Ophthalmology (Eye & Ear Hospital) - Research Publications
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ItemAssociations of retinal microvascular caliber with intermediate phenotypes of large arterial function and structure: A systematic review and meta-analysis(WILEY, 2019-10)OBJECTIVE: Intermediate phenotypes of microcirculation (retinal microvascular caliber) are associated with cardiovascular (CV) risk factors and independently predict CV events. However, the effect of microcirculation variation on the vascular system is unclear. We conducted a systematic review and meta-analysis of observational studies to quantify associations of retinal microvascular caliber (arteriolar, venular caliber, arteriole-to-venule ratio) and preclinical CV measures (large arterial function and structure). METHODS: We identified studies in MEDLINE, EMBASE, and PubMed (1946 to March 2018) studying (a) general population samples and (b) patients with cardiometabolic disease. Study-specific correlation estimates were combined into meta-analysis where possible. RESULTS: Of 1294 studies identified, 26 met inclusion criteria (general population 16, patients 10), of which five studies were included in meta-analysis. Most studied middle-aged adults cross-sectionally, with one childhood study. Large arterial function and structure were predominantly assessed by pulse wave velocity and carotid intima-media thickness, respectively. Only arteriolar caliber was consistently associated with arterial function and structure, with stronger associations observed in cardiometabolic patients. Narrower (worse) arteriolar caliber was associated with faster (poorer) pulse wave velocity (correlation coefficient (r) -0.17, 95% CI -0.25 to -0.10) and greater (poorer) intima-media thickness (r -0.05, 95%CI -0.09 to -0.02) across all adult participants. CONCLUSIONS: Retinal arteriolar, but not venular caliber, was modestly associated with large arterial function and weakly associated with large arterial structure, with stronger evidence in patients with cardiometabolic disease. This suggests that preclinical changes in large arteries and the microcirculation have some shared but mainly unique pathways to associate with cardiovascular disease.
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ItemMyopia - A 21st Century Public Health Issue (vol 60, pg1888, 2019)(ASSOC RESEARCH VISION OPHTHALMOLOGY INC, 2019-05)
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ItemGenome-wide association study for refractive astigmatism reveals genetic co-determination with spherical equivalent refractive error: the CREAM consortium(SPRINGER, 2015-02)To identify genetic variants associated with refractive astigmatism in the general population, meta-analyses of genome-wide association studies were performed for: White Europeans aged at least 25 years (20 cohorts, N = 31,968); Asian subjects aged at least 25 years (7 cohorts, N = 9,295); White Europeans aged <25 years (4 cohorts, N = 5,640); and all independent individuals from the above three samples combined with a sample of Chinese subjects aged <25 years (N = 45,931). Participants were classified as cases with refractive astigmatism if the average cylinder power in their two eyes was at least 1.00 diopter and as controls otherwise. Genome-wide association analysis was carried out for each cohort separately using logistic regression. Meta-analysis was conducted using a fixed effects model. In the older European group the most strongly associated marker was downstream of the neurexin-1 (NRXN1) gene (rs1401327, P = 3.92E-8). No other region reached genome-wide significance, and association signals were lower for the younger European group and Asian group. In the meta-analysis of all cohorts, no marker reached genome-wide significance: The most strongly associated regions were, NRXN1 (rs1401327, P = 2.93E-07), TOX (rs7823467, P = 3.47E-07) and LINC00340 (rs12212674, P = 1.49E-06). For 34 markers identified in prior GWAS for spherical equivalent refractive error, the beta coefficients for genotype versus spherical equivalent, and genotype versus refractive astigmatism, were highly correlated (r = -0.59, P = 2.10E-04). This work revealed no consistent or strong genetic signals for refractive astigmatism; however, the TOX gene region previously identified in GWAS for spherical equivalent refractive error was the second most strongly associated region. Analysis of additional markers provided evidence supporting widespread genetic co-susceptibility for spherical and astigmatic refractive errors.
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ItemComparison of Anterior Segment Optical Tomography Parameters Measured Using a Semi-Automatic Software to Standard Clinical Instruments(PUBLIC LIBRARY SCIENCE, 2013-06-04)OBJECTIVE: To compare anterior segment parameters measured using a semi-automatic software (Zhongshan Angle Assessment Program, ZAP) applied to anterior segment optical coherence tomography (AS-OCT) images, with commonly used instruments. METHODS: Cross-sectional study of a total of 1069 subjects (1069 eyes) from three population-based studies of adults aged 40-80 years. All subjects underwent AS-OCT imaging and ZAP software was applied to determine anterior chamber depth (ACD), central corneal thickness (CCT), anterior and keratometry (K) - readings. These were compared to auto-refraction, keratometry and ocular biometry measured using an IOLMaster, ultrasound pachymeter and auto-refractor respectively. Agreements between AS-OCT (ZAP) and clinical instrument modalities were described using Bland-Altman, 95% limits of agreement (LOA). RESULTS: The mean age of our subjects was 56.9±9.5 years and 50.9% were male. The mean AS-OCT (ZAP) parameters of our study cohort were: ACD 3.29±0.35 mm, CCT 560.75±35.07 µm; K-reading 46.79±2.72 D. There was good agreement between the measurements from ZAP analysis and each instrument and no violations in the assumptions of the LOA; albeit with a systematic bias for each comparison: AS-OCT consistently measured a deeper ACD compared to IOLMaster (95% LOA -0.24, 0.55); and a thicker CCT for the AS-OCT compared to ultrasound pachymetry (16.8±0.53 µm 95% LOA -17.3, 50.8). AS-OCT had good agreement with auto-refractor with at least 95% of the measurements within the prediction interval (P value <0.001). CONCLUSION: This study demonstrates that there is good agreement between the measurements from the AS-OCT (ZAP) and conventional tools. However, small systematic biases remain that suggest that these measurement tools may not be interchanged.
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ItemChildhood gene-environment interactions and age-dependent effects of genetic variants associated with refractive error and myopia: The CREAM Consortium(NATURE PORTFOLIO, 2016-05-13)Myopia, currently at epidemic levels in East Asia, is a leading cause of untreatable visual impairment. Genome-wide association studies (GWAS) in adults have identified 39 loci associated with refractive error and myopia. Here, the age-of-onset of association between genetic variants at these 39 loci and refractive error was investigated in 5200 children assessed longitudinally across ages 7-15 years, along with gene-environment interactions involving the major environmental risk-factors, nearwork and time outdoors. Specific variants could be categorized as showing evidence of: (a) early-onset effects remaining stable through childhood, (b) early-onset effects that progressed further with increasing age, or (c) onset later in childhood (N = 10, 5 and 11 variants, respectively). A genetic risk score (GRS) for all 39 variants explained 0.6% (P = 6.6E-08) and 2.3% (P = 6.9E-21) of the variance in refractive error at ages 7 and 15, respectively, supporting increased effects from these genetic variants at older ages. Replication in multi-ancestry samples (combined N = 5599) yielded evidence of childhood onset for 6 of 12 variants present in both Asians and Europeans. There was no indication that variant or GRS effects altered depending on time outdoors, however 5 variants showed nominal evidence of interactions with nearwork (top variant, rs7829127 in ZMAT4; P = 6.3E-04).
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ItemMeta-analysis of gene-environment-wide association scans accounting for education level identifies additional loci for refractive error(NATURE PUBLISHING GROUP, 2016-04)Myopia is the most common human eye disorder and it results from complex genetic and environmental causes. The rapidly increasing prevalence of myopia poses a major public health challenge. Here, the CREAM consortium performs a joint meta-analysis to test single-nucleotide polymorphism (SNP) main effects and SNP × education interaction effects on refractive error in 40,036 adults from 25 studies of European ancestry and 10,315 adults from 9 studies of Asian ancestry. In European ancestry individuals, we identify six novel loci (FAM150B-ACP1, LINC00340, FBN1, DIS3L-MAP2K1, ARID2-SNAT1 and SLC14A2) associated with refractive error. In Asian populations, three genome-wide significant loci AREG, GABRR1 and PDE10A also exhibit strong interactions with education (P<8.5 × 10(-5)), whereas the interactions are less evident in Europeans. The discovery of these loci represents an important advance in understanding how gene and environment interactions contribute to the heterogeneity of myopia.
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ItemDeterminants of Posterior Corneal Biometric Measurements in a Multi-Ethnic Asian Population(PUBLIC LIBRARY SCIENCE, 2014-07-09)PURPOSE: To describe the corneal and anterior segment determinants of posterior corneal arc length (PCAL) and posterior corneal curvature (PCC). METHODS: Cross-sectional, population-based study of 1069 subjects (1069 eyes) aged 40-80 years, from three major Asian ethnic groups. All underwent anterior segment optical coherence tomography imaging and analysis with Zhongshan Angle Assessment Program. Our main outcome measures were determinants of PCAL and PCC using adjusted, multivariate linear regression analysis, adjusted for confounders to obtain the estimated marginal means (EMM) with standard error (SE). RESULTS: The overall mean (± SD) of PCC was: 6.51±0.39 mm; and PCAL was: 12.52±0.59 mm. Malays had a relatively longer PCAL (EMM = 12.74 mm, SE = 0.04 mm) than Chinese (EMM = 12.48 mm, SE = 0.03 mm, P<0.001), and Indians (EMM = 12.42 mm, SE = 0.03 mm, P<0.001). Anterior segment parameters had weak-moderate correlations with PCAL, which included: anterior chamber depth (ACD) (r = 0.55, P<0.001), PCC (r = 0.27, P<0.001), anterior corneal curvature (ACC) (r = 0.14, P<0.001) and central corneal thickness (CCT) (r = -0.07, P = 0.023). In multivariate analysis, anterior segment parameters explained only 37.6% of the variance of PCAL, with ACD being the most important determinant (partial R2 = 0.300; P<0.001). The determinants of PCC included ACC, PCAL and CCT (explaining 72.1% variation of PCC), with ACC being the most important determinant (partial R2 = 0.683; P<0.001). CONCLUSION: There was moderate correlation of PCAL with ACD, but anterior segment parameters accounted for only a small proportion of the variation in PCAL. The significant differences in PCAL and PCC amongst different Asian ethnic groups suggests that there is a need to consider this factor when planning for anterior segment surgeries such as endothelial keratoplasty.
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ItemMyopia - A 21st Century Public Health Issue(ASSOC RESEARCH VISION OPHTHALMOLOGY INC, 2019-02)
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ItemRetinal microvasculature: population epidemiology and concordance in Australian children aged 11-12 years and their parents(BMJ PUBLISHING GROUP, 2019-07-04)OBJECTIVES: To describe distributions and concordance of retinal microvasculature measurements in a population-based sample of Australian parent-child dyads at child age 11-12 years. DESIGN: Cross-sectional Child Health CheckPoint study, between waves 6 and 7 of the national population-based Longitudinal Study of Australian Children (LSAC). SETTING: Assessment centres in seven Australian cities, February 2015-March 2016. PARTICIPANTS: Of the 1874 participating families, 1288 children (51% girls) and 1264 parents (87% mothers, mean age 43.7) were analysed. Diabetic participants and non-biological pairs were excluded from concordance analyses. OUTCOME MEASURES: Retinal photographs were taken by non-mydriatic fundus camera. Trained graders scored vascular calibre using semi-automated software, yielding estimates of central retinal arteriolar equivalent (CRAE) and central retinal venular equivalent (CRVE) and arteriolar-venular ratio (AVR). Pearson's correlation coefficients and multivariable linear regression models assessed parent-child concordance. Survey weights and methods accounted for LSAC's complex sampling, stratification and clustering within postcodes. RESULTS: Mean (SD) of CRAE and CRVE were larger in children (159.5 (11.8) and 231.1 (16.5) μm, respectively) than parents (151.5 (14.0) and 220.6 (19.0) μm), yielding similar AVR (children 0.69 (0.05), parents 0.69 (0.06)). Correlation coefficients for parent-child pairs were 0.22 (95% CI 0.16 to 0.27) for CRAE, 0.23 (95% CI 0.17 to 0.28) for CRVE and 0.18 (95% CI 0.13 to 0.24) for AVR. Mother-child and father-child values were similar (0.20 and 0.32 for CRAE, 0.22 and 0.29 for CRVE, respectively). Relationships attenuated slightly on adjustment for age, sex, blood pressure, diabetes and body mass index. Percentiles and concordance are presented for the whole sample and by sex. CONCLUSIONS: Arteriolar and venular calibre were similar to previously documented measures in midlife adult and late childhood populations. Population parent-child concordance values align with moderate polygenic heritability reported in smaller studies.