Anthony P. Khawaja

The Association between Time Spent Outdoors and Myopia in Children and Adolescents: A Systematic Review and Meta-analysis.

OBJECTIVE To summarize relevant evidence investigating the association between time spent outdoors and myopia in children and adolescents (up to 20 years). DESIGN Systematic review and meta-analysis. PARTICIPANTS Results from 7 cross-sectional studies were pooled in a meta-analysis. A further 16 studies (8 cross-sectional not meeting criteria for meta-analysis; 7 prospective cohort studies; 1 randomized, controlled trial [RCT]) were reported in the systematic review. METHODS The literature search included 4 databases (Medline, Embase, Web of Science, and Cochrane Central Register of Controlled Trials [CENTRAL]), and reference lists of retrieved studies. Estimates of association were pooled using random effects meta-analysis. We summarized data examining the association between time spent outdoors and prevalent myopia, incident myopia, and myopic progression. MAIN OUTCOME MEASURES Pooled odds ratios (ORs) and 95% confidence intervals (CIs) for myopia for each additional hour spent outdoors per week from a meta-analysis. RESULTS The pooled OR for myopia indicated a 2% reduced odds of myopia per additional hour of time spent outdoors per week, after adjustment for covariates (OR, 0.981; 95% CI, 0.973-0.990; P<0.001; I(2), 44.3%). This is equivalent to an OR of 0.87 for an additional hour of time spent outdoors each day. Three prospective cohort studies provided estimates of risk of incident myopia according to time spent outdoors, adjusted for possible confounders, although estimates could not be pooled, and the quality of studies and length of follow-up times varied. Three studies (2 prospective cohort and 1 RCT) investigated time spent outdoors and myopic progression and found increasing time spent outdoors significantly reduced myopic progression. CONCLUSIONS The overall findings indicate that increasing time spent outdoors may be a simple strategy by which to reduce the risk of developing myopia and its progression in children and adolescents. Therefore, further RCTs are warranted to investigate the efficacy of increasing time outdoors as a possible intervention to prevent myopia and its progression.

Increasing Prevalence of Myopia in Europe and the Impact of Education

Purpose To investigate whether myopia is becoming more common across Europe and explore whether increasing education levels, an important environmental risk factor for myopia, might explain any temporal trend. Design Meta-analysis of population-based, cross-sectional studies from the European Eye Epidemiology (E3) Consortium. Participants The E3 Consortium is a collaborative network of epidemiological studies of common eye diseases in adults across Europe. Refractive data were available for 61 946 participants from 15 population-based studies performed between 1990 and 2013; participants had a range of median ages from 44 to 78 years. Methods Noncycloplegic refraction, year of birth, and highest educational level achieved were obtained for all participants. Myopia was defined as a mean spherical equivalent ≤−0.75 diopters. A random-effects meta-analysis of age-specific myopia prevalence was performed, with sequential analyses stratified by year of birth and highest level of educational attainment. Main Outcome Measures Variation in age-specific myopia prevalence for differing years of birth and educational level. Results There was a significant cohort effect for increasing myopia prevalence across more recent birth decades; age-standardized myopia prevalence increased from 17.8% (95% confidence interval [CI], 17.6–18.1) to 23.5% (95% CI, 23.2–23.7) in those born between 1910 and 1939 compared with 1940 and 1979 (P = 0.03). Education was significantly associated with myopia; for those completing primary, secondary, and higher education, the age-standardized prevalences were 25.4% (CI, 25.0–25.8), 29.1% (CI, 28.8–29.5), and 36.6% (CI, 36.1–37.2), respectively. Although more recent birth cohorts were more educated, this did not fully explain the cohort effect. Compared with the reference risk of participants born in the 1920s with only primary education, higher education or being born in the 1960s doubled the myopia prevalence ratio–2.43 (CI, 1.26–4.17) and 2.62 (CI, 1.31–5.00), respectively—whereas individuals born in the 1960s and completing higher education had approximately 4 times the reference risk: a prevalence ratio of 3.76 (CI, 2.21–6.57). Conclusions Myopia is becoming more common in Europe; although education levels have increased and are associated with myopia, higher education seems to be an additive rather than explanatory factor. Increasing levels of myopia carry significant clinical and economic implications, with more people at risk of the sight-threatening complications associated with high myopia.

Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma

Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. To identify new susceptibility loci, we performed meta-analysis on genome-wide association study (GWAS) results from eight independent studies from the United States (3,853 cases and 33,480 controls) and investigated the most significantly associated SNPs in two Australian studies (1,252 cases and 2,592 controls), three European studies (875 cases and 4,107 controls) and a Singaporean Chinese study (1,037 cases and 2,543 controls). A meta-analysis of the top SNPs identified three new associated loci: rs35934224[T] in TXNRD2 (odds ratio (OR) = 0.78, P = 4.05 × 10−11) encoding a mitochondrial protein required for redox homeostasis; rs7137828[T] in ATXN2 (OR = 1.17, P = 8.73 × 10−10); and rs2745572[A] upstream of FOXC1 (OR = 1.17, P = 1.76 × 10−10). Using RT-PCR and immunohistochemistry, we show TXNRD2 and ATXN2 expression in retinal ganglion cells and the optic nerve head. These results identify new pathways underlying POAG susceptibility and suggest new targets for preventative therapies.

A new tool for converting food frequency questionnaire data into nutrient and food group values: FETA research methods and availability

Objectives To describe the research methods for the development of a new open source, cross-platform tool which processes data from the European Prospective Investigation into Cancer and Nutrition Norfolk Food Frequency Questionnaire (EPIC-Norfolk FFQ). A further aim was to compare nutrient and food group values derived from the current tool (FETA, FFQ EPIC Tool for Analysis) with the previously validated but less accessible tool, CAFÉ (Compositional Analyses from Frequency Estimates). The effect of text matching on intake data was also investigated. Design Cross-sectional analysis of a prospective cohort study—EPIC-Norfolk. Setting East England population (city of Norwich and its surrounding small towns and rural areas). Participants Complete FFQ data from 11 250 men and 13 602 women (mean age 59 years; range 40–79 years). Outcome measures Nutrient and food group intakes derived from FETA and CAFÉ analyses of EPIC-Norfolk FFQ data. Results Nutrient outputs from FETA and CAFÉ were similar; mean (SD) energy intake from FETA was 9222 kJ (2633) in men, 8113 kJ (2296) in women, compared with CAFÉ intakes of 9175 kJ (2630) in men, 8091 kJ (2298) in women. The majority of differences resulted in one or less quintile change (98.7%). Only mean daily fruit and vegetable food group intakes were higher in women than in men (278 vs 212 and 284 vs 255 g, respectively). Quintile changes were evident for all nutrients, with the exception of alcohol, when text matching was not executed; however, only the cereals food group was affected. Conclusions FETA produces similar nutrient and food group values to the previously validated CAFÉ but has the advantages of being open source, cross-platform and complete with a data-entry form directly compatible with the software. The tool will facilitate research using the EPIC-Norfolk FFQ, and can be customised for different study populations.

Cohort Profile: A prospective cohort study of objective physical and cognitive capability and visual health in an ageing population of men and women in Norfolk (EPIC-Norfolk 3)

The European Prospective Investigation of Cancer (EPIC) is a 10-country collaborative study in which EPIC-Norfolk is one of the UK centres. EPIC-Norfolk examined 25 639 men and women resident in East Anglia (aged 40–79 years), between 1993 and 1997. The EPIC collaboration was set up to examine the dietary determinants of cancer, but the remit in the EPIC-Norfolk cohort was broadened from the outset to include determinants of other health conditions and chronic diseases. EPIC-Norfolk completed a third round of health examinations (EPIC-Norfolk 3 or 3HC) in December 2011, on 8623 participants in the age range 48–92 years. EPIC-Norfolk focused on objective measures of cognitive function, physical capability and visual health, adapting this existing mid-life cohort to the current need to investigate healthy and independent living for ageing societies. With a wealth of longitudinal data and a biobank (including DNA) collected at up to three separate time points, EPIC-Norfolk offers the unique opportunity to investigate the association of lifestyle and biological factors, including genetic exposures, with a range of health outcomes in middle and later life. Information for data access can be found on the study website, details as given in this cohort profile.

Longitudinal Changes of Angle Configuration in Primary Angle-Closure Suspects: The Zhongshan Angle-Closure Prevention Trial

OBJECTIVE To determine longitudinal changes in angle configuration in the eyes of primary angle-closure suspects (PACS) treated by laser peripheral iridotomy (LPI) and in untreated fellow eyes. DESIGN Longitudinal cohort study. PARTICIPANTS Primary angle-closure suspects aged 50 to 70 years were enrolled in a randomized, controlled clinical trial. METHODS Each participant was treated by LPI in 1 randomly selected eye, with the fellow eye serving as a control. Angle width was assessed in a masked fashion using gonioscopy and anterior segment optical coherence tomography (AS-OCT) before and at 2 weeks, 6 months, and 18 months after LPI. MAIN OUTCOME MEASURES Angle width in degrees was calculated from Shaffer grades assessed under static gonioscopy. Angle configuration was also evaluated using angle opening distance (AOD250, AOD500, AOD750), trabecular-iris space area (TISA500, TISA750), and angle recess area (ARA) measured in AS-OCT images. RESULTS No significant difference was found in baseline measures of angle configuration between treated and untreated eyes. At 2 weeks after LPI, the drainage angle on gonioscopy widened from a mean of 13.5° at baseline to a mean of 25.7° in treated eyes, which was also confirmed by significant increases in all AS-OCT angle width measures (P<0.001 for all variables). Between 2 weeks and 18 months after LPI, a significant decrease in angle width was observed over time in treated eyes (P<0.001 for all variables), although the change over the first 5.5 months was not statistically significant for angle width measured under gonioscopy (P = 0.18), AOD250 (P = 0.167) and ARA (P = 0.83). In untreated eyes, angle width consistently decreased across all follow-up visits after LPI, with a more rapid longitudinal decrease compared with treated eyes (P values for all variables ≤0.003). The annual rate of change in angle width was equivalent to 1.2°/year (95% confidence interval [CI], 0.8-1.6) in treated eyes and 1.6°/year (95% CI, 1.3-2.0) in untreated eyes (P<0.001). CONCLUSIONS Angle width of treated eyes increased markedly after LPI, remained stable for 6 months, and then decreased significantly by 18 months after LPI. Untreated eyes experienced a more consistent and rapid decrease in angle width over the same time period.

Systemic Medication and Intraocular Pressure in a British Population The EPIC-Norfolk Eye Study

Objective To determine the association between systemic medication use and intraocular pressure (IOP) in a population of older British men and women. Design Population-based, cross-sectional study. Participants We included 7093 participants from the European Prospective Investigation into Cancer–Norfolk Eye Study. Exclusion criteria were a history of glaucoma therapy (medical, laser, or surgical), IOP asymmetry between eyes of >5 mmHg, and missing data for any covariables. The mean age of participants was 68 years (range, 48–92) and 56% were women. Methods We measured IOP using the Ocular Response Analyzer. Three readings were taken per eye and the best signal value of the Goldmann-correlated IOP value considered. Participants were asked to bring all their medications and related documentation to the health examination, and these were recorded by the research nurse using an electronic case record form. The medication classes examined were angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, α-blockers, β-blockers, calcium channel blockers, diuretics, nitrates, statins, insulin, biguanides, sulfonylureas, aspirin, and other nonsteroidal anti-inflammatory drugs. We examined associations between medication use and IOP using multivariable linear regression models adjusted for age, sex, and body mass index. Models containing diabetic medication were further adjusted for glycosylated hemoglobin levels. Main Outcome Measures Mean IOP of the right and left eyes. Results Use of systemic β-blockers (−0.92 mmHg; 95% CI, −1.19, −0.65; P<0.001) and nitrates (−0.63 mmHg; 95% CI, −1.12, −0.14; P = 0.011) were independently associated with lower IOP. The observed associations between statin or aspirin use with IOP were no longer significant after adjustment for β-blocker use. Conclusions This is the first population-based study to demonstrate and quantify clinically significant differences in IOP among participants using systemic β-blockers or nitrates. Lower IOP observed in participants using statins or aspirin was explained by concurrent systemic β-blocker use. The study findings may have implications for the management of glaucoma patients with comorbidity, and may provide insight into the pathophysiologic processes underlying IOP.

New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics

Primary open-angle glaucoma (POAG), the most common optic neuropathy, is a heritable disease. Siblings of POAG cases have a ten-fold increased risk of developing the disease. Intraocular pressure (IOP) and optic nerve head characteristics are used clinically to predict POAG risk. We conducted a genome-wide association meta-analysis of IOP and optic disc parameters and validated our findings in multiple sets of POAG cases and controls. Using imputation to the 1000 genomes (1000G) reference set, we identified 9 new genomic regions associated with vertical cup-disc ratio (VCDR) and 1 new region associated with IOP. Additionally, we found 5 novel loci for optic nerve cup area and 6 for disc area. Previously it was assumed that genetic variation influenced POAG either through IOP or via changes to the optic nerve head; here we present evidence that some genomic regions affect both IOP and the disc parameters. We characterized the effect of the novel loci through pathway analysis and found that pathways involved are not entirely distinct as assumed so far. Further, we identified a novel association between CDKN1A and POAG. Using a zebrafish model we show that six6b (associated with POAG and optic nerve head variation) alters the expression of cdkn1a. In summary, we have identified several novel genes influencing the major clinical risk predictors of POAG and showed that genetic variation in CDKN1A is important in POAG risk.

The EPIC-Norfolk Eye Study: rationale, methods and a cross-sectional analysis of visual impairment in a population-based cohort

Objectives To summarise the methods of the European Prospective Investigation of Cancer (EPIC)-Norfolk Eye Study, and to present data on the prevalence of visual impairment and associations with visual impairment in the participants. Design A population-based cross-sectional study nested within an on-going prospective cohort study (EPIC). Setting East England population (the city of Norwich and its surrounding small towns and rural areas). Participants A total of 8623 participants aged 48–92 years attended the Eye Study and underwent assessment of visual acuity, autorefraction, biometry, tonometry, corneal biomechanical measures, scanning laser polarimetry, confocal scanning laser ophthalmoscopy, fundal photography and automated perimetry. Outcome measures Visual impairment was defined according to the WHO classification and the UK driving standard, and was based on presenting visual acuity. Summary measures of other ophthalmic measurements are also presented. Results The prevalence (95% CI) of WHO-defined moderate-to-severe visual impairment and blindness was 0.74% (0.55% to 0.92%). The prevalence (95% CI) of presenting visual acuity worse than the UK driving standard was 5.87% (5.38% to 6.37%). Older age was significantly associated with visual impairment or blindness (p<0.001). Presenting visual acuity worse than UK driving standard was associated with older age (p<0.001), female sex (p=0.005) and lower educational level (p=0.022). Conclusions The prevalence of blindness and visual impairment in this selected population was low. Visual impairment was more likely in older participants, women and those with a lower educational level.

Visual acuity, self-reported vision and falls in the EPIC-Norfolk Eye study

Purpose To examine the relationship between visual acuity (VA) and self-reported vision (SRV) in relation to falls in 8317 participants of the European Prospective Investigation into Cancer-Norfolk Eye study. Methods All participants completed a health questionnaire that included a question regarding SRV and questions regarding the number of falls in the past year. Distance VA was measured using a logMAR chart for each eye. Poor SRV was defined as those reporting fair or poor distance vision. The relationship between VA and SRV and self-rated falls was analysed by logistic regression, adjusting for age, sex, physical activity, body mass index, chronic disease, medication use and grip strength. Results Of 8317 participants, 26.7% (95% CI 25.7% to 27.7%) had fallen in the past 12 months. Worse VA and poorer SRV were associated with one or more falls in multivariable analysis (OR for falls=1.31, 95% CI 1.04 to 1.66 and OR=1.32, 95% CI 1.09 to 1.61, respectively). Poorer SRV was significantly associated with falls even after adjusting for VA (OR=1.28, 95% CI 1.05 to 1.57). Conclusions SRV was associated with falls independently of VA and could be used as a simple proxy measure for other aspects of visual function to detect people requiring vision-related falls interventions.