The Ocular Epidemiology Research Group, led by Professor Wong Tien Yin and Professor Cheng Ching-Yu , conducts and coordinates epidemiological and population-based projects under the Singapore Epidemiology of Eye Diseases (SEED) programme. Our strategic vision is to provide novel knowledge in the population eye health to enable dissecting, detecting and preventing the most important eye diseases in both our children and ageing populations in Singapore and Asia, and also to promote and improve global eye health.
A world-leading research programme focusing specifically on the epidemiology and impact of eye diseases in Asia
Provide a one-stop “data portal” and information source on the epidemiology of Asian eye diseases
Cover an entire spectrum of prevalence, incidence, risk factors and impact of Asian eye diseases in 3 major racial/ethnic groups (Chinese, Malays, Indians)
To document the prevalence, incidence, risk factors and public health significance of blinding eye diseases in Singapore and Asia through the conduct of large scale epidemiological studies
To foster international collaborations with other public health and ophthalmic institutes in Asia and worldwide
To provide research expertise, training and consultation to other researchers and ophthalmic institutions in Singapore and Asia
The SEED programme includes more than 25,000 adult and children participants from 8 large population-based studies, with a focus on studying major eye diseases, including diabetic retinopathy, age-related macular degeneration, glaucoma, refractive errors and cataract.
The Ocular Epidemiology Research Group and SEED Programme bring together innovative and cutting-edge epidemiological research for a focus and theme-oriented strategy, with multi-disciplinary expertise in all aspects of clinical and epidemiological research. Our group has developed upon the following major focus areas:
Basic & Advanced Epidemiology
Genetic & Molecular Epidemiology
Infrastructure of Population Health
We provide data towards public health planning and resource allocation in the Asia-Pacific region. We have established Singapore as a leading hub of ophthalmic epidemiology, clinical and genetic research in Asia through particular focus on diseases that are prevalent in this region. We also provide research expertise, resource, and consultation to other research centres, hospitals and ophthalmic institutions in Singapore and Asia, and conduct training programmes for clinicians, research fellows, and graduate students interested in ophthalmic epidemiology.
1. Foong AW, et al. Rationale and methodology for a population-based study of eye diseases in Malay people: the Singapore Malay Eye Study (SiMES). Ophthalmic Epidemiol. 2007; 14:25-35.2. Lavanya R, et al. Methodology of the Singapore Indian Chinese Cohort (SICC) eye study: quantifying ethnic variations in the epidemiology of eye diseases in Asians.Ophthalmic Epidemiol. 2009; 16:325-36.3. Sabanayagam C, et al. Retinal microvascular caliber and chronic kidney disease in an Asian population. Am J Epidemiol. 2009; 169:625-32.4. Cheung CY, et al. Retinal vascular tortuosity, blood pressure, and cardiovascular risk factors. Ophthalmology. 2011; 118:812-8.5. Fan Q, et al. Genetic variants on chromosome 1q41 influence ocular axial length and high myopia. PLoS Genet. 2012; 8(6):e1002753.6. Ikram MK, et al. Retinal vascular caliber as a biomarker for diabetes microvascular complications. Diabetes Care 2013 36:750-9.7. Zheng Y, et al. How much eye care services do Asian populations need? Projection from the Singapore Epidemiology of Eye Disease (SEED) Study. Invest Ophthalmol Vis Sci 2013; 54:2171-7.8. Lu Y, et al. Genome-wide association analyses identify multiple loci associated with central corneal thickness and keratoconus. Nat Genet. 2013; 45:155-63.9. Verhoeven VJ, et al. Genome-wide meta-analyses of multiancestry cohorts identify multiple new susceptibility loci for refractive error and myopia. Nat Genet. 2013; 45:314-8.10. Cheng CY, et al. Nine loci for ocular axial length identified through genome-wide association studies, including shared loci with refractive error. Am J Hum Genet. 2013 August.
SEED Programme Directors
Prof Wong Tien Yin
Prof Cheng Ching-Yu
Assoc Prof Charumathi Sabanayagam
Dr Tham Yi Chung
Teo Cong Ling
Rosesita Binte Shaikh Mohamed
1) The Singapore Malay Eye Study 2 (SiMES-2) – Prospective Cohort Study of 6-year incidence, risk factors, and impact of major Asian Eye Diseases
The major eye diseases threatening vision in Singapore include age-related macular degeneration, diabetic retinopathy, cataract, glaucoma, and refractive errors. The challenge posed by these conditions highlights the need for accurate data, not only on the epidemiology, but also on specific modifiable risk factors and key pathogenic mechanisms for these conditions in Asia. Such data are currently quite limited.
In 2004-2006, we conducted the Singapore Malay Eye Study (SiMES-1), which examined 3,280 (78.7% response) Malays aged 40-80 years. SiMES-1 was strategically designed using the same standardized protocols as the Blue Mountains Eye Study in white Australians, so that direct comparison and data pooling could be achieved. Since 2007, SiMES-1 has become a landmark cross-sectional assessment of the prevalence, risk factors, and impacts of major eye diseases, producing >50 peer-reviewed publications, and generated a set of new hypothesis for the pathogenesis of eye diseases in Asians.
This study describes the 6-year follow-up of the cohort (SiMES-2), to be conducted from 2010-2013. It aims to assess the incidence, progression, risk factors and impacts of major eye diseases as well as access to eye care by Asian Malays. As the first truly comprehensive cohort study of eye disease in older Singaporeans, SiMES-2 will provide a unique opportunity to address clinically-relevant hypotheses/questions on the contribution of new risk factors for major eye diseases and will link baseline serum biomarkers and environmental factors with incident eye outcomes.
Strengths of the SiMES-2 include a well-established and characterized cohort, an experienced international team of clinician-epidemiologists, with the highest-quality baseline data including digital images, frozen serum, DNA and data collected on the widest range of baseline risk factors.
SiMES-2 will provide critical information on the major eye disease that is currently unavailable, from which to plan strategies that will lead to reduction of visual loss in Singapore and Asia.
• Rosman M, Zheng Y, Wong W, Lamoureux E, Saw SM, Tay WT, Wang JJ, Mitchell P, Tai ES, Wong TY. Singapore Malay Eye Study: Rationale and Methodology of 6-year follow-up Study (SiMES-2). Clin Experiment Ophthalmol. 2012 Aug; 40(6):557-68.• Sidhartha E, Gupta P, Liao J, Tham YC, Cheung CY, He M, Wong TY, Aung T, Cheng CY. Assessment of iris surface features and their relationship with iris thickness in Asian eyes. Ophthalmology. 2014. [E-pub ahead of print]
2) Does Genetic Variation in the CFH region of age-related macular degeneration patients allow bacteria to trigger the disease?
Age-related macular degeneration (AMD) is a chronic inflammatory degenerative disease and leading cause of vision loss in Singapore and worldwide. While disease etiology remains unknown, genetic studies have identified strong associations with complement factor H gene (CFH) and CFH-related family of genes (CFHR).
More recently, in a genome wide association study of Meningococcal disease carried out at Genome Institute of Singapore, we have identified polymorphisms within same CFH region that also confer susceptibility to this Neisseria meningitidis infection.
While infection has previously been proposed to trigger inflammation seen in AMD, few infectious agents have been investigated with no clear conclusions. However, recent studies have also revealed how bacteria exploit CFH to protect themselves against complement-mediated killing.
This study will comprehensibly investigate and test novel hypothesis that an interaction between a genetically predisposed host and bacterium may cause AMD.
To test this hypothesis, we will recruit 300 late neovascular (“wet”) AMD cases from two tertiary eye clinics, 300 early (“dry”) AMD cases and 900 age-matched population controls from an on-going population-based study in Singapore. In these 1,500 subjects, we will use comprehensive next generation sequencing approaches to discover new CFH region polymorphisms and also determine nature of bacterial populations colonizing ocular surface and throat (which is anatomically connected to eye).
While independently providing comprehensive data on roles of CFH region and human associated bacterial communities in Chinese AMD subjects, interactions between these findings may lead to a new mechanistic understanding of AMD.
This novel translational project, bringing together clinician scientists and resources of Singapore Eye Research Institute (SERI), clinicians from the Singapore National Eye Centre (SNEC) and Tan Tock Seng Hospital (TTSH), with scientists and genomic capabilities of the Genome Institute of Singapore (GIS), may directly lead to a new understanding of cause of AMD, opening novel diagnostic and therapeutic options.
• Lamoureux EL, Mitchell P, Rees G, Cheung G, Yeo I, Lee SY, Liu E, Wong TY. Impact of Early and Late Age-Related Macular Degeneration on Vision-Specific Functioning.Br J Ophthalmol. 2011 May; 95(5):666-70• Cheung CM, Bhargava M, Laude A, Koh ACh, Xiang L, Wong D, Niang T, Lim TH, Gopal L, Wong TY. Asian age-related macular degeneration phenotyping study: rationale, design and protocol of a prospective cohort study. Clin Experiment Ophthalmol. 2012 Sep-Oct;40(7):727-35
3) Iris and Choroidal Characteristics in Asian Eyes: Elucidating the Mechanism of Primary Angle Closure Glaucoma
Primary angle closure glaucoma (PACG) is common and visually destructive, particularly in Southeast Asia. The mechanism of PACG has not been fully understood. Our hypothesis is that iris features, choroidal thickness, and their physiological changes in persons with narrow anterior chamber angle may confer significant risk to the development of PACG. First, we aim to develop a new grading scheme for qualitative iris surface features specifically for Asian eyes. We will conduct a case-control study of 200 patients with angle closure disease and 200 normal controls to compare their difference in iris surface features. Second, we aim to use high-resolution spectral-domain optical coherence tomography, with recently developed enhance depth imaging technique, to measure and compare static iris and choroidal parameters between the two groups. Furthermore, we will perform two physiological stress tests, Valsalva maneuver and the water drinking test, in 40 patients with angle closure disease and 40 normal controls to investigate the dynamic changes in iris volume and choroid thickness. Our study will provide the first knowledge on iris surface features in angle closure patients, and will result in significant progress in our understanding of the mechanisms of PACG, which is one of the leading causes of blindness worldwide.
Assoc Prof Shamira Perera
• Ku J.Y., Nongpiur M.E., Park J., Narayanaswamy A.K., Perera S.A., Tun T.A., Kumar R.S., Baskaran M., Aung T. Qualitative evaluation of the iris and ciliary body by ultrasound biomicroscopy in subjects with angle closure. J Glaucoma. 2013 Feb 19• Narayanaswamy A., Zheng C., Perera S.A., Htoon H.M., Friedman D.S., Tun T.A., He M., Baskaran M., Aung T. Variations in iris volume with physiologic mydriasis in subtypes of primary angle closure glaucoma. Invest Ophthalmol Vis Sci. 2013 Jan 23; 54(1):708-13.
4) Automatic Glaucoma Screening Through Cup-to-Disc Ratio (CDR) Measurement
Glaucoma is a chronic and irreversible neurodegenerative disease in which the optic nerve is progressively damaged, leading to deterioration in vision and quality of life. It is the leading cause of irreversible blindness worldwide, affecting 60 million people in 2010. The prevalence of glaucoma contributes significantly to medical costs.
Due to the irreversible nature of glaucoma, early case detection is highly crucial for timely treatment to halt or slow down the progression of the disease in early stages, thus preventing further vision loss. However, to date there is no sustainable, effective tool to screen for glaucoma. We therefore propose the project Glaucoma Screening through Automated Cup-to-Disc (CDR) Measurement, which will establish a new system for glaucoma screening.
The Phase 1 of the project will intensively refine the algorithm of automated CDR measurements. The Phase 2 will evaluate the diagnostic performance of the refined algorithm, including a) reproducibility assessment of the automated CDR measurements from retinal fundus photographs, b) agreement evaluation between the algorithm and clinician’s and other optic disc imaging devices’ grading, and c) performance (sensitivity and specificity) determination as a screening tool in population cohorts. The Phase 3 is to conduct a pilot study in primary health care clinics to assess feasibility and effectiveness of using the system for glaucoma screening.
This system will be the first of its kind worldwide to use retinal fundus photographs for glaucoma screening. The advancement of this latest intelligent medical image-processing algorithm using simple retinal images will serve to complement existing clinical practices and aid in the integration of glaucoma screening in polyclinics. Successful validation of the software will not only lead to the translation into potential commercialization, but also pave the way for the establishment of a cost-effective and sustainable glaucoma screening strategy in Singapore and in the rest of the world.
• Xu Y, Xu D, Lin S, Liu J, Cheng J, Cheung CY, Aung T, Wong TY. Sliding window and regression based cup detection in digital fundus images for glaucoma diagnosis. Med Image Comput Comput Assist Interv. 2011; 14 (Pt 3):1-8• Cheng J., Liu J., Xu Y., Yin F., Wong D.W.K., Tan N.-M., Tao D., Cheng C.-Y., Aung T., Wong T.Y. Superpixel classification based optic disc and optic cup segmentation for glaucoma screening. IEEE Trans Med Imaging. 2013 Jun; 32(6):1019-32
5) Diabetic Retinopathy: Novel Methods in Detection, Pathogenesis, and Treatment
Diabetic Retinopathy (DR), characterized by retinal microvascular damage and neovascularization, remains a leading cause of vision loss in Singapore and worldwide. Singapore has one of the highest rates of diabetes, affecting nearly 10 percent of the population aged between 18 and 69. While improved blood glucose and blood pressure control have been shown to reduce the risks of DR, many people remain poorly controlled. A recent population-based study in Singapore indicates that only 19.2% and 11.5% of people with DR have optimal glycemic and BP control, respectively. Thus, in order to have a better understanding of basic mechanisms of DR, new methods to detect early signs of DR and new treatments are needed to more effectively manage DR and reduce its impact.
We hypothesize that the most characteristic feature in the early events during the pathogenesis of DR involves hyperglycemia-induced oxidative damage in the retinal endothelial cells, and that this can be measured and analyzed by the Pupillary Light Reflex (PLR) imaging technique, developed in Singapore, and arrested using novel aqueous green compounds against the reactive oxidative species produced in a AKimba mouse model of DR. The long-term goal is to establish (i) a novel imaging technique using PLR for the early detection, diagnosis and quantification of retinal damage in DR; (ii) a clearer molecular understanding of the pathogenesis of DR using a AKimba mouse model; and (iii) use of newer aqueous green compounds like imidazolium salts (IMSs) to treat and reverse signs of DR.
In order to accomplish our goals, the present proposal will amalgamate the basic science/technological expertise of IBN-A*STAR and NUS, particularly in animal imaging and small therapeutic compounds with the clinical and epidemiological expertise of SERI-SNEC and NUS in the field of diabetes and DR. This proposal will also integrate our international partners from Lions Eye Institute, Australia.
• Cheung CM, Bhargava M, Laude A, Koh ACh, Xiang L, Wong D, Niang T, Lim TH, Gopal L, Wong TY. Asian age-related macular degeneration phenotyping study: rationale, design and protocol of a prospective cohort study. Clin Experiment Ophthalmol. 2012 Sep-Oct; 40(7):727-35• Sasongko MB, Wong TY, Nguyen TT, Shaw JE, Jenkins AJ, Wang JJ. Novel versus traditional risk markers for diabetic retinopathy. Diabetologia. 2012 Mar;55(3):666-70
6) Angle Closure Glaucoma: Novel methods for Imaging, Risk Assessment and Screening
Glaucoma is the leading cause of irreversible blindness worldwide, with primary angle closure glaucoma (PACG) a major form of glaucoma in Singapore and Asia.
The emergence of new imaging technologies such as anterior segment OCT has contributed greatly to identifying and understanding the pathways critical to the PACG disease process. Recent studies from SERI have identified several novel risk factors for angle closure. Our findings as well as others have demonstrated that the underlying mechanism(s) of angle closure varies from person to person. Identifying and understanding the mechanisms and pathways involved in the disease are essential for its proper management. Patient management may be tailored according to the predominant mechanism, as it is likely that responses to therapies will vary. Clinical care can likely be improved if we create a composite risk for each individual that captures the predominant mechanism involved in the disease process and the relative contribution of other factors.
In this study, we plan to develop a quantitative and predictive machine learning approach for angle closure risk assessment, based on established and recently identified disease markers. In collaboration with an industry partner, we will also develop and evaluate new methods of angle imaging that are better than current technologies. The new algorithm and imaging methods will then be validated in the Singapore population. It is hoped that these advancements will improve the process of detecting angle closure in order to institute earlier treatment, and will be of use to clinicians to select the most appropriate management for each patient. The findings of this study will have great relevance for glaucoma management in Singapore, and also be applicable to countries like China with high prevalence of PACG. Ultimately, the research outlined in this proposal will help in the prevention of blindness from this major cause of visual morbidity.
• Xu Y, Liu J, Tan NM, Lee BH, Wong DW, Baskaran M, Perera SA, Aung T. Anterior chamber angle classification using multiscale histograms of oriented gradients for glaucoma subtype identification. Conf Proc IEEE Eng Med Biol Soc. 2012; 2012:3167-70• Narayanaswamy A, Baskaran M, Zheng Y, Lavanya R, Wu R, Wong WL, Saw SM, Cheng CY, Wong TY, Aung T. The prevalence and types of glaucoma in an urban Indian population: The Singapore Indian Eye Study. Invest Ophthalmol Vis Sci. 2013 Jul 10;54(7):4621-7• Wang B, Aung T, Marella M, Zheng Y, Wong TY, Perera S, Wong TT, Ho CL, Lamoureux EL. Impact of bilateral open and closed-angle glaucoma on glaucoma-specific functioning in Asians. JGlaucoma. 2013 Apr-May; 22(4):330-5
7) Novel Biomarkers of Kidney and Eye Diseases (Singapore Kidney Eye Study)
Chronic kidney disease (CKD) is an emerging public health problem associated with adverse renal and cardiovascular outcomes and age related macular degeneration (AMD) is a leading cause of irreversible blindness worldwide. Renal and retinal diseases share similar pathogenetic mechanisms including inflammation, oxidative stress and microvascular dysfunction and vascular risk factors. Therefore, identification of new, modifiable risk factors or biomarkers for CKD and AMD may present new avenues for understanding the underlying disease pathogenesis and possibly prevention and treatment.
The objective of the current proposal is to study the association between novel biomarkers including serum 25-hydroxy vitamin D (25[OH]D), serum adiponectin, leptin and plasma-free F2-isoprostane and plasma protein carbonyl and the risk of CKD and AMD in a multi-ethnic Asian population including Chinese, Malays and Indians in Singapore. We propose to conduct a nested case-control study selecting cases (n=1170 for CKD, and n=740 for AMD) and controls (n=1200) from four well-established cohorts including Chinese, Malay and Indians in Singapore namely, the Singapore Malay eye Study (SiMES), the Singapore Indian Eye Study (SiNDI), the Singapore Chinese Eye Study (SCES) and the Singapore Prospective Study Program (SP2). In these cohorts, we already have data on all our study outcomes and potential confounding variables including smoking, alcohol intake, self-reported history of diseases, body mass index, blood pressure, plasma glucose, and serum lipids collected from detailed questionnaire, physical and laboratory examination. We will use stored blood at baseline to additionally measure the proposed novel biomarkers. The current proposal takes advantage of the existing strengths and resources of the four study cohorts to address our multiple study aims in an efficient and cost-effective manner.
The study is significant because if our hypotheses are supported, the proposed novel biomarkers will help in early detection of CKD and AMD and also provide insights into the underlying mechanisms.
8) Retinal Vascular Imaging Study in Transient Ischemic Attacks (REVISTA)
Transient ischemic attacks (TIA) represent a heterogeneous group with a wide range of symptoms and pathophysiology. Nevertheless, many patients with TIA are at an increased risk of developing a full clinical stroke. While a role of microvascular pathology is increasingly recognized in the pathogenesis of acute stroke, the exact role for small vessel disease in TIA pathogenesis is less certain.
The eye provides a “window” to the brain. Our previous research has shown “proof-of-concept” that retinal changes provide insights into microvascular pathology and predict the risk of stroke.The major objective of this proposal is to examine the contribution of microvascular pathology in the pathophysiology of TIA using novel retinal vascular imaging. Based on the overall objective, the following specific aims will be addressed in this application:
Specific Aim 1: To compare structural microvascular abnormalities, measured both quantitatively and qualitatively, in patients with TIAs and population controls.Specific Aim 2: To examine the role of functional microvascular changes, as measured by the dynamic vessel analyzer (DVA) in the pathophysiology of TIAs. The DVA measures nitric oxide-regulated vasodilatation that occurs in response to an increased retinal metabolic activity induced by diffuse luminance flickering light.Specific Aim 3: To examine whether structural and functional imaging biomarkers are associated with a future stroke in patients who suffered a TIA.
For this project, we propose to recruit a prospective cohort of new TIA patients from the Singapore General Hospital. Baseline data collection will include anthropometry, biochemistry, and neuro- and retinal imaging. Retinal imaging measures of patients with TIA will be compared to population controls. Patients with TIA will then be followed over time for incident strokes. These retinal vascular imaging techniques will provide novel insights into TIA pathophysiology, and may be of additional value in the prediction of incident stroke in patients with TIA.
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