Search

The eye is the window through which light is transmitted and visual sensory signalling originates. It is also a window through which elements of the cardiovascular and nervous systems can be directly inspected, using ophthalmoscopy or retinal imaging. Measurements of ocular parameters may therefore offer important information on the physiology and homeostasis of these two important systems. Here we report the results of a genetic characterisation of retinal vasculature. Four genome-wide association studies performed on different aspects of retinal vasculometry phenotypes, such as arteriolar and venular tortuosity and width, found significant similarities between retinal vascular characteristics and cardiometabolic health. Our analyses identified 119 different regions of association with traits of retinal vasculature, including 89 loci associated arteriolar tortuosity, the strongest of which was rs35131825 (p = 2.00×10−108), 2 loci with arteriolar width (rs12969347, p = 3.30×10−09 and rs5442, p = 1.9E-15), 17 other loci associated with venular tortuosity and 11 novel associations with venular width. Our causal inference analyses also found that factors linked to arteriolar tortuosity cause elevated diastolic blood pressure and not vice versa. Author summary: Vessels at the back of the eye (the "retina") can be imaged easily. This paper reports on the largest genetic study of retinal vessel shape and size characteristics so far undertaken, to the best of our knowledge. Our study is novel in using an automated artificial intelligence imaging approach to distinguish between arteries and veins, and in demonstrating more genetic associations with vessel characteristics than any previous study (119 genetic loci in all). We also show that the tortuosity of retinal arteries is the most strongly genetically determined vessel characteristic (replicated remarkable well in a separate second large dataset). In addition, using a particular type of genetic analysis (so called "Mendelian Randomization") we show for the first time that the tortuosity of arteries in the retina is causally related to elevated diastolic blood pressure and not the other way around. This is important as it provides unique insights into the mechanism of elevated blood pressure and hypertension, providing pointers to novel therapeutic targets for future treatment. [ABSTRACT FROM AUTHOR]

Importance: Efforts are underway to incorporate retinal neurodegeneration in the diabetic retinopathy severity scale. However, there is no established measure to quantify diabetic retinal neurodegeneration (DRN). Objective: We compared total retinal, macular retinal nerve fiber layer (mRNFL) and ganglion cell-inner plexiform layer (GC-IPL) thickness among participants with and without diabetes (DM) in a population-based cohort. Design/setting/participants: Cross-sectional analysis, using the UK Biobank data resource. Separate general linear mixed models (GLMM) were created using DM and glycated hemoglobin as predictor variables for retinal thickness. Sub-analyses included comparing thickness measurements for patients with no/mild diabetic retinopathy (DR) and evaluating factors associated with retinal thickness in participants with and without diabetes. Factors found to be significantly associated with DM or thickness were included in a multiple GLMM. Exposure: Diagnosis of DM was determined via self-report of diagnosis, medication use, DM-related complications or glycated hemoglobin level of ≥ 6.5%. Main outcomes and measures: Total retinal, mRNFL and GC-IPL thickness. Results: 74,422 participants (69,985 with no DM; 4,437 with DM) were included. Median age was 59 years, 46% were men and 92% were white. Participants with DM had lower total retinal thickness (-4.57 μm, 95% CI: -5.00, -4.14; p<0.001), GC-IPL thickness (-1.73 μm, 95% CI: -1.86, -1.59; p<0.001) and mRNFL thickness (-0.68 μm, 95% CI: -0.81, -0.54; p<0.001) compared to those without DM. After adjusting for co-variates, in the GLMM, total retinal thickness was 1.99 um lower (95% CI: -2.47, -1.50; p<0.001) and GC-IPL was 1.02 μm lower (95% CI: -1.18, -0.87; p<0.001) among those with DM compared to without. mRNFL was no longer significantly different (p = 0.369). GC-IPL remained significantly lower, after adjusting for co-variates, among those with DM compared to those without DM when including only participants with no/mild DR (-0.80 μm, 95% CI: -0.98, -0.62; p<0.001). Total retinal thickness decreased 0.40 μm (95% CI: -0.61, -0.20; p<0.001), mRNFL thickness increased 0.20 μm (95% CI: 0.14, 0.27; p<0.001) and GC-IPL decreased 0.26 μm (95% CI: -0.33, -0.20; p<0.001) per unit increase in A1c after adjusting for co-variates. Among participants with diabetes, age, DR grade, ethnicity, body mass index, glaucoma, spherical equivalent, and visual acuity were significantly associated with GC-IPL thickness. Conclusion: GC-IPL was thinner among participants with DM, compared to without DM. This difference persisted after adjusting for confounding variables and when considering only those with no/mild DR. This confirms that GC-IPL thinning occurs early in DM and can serve as a useful marker of DRN. [ABSTRACT FROM AUTHOR]

Purpose: To describe corneal astigmatism in the UK Biobank population and to look for associations with other biometric variables and socio-demographic factors. Methods: This analysis included a subsample of 107,452 participants of the UK Biobank study who underwent an enhanced ophthalmic examination including autorefractor keratometry (Tomey RC 5000, Tomey Corp., Nagoya, Japan). Participants were recruited from across the United Kingdom between 2006 and 2010, and all were between 40 to 69 years. After quality control and applying relevant exclusions, data on corneal astigmatism on 83,751 participants were included for analysis. Potential associations were tested through univariable regression and significant parameters carried forward for multivariable analysis. Results: In univariable analysis, the characteristics significantly associated with higher corneal astigmatism (P<0.001), by order of magnitude were, female gender, white ethnicity, lighter skin colour, use of UV protection, lower alcohol intake, lower corneal-compensated intraocular pressure (ccIOP), older age at completion of education, younger age, higher Townsend deprivation index, lower height and lower systolic blood pressure. After inclusion in the multivariable analysis, gender, skin colour, alcohol intake, age at completion of full-time education, ccIOP, age and Townsend deprivation score remained significant (all P<0.001). Increased corneal astigmatism was also found to be significantly associated with amblyopia or strabismus. Conclusions: This analysis confirms previous associations with astigmatism such as younger age and female gender, and identified novel risk factors including lighter skin colour, lower alcohol intake, later age having completed full time education later, lower ccIOP and higher Townsend deprivation index. Further research is needed to investigate these novel associations. [ABSTRACT FROM AUTHOR]

Purpose: To describe an approach to the use of optical coherence tomography (OCT) imaging in large, population-based studies, including methods for OCT image acquisition, storage, and the remote, rapid, automated analysis of retinal thickness. Methods: In UK Biobank, OCT images were acquired between 2009 and 2010 using a commercially available “spectral domain” OCT device (3D OCT-1000, Topcon). Images were obtained using a raster scan protocol, 6 mm x 6 mm in area, and consisting of 128 B-scans. OCT image sets were stored on UK Biobank servers in a central repository, adjacent to high performance computers. Rapid, automated analysis of retinal thickness was performed using custom image segmentation software developed by the Topcon Advanced Biomedical Imaging Laboratory (TABIL). This software employs dual-scale gradient information to allow for automated segmentation of nine intraretinal boundaries in a rapid fashion. Results: 67,321 participants (134,642 eyes) in UK Biobank underwent OCT imaging of both eyes as part of the ocular module. 134,611 images were successfully processed with 31 images failing segmentation analysis due to corrupted OCT files or withdrawal of subject consent for UKBB study participation. Average time taken to call up an image from the database and complete segmentation analysis was approximately 120 seconds per data set per login, and analysis of the entire dataset was completed in approximately 28 days. Conclusions: We report an approach to the rapid, automated measurement of retinal thickness from nearly 140,000 OCT image sets from the UK Biobank. In the near future, these measurements will be publically available for utilization by researchers around the world, and thus for correlation with the wealth of other data collected in UK Biobank. The automated analysis approaches we describe may be of utility for future large population-based epidemiological studies, clinical trials, and screening programs that employ OCT imaging. [ABSTRACT FROM AUTHOR]

Purpose: To report the methodology and findings of a large scale investigation of burden and distribution of refractive error, from a contemporary and ethnically diverse study of health and disease in adults, in the UK. Methods: U K Biobank, a unique contemporary resource for the study of health and disease, recruited more than half a million people aged 40–69 years. A subsample of 107,452 subjects undertook an enhanced ophthalmic examination which provided autorefraction data (a measure of refractive error). Refractive error status was categorised using the mean spherical equivalent refraction measure. Information on socio-demographic factors (age, gender, ethnicity, educational qualifications and accommodation tenure) was reported at the time of recruitment by questionnaire and face-to-face interview. Results: Fifty four percent of participants aged 40–69 years had refractive error. Specifically 27% had myopia (4% high myopia), which was more common amongst younger people, those of higher socio-economic status, higher educational attainment, or of White or Chinese ethnicity. The frequency of hypermetropia increased with age (7% at 40–44 years increasing to 46% at 65–69 years), was higher in women and its severity was associated with ethnicity (moderate or high hypermetropia at least 30% less likely in non-White ethnic groups compared to White). Conclusions: Refractive error is a significant public health issue for the UK and this study provides contemporary data on adults for planning services, health economic modelling and monitoring of secular trends. Further investigation of risk factors is necessary to inform strategies for prevention. There is scope to do this through the planned longitudinal extension of the UK Biobank study. [ABSTRACT FROM AUTHOR]

Purpose: To examine the cross sectional and longitudinal relationship between cardiovascular risk factors and age-related macular degeneration (AMD) in a large British cohort study. Methods: The EPIC Norfolk Eye study is nested in a larger prospective cohort study. Data on cardiovascular risk factors were collected at baseline (1993-1997) and follow up (2006-2011) via clinical examination, validated lifestyle questionnaires and serum blood samples. AMD was ascertained using standardised grading of fundus photographs at the follow up. Logistic regression was used to examine associations between baseline and follow up risk factors with AMD. Results: 5,344 pairs (62.0% of total 8623) of fundus photographs were of sufficient quality for grading of AMD in participants with mean age of 67.4 years old (range 44-91) at diagnosis. There were 28 cases of late AMD (0.5%, 95% confidence interval (CI)=0.3-0.8%) and 645 cases of early AMD (12.1%, 95%CI=11.2-13.0.%). In multivariable analysis, older people with higher levels of baseline high density lipoprotein- cholesterol (HDL-C ) and C-reactive protein (CRP) were more likely to have any signs of AMD, after adjusting for sex, education, smoking, and systolic blood pressure. In cross sectional analysis, only older age and higher HDL were significantly associated with AMD. Conclusions: We have found that older age and higher levels of CRP and HDL-C were associated with increased odds of AMD in this population in the longitudinal analysis, but older age and HDL-C, not CRP was significantly associated with AMD in the cross sectional analysis. The prevalence of AMD in this cohort was low compared to other cohorts in Europe, the US and Australia, and probably reflects the some selection biases in follow up participation as well as the low rate of smoking among our healthy participants. [ABSTRACT FROM AUTHOR]

Purpose: To assess the suitability of retinal images held in the UK Biobank - the largest retinal data repository in a prospective population-based cohort - for computer assisted vascular morphometry, generating measures that are commonly investigated as candidate biomarkers of systemic disease. Methods: Non-mydriatic fundus images from both eyes of 2,690 participants - people with a self-reported history of myocardial infarction (n=1,345) and a matched control group (n=1,345) - were analysed using VAMPIRE software. These images were drawn from those of 68,554 UK Biobank participants who underwent retinal imaging at recruitment. Four operators were trained in the use of the software to measure retinal vascular tortuosity and bifurcation geometry. Results: Total operator time was approximately 360 hours (4 minutes per image). 2,252 (84%) of participants had at least one image of sufficient quality for the software to process, i.e. there was sufficient detection of retinal vessels in the image by the software to attempt the measurement of the target parameters. 1,604 (60%) of participants had an image of at least one eye that was adequately analysed by the software, i.e. the measurement protocol was successfully completed. Increasing age was associated with a reduced proportion of images that could be processed (p=0.0004) and analysed (p<0.0001). Cases exhibited more acute arteriolar branching angles (p=0.02) as well as lower arteriolar and venular tortuosity (p<0.0001). Conclusions: A proportion of the retinal images in UK Biobank are of insufficient quality for automated analysis. However, the large size of the UK Biobank means that tens of thousands of images are available and suitable for computational analysis. Parametric information measured from the retinas of participants with suspected cardiovascular disease was significantly different to that measured from a matched control group. [ABSTRACT FROM AUTHOR]

Aim: Crowdsourcing is the process of simplifying and outsourcing numerous tasks to many untrained individuals. Our aim was to assess the performance and repeatability of crowdsourcing in the classification of normal and glaucomatous discs from optic disc images. Methods: Optic disc images (N = 127) with pre-determined disease status were selected by consensus agreement from grading experts from a large cohort study. After reading brief illustrative instructions, we requested that knowledge workers (KWs) from a crowdsourcing platform (Amazon MTurk) classified each image as normal or abnormal. Each image was classified 20 times by different KWs. Two study designs were examined to assess the effect of varying KW experience and both study designs were conducted twice for consistency. Performance was assessed by comparing the sensitivity, specificity and area under the receiver operating characteristic curve (AUC). Results: Overall, 2,540 classifications were received in under 24 hours at minimal cost. The sensitivity ranged between 83–88% across both trials and study designs, however the specificity was poor, ranging between 35–43%. In trial 1, the highest AUC (95%CI) was 0.64(0.62–0.66) and in trial 2 it was 0.63(0.61–0.65). There were no significant differences between study design or trials conducted. Conclusions: Crowdsourcing represents a cost-effective method of image analysis which demonstrates good repeatability and a high sensitivity. Optimisation of variables such as reward schemes, mode of image presentation, expanded response options and incorporation of training modules should be examined to determine their effect on the accuracy and reliability of this technique in retinal image analysis. [ABSTRACT FROM AUTHOR]

Aim: Crowdsourcing is the process of outsourcing numerous tasks to many untrained individuals. Our aim was to assess the performance and repeatability of crowdsourcing for the classification of retinal fundus photography. Methods: One hundred retinal fundus photograph images with pre-determined disease criteria were selected by experts from a large cohort study. After reading brief instructions and an example classification, we requested that knowledge workers (KWs) from a crowdsourcing platform classified each image as normal or abnormal with grades of severity. Each image was classified 20 times by different KWs. Four study designs were examined to assess the effect of varying incentive and KW experience in classification accuracy. All study designs were conducted twice to examine repeatability. Performance was assessed by comparing the sensitivity, specificity and area under the receiver operating characteristic curve (AUC). Results: Without restriction on eligible participants, two thousand classifications of 100 images were received in under 24 hours at minimal cost. In trial 1 all study designs had an AUC (95%CI) of 0.701(0.680–0.721) or greater for classification of normal/abnormal. In trial 1, the highest AUC (95%CI) for normal/abnormal classification was 0.757 (0.738–0.776) for KWs with moderate experience. Comparable results were observed in trial 2. In trial 1, between 64–86% of any abnormal image was correctly classified by over half of all KWs. In trial 2, this ranged between 74–97%. Sensitivity was ≥96% for normal versus severely abnormal detections across all trials. Sensitivity for normal versus mildly abnormal varied between 61–79% across trials. Conclusions: With minimal training, crowdsourcing represents an accurate, rapid and cost-effective method of retinal image analysis which demonstrates good repeatability. Larger studies with more comprehensive participant training are needed to explore the utility of this compelling technique in large scale medical image analysis. [ABSTRACT FROM AUTHOR]

Optical Coherence Tomography (OCT) enables non-invasive imaging of the retina and is used to diagnose and manage ophthalmic diseases including glaucoma. We present the first large-scale genome-wide association study of inner retinal morphology using phenotypes derived from OCT images of 31,434 UK Biobank participants. We identify 46 loci associated with thickness of the retinal nerve fibre layer or ganglion cell inner plexiform layer. Only one of these loci has been associated with glaucoma, and despite its clear role as a biomarker for the disease, Mendelian randomisation does not support inner retinal thickness being on the same genetic causal pathway as glaucoma. We extracted overall retinal thickness at the fovea, representative of foveal hypoplasia, with which three of the 46 SNPs were associated. We additionally associate these three loci with visual acuity. In contrast to the Mendelian causes of severe foveal hypoplasia, our results suggest a spectrum of foveal hypoplasia, in part genetically determined, with consequences on visual function., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: APK is a paid consultant to Aerie, Allergan, Google Health, Novartis, Reichert, Santen and Thea. LRP is consultant for Verily, Eyenovia, Bausch+Lomb, and Nicox. JW is consultant for Allergan, Editas, Maze, Regenxbio and has a sponsored research grant from Aerpio.

Current estimates suggest 50% of glaucoma blindness worldwide is caused by primary angle-closure glaucoma (PACG) but the causative gene is not known. We used genetic linkage and whole genome sequencing to identify Spermatogenesis Associated Protein 13, SPATA13 (NM&#95;001166271; NP&#95;001159743, SPATA13 isoform I), also known as ASEF2 (Adenomatous polyposis coli-stimulated guanine nucleotide exchange factor 2), as the causal gene for PACG in a large seven-generation white British family showing variable expression and incomplete penetrance. The 9 bp deletion, c.1432&#95;1440del; p.478&#95;480del was present in all affected individuals with angle-closure disease. We show ubiquitous expression of this transcript in cell lines derived from human tissues and in iris, retina, retinal pigment and ciliary epithelia, cornea and lens. We also identified eight additional mutations in SPATA13 in a cohort of 189 unrelated PACS/PAC/PACG samples. This gene encodes a 1277 residue protein which localises to the nucleus with partial co-localisation with nuclear speckles. In cells undergoing mitosis SPATA13 isoform I becomes part of the kinetochore complex co-localising with two kinetochore markers, polo like kinase 1 (PLK-1) and centrosome-associated protein E (CENP-E). The 9 bp deletion reported in this study increases the RAC1-dependent guanine nucleotide exchange factors (GEF) activity. The increase in GEF activity was also observed in three other variants identified in this study. Taken together, our data suggest that SPATA13 is involved in the regulation of mitosis and the mutations dysregulate GEF activity affecting homeostasis in tissues where it is highly expressed, influencing PACG pathogenesis., Competing Interests: The authors have declared that no competing interests exist.

Anterior chamber depth (ACD) is a key anatomical risk factor for primary angle closure glaucoma (PACG). We conducted a genome-wide association study (GWAS) on ACD to discover novel genes for PACG on a total of 5,308 population-based individuals of Asian descent. Genome-wide significant association was observed at a sequence variant within ABCC5 (rs1401999; per-allele effect size =  -0.045 mm, P = 8.17 × 10(-9)). This locus was associated with an increase in risk of PACG in a separate case-control study of 4,276 PACG cases and 18,801 controls (per-allele OR = 1.13 [95% CI: 1.06-1.22], P = 0.00046). The association was strengthened when a sub-group of controls with open angles were included in the analysis (per-allele OR = 1.30, P = 7.45 × 10(-9); 3,458 cases vs. 3,831 controls). Our findings suggest that the increase in PACG risk could in part be mediated by genetic sequence variants influencing anterior chamber dimensions.

Aim: Crowdsourcing is the process of outsourcing numerous tasks to many untrained individuals. Our aim was to assess the performance and repeatability of crowdsourcing for the classification of retinal fundus photography., Methods: One hundred retinal fundus photograph images with pre-determined disease criteria were selected by experts from a large cohort study. After reading brief instructions and an example classification, we requested that knowledge workers (KWs) from a crowdsourcing platform classified each image as normal or abnormal with grades of severity. Each image was classified 20 times by different KWs. Four study designs were examined to assess the effect of varying incentive and KW experience in classification accuracy. All study designs were conducted twice to examine repeatability. Performance was assessed by comparing the sensitivity, specificity and area under the receiver operating characteristic curve (AUC)., Results: Without restriction on eligible participants, two thousand classifications of 100 images were received in under 24 hours at minimal cost. In trial 1 all study designs had an AUC (95%CI) of 0.701(0.680-0.721) or greater for classification of normal/abnormal. In trial 1, the highest AUC (95%CI) for normal/abnormal classification was 0.757 (0.738-0.776) for KWs with moderate experience. Comparable results were observed in trial 2. In trial 1, between 64-86% of any abnormal image was correctly classified by over half of all KWs. In trial 2, this ranged between 74-97%. Sensitivity was ≥ 96% for normal versus severely abnormal detections across all trials. Sensitivity for normal versus mildly abnormal varied between 61-79% across trials., Conclusions: With minimal training, crowdsourcing represents an accurate, rapid and cost-effective method of retinal image analysis which demonstrates good repeatability. Larger studies with more comprehensive participant training are needed to explore the utility of this compelling technique in large scale medical image analysis.

Intraocular pressure (IOP) is a highly heritable risk factor for primary open-angle glaucoma and is the only target for current glaucoma therapy. The genetic factors which determine IOP are largely unknown. We performed a genome-wide association study for IOP in 11,972 participants from 4 independent population-based studies in The Netherlands. We replicated our findings in 7,482 participants from 4 additional cohorts from the UK, Australia, Canada, and the Wellcome Trust Case-Control Consortium 2/Blue Mountains Eye Study. IOP was significantly associated with rs11656696, located in GAS7 at 17p13.1 (p=1.4×10(-8)), and with rs7555523, located in TMCO1 at 1q24.1 (p=1.6×10(-8)). In a meta-analysis of 4 case-control studies (total N = 1,432 glaucoma cases), both variants also showed evidence for association with glaucoma (p=2.4×10(-2) for rs11656696 and p=9.1×10(-4) for rs7555523). GAS7 and TMCO1 are highly expressed in the ciliary body and trabecular meshwork as well as in the lamina cribrosa, optic nerve, and retina. Both genes functionally interact with known glaucoma disease genes. These data suggest that we have identified two clinically relevant genes involved in IOP regulation., Competing Interests: The authors have declared that no competing interests exist.