Top 100 cited articles in ophthalmic epidemiology between 2006 and 2016

AIM: To identify the most-cited articles in ophthalmic epidemiology over the last decade. METHODS: We performed a cited reference search on articles that were included in the ISI Web of Science database using the terms “Epidemi*” AND “ophthalm*” AND “population*” during year 2006 to 2016. TOP 100 most cited articles (T100) in ophthalmic epidemiology were short listed and analysed using bibliometrics. RESULTS: These top 100 articles in ophthalmic epidemiology were cited between 61 to 333 times. Of these T100 articles, 36% originated from United States, and 34% were published in the Ophthalmology journal. The three major topics identified were age-related macular degeneration (AMD, n=23), glaucoma (n=16) and visual impairment (n=12). The top-cited article was a study on outdoor activities and its association with the prevalence of myopia in school-aged children, published in 2008. CONCLUSION: This bibliometric analysis provides useful insights into the current development in ophthalmic epidemiology in the past decade and can help recognizing the quality of the researches, discoveries, and trends steering ophthalmic epidemiology

Association of Common SIX6 Polymorphisms With Peripapillary Retinal Nerve Fiber Layer Thickness: The Singapore Chinese Eye Study

PURPOSE. Recently the common SIX6 missense variant rs33912345 was found to be highly associated with glaucoma. The aim of this study was to investigate the association between this SIX6 variant and peripapillary retinal nerve fiber layer (RNFL) thickness measured by spectral-domain optical coherence tomography (SD-OCT) in a population setting. METHODS. Study subjects were enrolled from the Singapore Chinese Eye Study (SCES), a population-based survey of Singaporean Chinese aged 40 years or older. Subjects underwent a comprehensive ocular examination. Spectral-domain OCT was used to measure RNFL thicknesses. Genotyping of SIX6 rs33912345 (Asn141His) was performed using HumanExome BeadChip. RESULTS. A total of 2129 eyes from 1243 SCES subjects (mean age: 55.0 6 7.4 years) with rs33912345 genotype data and SD-OCT images were included for the analysis. Of these, 26 eyes of 21 subjects had glaucoma. The frequency of rs33912345 risk variant C (His141) was 80% in the study subjects. Each rs33912345 C allele was associated with a decrease of 1.44 lm in RNFL thickness after adjusting for age, sex, genetic principal components, and axial length (P ¼ 0.001). These associations remained similar in 2096 nonglaucoma eyes in which each C allele was associated with a decrease of 1.39 lm in RNFL thickness (P ¼ 0.001). The strongest association was observed in the superior RNFL sector (a decrease of 2.83 lm per risk allele, P < 0.001) followed by the inferior RNFL sector (a decrease of 2.24 lm per risk allele, P ¼ 0.003), while the association did not reach significance in the nasal and temporal sectors. CONCLUSIONS. Nonglaucomatous individuals with the SIX6 missense variant have reduced RNFL thickness in regions known to be particularly affected in those with glaucoma. This may be the primary mechanism for increased risk of POAG in individuals who carry the SIX6 His141 risk variant

Determinants of lamina cribrosa depth in healthy Asian eyes: the Singapore Epidemiology Eye Study

Aim To investigate the determinants of lamina cribrosa depth (LCD) in healthy eyes of Chinese and Indian Singaporean adults. Methods The optic nerve head (ONH) of the right eye of 1396 subjects (628 Chinese and 768 Indian subjects) was imaged with optical coherence tomography (OCT, Spectralis, Heidelberg, Germany). LCD was defined as the distance from the Bruch’s membrane opening (LCD-BMO) or the peripapillary sclera (LCD-PPS) reference plane to the laminar surface. A linear regression model was used to evaluate the relationship between the LCD and its determinants. Results Both LCDs were significantly different between the two races (LCD-BMO: 421.95 (95% CI 365.32 to 491.79) µm in Chinese vs 430.39 (367.46–509.81) µm in Indians, p=0.021; and LCD-PPS: 353.34 (300.98–421.45) µm in Chinese vs 376.76 (313.39–459.78) µm in Indians, p<0.001). In the multivariable regression analysis, the LCD-PPS of the whole cohort was independently associated with females (β=−31.93, p<0.001), Indians subjects (β=21.39, p=0.004) (Chinese as the reference), axial length (Axl) (β=−6.68, p=0.032), retinal nerve fibre layer thickness (RNFL) (β=0.71, p=0.019), choroidal thickness (ChT) (β=0.41, p<0.001), vertical cup disc ratio (VCDR) (β=24.42, p<0.001) and disc size (β=−60.75, p=0.001). For every 1 year older in age, the LCD-PPS was deeper on average by 1.95 µm in Chinese subjects (p=0.01) but there was no association in Indians subjects (p=0.851). Conclusions The LCD was influenced by age, gender, race, Axl, RNFL, ChT, VCDR and disc size. This normative LCD database may facilitate a more accurate assessment of ONH cupping using OCT in Asian populations

Author Correction: Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases.

Emmanuelle Souzeau, who contributed to analysis of data, was inadvertently omitted from the author list in the originally published version of this Article. This has now been corrected in both the PDF and HTML versions of the Article

Validation of a deep-learning-based retinal biomarker (Reti-CVD) in the prediction of cardiovascular disease: data from UK Biobank

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

Cardiovascular disease risk assessment using a deep-learning-based retinal biomarker: a comparison with existing risk scores.

AimsThis study aims to evaluate the ability of a deep-learning-based cardiovascular disease (CVD) retinal biomarker, Reti-CVD, to identify individuals with intermediate- and high-risk for CVD.Methods and resultsWe defined the intermediate- and high-risk groups according to Pooled Cohort Equation (PCE), QRISK3, and modified Framingham Risk Score (FRS). Reti-CVD's prediction was compared to the number of individuals identified as intermediate- and high-risk according to standard CVD risk assessment tools, and sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated to assess the results. In the UK Biobank, among 48 260 participants, 20 643 (42.8%) and 7192 (14.9%) were classified into the intermediate- and high-risk groups according to PCE, and QRISK3, respectively. In the Singapore Epidemiology of Eye Diseases study, among 6810 participants, 3799 (55.8%) were classified as intermediate- and high-risk group according to modified FRS. Reti-CVD identified PCE-based intermediate- and high-risk groups with a sensitivity, specificity, PPV, and NPV of 82.7%, 87.6%, 86.5%, and 84.0%, respectively. Reti-CVD identified QRISK3-based intermediate- and high-risk groups with a sensitivity, specificity, PPV, and NPV of 82.6%, 85.5%, 49.9%, and 96.6%, respectively. Reti-CVD identified intermediate- and high-risk groups according to the modified FRS with a sensitivity, specificity, PPV, and NPV of 82.1%, 80.6%, 76.4%, and 85.5%, respectively.ConclusionThe retinal photograph biomarker (Reti-CVD) was able to identify individuals with intermediate and high-risk for CVD, in accordance with existing risk assessment tools

A genome-wide association study of corneal astigmatism:The CREAM Consortium

Purpose: To identify genes and genetic markers associated with corneal astigmatism. Methods: A meta-analysis of genome-wide association studies (GWASs) of corneal astigmatism undertaken for 14 European ancestry (n=22,250) and 8 Asian ancestry (n=9,120) cohorts was performed by the Consortium for Refractive Error and Myopia. Cases were defined as having >0.75 diopters of corneal astigmatism. Subsequent gene-based and gene-set analyses of the meta-analyzed results of European ancestry cohorts were performed using VEGAS2 and MAGMA software. Additionally, estimates of single nucleotide polymorphism (SNP)-based heritability for corneal and refractive astigmatism and the spherical equivalent were calculated for Europeans using LD score regression. Results: The meta-analysis of all cohorts identified a genome-wide significant locus near the platelet-derived growth factor receptor alpha (PDGFRA) gene: top SNP: rs7673984, odds ratio=1.12 (95% CI:1.08–1.16), p=5.55×10−9. No other genome-wide significant loci were identified in the combined analysis or European/Asian ancestry-specific analyses. Gene-based analysis identified three novel candidate genes for corneal astigmatism in Europeans—claudin-7 (CLDN7), acid phosphatase 2, lysosomal (ACP2), and TNF alpha-induced protein 8 like 3 (TNFAIP8L3). Conclusions: In addition to replicating a previously identified genome-wide significant locus for corneal astigmatism near the PDGFRA gene, gene-based analysis identified three novel candidate genes, CLDN7, ACP2, and TNFAIP8L3, that warrant further investigation to understand their role in the pathogenesis of corneal astigmatism. The much lower number of genetic variants and genes demonstrating an association with corneal astigmatism compared to published spherical equivalent GWAS analyses suggest a greater influence of rare genetic variants, non-additive genetic effects, or environmental factors in the development of astigmatism.peerReviewe

Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases

Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r =-0.62, P = 5.30 × 10-5) but not between CCT and primary open-angle glaucoma (r =-0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation

X-chromosome and kidney function:evidence from a multi-trait genetic analysis of 908,697 individuals reveals sex-specific and sex-differential findings in genes regulated by androgen response elements

X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits (n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 for uric acid and 16 for estimated glomerular filtration rate (eGFR), including four novel eGFR loci containing the functionally plausible prioritized genes ACSL4, CLDN2, TSPAN6 and the female-specific DRP2. Further, we identified five novel sex-interactions, comprising male-specific effects at FAM9B and AR/EDA2R, and three sex-differential findings with larger genetic effect sizes in males at DCAF12L1 and MST4 and larger effect sizes in females at HPRT1. All prioritized genes in loci showing significant sex-interactions were located next to androgen response elements (ARE). Five ARE genes showed sex-differential expressions. This study contributes new insights into sex-dimorphisms of kidney traits along with new prioritized gene targets for further molecular research.</p