and then re-evaluated for accuracy. Findings: ChatGPT-4.0 demonstrated superior accuracy, with 80.6% of responses rated as ‘good’, compared to 61.3% in ChatGPT-3.5 and 54.8% in Google Bard (Pearson's chi-squared test, all p ≤ 0.009). All three LLM-Chatbots showed high mean comprehensiveness scores (Google Bard: 4.35; ChatGPT-4.0: 4.23; ChatGPT-3.5: 4.11, out of a maximum score of 5). All LLM-Chatbots also demonstrated substantial self-correction capabilities: 66.7% (2 in 3) of ChatGPT-4.0's, 40% (2 in 5) of ChatGPT-3.5's, and 60% (3 in 5) of Google Bard's responses improved after self-correction. The LLM-Chatbots performed consistently across domains, except for ‘treatment and prevention’. However, ChatGPT-4.0 still performed superiorly in this domain, receiving 70% ‘good’ ratings, compared to 40% in ChatGPT-3.5 and 45% in Google Bard (Pearson's chi-squared test, all p ≤ 0.001). Interpretation: Our findings underscore the potential of LLMs, particularly ChatGPT-4.0, for delivering accurate and comprehensive responses to myopia-related queries. Continuous strategies and evaluations to improve LLMs’ accuracy remain crucial. Funding: Dr Yih-Chung Tham was supported by the National Medical Research Council of Singapore (NMRC/MOH/HCSAINV21nov-0001).

Abstract To determine the differential impact of the irreversible eye diseases on vision-related quality of life (VRQoL) in a multi-ethnic Asian population. 2652 participants from the Singapore Epidemiology of Eye Disease Study, with any of the following early and late-stage eye conditions including age-related macular degeneration (AMD, n = 158), diabetic retinopathy (DR, n = 105; non vision threatening [non-VTDR]; VTDR), glaucoma (n = 57) and myopic macular degeneration (MMD, n = 106), or none of the above (controls, 2226 [83.9%]) were included. Rasch-scaled scores of the Emotional well-being Mobility and Reading subscales of the Impact of Vision Impairment (IVI) questionnaire, collectively referred to as “VRQoL” were assessed. Multivariable linear regression analyses and pairwise comparisons adjusting for age, gender, ethnicity, socio-economic status, BMI, smoking, alcohol use, presence of systemic diseases and presenting VI were performed to assess and compare the impact of the presence and severity of each eye condition on the three IVI domains. Multivariable adjusted pairwise comparisons of VRQoL between early stages of the four eye diseases showed no significant differences (all P > 0.05). For late stage diseases, individuals with VTDR had significantly larger decrements in Emotional well-being compared to glaucoma (β − 0.81; 95% CI − 1.47 to − 0.16) and MMD (β − 1.17; 95% CI − 2.16 to − 0.18); and Reading decrements compared to glaucoma (β − 0.66; 95% CI − 1.22 to − 0.11). When compared to late glaucoma, individuals with late AMD (β − 0.76; 95% CI − 1.50 to − 0.01) had significantly larger IVI Mobility subscale decrements. VTDR and late AMD, appear to have the greatest impact on VRQoL, compared to late glaucoma and MMD, suggesting a differential impact of late-stage eye disease categorization on VRQoL.

Abstract 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.

BACKGROUND Cytochrome P450 family 8 subfamily B member 1 (CYP8B1) generates 12α-hydroxylated bile acids (BAs) that are associated with insulin resistance in humans.METHODS To determine whether reduced CYP8B1 activity improves insulin sensitivity, we sequenced CYP8B1 in individuals without diabetes and identified carriers of complete loss-of-function (CLOF) mutations utilizing functional assays.RESULTS Mutation carriers had lower plasma 12α-hydroxylated/non–12α-hydroxylated BA and cholic acid (CA)/chenodeoxycholic acid (CDCA) ratios compared with age-, sex-, and BMI-matched controls. During insulin clamps, hepatic glucose production was suppressed to a similar magnitude by insulin, but glucose infusion rates to maintain euglycemia were higher in mutation carriers, indicating increased peripheral insulin sensitivity. Consistently, a polymorphic CLOF CYP8B1 mutation associated with lower fasting insulin in the AMP-T2D-GENES study. Exposure of primary human muscle cells to mutation-carrier CA/CDCA ratios demonstrated increased FOXO1 activity, and upregulation of both insulin signaling and glucose uptake, which were mediated by increased CDCA. Inhibition of FOXO1 attenuated the CDCA-mediated increase in muscle insulin signaling and glucose uptake. We found that reduced CYP8B1 activity associates with increased insulin sensitivity in humans.CONCLUSION Our findings suggest that increased circulatory CDCA due to reduced CYP8B1 activity increases skeletal muscle insulin sensitivity, contributing to increased whole-body insulin sensitization.FUNDING Biomedical Research Council/National Medical Research Council of Singapore.

Abstract 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.

Artificial Intelligence (AI) analytics has been used to predict, classify, and aid clinical management of multiple eye diseases. Its robust performances have prompted researchers to expand the use of AI into predicting systemic, non-ocular diseases and parameters based on ocular images. Herein, we discuss the reasons why the eye is well-suited for systemic applications, and review the applications of deep learning on ophthalmic images in the prediction of demographic parameters, body composition factors, and diseases of the cardiovascular, hematological, neurodegenerative, metabolic, renal, and hepatobiliary systems. Three main imaging modalities are included—retinal fundus photographs, optical coherence tomographs and external ophthalmic images. We examine the range of systemic factors studied from ophthalmic imaging in current literature and discuss areas of future research, while acknowledging current limitations of AI systems based on ophthalmic images.

Abstract We evaluated the 6-year incidence and risk factors of pterygium in a multi-ethnic Asian population. Participants who attended the baseline visit of the Singapore Epidemiology of Eye Diseases Study (year 2004–2011) and returned six years later, were included in this study. Pterygium was diagnosed based on anterior segment photographs. Incident pterygium was defined as presence of pterygium at 6-year follow-up in either eye, among individuals without pterygium at baseline. Multivariable logistic regression models were used to determine factors associated with incident pterygium, adjusting for baseline age, gender, ethnicity, body mass index, occupation type, educational level, income status, smoking, alcohol consumption, presence of hypertension, diabetes and hyperlipidemia. The overall age-adjusted 6-year incidence of pterygium was 1.2% (95% confidence interval [CI] 1.0–1.6%); with Chinese (1.9%; 95% CI 1.4%-2.5%) having the highest incidence rate followed by Malays (1.4%; 95% CI 0.9%-2.1%) and Indians (0.3%; 95% CI 0.3–0.7%). In multivariable analysis, Chinese (compared with Indians; odds ratio [OR] = 4.21; 95% CI 2.12–9.35) and Malays (OR 3.22; 95% CI 1.52–7.45), male (OR 2.13; 95% CI 1.26–3.63), outdoor occupation (OR 2.33; 95% CI 1.16–4.38), and smoking (OR 0.41; 95% CI 0.16–0.87) were significantly associated with incident pterygium. Findings from this multi-ethnic Asian population provide useful information in identifying at-risk individuals for pterygium.

Abstract Population-based data investigating generational differences in the risk of incident cardiovascular disease (CVD) and its risk determinants are rare. We examined the 6-year incidence of CVD and its risk factors in first- and second-generation ethnic Indians living in Singapore. 1749 participants (mean age [SD]: 55.5 [8.8] years; 47.5% male) from a population-based, longitudinal study of Indian adults were included for incident CVD outcome. Incident CVD was defined as self-reported myocardial infarction, angina pectoris or stroke which developed between baseline and follow-up. CVD-related risk factors included incident diabetes, hypertension, hyperlipidemia, obesity and chronic kidney disease (CKD). For incident CVD outcome, of the 1749 participants, 406 (23.2%) and 1343 (76.8%) were first and second-generation Indians, respectively. Of these, 73 (4.1%) reported incident CVD. In multivariable models, second-generation individuals had increased risk of developing CVD (RR = 2.04; 95% CI 1.04, 3.99; p = 0.038), hyperlipidemia (RR = 1.27; 95% CI 1.06, 1.53; p = 0.011), and CKD (RR = 1.92; 95% CI 1.22, 3.04; p = 0.005), compared to first-generation Indians. Second-generation Indians have increased risk of developing CVD and its associated risk factors such as hyperlipidemia and CKD compared to first-generation immigrants, independent of traditional CVD risk factors. More stratified and tailored CVD prevention strategies on second and subsequent generations of Indian immigrants in Singapore are warranted.

Abstract Recent genome-wide association studies (GWAS) have identified multiple loci associated with coronary artery disease (CAD) among predominantly Europeans. However, their relevance to multi-ethnic populations from Southeast Asia is largely unknown. We performed a meta-analysis of four GWAS comprising three Chinese studies and one Malay study (Total N = 2,169 CAD cases and 7,376 controls). Top hits (P T, G185C) in APOA5 for CAD that reached robust genome-wide significance (Meta P = 7.09 × 10−10, OR = 1.636). Conditional probability analysis indicated that the association at rs2075291 was independent of previously reported index SNP rs964184 in APOA5. We further replicated 10 loci previously identified among predominantly Europeans (P: 1.33 × 10−7–0.047). Seven pathways (P: 1.10 × 10−5–0.019) were identified. We identified a missense SNP, rs2075291, in APOA5 associated with CAD at a genome-wide significance level and provided new insights into pathways contributing to the susceptibility to CAD in the multi-ethnic populations from Southeast Asia.

Abstract Bilateral neovascular age-related macular degeneration (AMD) causes much more handicaps for patients than unilateral neovascular AMD. Although several AMD-susceptibility genes have been evaluated for their associations to bilaterality, genome-wide association study (GWAS) on bilaterality has been rarely reported. In the present study, we performed GWAS using neovascular AMD cases in East Asian. The discovery stage compared 581,252 single nucleotide polymorphisms (SNPs) between 803 unilateral and 321 bilateral Japanese cases but no SNP showed genome-wide significance, while SNPs at six regions showed P-value

BackgroundClinical trials have shown beneficial effects of blood pressure (BP) control in reducing the risk of diabetic retinopathy (DR). However, association between BP control and DR in population-based studies is not clear. We aimed to examine the association of hypertension and BP control with DR.MethodsWe analysed data from a population-based cross-sectional study of Chinese, Malay and Indians adults with diabetes and hypertension (2004-2011, n = 2189, aged 40-80 years) in Singapore. DR severity was assessed from retinal photographs and graded for any- and vision-threatening DR (VTDR) using the modified Airlie House classification. Hypertension status was classified into (1) good control: on treatment (SBP < 130 and DBP < 80 mm Hg), (2) moderate control: on treatment, with BP levels other than group 1 and 3, (3) poor control: on treatment (SBP ≥140 and DBP ≥ 90 mm Hg), (4) untreated hypertension, any BP level. SBP, DBP and pulse pressure (PP) were analyzed as categories and as continuous variables. The association between BP and DR was assessed using multivariable logistic regression models.ResultsThe prevalence of any-DR and VTDR in the study population was 33.8% and 9.0% respectively. Both poorly controlled and untreated hypertension were significantly associated with any-DR with odds ratio (OR) (95% confidence interval [CI]) of 1.97 (1.39-2.83), and 2.01 [1.34-3.05]. Among BP components, SBP and PP were associated with both any-DR and VTDR with OR (95% CI) of 1.45 (1.28-1.65) and 1.61 (1.41-1.84) for any-DR, and 1.44 (1.19-1.76) and 1.67 (1.37-2.06) for VTDR.ConclusionIn a population-based sample of Asian adults with diabetes and hypertension, treated but poorly controlled as well as untreated hypertension were significantly associated with any-DR. Among the BP components, higher SBP and PP levels were associated with both any-DR and VTDR. Further longitudinal studies are necessary to confirm our findings.

Background: Chronic kidney disease (CKD) has been shown to be associated with diabetic retinopathy (DR) and age-related macular degeneration (AMD), leading causes of blindness in elderly adults in previous studies. However, the association of CKD with visual impairment (VI) is not clear. We aimed to examine the association of CKD with VI and other age-related ocular diseases in a population-based sample of Asian adults. Methods: We analyzed data from 10,033 adults aged 40–80 years who participated in the Singapore Epidemiology of Eye Diseases (SEED, 2004–11) Study. CKD was defined as an estimated glomerular filtration rate (eGFR)

BackgroundChronic kidney disease (CKD) contributes significant morbidity and mortality among Asians; hence interventions should focus on those most at-risk of progression. However, current end stage renal failure (ESRF) risk stratification tools are complex and not validated in multi-ethnic Asians. We hence aimed to develop an ESRF risk prediction model by taking into account ethnic differences within a fairly homogenous socioeconomic setting and using parameters readily accessible to primary care clinicians managing the vast majority of patients with CKD.MethodsWe performed a prospective cohort study of 1970 adults with CKD estimated glomerular filtration rate 30 mg/g from the population-based Singapore Epidemiology of Eye Diseases study (n = 10,033). Outcome was incident ESRF, ascertained by linkage to the Singapore Renal Registry until 2015.ResultsMean follow up was 8.5 ± 1.8 years and ESRF occurred in 32 individuals (1.6%). ESRF incidence rates were 2.8, 0.8 and 2.6 per 1000 patient years in Malays, Indians and Chinese respectively. The best ESRF prediction model included age, gender, eGFR and albuminuria (calibration χ2 = 0.45, P = 0.93; C-statistic 0.933, 95% confidence interval (CI) 0.889-0.978, p = 0.01; AIC 356). Addition of ethnicity improved discrimination marginally (C statistic 0.942, 95% CI 0.903-0.981, p = 0.21). Addition of clinical variables such as diabetes and hyperlipidemia did not improve model performance significantly.ConclusionWe affirmed the utility of commonly available clinical information (age, gender, eGFR and UACR) in prognosticating ESRF for multi-ethnic Asians with CKD.

[This corrects the article DOI: 10.1371/journal.pone.0220143.].

PurposeTo evaluate the roles of known myopia-associated genetic variants for development of myopic macular degeneration (MMD) in individuals with high myopia (HM), using case-control studies from the Consortium of Refractive Error and Myopia (CREAM).MethodsA candidate gene approach tested 50 myopia-associated loci for association with HM and MMD, using meta-analyses of case-control studies comprising subjects of European and Asian ancestry aged 30 to 80 years from 10 studies. Fifty loci with the strongest associations with myopia were chosen from a previous published GWAS study. Highly myopic (spherical equivalent [SE] ≤ -5.0 diopters [D]) cases with MMD (N = 348), and two sets of controls were enrolled: (1) the first set included 16,275 emmetropes (SE ≤ -0.5 D); and (2) second set included 898 highly myopic subjects (SE ≤ -5.0 D) without MMD. MMD was classified based on the International photographic classification for pathologic myopia (META-PM).ResultsIn the first analysis, comprising highly myopic cases with MMD (N = 348) versus emmetropic controls without MMD (N = 16,275), two SNPs were significantly associated with high myopia in adults with HM and MMD: (1) rs10824518 (P = 6.20E-07) in KCNMA1, which is highly expressed in human retinal and scleral tissues; and (2) rs524952 (P = 2.32E-16) near GJD2. In the second analysis, comprising highly myopic cases with MMD (N = 348) versus highly myopic controls without MMD (N = 898), none of the SNPs studied reached Bonferroni-corrected significance.ConclusionsOf the 50 myopia-associated loci, we did not find any variant specifically associated with MMD, but the KCNMA1 and GJD2 loci were significantly associated with HM in highly myopic subjects with MMD, compared to emmetropes.

AIMS:To determine the diagnostic performance of macular ganglion cell-inner plexiform layer (GCIPL) thickness measured by spectral-domain optical coherence tomography (SD-OCT) for glaucoma detection in a Chinese population in comparison with optic nerve head (ONH) and retinal nerve fiber layer (RNFL) parameters measured by both SD-OCT and Heidelberg Retina Tomography 3 (HRT-3). METHODS:Adults aged 40 to 80 years were recruited from the population-based study (n = 3353, response rate 72.8%). Macular cube 200x200 scan was performed with Cirrus SD-OCT (version 6.0, Carl Zeiss Meditec Inc, Dublin, CA) for GCIPL thickness measurement. ONH and RNFL imaging was performed with Cirrus SD-OCT and HRT-3 (Heidelberg Engineering, Heidelberg, Germany). Glaucoma was defined according to International Society for Geographical and Epidemiological Ophthalmology criteria. RESULTS:In total, 86 eyes of 60 subjects with glaucoma and 1709 eyes of 1001 non-glaucoma participants were included. The best performing parameters for Cirrus SD-OCT GCIPL, Cirrus SD-OCT ONH and HRT-3 were minimum GCIPL thickness (Area under receiver-operating curve [AUC] = 0.89, 95% CI 0.83-0.95), vertical cup-disc ratio (CDR) (AUC = 0.94, 0.91-0.98) and vertical CDR (AUC = 0.86, 0.81-0.92), respectively. At 85% specificity, vertical CDR measured using Cirrus OCT ONH scan showed the highest sensitivity (88.64%, 95% CI 75.4-96.2) compared to minimum GCIPL thickness with sensitivity of 60.53% (95% CI 46.4-73.0) (p

Abnormal durations of sleep have been associated with risk of diabetes. However, it is not clear if sleep duration is associated with diabetic retinopathy (DR).In a cross-sectional study, we included 1,231 (Malay, n = 395; Indian, n = 836) adults (mean age 64.4 ± 9.0 years, 50.4% female) with diabetes from the second visit of two independent population-based cohort studies (2011-15) in Singapore. Self-reported habitual sleep duration was categorized as short (

Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10-5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10-8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10-8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.

BackgroundGlycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes.Methods & findingsUsing genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95% CI 1.04-1.06, per HbA1c-raising allele, p = 3 × 10-29); whereas GS-E was not (OR = 1.00, 95% CI 0.99-1.01, p = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked G6PD G202A variant (T-allele frequency 11%) was associated with an absolute decrease in HbA1c of 0.81%-units (95% CI 0.66-0.96) per allele in hemizygous men, and 0.68%-units (95% CI 0.38-0.97) in homozygous women. The G6PD variant may cause approximately 2% (N = 0.65 million, 95% CI 0.55-0.74) of African American adults with T2D to remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants.ConclusionsAs G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G6PD deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses.

BACKGROUND/AIMS:To determine the association between aspirin use and diabetic retinopathy (DR) among persons with diabetes, in a population-based, cross-sectional study. METHODS:Subjects with diabetes aged >40 years from the Singapore Epidemiology of Eye Diseases Study were enrolled in this study. Retinal photographs were graded for DR according to the modified Airlie House classification system. Vision threatening diabetic retinopathy (VTDR) was defined as the presence of severe non-proliferative DR, or proliferative DR, or clinically significant macular oedema. The association between aspirin use and the presence of DR or VTDR was assessed using multivariable logistic regression models including age, gender, ethnicity, socioeconomic status, HbA1c, systolic blood pressure, anti-hypertension medicine, total cholesterol, anti-cholesterol medicine, BMI, current smoking status, diabetes duration, history of cardiovascular disease (CVD) and chronic kidney disease (CKD.). RESULTS:A total of 2,061 participants with diabetes and complete record of relevant systemic and DR data were included. Of these, 711 (34.5%) had any stage of DR, and among these 177 (8.6%) had VTDR. After adjusting for co-variables listed, the association between aspirin use and VTDR was significant (OR = 1.69, P = 0.019), while the association between aspirin use and any DR was borderline (OR = 1.31, P = 0.063). Aspirin use was not associated with either DR or VTDR after additional adjustment of CVD and CKD. Further stratification by history of CVD or CKD showed no association between aspirin use and DR/VTDR in either subgroup. CONCLUSION:Aspirin use was not significantly associated with DR but might be an indicator of diabetic complications (CVD, CKD) that were co-present with more severe DR type. Future longitudinal studies are warranted to confirm our findings.

To determine the prevalence, risk factors, and impact of undiagnosed visually significant cataract in an Asian population.The Singapore Epidemiology of Eye Diseases is a population-based study where 8,697 adults of Malay, Indian, and Chinese ethnicities aged > 40 years were invited for an eye examination, including lens photograph, to establish cataract diagnosis. Visually significant cataract was defined by Wisconsin Cataract Grading System and a best-corrected visual acuity

To determine the differential effects of genetic polymorphism in CFH and ARMS2 on risk of age-related macular degeneration (AMD) between phakic vs. pseudophakic/aphakic eyes.9,529 eyes of 4,918 participants from the Singapore Malay Eye Study and Singapore Indian Eye Study were analyzed. Participants had detailed eye examinations, including slit-lamp examinations and dilated fundus photography. AMD grading was performed according to the Wisconsin age-related maculopathy grading system. Lens status was defined. Single nucleotide polymorphisms (SNPs) rs10801555 (Y402H) within CFH and rs3750847 in ARMS2 were assessed. The main outcome measure was early AMD or any AMD.No significant associations between the CFH Y402H genotypes and early AMD were found in phakic individuals. In contrast, among pseudophakic/aphakic individuals, the CFH Y402H risk genotypes were significantly associated with higher odds of early AMD, with an OR of 1.57 (95% CI: 1.07-2.29) for GA genotype and 2.40 (95% CI: 1.25-4.61) for AA genotype, compared to those with GG genotype. There was significant interaction between pseudophakic/aphakic status and CFH Y402H variant on risk of early AMD (p = 0.037), adjusting for age, gender, and the first 5 genetic principal components. No significant interaction was found between lens status and ARMS2 rs3750847.CFH genetic polymorphism and pseudophakic/aphakic status may have a potential synergistic effect on early AMD, suggesting roles for the complement system and related pathways in the pathogenesis of AMD in eyes after cataract surgery.

To investigate the independent relationship of individual- and area-level socio-economic status (SES) with the presence and severity of visual impairment (VI) in an Asian population.Cross-sectional data from 9993 Chinese, Malay and Indian adults aged 40-80 years who participated in the Singapore Epidemiology of eye Diseases (2004-2011) in Singapore. Based on the presenting visual acuity (PVA) in the better-seeing eye, VI was categorized into normal vision (logMAR≤0.30), low vision (logMAR>0.30

Measurement error of a phenotypic trait reduces the power to detect genetic associations. We examined the impact of sample size, allele frequency and effect size in presence of measurement error for quantitative traits. The statistical power to detect genetic association with phenotype mean and variability was investigated analytically. The non-centrality parameter for a non-central F distribution was derived and verified using computer simulations. We obtained equivalent formulas for the cost of phenotype measurement error. Effects of differences in measurements were examined in a genome-wide association study (GWAS) of two grading scales for cataract and a replication study of genetic variants influencing blood pressure. The mean absolute difference between the analytic power and simulation power for comparison of phenotypic means and variances was less than 0.005, and the absolute difference did not exceed 0.02. To maintain the same power, a one standard deviation (SD) in measurement error of a standard normal distributed trait required a one-fold increase in sample size for comparison of means, and a three-fold increase in sample size for comparison of variances. GWAS results revealed almost no overlap in the significant SNPs (p

PURPOSE: To evaluate a simplified method to measure choroidal thickness (CT) using commercially available enhanced depth imaging (EDI) spectral domain optical coherence tomography (SD-OCT). METHODS: We measured CT in 31 subjects without ocular diseases using Spectralis EDI SD-OCT. The choroid-scleral interface of the acquired images was first enhanced using a post-processing compensation algorithm. The enhanced images were then analysed using Photoshop. Two graders independently graded the images to assess inter-grader reliability. One grader re-graded the images after 2 weeks to determine intra-grader reliability. Statistical analysis was performed using intra-class correlation coefficient (ICC) and Bland-Altman plot analyses. RESULTS: Using adaptive compensation both the intra-grader reliability (ICC: 0.95 to 0.97) and inter-grader reliability (ICC: 0.93 to 0.97) were perfect for all five locations of CT. However, with the conventional technique of manual CT measurements using built-in callipers provided with the Heidelberg explorer software, the intra- (ICC: 0.87 to 0.94) and inter-grader reliability (ICC: 0.90 to 0.93) for all the measured locations is lower. Using adaptive compensation, the mean differences (95% limits of agreement) for intra- and inter-grader sub-foveal CT measurements were -1.3 (-3.33 to 30.8) µm and -1.2 (-36.6 to 34.2) µm, respectively. CONCLUSIONS: The measurement of CT obtained from EDI SD-OCT using our simplified method was highly reliable and efficient. Our method is an easy and practical approach to improve the quality of choroidal images and the precision of CT measurement.

This longitudinal research study aimed to develop a pregraduation clinical training program for nursing students before graduation and evaluate its effect on students’ self-perceived clinical competence, clinical stress, and intention to leave current job. A sample of 198 students returned the questionnaires before and after the program. They were followed up at 3, 6, and 12 months after graduation. Results showed that posttest clinical competence was significantly higher than pretest competence, positively related to clinical competence at 3 and 12 months, and negatively related to clinical stress at 3 months. The clinical competence at 3 months was positively related to clinical competence at 6 and 12 months, and clinical competence at 6 months was related to intention to leave at 12 months. Intention to leave at 6 months was positively related to intention to leave at 3 and 12 months. Clinical stress at 3 months was positively related to clinical stress at 6 and 12 months, but not related to intention to leave at any time points. The training program improved students’ clinical competence. The stressful time that was correlated with new graduate nurses’ intention to leave their job was between the sixth and twelfth months after employment.

OBJECTIVE: To determine the prevalence of cataract surgery and factors associated with post-surgical visual outcomes in migrant Indians living in Singapore. RESEARCH DESIGN AND METHODS: We conducted a population-based study in 3,400 Indian immigrants residing in Singapore-the Singapore Indian Eye Study (SINDI). All participants underwent comprehensive medical eye examination and a standardized interview. Post-operative visual impairment (VI) was defined as best-corrected or presenting visual acuity (BCVA or PVA) of 20/60 or worse. RESULTS: The age- and gender-standardized prevalence of cataract surgery was 9.7% (95% confidence interval [CI]: 8.9%, 10.7%) in Singapore resident Indians. Post-operative VI defined by BCVA occurred in 10.9% eyes (87/795). The main causes of post-operative VI were diabetic retinopathy (20.7%), posterior capsular opacification (18.4%), and age-related macular degeneration (12.6%). Undercorrected refractive error doubled the prevalence of post-operative VI when PVA was used. CONCLUSIONS: The rate of cataract surgery is about 10% in Indian residents in Singapore. Socioeconomic variables and migration had no significant impact on the prevalence of cataract surgery. Diabetic retinopathy was a major cause of post-operative VI in migrant Indians living in Singapore. Uncorrected postoperative refractive error remains an efficient way to improve vision.

Glycated hemoglobin A1C (HbA1C) level is used as a diagnostic marker for diabetes mellitus and a predictor of diabetes associated complications. Genome-wide association studies have identified genetic variants associated with HbA1C level. Most of these studies have been conducted in populations of European ancestry. Here we report the findings from a meta-analysis of genome-wide association studies of HbA1C levels in 6,682 non-diabetic subjects of Chinese, Malay and South Asian ancestries. We also sought to examine the associations between HbA1C associated SNPs and microvascular complications associated with diabetes mellitus, namely chronic kidney disease and retinopathy. A cluster of 6 SNPs on chromosome 17 showed an association with HbA1C which achieved genome-wide significance in the Malays but not in Chinese and Asian Indians. No other variants achieved genome-wide significance in the individual studies or in the meta-analysis. When we investigated the reproducibility of the findings that emerged from the European studies, six loci out of fifteen were found to be associated with HbA1C with effect sizes similar to those reported in the populations of European ancestry and P-value ≤ 0.05. No convincing associations with chronic kidney disease and retinopathy were identified in this study.

BACKGROUND:Mild retinopathy (microaneurysms or dot-blot hemorrhages) is observed in persons without diabetes or hypertension and may reflect microvascular disease in other organs. We conducted a genome-wide association study (GWAS) of mild retinopathy in persons without diabetes. METHODS:A working group agreed on phenotype harmonization, covariate selection and analytic plans for within-cohort GWAS. An inverse-variance weighted fixed effects meta-analysis was performed with GWAS results from six cohorts of 19,411 Caucasians. The primary analysis included individuals without diabetes and secondary analyses were stratified by hypertension status. We also singled out the results from single nucleotide polymorphisms (SNPs) previously shown to be associated with diabetes and hypertension, the two most common causes of retinopathy. RESULTS:No SNPs reached genome-wide significance in the primary analysis or the secondary analysis of participants with hypertension. SNP, rs12155400, in the histone deacetylase 9 gene (HDAC9) on chromosome 7, was associated with retinopathy in analysis of participants without hypertension, -1.3±0.23 (beta ± standard error), p = 6.6×10(-9). Evidence suggests this was a false positive finding. The minor allele frequency was low (∼2%), the quality of the imputation was moderate (r(2) ∼0.7), and no other common variants in the HDAC9 gene were associated with the outcome. SNPs found to be associated with diabetes and hypertension in other GWAS were not associated with retinopathy in persons without diabetes or in subgroups with or without hypertension. CONCLUSIONS:This GWAS of retinopathy in individuals without diabetes showed little evidence of genetic associations. Further studies are needed to identify genes associated with these signs in order to help unravel novel pathways and determinants of microvascular diseases.

The risk of type 2 diabetes is approximately 2-fold higher in African Americans than in European Americans even after adjusting for known environmental risk factors, including socioeconomic status (SES), suggesting that genetic factors may explain some of this population difference in disease risk. However, relatively few genetic studies have examined this hypothesis in a large sample of African Americans with and without diabetes. Therefore, we performed an admixture analysis using 2,189 ancestry-informative markers in 7,021 African Americans (2,373 with type 2 diabetes and 4,648 without) from the Atherosclerosis Risk in Communities Study, the Jackson Heart Study, and the Multiethnic Cohort to 1) determine the association of type 2 diabetes and its related quantitative traits with African ancestry controlling for measures of SES and 2) identify genetic loci for type 2 diabetes through a genome-wide admixture mapping scan. The median percentage of African ancestry of diabetic participants was slightly greater than that of non-diabetic participants (study-adjusted difference = 1.6%, P