Publications by authors named "Tien Y Wong"

581 Publications

Alzheimer's disease research progress in Australia: The Alzheimer's Association International Conference Satellite Symposium in Sydney.

Alzheimers Dement 2021 May 31. Epub 2021 May 31.

Departments of Neuroscience and Neurology, Center for Translational Research in Neurodegenerative Disease, Normal Fixel Center for Neurological Diseases, University of Florida College of Medicine, Gainesville, Florida, USA.

The Alzheimer's Association International Conference held its sixth Satellite Symposium in Sydney, Australia in 2019, highlighting the leadership of Australian researchers in advancing the understanding of and treatment developments for Alzheimer's disease (AD) and other dementias. This leadership includes the Australian Imaging, Biomarker, and Lifestyle Flagship Study of Ageing (AIBL), which has fueled the identification and development of many biomarkers and novel therapeutics. Two multimodal lifestyle intervention studies have been launched in Australia; and Australian researchers have played leadership roles in other global studies in diverse populations. Australian researchers have also played an instrumental role in efforts to understand mechanisms underlying vascular contributions to cognitive impairment and dementia; and through the Women's Healthy Aging Project have elucidated hormonal and other factors that contribute to the increased risk of AD in women. Alleviating the behavioral and psychological symptoms of dementia has also been a strong research and clinical focus in Australia.
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http://dx.doi.org/10.1002/alz.12380DOI Listing
May 2021

Accuracy of a Deep Learning System for Classification of Papilledema Severity on Ocular Fundus Photographs.

Neurology 2021 May 19. Epub 2021 May 19.

Singapore Eye Research Institute, Singapore

Objective: To evaluate the performance of a deep learning system (DLS) in classifying the severity of papilledema associated with increased intracranial pressure, on standard retinal fundus photographs.

Methods: A DLS was trained to automatically classify papilledema severity in 965 patients (2103 mydriatic fundus photographs), representing a multiethnic cohort of patients with confirmed elevated intracranial pressure. Training was performed on 1052 photographs with mild/moderate papilledema (MP) and 1051 photographs with severe papilledema (SP) classified by a panel of experts. The performance of the DLS and that of three independent neuro-ophthalmologists were tested in 111 patients (214 photographs, 92 with MP and 122 with SP), by calculating the area under the receiver operating characteristics curve (AUC), accuracy, sensitivity and specificity. Kappa agreement scores between the DLS and each of the three graders and among the three graders were calculated.

Results: The DLS successfully discriminated between photographs of MP and SP, with an AUC of 0.93 (95%CI: 0.89-0.96) and an accuracy, sensitivity and specificity of 87.9%, 91.8% and 86.2%, respectively. This performance was comparable with that of the three neuro-ophthalmologists (84.1%, 91.8% and 73.9%, =0.19, =1, =0.09, respectively). Misclassification by the DLS was mainly observed for moderate papilledema (Frisén grade 3). Agreement scores between the DLS and the neuro-ophthalmologists' evaluation was 0.62 (CI 95% 0.57-0.68), whereas the inter-grader agreement among the three neuro-ophthalmologists was 0.54 (CI 95% 0.47-0.62).

Conclusions: Our DLS accurately classified the severity of papilledema on an independent set of mydriatic fundus photographs, achieving a comparable performance with that of independent neuro-ophthalmologists.

Classification Of Evidence: This study provides Class II evidence that a deep learning system using mydriatic retinal fundus photographs accurately classified the severity of papilledema associated in patients with a diagnosis of increased intracranial pressure.
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http://dx.doi.org/10.1212/WNL.0000000000012226DOI Listing
May 2021

Prevalence, Associated Factors and Health-related Quality of Life of Dual Sensory Impairment in Residential Care Facilities in Singapore.

Ophthalmic Epidemiol 2021 May 17:1-9. Epub 2021 May 17.

Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.

: To investigate the prevalence of dual sensory impairment (DSI), its associated factors and relationship with health-related quality of life (HR-QoL) in residential care facilities (RCF) in Singapore. This was a cross-sectional study of 123 residents aged ≥40 years from six RCFs, conducted between 2016 and 2018. DSI was defined as concomitant presenting visual acuity (better-eye) >0.3 logarithm of the minimum angle of resolution and a pure-tone air conduction threshold (better-ear) >40 dB HL in any of the four tested frequencies (500, 1000, 2000 and 4000 Hz). HR-QoL was quantified using the EuroQol five-dimension questionnaire. Multivariable Poisson regression was used to determine the associated factors of DSI. Multivariable linear regression was used to determine the association between DSI and HR-QoL adjusted for traditional confounders. Of the 123 residents (age [mean±standard deviation] 75.3 ± 10.8 years; 56.9% male), 97 (78.9%[95% confidence interval(CI):71.6%, 86.1%]) had DSI, with 110 (98.2%) not on follow-up care for their sensory disabilities. In multivariable models, male gender (prevalence ratio(PR) [95%CI] = 1.3[1.1, 1.6]), older age (per 10-year increase (1.2[1.1, 1.3])), education ≤6 years (1.3[1.1, 1.7]) and the presence of cataract (1.3[1.0, 1.7]) were independently associated with DSI. DSI was independently associated with a substantial worsening in HR-QoL (β = -0.61; 95%CI: -0.76, -0.45; < .001). DSI affects four in five residential care residents and is substantially associated with reductions in HR-QoL in these residents. Our finding highlights an urgent need for the implementation of routine vision and hearing screening and follow-up care for residents living in these facilities.
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http://dx.doi.org/10.1080/09286586.2021.1926515DOI Listing
May 2021

Visual Impairment, Major Eye Diseases and Mortality in a multi-ethnic Asian population and a Meta-analysis of Prospective Studies.

Am J Ophthalmol 2021 May 6. Epub 2021 May 6.

Singapore Eye Research Institute, Singapore National Eye Centre, Singapore; Ophthalmology and Visual Sciences Academic Clinical Program, Duke-NUS Medical School, Singapore. Electronic address:

Purpose: Vision impairment (VI) is associated with poor quality of life and increased risk of falls. Few prospective data are available on the impact of VI and the major eye diseases on mortality risk in Asians.

Design: Prospective cohort study with meta-analysis METHODS: We conducted a multi-ethnic prospective study of adults (40-80 years) in the Singapore Epidemiology of Eye Diseases Study (baseline 2004-11). All-cause mortality was obtained from the National Death Registry until May 2017. VI was defined by best-corrected visual acuity (BCVA) <20/40 in the better eye. Major eye diseases were assessed using standard protocols. We examined associations using multivariable-adjusted Cox proportional-hazards regression models. Finally, we conducted a meta-analysis on the associations between VI and mortality.

Results: Of 9,986 participants, 1210 deaths occurred (12.1%) over a median follow-up of 8.8 years. Compared to those with normal vision, persons with VI had increased risk of mortality (hazards ratio 1.53, 95% confidence interval [1.30-1.81] in multivariable models. In ethnicity-specific analyses, this association was significant across Chinese (1.63 [1.08-2.48]), Malays (1.31 [1.06-1.62]), and Indians (2.25[1.61-3.15]). Cataract, under-corrected refractive errors (URE) and diabetic retinopathy (DR) were significantly associated with mortality (HRs: 1.30, 1.22 and 1.54 respectively). In a meta-analysis of 12 studies including 58034 persons, VI was associated with 30% increased risk of mortality (1.3, [1.2-1.5]).

Conclusions: In this multi-ethnic Asian population, VI and preventable eye conditions (cataract, URE and DR) were associated with mortality, emphasizing the need for early detection and intervention to prevent and treat VI and major eye diseases.
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http://dx.doi.org/10.1016/j.ajo.2021.04.026DOI Listing
May 2021

Non-ICGA treatment criteria for Suboptimal Anti-VEGF Response for Polypoidal Choroidal Vasculopathy: APOIS PCV Workgroup Report 2.

Ophthalmol Retina 2021 Apr 16. Epub 2021 Apr 16.

Department of Ophthalmology and Visual Sciences The Chinese University of Hong Kong Hong Kong Eye Hospital, Hong Kong.

Purpose: To develop and validate OCT and color fundus photography (CFP) criteria in differentiating polypoidal choroidal vasculopathy (PCV) from typical neovascular age-related macular degeneration (nAMD) in eyes with suboptimal response to anti-vascular endothelial growth factor (VEGF) monotherapy and to determine whether OCT alone can be used to guide photodynamic therapy (PDT) treatment.

Design: Clinical study evaluating diagnostic accuracy.

Participants: Patients with nAMD who received 3-month anti-VEGF monotherapy but had persistent activity defined as subretinal fluid or intraretinal fluid at month 3 assessments.

Methods: In phase 1, international retina experts evaluated OCT and CFP of eyes with nAMD to identify the presence or absence of features due to PCV. The performance of individual and combinations of these features were compared with ICGA. In phase 2, these criteria were applied to an independent image set to assess generalizability. In a separate exercise, retinal experts drew proposed PDT treatment spots using only OCT and near-infrared (NIR) images in eyes with PCV and persistent activity. The location and size of proposed spot were compared with ICGA to determine the extent of coverage of polypoidal lesions (PLs) and branching neovascular network (BNN).

Main Outcome Measures: Sensitivity and specificity of CFP and OCT criteria to differentiate PCV from nAMD and accuracy of coverage of OCT-guided PDT compared with ICGA.

Results: In eyes with persistent activity, the combination of 3 non-ICGA-based criteria (sharp-peaked pigment epithelial detachment [PED], subretinal pigment epithelium [RPE] ring-like lesion, and orange nodule) to detect PCV showed good agreement compared with ICGA, with an area under the receiver operating characteristic curve of 0.85. Validation using both an independent image set and assessors achieved an accuracy of 0.77. Compared with ICGA, the OCT-guided PDT treatment spot covered 100% of PL and 90% of the BNN.

Conclusions: In nAMD eyes with persistent activity, OCT and CFP can differentiate PCV from typical nAMD, which may allow the option of adjunct PDT treatment. Furthermore, OCT alone can be used to plan adjunct PDT treatment without the need for ICGA, with consistent and complete coverage of PL.
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http://dx.doi.org/10.1016/j.oret.2021.04.002DOI Listing
April 2021

Patterns and Characteristics of a Clinical Implementation of a Self-Monitoring Program for Retina Diseases during the COVID-19 Pandemic.

Ophthalmol Retina 2021 Feb 19. Epub 2021 Feb 19.

Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Republic of Singapore; Duke-NUS Medical School, National University of Singapore, Singapore, Republic of Singapore.

Purpose: We describe the large-scale self-initiated recruitment of patients to a self-monitoring initiative for macular pathologic features during the coronavirus disease 2019 (COVID-19) pandemic.

Design: Observational study with retrospective analysis.

Participants: A total of 2272 patients from the Singapore National Eye Centre (SNEC) whose visits were rescheduled over lockdown (April 13-June 1, 2020) were offered participation in a self-monitoring initiative administered by SNEC with the Alleye application (Switzerland) as the testing instrument.

Methods: This was an observational study with retrospective analysis. Demographics and characteristics were compared between those who signed up and those who did not. Similar comparisons were made between patients who complied with the initiative versus those who did not. Outcomes were tracked for 6 months starting from the commencement of lockdown.

Main Outcome Measures: Participation and compliance rates and characteristics of patients who were more likely to participate and comply with the initiative.

Results: Seven hundred thirty-two patients (32%) participated in this self-monitoring initiative. Those who participated were younger (62 years of age vs. 68 years of age; P < 0.001), men, and living with family. Patients not receiving treatment and those with poorer vision in the worse-seeing eye were more likely to participate. When grouped according to diagnosis, the proportion who participated was highest for diabetic macular edema (52%), nonneovascular age-related macular degeneration (AMD; 42%), diabetic retinopathy (35%), retinal vein occlusions (18%), and neovascular AMD (15%; P < 0.001). Testing compliance rate was 43% (315/732). Patients who complied with the initiative were older, were receiving treatment, and had poorer vision in the worse-seeing eye. Trigger events occurred in 33 patients, with 5 patients having clinically verified disease progression (1.6%).

Conclusions: We provide clinical data on characteristics of patients with stable retinal diseases who were offered, participated in, and complied with a self-monitoring program. The lower participation rate compared with standardized clinical studies reflects the difficulties in implementation for such initiatives in clinical settings. Despite this, self-monitoring continues to show promise in relieving clinic resources, suggesting the feasibility of scaling such programs beyond the COVID-19 pandemic.
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http://dx.doi.org/10.1016/j.oret.2021.02.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8160297PMC
February 2021

Deep Learning Approach for Automated Detection of Myopic Maculopathy and Pathologic Myopia in Fundus Images.

Ophthalmol Retina 2021 Feb 18. Epub 2021 Feb 18.

Department of Ophthalmology and Visual Science, Tokyo Medical and Dental University, Tokyo, Japan. Electronic address:

Purpose: To determine whether eyes with pathologic myopia can be identified and whether each type of myopic maculopathy lesion on fundus photographs can be diagnosed by deep learning (DL) algorithms.

Design: A DL algorithm was developed to recognize myopic maculopathy features and to categorize the myopic maculopathy automatically.

Participants: We examined 7020 fundus images from 4432 highly myopic eyes obtained from the Advanced Clinical Center for Myopia.

Methods: Deep learning (DL) algorithms were developed to recognize the key features of myopic maculopathy with 5176 fundus images. These algorithms were also used to develop a Meta-analysis for Pathologic Myopia (META-PM) study categorizing system (CS) by adding a specific processing layer. Models and the system were evaluated by 1844 fundus image. The area under the receiver operating characteristic curve (AUC), sensitivity, and specificity were used to determine the performance of each DL algorithm. The rate of correct predictions was used to determine the performance of the META-PM study CS.

Main Outcome Measures: Four trained DL models were able to recognize the lesions of myopic maculopathy accurately with high sensitivity and specificity. The META-PM study CS also showed a high accuracy and was qualified to be used in a semiautomated way during screening for myopic maculopathy in highly myopic eyes.

Results: The sensitivity of the DL models was 84.44% for diffuse atrophy, 87.22% for patchy atrophy, 85.10% for macular atrophy, and 37.07% for choroidal neovascularization, and the AUC values were 0.970, 0.978, 0.982, and 0.881, respectively. The rate of total correct predictions from the META-PM study CS was 87.53%, with rates of 90.18%, 95.28%, 97.50%, and 91.14%, respectively, for each type of lesion. The META-PM study CS showed an overall rate of 92.08% in detecting pathologic myopia correctly, which was defined as having myopic maculopathy equal to or more serious than diffuse atrophy.

Conclusions: The novel DL models and system can achieve high sensitivity and specificity in identifying the different types of lesions of myopic maculopathy. These results will assist in the screening for pathologic myopia and subsequent protection of patients against low vision and blindness caused by myopic maculopathy.
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http://dx.doi.org/10.1016/j.oret.2021.02.006DOI Listing
February 2021

Digital health during COVID-19: lessons from operationalising new models of care in ophthalmology.

Lancet Digit Health 2021 02;3(2):e124-e134

Singapore Eye Research Institute, Singapore National Eye Centre, Singapore; Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Duke-NUS Medical School, Singapore. Electronic address:

The COVID-19 pandemic has resulted in massive disruptions within health care, both directly as a result of the infectious disease outbreak, and indirectly because of public health measures to mitigate against transmission. This disruption has caused rapid dynamic fluctuations in demand, capacity, and even contextual aspects of health care. Therefore, the traditional face-to-face patient-physician care model has had to be re-examined in many countries, with digital technology and new models of care being rapidly deployed to meet the various challenges of the pandemic. This Viewpoint highlights new models in ophthalmology that have adapted to incorporate digital health solutions such as telehealth, artificial intelligence decision support for triaging and clinical care, and home monitoring. These models can be operationalised for different clinical applications based on the technology, clinical need, demand from patients, and manpower availability, ranging from out-of-hospital models including the hub-and-spoke pre-hospital model, to front-line models such as the inflow funnel model and monitoring models such as the so-called lighthouse model for provider-led monitoring. Lessons learnt from operationalising these models for ophthalmology in the context of COVID-19 are discussed, along with their relevance for other specialty domains.
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http://dx.doi.org/10.1016/S2589-7500(20)30287-9DOI Listing
February 2021

Independent and Synergistic Effects of High Blood Pressure and Obesity on Retinal Vasculature in Young Children: The Hong Kong Children Eye Study.

J Am Heart Assoc 2021 Feb 26;10(3):e018485. Epub 2021 Jan 26.

Department of Ophthalmology and Visual Sciences The Chinese University of Hong Kong Hong Kong SAR China.

Background High blood pressure (BP) and obesity are becoming increasingly prevalent among children globally. Although prior studies have shown their adverse impacts on macrovascular health, less is known about their effects on microvascular heath. This study aims to evaluate the independent and synergistic effects of hypertensive BP and obesity on retinal vasculature in young children. Method and Results 1006 children aged 6 to 8 years were recruited from the Hong Kong Children Eye Study. Quantitative retinal vascular parameters, including central retinal arteriolar and venular equivalents and retinal arteriolar and venular fractal dimensions, were measured from retinal photographs following a standardized protocol. BP and body mass index were categorized according to reference values from American Academy of Pediatrics and International Obesity Task Force guidelines respectively. Children with hypertensive systolic BP had the narrowest central retinal arteriolar equivalents compared with children with either elevated or normotensive systolic BP (162.4, 164.6, and 167.1 µm; -trend <0.001). Increased standardized systolic BP was associated with narrower central retinal arteriolar equivalents (β=-2.276 µm, <0.001), wider central retinal venular equivalents (1.177, =0.007), and decreased arteriolar fractal dimensions (β=-0.004, =0.034). Children with obesity had the smallest arteriolar fractal dimensions compared with children with overweightness and normal weight (1.211, 1.234, and 1.240; -trend=0.004). Children with both hypertensive BP and either overweightness or obesity had the narrowest central retinal arteriolar equivalents and smallest arteriolar (-trend<0.001 and -trend=0.007). Conclusions Our findings demonstrate the potential synergistic or additive effects for both hypertensive BP and obesity on retinal vasculature in children.
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http://dx.doi.org/10.1161/JAHA.120.018485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955451PMC
February 2021

Vision, vision-specific functioning and mobility, and their relationship with clinically assessed cognitive impairment.

Age Ageing 2021 Jan 22. Epub 2021 Jan 22.

Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.

Background: The relationship between self-reported visual disability and cognitive impairment in older individuals is unclear.

Objective: To determine the relationship of vision-specific functioning (VSF), vision-specific mobility (VSM) and visual acuity (VA) with clinically assessed cognitive impairment in the Epidemiology of Dementia in Singapore study.

Design: Cross-sectional.

Setting: Population-based.

Subjects: Eight hundred and seventy-four adults aged ≥60 years at higher risk of possible cognitive impairment by the Abbreviated Mental Test and progressive forgetfulness question.

Methods: VSF and VSM were measured using Rasch-transformed continuous scores of two Impact of Vision Impairment questionnaire domains. Cognitive impairment was objectively determined using detailed neuropsychological testing and defined as no cognitive impairment (NCI), mild cognitive impairment-no dementia (CIND), moderate CIND only and moderate CIND or dementia. Associations were assessed using multinomial logistic regression models.

Results: Of the 874 participants (49.0% males, mean age (SD) 65.5 (7.0) years), 277, 281 and 316 had NCI, mild CIND and moderate CIND or dementia, respectively. Compared to NCI, the odds of moderate CIND, and moderate CIND or dementia increased for every SD worsening in VSF (OR: 1.44, 95% CI 1.14-1.82, and OR: 1.52, 95%CI 1.19-1.94, respectively) and VSM (OR: 1.42, 95%CI 1.11-1.81, and OR: 1.50, 95%CI 1.15-1.95). Similarly, the odds of mild CIND (OR: 1.62, 95%CI 1.19-2.22), moderate CIND (OR: 1.93, 95%CI 1.45-2.58), and moderate CIND or dementia (OR: 2.25, 95%CI 1.62-3.11) increased significantly with every SD worsening of VA.

Conclusions: Our results emphasise the importance of interventions to prevent vision loss and improve quality of life to reduce likelihood of age-related cognitive decline.
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http://dx.doi.org/10.1093/ageing/afaa276DOI Listing
January 2021

High-salt intake affects retinal vascular tortuosity in healthy males: an exploratory randomized cross-over trial.

Sci Rep 2021 Jan 12;11(1):801. Epub 2021 Jan 12.

Section of Nephrology, Department of Internal Medicine, Amsterdam Cardiovascular Sciences, A3-272, Amsterdam UMC, University of Amsterdam, location AMC, Meibergdreef 9, Amsterdam, 1105 AZ, The Netherlands.

The retinal microcirculation is increasingly receiving credit as a relatively easily accessible microcirculatory bed that correlates closely with clinical cardiovascular outcomes. The effect of high salt (NaCl) intake on the retinal microcirculation is currently unknown. Therefore, we performed an exploratory randomized cross-over dietary intervention study in 18 healthy males. All subjects adhered to a two-week high-salt diet and low-salt diet, in randomized order, after which fundus photographs were taken and assessed using a semi-automated computer-assisted program (SIVA, version 4.0). Outcome parameters involved retinal venular and arteriolar tortuosity, vessel diameter, branching angle and fractal dimension. At baseline, participants had a mean (SD) age of 29.8 (4.4) years and blood pressure of 117 (9)/73 (5) mmHg. Overall, high-salt diet significantly increased venular tortuosity (12.2%, p = 0.001). Other retinal parameters were not significantly different between diets. Changes in arteriolar tortuosity correlated with changes in ambulatory systolic blood pressure (r = - 0.513; p = 0.04). In conclusion, high-salt diet increases retinal venular tortuosity, and salt-induced increases in ambulatory systolic blood pressure associate with decreases in retinal arteriolar tortuosity. Besides potential eye-specific consequences, both phenomena have previously been associated with hypertension and other cardiovascular risk factors, underlining the deleterious microcirculatory effects of high salt intake.
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http://dx.doi.org/10.1038/s41598-020-79753-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803999PMC
January 2021

A novel tool to assess the quality of RWE to guide the management of retinal disease.

Acta Ophthalmol 2020 Dec 28. Epub 2020 Dec 28.

CHU Bordeaux, Service d'Ophtalmologie, France.

Despite the growing importance of real-world evidence (RWE) for guiding clinical decisions in retinal disease, there is currently no widely used guidance available for assessing the quality and relevance of RWE studies in ophthalmology. This paper summarizes the development of a user-friendly tool that facilitates assessment of the quality of available RWE for neovascular age-related macular degeneration (nAMD), diabetic macular oedema (DME) and retinal vein occlusion (RVO). A literature search was conducted to identify tools developed to assess the quality of RWE, in order to identify the most appropriate framework on which to base this tool. The Good Research for Comparative Effectiveness (GRACE) guidelines was chosen for this purpose as it is designed to assess the quality of observational studies and has been extensively validated, including demonstration of strong sensitivity and specificity. The GRACE guidelines were adapted to develop a straightforward tabular tool that allows simple assessment and comparison of the quality of published evidence in retinal disease for researchers and physicians alike, and includes guidance on treatment details, outcome measures, study population, and controlling for bias. The newly developed tool provides a simple method to support assessment of the strength of evidence and certainty of conclusions drawn from RWE in retinal disease, to ensure clinical decision-making is influenced by the highest quality evidence.
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http://dx.doi.org/10.1111/aos.14698DOI Listing
December 2020

A deep learning algorithm to detect chronic kidney disease from retinal photographs in community-based populations.

Lancet Digit Health 2020 06 12;2(6):e295-e302. Epub 2020 May 12.

Singapore Eye Research Institute, Singapore National Eye Centre, Singapore; Ophthalmology and Visual Sciences Academic Clinical Program, Duke-NUS Medical School, Singapore. Electronic address:

Background: Screening for chronic kidney disease is a challenge in community and primary care settings, even in high-income countries. We developed an artificial intelligence deep learning algorithm (DLA) to detect chronic kidney disease from retinal images, which could add to existing chronic kidney disease screening strategies.

Methods: We used data from three population-based, multiethnic, cross-sectional studies in Singapore and China. The Singapore Epidemiology of Eye Diseases study (SEED, patients aged ≥40 years) was used to develop (5188 patients) and validate (1297 patients) the DLA. External testing was done on two independent datasets: the Singapore Prospective Study Program (SP2, 3735 patients aged ≥25 years) and the Beijing Eye Study (BES, 1538 patients aged ≥40 years). Chronic kidney disease was defined as estimated glomerular filtration rate less than 60 mL/min per 1·73m. Three models were trained: 1) image DLA; 2) risk factors (RF) including age, sex, ethnicity, diabetes, and hypertension; and 3) hybrid DLA combining image and RF. Model performances were evaluated using the area under the receiver operating characteristic curve (AUC).

Findings: In the SEED validation dataset, the AUC was 0·911 for image DLA (95% CI 0·886 -0·936), 0·916 for RF (0·891-0·941), and 0·938 for hybrid DLA (0·917-0·959). Corresponding estimates in the SP2 testing dataset were 0·733 for image DLA (95% CI 0·696-0·770), 0·829 for RF (0·797-0·861), and 0·810 for hybrid DLA (0·776-0·844); and in the BES testing dataset estimates were 0·835 for image DLA (0·767-0·903), 0·887 for RF (0·828-0·946), and 0·858 for hybrid DLA (0·794-0·922). AUC estimates were similar in subgroups of people with diabetes (image DLA 0·889 [95% CI 0·850-0·928], RF 0·899 [0·862-0·936], hybrid 0·925 [0·893-0·957]) and hypertension (image DLA 0·889 [95% CI 0·860-0·918], RF 0·889 [0·860-0·918], hybrid 0·918 [0·893-0·943]).

Interpretation: A retinal image DLA shows good performance for estimating chronic kidney disease, underlying the feasibility of using retinal photography as an adjunctive or opportunistic screening tool for chronic kidney disease in community populations.

Funding: National Medical Research Council, Singapore.
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http://dx.doi.org/10.1016/S2589-7500(20)30063-7DOI Listing
June 2020

Artificial intelligence for teleophthalmology-based diabetic retinopathy screening in a national programme: an economic analysis modelling study.

Lancet Digit Health 2020 05 23;2(5):e240-e249. Epub 2020 Apr 23.

Singapore Eye Research Institute, Singapore National Eye Centre, Singapore; Tan Tock Seng Hospital, National Healthcare Group, Singapore; State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yet-Sen University, Guangzhou, China. Electronic address:

Background: Deep learning is a novel machine learning technique that has been shown to be as effective as human graders in detecting diabetic retinopathy from fundus photographs. We used a cost-minimisation analysis to evaluate the potential savings of two deep learning approaches as compared with the current human assessment: a semi-automated deep learning model as a triage filter before secondary human assessment; and a fully automated deep learning model without human assessment.

Methods: In this economic analysis modelling study, using 39 006 consecutive patients with diabetes in a national diabetic retinopathy screening programme in Singapore in 2015, we used a decision tree model and TreeAge Pro to compare the actual cost of screening this cohort with human graders against the simulated cost for semi-automated and fully automated screening models. Model parameters included diabetic retinopathy prevalence rates, diabetic retinopathy screening costs under each screening model, cost of medical consultation, and diagnostic performance (ie, sensitivity and specificity). The primary outcome was total cost for each screening model. Deterministic sensitivity analyses were done to gauge the sensitivity of the results to key model assumptions.

Findings: From the health system perspective, the semi-automated screening model was the least expensive of the three models, at US$62 per patient per year. The fully automated model was $66 per patient per year, and the human assessment model was $77 per patient per year. The savings to the Singapore health system associated with switching to the semi-automated model are estimated to be $489 000, which is roughly 20% of the current annual screening cost. By 2050, Singapore is projected to have 1 million people with diabetes; at this time, the estimated annual savings would be $15 million.

Interpretation: This study provides a strong economic rationale for using deep learning systems as an assistive tool to screen for diabetic retinopathy.

Funding: Ministry of Health, Singapore.
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http://dx.doi.org/10.1016/S2589-7500(20)30060-1DOI Listing
May 2020

Reporting on deep learning algorithms in health care.

Lancet Digit Health 2019 11;1(7):e328-e329

Singapore Eye Research Institute, Singapore National Eye Centre, Singapore; Ophthalmology and Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School, Singapore. Electronic address:

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http://dx.doi.org/10.1016/S2589-7500(19)30132-3DOI Listing
November 2019

Evolution of treatment paradigms in neovascular age-related macular degeneration: a review of real-world evidence.

Br J Ophthalmol 2020 Oct 31. Epub 2020 Oct 31.

Service D'ophtalmologie, CHU de Bordeaux, Bordeaux, France.

The aim of this work was to evaluate the contribution of real-world evidence (RWE) in changing anti-vascular endothelial growth factor (VEGF) therapy treatment practices and improving real-world treatment strategies for neovascular age-related macular degeneration (nAMD).A PubMed literature search was performed to review the large number of English-language studies conducted to investigate the real-world effectiveness of anti-VEGF (aflibercept and ranibizumab) treatment paradigms available for nAMD.The evidence for pro re nata (PRN), treat-and-extend (T&E) and fixed bimonthly dosing regimens for anti-VEGF treatment of nAMD were reviewed and findings are summarised. RWE demonstrated that T&E regimens optimise visual outcomes while reducing burden on patients, clinics and physicians, compared with both fixed-dose and PRN regimens.RWE has helped to develop and improve real-world treatment strategies in nAMD, with the aim of optimising visual outcomes and reducing treatment burden in clinical practice. Of the various regimens, a T&E regimen is most likely to adequately balance clinical outcomes and treatment burden for patients with nAMD.
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http://dx.doi.org/10.1136/bjophthalmol-2020-317434DOI Listing
October 2020

Validation of a New Diabetic Retinopathy Knowledge and Attitudes Questionnaire in People with Diabetic Retinopathy and Diabetic Macular Edema.

Transl Vis Sci Technol 2020 09 30;9(10):32. Epub 2020 Sep 30.

Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.

Purpose: A validated questionnaire assessing diabetic retinopathy (DR)- and diabetic macular edema (DME)-related knowledge (K) and attitudes (A) is lacking. We developed and validated the Diabetic Retinopathy Knowledge and Attitudes (DRKA) questionnaire and explored the association between K and A and the self-reported difficulty accessing DR-related information (hereafter referred to as Access).

Methods: In this mixed-methods study, eight focus groups with 36 people with DR or DME (mean age, 60.1 ± 8.0 years; 53% male) were conducted to develop content (phase 1). In phase 2, we conducted 10 cognitive interviews to refine item phrasing. In phase 3, we administered 28-item K and nine-item A pilot questionnaires to 200 purposively recruited DR/DME patients (mean age, 59.0 ± 10.6 years; 59% male). The psychometric properties of DRKA were assessed using Rasch and classical methods. The association between K and A and DR-related Access was assessed using univariable linear regression of mean K/A scores against Access.

Results: Following Rasch-guided amendments, the final 22-item K and nine-item A scales demonstrated adequate psychometric properties, although precision remained borderline. The scales displayed excellent discriminant validity, with K/A scores increasing as education level increased. Compared to those with low scores, those with high K/A scores were more likely to report better access to DR-related information, with K scores of 0.99 ± 0.86 for no difficulty; 0.79 ± 1.05 for a little difficulty; and 0.24 ± 0.85 for moderate or worse difficulty ( < 0.001).

Conclusions: The psychometrically robust 31-item DRKA questionnaire can measure DR- and DME-related knowledge and attitudes.

Translational Relevance: The DRKA questionnaire may be useful for interventions to improve DR-related knowledge and attitudes and, in turn, optimize health behaviors and health literacy.
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http://dx.doi.org/10.1167/tvst.9.10.32DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7533728PMC
September 2020

A deep-learning system for the assessment of cardiovascular disease risk via the measurement of retinal-vessel calibre.

Nat Biomed Eng 2020 Oct 12. Epub 2020 Oct 12.

Singapore Eye Research Institute, Singapore National Eye Center, Singapore, Singapore.

Retinal blood vessels provide information on the risk of cardiovascular disease (CVD). Here, we report the development and validation of deep-learning models for the automated measurement of retinal-vessel calibre in retinal photographs, using diverse multiethnic multicountry datasets that comprise more than 70,000 images. Retinal-vessel calibre measured by the models and by expert human graders showed high agreement, with overall intraclass correlation coefficients of between 0.82 and 0.95. The models performed comparably to or better than expert graders in associations between measurements of retinal-vessel calibre and CVD risk factors, including blood pressure, body-mass index, total cholesterol and glycated-haemoglobin levels. In retrospectively measured prospective datasets from a population-based study, baseline measurements performed by the deep-learning system were associated with incident CVD. Our findings motivate the development of clinically applicable explainable end-to-end deep-learning systems for the prediction of CVD on the basis of the features of retinal vessels in retinal photographs.
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http://dx.doi.org/10.1038/s41551-020-00626-4DOI Listing
October 2020

Digital technology, tele-medicine and artificial intelligence in ophthalmology: A global perspective.

Prog Retin Eye Res 2021 05 6;82:100900. Epub 2020 Sep 6.

Singapore National Eye Center, Duke-NUS Medical School Singapore, Singapore. Electronic address:

The simultaneous maturation of multiple digital and telecommunications technologies in 2020 has created an unprecedented opportunity for ophthalmology to adapt to new models of care using tele-health supported by digital innovations. These digital innovations include artificial intelligence (AI), 5th generation (5G) telecommunication networks and the Internet of Things (IoT), creating an inter-dependent ecosystem offering opportunities to develop new models of eye care addressing the challenges of COVID-19 and beyond. Ophthalmology has thrived in some of these areas partly due to its many image-based investigations. Tele-health and AI provide synchronous solutions to challenges facing ophthalmologists and healthcare providers worldwide. This article reviews how countries across the world have utilised these digital innovations to tackle diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, glaucoma, refractive error correction, cataract and other anterior segment disorders. The review summarises the digital strategies that countries are developing and discusses technologies that may increasingly enter the clinical workflow and processes of ophthalmologists. Furthermore as countries around the world have initiated a series of escalating containment and mitigation measures during the COVID-19 pandemic, the delivery of eye care services globally has been significantly impacted. As ophthalmic services adapt and form a "new normal", the rapid adoption of some of telehealth and digital innovation during the pandemic is also discussed. Finally, challenges for validation and clinical implementation are considered, as well as recommendations on future directions.
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http://dx.doi.org/10.1016/j.preteyeres.2020.100900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7474840PMC
May 2021

Computerized Adaptive Tests: Efficient and Precise Assessment of the Patient-Centered Impact of Diabetic Retinopathy.

Transl Vis Sci Technol 2020 06 3;9(7). Epub 2020 Jun 3.

Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.

Purpose: Evaluate efficiency, precision, and validity of RetCAT, which comprises ten diabetic retinopathy (DR) quality of life (QoL) computerized adaptive tests (CATs).

Methods: In this cross-sectional clinical study, 183 English and/or Mandarin-speaking participants with DR (mean age ± standard deviation [SD] 56.4 ± 11.9 years; 38% proliferative DR [worse eye]) were recruited from retinal clinics in Singapore. Participants answered the RetCAT tests (Symptoms, Activity Limitation, Mobility, Emotional, Health Concerns, Social, Convenience, Economic, Driving, and Lighting), which were capped at seven items each, and other questionnaires, and underwent eye tests. Our primary evaluation focused on RetCAT efficiency (i.e. standard error of measurement [SEM] ± SD achieved and time needed to complete each CAT). Secondary evaluations included an assessment of RetCAT's test precision and validity.

Results: Mean SEM across all RetCAT tests was 0.351, ranging from 0.272 ± 0.130 for Economic to 0.484 ± 0.130 for Emotional. Four tests (Mobility, Social, Convenience, and Driving) had a high level of measurement error. The median time to take each RetCAT test was 1.79 minutes, ranging from 1.12 (IQR [interquartile range] 1.63) for Driving to 3.28 (IQR 2.52) for Activity Limitation. Test precision was highest for participants at the most impaired end of the spectrum. Most RetCAT tests displayed expected correlations with other scales (convergent/divergent validity) and were sensitive to DR and/or vision impairment severity levels (criterion validity).

Conclusions: RetCAT can provide efficient, precise, and valid measurement of DR-related QoL impact. Future application of RetCAT will employ a stopping rule based on SE rather than number of items to ensure that all tests can detect meaningful differences in person abilities. Responsiveness of RetCAT to treatment interventions must also be determined.

Translational Relevance: RetCAT may be useful for measuring the patient-centered impact of DR severity and disease progression and evaluating the effectiveness of new therapies.
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http://dx.doi.org/10.1167/tvst.9.7.3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414626PMC
June 2020

A systematic review and participant-level meta-analysis found little association of retinal microvascular caliber with reduced kidney function.

Kidney Int 2021 03 15;99(3):696-706. Epub 2020 Aug 15.

Centre for Public Health, Queen's University Belfast, Belfast, Northern Ireland, UK. Electronic address:

Previously, variation in retinal vascular caliber has been reported in association with chronic kidney disease (CKD) but findings remain inconsistent. To help clarify this we conducted individual participant data meta-analysis and aggregate data meta-analysis on summary estimates to evaluate cross-sectional associations between retinal vascular caliber and CKD. A systematic review was performed using Medline and EMBASE for articles published until October 2018. The aggregate analysis used a two-stage approach combining summary estimates from eleven studies (44,803 patients) while the individual participant analysis used a one-stage approach combining raw data from nine studies (33,222 patients). CKD stages 3-5 was defined as an estimated glomerular filtration rate under 60 mL/min/1.73m. Retinal arteriolar and venular caliber (central retinal arteriolar and venular equivalent) were assessed from retinal photographs using computer-assisted methods. Logistic regression estimated relative risk of CKD stages 3-5 associated with a 20 μm decrease (approximately one standard deviation) in central retinal arteriolar and venular equivalent. Prevalence of CKD stages 3-5 was 11.2% of 33,222 and 11.3% of 44,803 patients in the individual participant and aggregate data analysis, respectively. No significant associations were detected in adjusted analyses between central retinal arteriolar and venular equivalent and CKD stages 3-5 in the aggregate analysis for central retinal arteriolar relative risk (0.98, 95% confidence interval 0.94-1.03); venular equivalent (0.99, 0.95-1.04) or individual participant central retinal arteriolar (0.99, 0.95-1.04) or venular equivalent (1.01, 0.97-1.05). Thus, meta-analysis provided little evidence to suggest that cross sectional direct measurements of retinal vascular caliber was associated with CKD stages 3-5 in the general population. Hence, meta-analyses of longitudinal studies evaluating the association between retinal parameters and CKD stages 3-5 may be warranted.
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http://dx.doi.org/10.1016/j.kint.2020.06.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898278PMC
March 2021

Polypoidal Choroidal Vasculopathy: Consensus Nomenclature and Non-Indocyanine Green Angiograph Diagnostic Criteria from the Asia-Pacific Ocular Imaging Society PCV Workgroup.

Ophthalmology 2021 Mar 11;128(3):443-452. Epub 2020 Aug 11.

Nune Eye Hospital, Seoul, South Korea.

Purpose: To develop consensus terminology in the setting of polypoidal choroidal vasculopathy (PCV) and to develop and validate a set of diagnostic criteria not requiring indocyanine green angiography (ICGA) for differentiating PCV from typical neovascular age-related macular degeneration (nAMD) based on a combination of OCT and color fundus photography findings.

Design: Evaluation of diagnostic test results.

Participants: Panel of retina specialists.

Methods: As part of the Asia-Pacific Ocular Imaging Society, an international group of experts surveyed and discussed the published literature regarding the current nomenclature and lesion components for PCV, and proposed an updated consensus nomenclature that reflects our latest understanding based on imaging and histologic reports. The workgroup evaluated a set of diagnostic features based on OCT images and color fundus photographs for PCV that may distinguish it from typical nAMD and assessed the performance of individual and combinations of these non-ICGA features, aiming to propose a new set of diagnostic criteria that does not require the use of ICGA. The final recommendation was validated in 80 eyes from 2 additional cohorts.

Main Outcome Measures: Consensus nomenclature system for PCV lesion components and non-ICGA-based criteria to differentiate PCV from typical nAMD.

Results: The workgroup recommended the terms polypoidal lesion and branching neovascular network for the 2 key lesion components in PCV. For the diagnosis of PCV, the combination of 3 OCT-based major criteria (sub-retinal pigment epithelium [RPE] ring-like lesion, en face OCT complex RPE elevation, and sharp-peaked PED) achieved an area under the receiver operating characteristic curve of 0.90. Validation of this new scheme in a separate subset 80 eyes achieved an accuracy of 82%.

Conclusions: We propose updated terminology for PCV lesion components that better reflects the nature of these lesions and is based on international consensus. A set of practical diagnostic criteria applied easily to spectral-domain OCT results can be used for diagnosing PCV with high accuracy in clinical settings in which ICGA is not performed routinely.
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http://dx.doi.org/10.1016/j.ophtha.2020.08.006DOI Listing
March 2021

Artificial intelligence for diabetic retinopathy screening, prediction and management.

Curr Opin Ophthalmol 2020 Sep;31(5):357-365

Singapore Eye Research Institute, Singapore National Eye Center.

Purpose Of Review: Diabetic retinopathy is the most common specific complication of diabetes mellitus. Traditional care for patients with diabetes and diabetic retinopathy is fragmented, uncoordinated and delivered in a piecemeal nature, often in the most expensive and high-resource tertiary settings. Transformative new models incorporating digital technology are needed to address these gaps in clinical care.

Recent Findings: Artificial intelligence and telehealth may improve access, financial sustainability and coverage of diabetic retinopathy screening programs. They enable risk stratifying patients based on individual risk of vision-threatening diabetic retinopathy including diabetic macular edema (DME), and predicting which patients with DME best respond to antivascular endothelial growth factor therapy.

Summary: Progress in artificial intelligence and tele-ophthalmology for diabetic retinopathy screening, including artificial intelligence applications in 'real-world settings' and cost-effectiveness studies are summarized. Furthermore, the initial research on the use of artificial intelligence models for diabetic retinopathy risk stratification and management of DME are outlined along with potential future directions. Finally, the need for artificial intelligence adoption within ophthalmology in response to coronavirus disease 2019 is discussed. Digital health solutions such as artificial intelligence and telehealth can facilitate the integration of community, primary and specialist eye care services, optimize the flow of patients within healthcare networks, and improve the efficiency of diabetic retinopathy management.
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http://dx.doi.org/10.1097/ICU.0000000000000693DOI Listing
September 2020

Comparison of Ranibizumab With or Without Verteporfin Photodynamic Therapy for Polypoidal Choroidal Vasculopathy: The EVEREST II Randomized Clinical Trial.

JAMA Ophthalmol 2020 09;138(9):935-942

Eye & Retina Surgeons, Camden Medical Centre, Singapore.

Importance: The 2-year efficacy and safety of combination therapy of ranibizumab administered together with verteporfin photodynamic therapy (vPDT) compared with ranibizumab monotherapy in participants with polypoidal choroidal vasculopathy (PCV) are unclear.

Objective: To compare treatment outcomes of ranibizumab, 0.5 mg, plus prompt vPDT combination therapy with ranibizumab, 0.5 mg, monotherapy in participants with PCV for 24 months.

Design, Setting, And Participants: This 24-month, phase IV, double-masked, multicenter, randomized clinical trial (EVEREST II) was conducted among Asian participants from August 7, 2013, to March 2, 2017, with symptomatic macular PCV confirmed using indocyanine green angiography.

Interventions: Participants (N = 322) were randomized 1:1 to ranibizumab, 0.5 mg, plus vPDT (combination therapy group; n = 168) or ranibizumab, 0.5 mg, plus sham PDT (monotherapy group; n = 154). All participants received 3 consecutive monthly ranibizumab injections, followed by a pro re nata regimen. Participants also received vPDT (combination group) or sham PDT (monotherapy group) on day 1, followed by a pro re nata regimen based on the presence of active polypoidal lesions.

Main Outcomes And Measures: Evaluation of combination therapy vs monotherapy at 24 months in key clinical outcomes, treatment exposure, and safety. Polypoidal lesion regression was defined as the absence of indocyanine green hyperfluorescence of polypoidal lesions.

Results: Among 322 participants (mean [SD] age, 68.1 [8.8] years; 225 [69.9%] male), the adjusted mean best-corrected visual acuity (BCVA) gains at month 24 were 9.6 letters in the combination therapy group and 5.5 letters in the monotherapy group (mean difference, 4.1 letters; 95% CI, 1.0-7.2 letters; P = .005), demonstrating that combination therapy was superior to monotherapy by the BCVA change from baseline to month 24. Combination therapy was superior to monotherapy in terms of complete polypoidal lesion regression at month 24 (81 of 143 [56.6%] vs 23 of 86 [26.7%] participants; P < .001). Participants in the combination group received fewer ranibizumab injections (median, 6.0 [interquartile range (IQR), 4.0-11.0]) than the monotherapy group (median, 12.0 [IQR, 7.0-17.0]) up to month 24. The combination group required a median of 2.0 (IQR, 1.0-3.0) vPDT treatments for 24 months, with 75 of 168 participants (44.6%) requiring only 1 vPDT treatment.

Conclusions And Relevance: The 24-month data findings confirm that ranibizumab therapy, given as monotherapy or in combination with vPDT, is efficacious and safe for treatment of PCV. Combination therapy with vPDT added to ranibizumab achieved superior BCVA gain, increased odds of complete polypoidal lesion regression, and fewer treatment episodes compared with ranibizumab monotherapy.

Trial Registration: ClinicalTrials.gov Identifier: NCT01846273.
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http://dx.doi.org/10.1001/jamaophthalmol.2020.2443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7366282PMC
September 2020

Assessment of retinal neurodegeneration with spectral-domain optical coherence tomography: a systematic review and meta-analysis.

Eye (Lond) 2021 May 24;35(5):1317-1325. Epub 2020 Jun 24.

Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, SAR, China.

Objectives: To comprehensively assess diabetic retinopathy neurodegeneration (DRN) as quantified by retinal neuronal and axonal layers measured with spectral-domain optical coherence tomography (SD-OCT) in subjects with diabetes mellitus (DM).

Methods: Articles on the topic of examining macular ganglion cell-inner plexiform layer (m-GCIPL), macular retinal nerve fibre layer (m-RNFL), macular ganglion cell complex (m-GCC), and peripapillary RNFL (p-RNFL) measured with SD-OCT in DM subjects without DR (NDR) or with non-proliferative DR (NPDR) were searched in PubMed and Embase up to November 31, 2019. Standardized mean difference (SMD) as effect size were pooled using random-effects model.

Results: Thirty-six studies searched from online databases and the CUHK DM cohort were included in the meta-analysis. In the comparison between NDR and control, macular measures including mean m-GCIPL (SMD = -0.26, p = 0.003), m-RNFL (SMD = -0.26, p = 0.046), and m-GCC (SMD = -0.28; p = 0.009) were significantly thinner in the NDR group. In the comparison between NPDR and NDR, only mean p-RNFL was significantly thinner in the NPDR group (SMD = -0.27; p = 0.03), but not other macular measures.

Conclusions: Thinning of retinal neuronal and axonal layers at macula as measured by SD-OCT are presented in eyes with NDR, supporting DRN may be the early pathogenesis in the DM patients without the presence of clinical signs of DR. In the future, these SD-OCT measures may be used as surrogates of DRN to stratify DM patients with a high risk of DR, and may be used as a therapeutic target if neuroprotection treatment for DR is available.
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http://dx.doi.org/10.1038/s41433-020-1020-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8182828PMC
May 2021

Association of Retinal Microvascular Signs with Incident Atrial Fibrillation: The Multi-Ethnic Study of Atherosclerosis.

Ophthalmol Retina 2021 01 19;5(1):78-85. Epub 2020 Jun 19.

Department of Preventive Medicine, Northwestern University, Chicago, Illinois.

Purpose: Microvascular diseases may contribute to the occurrence of atrial fibrillation (AF). Retinal microvascular signs that are similar to other microvasculature in the body and can be visualized directly via ophthalmoscopy may provide insights into such a relationship.

Design: Prospective, longitudinal, multiethnic study.

Participants: We examined the association between retinal microvascular signs and incident AF in 4994 participants 47 to 86 years of age and free of prior AF who underwent fundus photography from 2002 through 2004 and were followed up through 2015 in the Multi-Ethnic Study of Atherosclerosis (MESA).

Methods: Retinal microvascular signs evaluated include central retinal arteriolar equivalent and central retinal venular equivalent (CRVE) and presence of any retinopathy signs (e.g., retinal microaneurysms or hemorrhages). A multivariate Cox regression analysis was used to determine the relationship while adjusting for traditional risk factors, alcohol intake, body mass index, diabetes status, chronic kidney disease status, hemoglobin A1c level, C-reactive protein level, medications, and prevalent cardiovascular diseases or heart failure.

Main Outcome And Measures: Incident AF events were identified using 12-lead electrocardiographic findings, hospital discharge records, and Medicare claims data.

Results: During a median follow-up of 14.1 years, 643 AF events were identified. No association was found between any retinal microvascular signs and incident AF except for retinal focal arteriolar narrowing (hazard ratio, 1.75; 95% confidence interval, 1.06-2.87) in the overall population. However, in the subgroup analyses by gender, wider CRVE was associated with a higher risk of incident AF in women, but not in men (hazard ratio for every 10-μm increase in CRVE, 1.08 [95% confidence interval, 1.01-1.15] and 0.97 [95% confidence interval, 0.92-1.03], respectively; P = 0.041 for interaction).

Conclusions: No consistent pattern of association was found between retinal microvascular signs and incident AF. We observed an association in women, but not in men, of wider retinal venular calibers with incidence of AF. The reasons for a possible interaction are incompletely understood.
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http://dx.doi.org/10.1016/j.oret.2020.06.019DOI Listing
January 2021

Exploring Factors Underlying Ethnic Difference in Age-related Macular Degeneration Prevalence.

Ophthalmic Epidemiol 2020 10 8;27(5):399-408. Epub 2020 Jun 8.

Centre for Vision Research, Department of Ophthalmology, Westmead Institute for Medical Research, University of Sydney , Westmead, NSW, Australia.

Aims: To assess contributions of dietary and genetic factors to ethnic differences in AMD prevalence.

Design: Population-based analytical study.

Methods: In the Blue Mountains Eye Study, Australia (European ancestry n = 2826) and Multi-Ethnic Cohort Study, Singapore (Asian ancestry, n = 1900), AMD was assessed from retinal photographs. Patterns of dietary composition and scores of the Alternative Healthy Eating Index were computed using food frequency questionnaire data. Genetic susceptibility to AMD was determined using either single nucleotide polymorphisms (SNPs) of the c and genes, or combined odds-weighted genetic risk scores of 24 AMD-associated SNPs. Associations of AMD with ethnicity, diet, and genetics were assessed using logistic regression. Six potential mediators covering genetic, diet and lifestyle factors were assessed for their contributions to AMD risk difference between the two samples using mediation analyses.

Results: Age-standardized prevalence of any (early or late) AMD was higher in the European (16%) compared to Asian samples (9%, < .01). Mean AMD-related genetic risk scores were also higher in European (33.3 ± 4.4) than Asian (Chinese) samples (31.7 ± 3.7, < .001). In a model simultaneously adjusting for age, ethnicity, genetic susceptibility and Alternative Healthy Eating Index scores, only age and genetic susceptibility were significantly associated with AMD. Genetic risk scores contributed 19% of AMD risk difference between the two samples while intake of polyunsaturated fatty acids contributed 7.2%.

Conclusion: Genetic susceptibility to AMD was higher in European compared to Chinese samples and explained more of the AMD risk difference between the two samples than the dietary factors investigated.
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http://dx.doi.org/10.1080/09286586.2020.1762229DOI Listing
October 2020

Extended-Zone Retinal Vascular Caliber and Risk of Diabetic Retinopathy in Adolescents with Type 1 Diabetes.

Ophthalmol Retina 2020 12 21;4(12):1151-1157. Epub 2020 May 21.

Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Sydney, Australia; Discipline of Child and Adolescent Health, University of Sydney, Sydney, Australia. Electronic address:

Purpose: Retinal vascular caliber has been linked to diabetic retinopathy (DR). Newer imaging technologies allow analysis of retinal vascular caliber beyond the standard areas surrounding the optic disc. We investigated the vascular caliber in extended zones in prediction of DR in adolescents with type 1 diabetes.

Design: Prospective, longitudinal study.

Participants: Adolescents (n = 904) who attended the diabetes complications assessment service at the Children's Hospital at Westmead.

Methods: Retinal caliber was assessed from baseline retinal photographs with a semiautomated computer software Singapore I Vessel Assessment: standard zone retinal vessel calibers were summarized as central retinal arteriolar equivalent (CRAE) and central retinal venular equivalent (CRVE), and extended-zone vessels (>2 disc diameters from the optic disc margin) were summarized as mean width of arterioles (MWa) and mean width of venules (MWv).

Main Outcome Measures: Retinal vessel calibers at baseline (upper 3 quartiles vs. lowest quartiles [Q2-4 vs. Q1]) and moderate DR (stage 3 or more) were analyzed using multivariate generalized estimating equations, with results expressed as odds ratios (OR) and 95% confidence intervals (CIs).

Results: Among the 904 participants, baseline mean age ± standard deviation was 14.0 ± 1.5 years, hemoglobin A1C (HbA1C) level was 8.5 ± 1.3%, and median diabetes duration 4.6 years. After a median 3-year follow-up, 15% of adolescents demonstrated moderate DR. Wider extended-zone retinal arteriolar caliber (MWa; OR, 3.6 [95% CI, 2.06-6.1], comparing Q2-4 vs. Q1) and venular caliber (MWv; OR, 4.2 [95% CI, 2.2-7.5]) predicted moderate DR after adjusting for HbA1C and blood pressure. Standard zone CRAE and CRVE were not associated with moderate DR.

Conclusions: Extended-zone retinal vessel caliber predicts moderate DR in adolescents with type 1 diabetes.
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http://dx.doi.org/10.1016/j.oret.2020.05.009DOI Listing
December 2020

Detrimental Effect of Delayed Re-treatment of Active Disease on Outcomes in Neovascular Age-Related Macular Degeneration: The RAMPS Study.

Ophthalmol Retina 2020 09 1;4(9):871-880. Epub 2020 Apr 1.

Singapore Eye Research Institute, Singapore, Republic of Singapore; Singapore National Eye Centre, Singapore, Republic of Singapore; Duke-NUS Medical School, National University of Singapore, Singapore, Republic of Singapore. Electronic address:

Purpose: To assess the impact of delaying anti-vascular endothelial growth factor (VEGF) treatment of active disease at any point during a patient's treatment journey on clinical outcomes in a real-world cohort of patients with neovascular age-related macular degeneration (nAMD).

Design: Longitudinal cohort study.

Participants: Consecutive treatment-naive nAMD eyes commencing anti-VEGF monotherapy (bevacizumab, ranibizumab, or aflibercept) from January 2014 from a tertiary eye center in Singapore.

Methods: We conducted a real-world study using registry data comparing delayed re-treatment (defined as not receiving treatment at 2 or more monitoring visits when disease was graded as active) versus timely re-treatment (defined as receiving treatment when disease was active).

Main Outcome Measures: The primary outcome was the change in visual acuity (VA) in the timely and delayed re-treatment groups at 12 months.

Results: Data from 286 eyes were included and categorized into the timely (188 [66%]) or the delayed (98 ([34%]) group. The mean numbers of anti-VEGF injections over 12 months were similar: 5.6 (standard deviation [SD], 2.9) versus 4.9 (SD, 3.2; P = 0.11) for the timely and delayed groups, respectively. Timely treated patients showed larger gains in VA (6.4 letters [SD, 8.1 letters] vs. 1.2 letters [SD, 5.3 letters; P = 0.04), a higher proportion with VA of 6/12 or better (30% vs. 8%; P = 0.01), and greater reduction in OCT-measured central subfield thickness (135 μm [SD, 154 μm] vs. 87.8 μm [SD, 129 μm]; P = 0.04) at 12 months. A longer delay between detection of active disease and re-treatment was associated with poorer vision outcomes (0.02-letter decrease/day; P = 0.03; R = 0.29).

Conclusions: Although it has been established that adequate numbers of injections are required for favorable outcomes, timely re-treatment of active disease also is important. This should be emphasized to patients to ensure optimal outcomes in real-world clinical settings.
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http://dx.doi.org/10.1016/j.oret.2020.03.017DOI Listing
September 2020

Role of socio-economic factors in visual impairment and progression of diabetic retinopathy.

Br J Ophthalmol 2021 03 19;105(3):420-425. Epub 2020 May 19.

Singapore Eye Research Institute, Singapore Eye Research Institute, Singapore.

Background: To investigate the longitudinal associations between person-level and area-level socioeconomic status (PLSES and ALSES, respectively) with diabetic retinopathy (DR) and visual impairment (VI) in Asians with diabetes mellitus (DM).

Methods: In this population-based cohort study, we included 468 (39.4%) Malays and 721 (60.6%) Indians with DM, with a mean age (SD) of 58.9 (9.1) years; 50.6% were female and the mean follow-up duration was 6.2 (0.9) years. Individual PLSES parameters (education, monthly income and housing type) were quantified using questionnaires. ALSES was assessed using the Socioeconomic Disadvantage Index derived from Singapore's 2010 areal census (higher scores indicate greater disadvantage). Incident DR and VI were defined as absent at baseline but present at follow-up, while DR and VI progression were defined as a ≥1 step increase in severity category at follow-up. Modified Poisson regression analysis was used to determine the associations of PLSES and ALSES with incidence and progression of DR and VI, adjusting for relevant confounders.

Results: In multivariable models, per SD increase in ALSES score was associated with greater DR incidence (risk ratio (95% CI) 1.27 (1.13 to 1.44)), DR progression (1.10 (1.00 to 1.20)) and VI incidence (1.10 (1.04 to 1.16)), while lower PLSES variables were associated with increased DR (low income: 1.68 (1.21 to 2.34)) and VI (low income: 1.44 (1.13 to 1.83); ≤4 room housing: 2.00 (1.57 to 2.54)) incidence.

Conclusions: We found that both PLSES and ALSES variables were independently associated with DR incidence, progression and associated vision loss in Asians. Novel intervention strategies targeted at low socioeconomic status communities to decrease rates of DR and VI are warranted.
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http://dx.doi.org/10.1136/bjophthalmol-2020-316430DOI Listing
March 2021