Ophthalmology (Eye & Ear Hospital) - Research Publications
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ItemA genome-wide association study of corneal astigmatism: The CREAM Consortium(MOLECULAR VISION, 2018-02-05)PURPOSE: To identify genes and genetic markers associated with corneal astigmatism. METHODS: A meta-analysis of genome-wide association studies (GWASs) of corneal astigmatism undertaken for 14 European ancestry (n=22,250) and 8 Asian ancestry (n=9,120) cohorts was performed by the Consortium for Refractive Error and Myopia. Cases were defined as having >0.75 diopters of corneal astigmatism. Subsequent gene-based and gene-set analyses of the meta-analyzed results of European ancestry cohorts were performed using VEGAS2 and MAGMA software. Additionally, estimates of single nucleotide polymorphism (SNP)-based heritability for corneal and refractive astigmatism and the spherical equivalent were calculated for Europeans using LD score regression. RESULTS: The meta-analysis of all cohorts identified a genome-wide significant locus near the platelet-derived growth factor receptor alpha (PDGFRA) gene: top SNP: rs7673984, odds ratio=1.12 (95% CI:1.08-1.16), p=5.55×10-9. No other genome-wide significant loci were identified in the combined analysis or European/Asian ancestry-specific analyses. Gene-based analysis identified three novel candidate genes for corneal astigmatism in Europeans-claudin-7 (CLDN7), acid phosphatase 2, lysosomal (ACP2), and TNF alpha-induced protein 8 like 3 (TNFAIP8L3). CONCLUSIONS: In addition to replicating a previously identified genome-wide significant locus for corneal astigmatism near the PDGFRA gene, gene-based analysis identified three novel candidate genes, CLDN7, ACP2, and TNFAIP8L3, that warrant further investigation to understand their role in the pathogenesis of corneal astigmatism. The much lower number of genetic variants and genes demonstrating an association with corneal astigmatism compared to published spherical equivalent GWAS analyses suggest a greater influence of rare genetic variants, non-additive genetic effects, or environmental factors in the development of astigmatism.
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ItemAlterations in Retinal Microvascular Geometry in Young Type 1 Diabetes(AMER DIABETES ASSOC, 2010-06)OBJECTIVE: To describe retinal microvascular geometric parameters in young patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: Patients with type 1 diabetes (aged 12-20 years) had clinical assessments and retinal photography following standardized protocol at a tertiary-care hospital in Sydney. Retinal microvascular geometry, including arteriolar and venular tortuosity, branching angles, optimality deviation, and length-to-diameter ratio (LDR), were measured from digitized photographs. Associations of these geometric characteristics with diabetes duration, A1C level, systolic blood pressure (SBP), and other risk factors were assessed. RESULTS: Of 1,159 patients enrolled, 944 (81.4%) had gradable photographs and 170 (14.7%) had retinopathy. Older age was associated with decreased arteriolar (P = 0.024) and venular (P = 0.002) tortuosity, and female subjects had larger arteriolar branching angle than male subjects (P = 0.03). After adjusting for age and sex, longer diabetes duration was associated with larger arteriolar branching angle (P 8.5 vs.
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ItemRetinal vascular fractals and cognitive impairment.(S. Karger AG, 2014-05)BACKGROUND: Retinal microvascular network changes have been found in patients with age-related brain diseases such as stroke and dementia including Alzheimer's disease. We examine whether retinal microvascular network changes are also present in preclinical stages of dementia. METHODS: This is a cross-sectional study of 300 Chinese participants (age: ≥60 years) from the ongoing Epidemiology of Dementia in Singapore study who underwent detailed clinical examinations including retinal photography, brain imaging and neuropsychological testing. Retinal vascular parameters were assessed from optic disc-centered photographs using a semiautomated program. A comprehensive neuropsychological battery was administered, and cognitive function was summarized as composite and domain-specific Z-scores. Cognitive impairment no dementia (CIND) and dementia were diagnosed according to standard diagnostic criteria. RESULTS: Among 268 eligible nondemented participants, 78 subjects were categorized as CIND-mild and 69 as CIND-moderate. In multivariable adjusted models, reduced retinal arteriolar and venular fractal dimensions were associated with an increased risk of CIND-mild and CIND-moderate. Reduced fractal dimensions were associated with poorer cognitive performance globally and in the specific domains of verbal memory, visuoconstruction and visuomotor speed. CONCLUSION: A sparser retinal microvascular network, represented by reduced arteriolar and venular fractal dimensions, was associated with cognitive impairment, suggesting that early microvascular damage may be present in preclinical stages of dementia.
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ItemForecasting the burden of type 2 diabetes in Singapore using a demographic epidemiological model of Singapore.(BMJ, 2014)OBJECTIVE: Singapore is a microcosm of Asia as a whole, and its rapidly ageing, increasingly sedentary population heralds the chronic health problems other Asian countries are starting to face and will likely face in the decades ahead. Forecasting the changing burden of chronic diseases such as type 2 diabetes in Singapore is vital to plan the resources needed and motivate preventive efforts. METHODS: This paper describes an individual-level simulation model that uses evidence synthesis from multiple data streams-national statistics, national health surveys, and four cohort studies, and known risk factors-aging, obesity, ethnicity, and genetics-to forecast the prevalence of type 2 diabetes in Singapore. This comprises submodels for mortality, fertility, migration, body mass index trajectories, genetics, and workforce participation, parameterized using Markov chain Monte Carlo methods, and permits forecasts by ethnicity and employment status. RESULTS: We forecast that the obesity prevalence will quadruple from 4.3% in 1990 to 15.9% in 2050, while the prevalence of type 2 diabetes (diagnosed and undiagnosed) among Singapore adults aged 18-69 will double from 7.3% in 1990 to 15% in 2050, that ethnic Indians and Malays will bear a disproportionate burden compared with the Chinese majority, and that the number of patients with diabetes in the workforce will grow markedly. CONCLUSIONS: If the recent rise in obesity prevalence continues, the lifetime risk of type 2 diabetes in Singapore will be one in two by 2050 with concomitant implications for greater healthcare expenditure, productivity losses, and the targeting of health promotion programmes.
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ItemPolypoidal Choroidal Vasculopathy in Asians.(MDPI AG, 2015-04-24)Age related macular degeneration (AMD) in Asians has been suggested to differ from their Western counterparts in terms of epidemiology, pathogenesis, clinical presentation and treatment. In particular, polypoidal choroidal vasculopathy (PCV) appears to be the predominant subtype of exudative AMD in Asian populations, in contrast to choroidal neovascularization secondary to AMD (CNV-AMD) in Western populations. Epidemiological data on PCV has been largely limited to hospital-based studies and there are currently no data on the incidence of PCV. Similarities and differences in risk factor profile between PCV and CNV-AMD point to some shared pathogenic mechanisms but also differential underlying mechanisms leading to the development of each phenotype. Serum biomarkers such as CRP, homocysteine and matrix metalloproteinases suggest underlying inflammation, atherosclerosis and deranged extracellular matrix metabolism as possible pathogenic mechanisms. In addition, recent advances in genome sequencing have revealed differences in genetic determinants of each subtype. While the standard of care for CNV-AMD is anti-vascular endothelial growth factor (VEGF) therapy, photodynamic therapy (PDT) has been the mainstay of treatment for PCV, although long-term visual prognosis remains unsatisfactory. The optimal treatment for PCV requires further clarification, particularly with different types of anti-VEGF agents and possible benefits of reduced fluence PDT.
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ItemDiabetic Retinopathy in 2011: Further Insights From New Epidemiological Studies and Clinical Trials(AMER DIABETES ASSOC, 2011-04)
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ItemPathways-driven sparse regression identifies pathways and genes associated with high-density lipoprotein cholesterol in two Asian cohorts.(Public Library of Science (PLoS), 2013-11)Standard approaches to data analysis in genome-wide association studies (GWAS) ignore any potential functional relationships between gene variants. In contrast gene pathways analysis uses prior information on functional structure within the genome to identify pathways associated with a trait of interest. In a second step, important single nucleotide polymorphisms (SNPs) or genes may be identified within associated pathways. The pathways approach is motivated by the fact that genes do not act alone, but instead have effects that are likely to be mediated through their interaction in gene pathways. Where this is the case, pathways approaches may reveal aspects of a trait's genetic architecture that would otherwise be missed when considering SNPs in isolation. Most pathways methods begin by testing SNPs one at a time, and so fail to capitalise on the potential advantages inherent in a multi-SNP, joint modelling approach. Here, we describe a dual-level, sparse regression model for the simultaneous identification of pathways and genes associated with a quantitative trait. Our method takes account of various factors specific to the joint modelling of pathways with genome-wide data, including widespread correlation between genetic predictors, and the fact that variants may overlap multiple pathways. We use a resampling strategy that exploits finite sample variability to provide robust rankings for pathways and genes. We test our method through simulation, and use it to perform pathways-driven gene selection in a search for pathways and genes associated with variation in serum high-density lipoprotein cholesterol levels in two separate GWAS cohorts of Asian adults. By comparing results from both cohorts we identify a number of candidate pathways including those associated with cardiomyopathy, and T cell receptor and PPAR signalling. Highlighted genes include those associated with the L-type calcium channel, adenylate cyclase, integrin, laminin, MAPK signalling and immune function.
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ItemAssessment of candidate ocular biomarkers of ageing in a South African adult population: relationship with chronological age and systemic biomarkers.(Elsevier BV, 2013)Certain anatomic and functional parameters of the eye change with increasing chronological age. They may, therefore, serve as potential biomarkers of ageing. We investigated associations between four such ocular parameters (lens density, retinal vessel calibre, corneal endothelial cells and retinal nerve fibre layer thickness) and two 'cellular' biomarkers of ageing (leukocyte telomere length and CDKN2A expression), with frailty (a clinical correlate of biological ageing) in a population of South African adults. All ocular parameters revealed an association with either telomere length or CDKN2A expression. However, lens density was most strongly correlated with age, increased CDKN2A expression, and with frailty (p=0.05 and 0.03, respectively). Narrow retinal arteriolar diameter, associated with increased chronological age, was also associated with increased CDK2NA expression (0.42 vs. 0.31, p=0.02) but not with frailty. Ocular parameters may aid in determining biological age, warranting investigation in longitudinal studies.
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ItemEthnic differences in the association between blood pressure components and chronic kidney disease in middle aged and older Asian adults.(Springer Science and Business Media LLC, 2013-04-17)BACKGROUND: Chronic kidney disease (CKD) is an emerging public health problem worldwide. Previous studies have shown an association between blood pressure (BP) and CKD. However, it is not clear if there are ethnic differences in this association. We examined the association between BP and CKD in a multi-ethnic Asian population in Singapore. METHODS: We analysed data from three large population-based studies conducted between 2004-2011, (n=3,167 Chinese, 3,082 Malays and 3,228 Indians) aged 40-80 years. CKD was defined as an estimated glomerular filtration rate <60 mL/min/1.73 m² from serum creatinine. Hypertension was defined as a self-reported current use of antihypertensive medication or systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg. We also analysed the association of CKD with individual BP components. RESULTS: The prevalence of both hypertension and CKD was higher among Malays (68.6, 21%) compared to Chinese (57.9, 5.9%) and Indians (56.0, 7.4%), but treatment for hypertension was lower among Malays (53.4%) compared to Chinese (89.8%) and Indians (83.1%). Hypertension was associated with CKD in all three ethnic groups (OR [95% CI] = 2.71 [1.59-4.63], 2.08 [1.62-2.68], 2.43 [1.66-3.57] in Chinese, Malays and Indians). Among the BP components, both systolic and diastolic BP were associated with CKD in Malays whereas, systolic BP was not significantly associated with CKD, and diastolic BP showed an inverse association which was explained by anti-hypertensive medication use in Chinese and Indians. CONCLUSIONS: Hypertension was associated with CKD in Chinese, Malays and Indians. However, the BP components were associated with CKD only in Malays.
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ItemAutomatic diagnosis of pathological myopia from heterogeneous biomedical data.(Public Library of Science (PLoS), 2013)Pathological myopia is one of the leading causes of blindness worldwide. The condition is particularly prevalent in Asia. Unlike myopia, pathological myopia is accompanied by degenerative changes in the retina, which if left untreated can lead to irrecoverable vision loss. The accurate diagnosis of pathological myopia will enable timely intervention and facilitate better disease management to slow down the progression of the disease. Current methods of assessment typically consider only one type of data, such as that from retinal imaging. However, different kinds of data, including that of genetic, demographic and clinical information, may contain different and independent information, which can provide different perspectives on the visually observable, genetic or environmental mechanisms for the disease. The combination of these potentially complementary pieces of information can enhance the understanding of the disease, providing a holistic appreciation of the multiple risks factors as well as improving the detection outcomes. In this study, we propose a computer-aided diagnosis framework for Pathological Myopia diagnosis through Biomedical and Image Informatics(PM-BMII). Through the use of multiple kernel learning (MKL) methods, PM-BMII intelligently fuses heterogeneous biomedical information to improve the accuracy of disease diagnosis. Data from 2,258 subjects of a population-based study, in which demographic and clinical information, retinal fundus imaging data and genotyping data were collected, are used to evaluate the proposed framework. The experimental results show that PM-BMII achieves an AUC of 0.888, outperforming the detection results from the use of demographic and clinical information 0.607 (increase 46.3%, p<0.005), genotyping data 0.774 (increase 14.7%, P<0.005) or imaging data 0.852 (increase 4.2%, p=0.19) alone. The accuracy of the results obtained demonstrates the feasibility of using heterogeneous data for improved disease diagnosis through our proposed PM-BMII framework.