Associations with intraocular pressure across Europe: The European Eye Epidemiology (E3) Consortium.

Raised intraocular pressure (IOP) is the most important risk factor for developing glaucoma, the second commonest cause of blindness globally. Understanding associations with IOP and variations in IOP between countries may teach us about mechanisms underlying glaucoma. We examined cross-sectional associations with IOP in 43,500 European adults from 12 cohort studies belonging to the European Eye Epidemiology (E3) consortium. Each study conducted multivariable linear regression with IOP as the outcome variable and results were pooled using random effects meta-analysis. The association of standardized study IOP with latitude was tested using meta-regression. Higher IOP was observed in men (0.18 mmHg; 95 % CI 0.06, 0.31; P = 0.004) and with higher body mass index (0.21 mmHg per 5 kg/m2; 95 % CI 0.14, 0.28; P < 0.001), shorter height (-0.17 mmHg per 10 cm; 95 % CI -0.25, -0.08; P < 0.001), higher systolic blood pressure (0.17 mmHg per 10 mmHg; 95 % CI 0.12, 0.22; P < 0.001) and more myopic refraction (0.06 mmHg per Dioptre; 95 % CI 0.03, 0.09; P < 0.001). An inverted U-shaped trend was observed between age and IOP, with IOP increasing up to the age of 60 and decreasing in participants older than 70 years. We found no significant association between standardized IOP and study location latitude (P = 0.76). Novel findings of our study include the association of lower IOP in taller people and an inverted-U shaped association of IOP with age. We found no evidence of significant variation in IOP across Europe. Despite the limited range of latitude amongst included studies, this finding is in favour of collaborative pooling of data from studies examining environmental and genetic determinants of IOP in Europeans.Medical Research Council (G1000143), Cancer Research UK (C864/A14136), Research into Ageing (262), Wellcome Trust, Richard Desmond Charitable Trust (via Fight for Sight), National Institute for Health Research, Stichting Lijf en Leven, Krimpen aan de Lek, MD Fonds, Utrecht, Rotterdamse Vereniging Blindenbelangen, Rotterdam, Stichting Oogfonds Nederland, Utrecht, Blindenpenning, Amsterdam, Blindenhulp, The Hague, Algemene Nederlandse Vereniging ter Voorkoming van Blindheid (ANVVB), Doorn, Landelijke Stichting voor Blinden en Slechtzienden, Utrecht, Swart van Essen, Rotterdam, Stichting Winckel-Sweep, Utrecht, Henkes Stichting, Rotterdam, Lameris Ootech BV, Nieuwegein, Medical Workshop, de Meern, NWO (Graduate Programme 2010 BOO (022.002.023)), Laboratoires Thea (Clermont-Ferrand, France), inter regional grant (PHRC) and the regional Council of Burgundy, European Community’s Seventh Framework Programme (FP7/2007-2013), Rheinland-Pfalz AZ 961-386261/733), Johannes Gutenberg-University of Mainz, Boehringer Ingelheim, PHILIPS Medical Systems, Novartis Pharma, Novartis European Union (European Social Fund—ESF), Greek National Strategic Reference Framework (NSRF) (Research Funding Program: THALES), European Social FundThis is the final version of the article. It first appeared from Springer via http://dx.doi.org/10.1007/s10654-016-0191-

Associations with intraocular pressure across Europe: The European Eye Epidemiology (E3) Consortium

Raised intraocular pressure (IOP) is the most important risk factor for developing glaucoma, the second commonest cause of blindness globally. Understanding associations with IOP and variations in IOP between countries may teach us about mechanisms underlying glaucoma. We examined cross-sectional associations with IOP in 43,500 European adults from 12 cohort studies belonging to the European Eye Epidemiology (E3) consortium. Each study conducted multivariable linear regression with IOP as the outcome variable and results were pooled using random effects meta-analysis. The association of standardized study IOP with latitude was tested using meta-regression. Higher IOP was observed in men (0.18 mmHg; 95 % CI 0.06, 0.31; P = 0.004) and with higher body mass index (0.21 mmHg per 5 kg/m2; 95 % CI 0.14, 0.28; P < 0.001), shorter height (−0.17 mmHg per 10 cm; 95 % CI –0.25, −0.08; P < 0.001), higher systolic blood pressure (0.17 mmHg per 10 mmHg; 95 % CI 0.12, 0.22; P < 0.001) and more myopic refraction (0.06 mmHg per Dioptre; 95 % CI 0.03, 0.09; P < 0.001). An inverted U-shaped trend was observed between age and IOP, with IOP increasing up to the age of 60 and decreasing in participants older than 70 years. We found no significant association between standardized IOP and study location latitude (P = 0.76). Novel findings of our study include the association of lower IOP in taller people and an inverted-U shaped association of IOP with age. We found no evidence of significant variation in IOP across Europe. Despite the limited range of latitude amongst included studies, this finding is in favour of collaborative pooling of data from studies examining environmental and genetic determinants of IOP in Europeans

Prevalence of Age Related Macular Degeneration in the portuguese population and associated risk factors. The contribution of the Epidemiologic Study of Mira and Lousã

Tese de doutoramento em Ciências da Saúde, na especialidade de Medicina, apresentada à Faculdade de Medicina da Universidade de CoimbraA degenerescência macular da idade (DMI) é considerada hoje como a terceira principal causa de cegueira no mundo e a que ocupa o primeiro lugar nos países desenvolvidos, considerando a população com idade igual ou superior a 55 anos. A par destas evidências, o envelhecimento global da população mundial coloca-a numa posição de primordial importância como problema de saúde pública. Os sinais fundoscópicos clínicos da doença precoce são a presença de drusen, associados ou não à presença de alterações pigmentares, constituindo estes sinais importantes marcadores de progressão para as formas tardias da doença. A DMI tardia é a forma responsável pela perda grave e irreversível de visão e inclui dois tipos morfologicamente distintos: a DMI neovascular (DMI-NV) e a atrofia geográfica (AG). A primeira representa cerca de 2/3 dos casos de DMI avançada e é responsável por 90% dos casos de cegueira relacionados com esta patologia. O recurso a agentes anti-fator do crescimento endotelial vascular revolucionou o tratamento da DMI-NV, permitindo controlar a evolução da doença em mais de 90% dos casos. Considerando a importância do diagnóstico precoce dos indivíduos em risco de desenvolvimento da DMI tardia, têm sido identificados múltiplos fatores de risco para a DMI, incluindo os oculares, genéticos, demográficos, nutricionais, ambientais e os relacionados com hábitos pessoais e estilos de vida. Porém, quer a evidência, quer a força de associação estimadas entre doença e fator de risco são muitas vezes inconsistentes. Até ao momento da realização do estudo que suporta esta tese, o Coimbra Eye Study, não existiam dados relativos a estimativas de prevalência da DMI na população portuguesa. Assim, o principal objetivo deste estudo consistiu em obter essa estimativa, e os objetivos secundários em avaliar os fatores de risco associados, assim como estabelecer a análise comparativa das taxas de prevalência e fatores de risco implicados, em duas subpopulações do centro de Portugal, com localização geográfica diferente e potencialmente com hábitos e estilos de vida também diferentes. A primeira estimativa de prevalência de DMI, ajustada ao sexo e idade, foi obtida numa população costeira do centro do país. Dos 4341 indivíduos contactados foram incluídos 3000 e, destes, 2975 foram incluídos na análise final. A prevalência de DMI precoce e tardia, ajustada ao sexo e idade foi de 6,99% e 0,67%, respetivamente. Os resultados primordiais revelaram uma prevalência das formas tardias de DMI inferior ao previamente reportado em outros estudos internacionais DMI-NV – 0,44% (95% CI: 0,23-0,75); AG – 0,27% (95% CI: 0,12-0,53). Tendo como principal objetivo obter uma estimativa de prevalência para a DMI numa amostra populacional mais ampla, incluímos, neste estudo, uma segunda população oriunda Sumário 12 do interior centro do país. Neste subgrupo populacional, dos 4999 indivíduos contactados, foram incluídos 3023, e 3021 submetidos à análise final. A estimativa de prevalência para a DMI precoce e tardia, foi, para esta subpopulação, de 15,39% e 1,29% respetivamente. Considerando a análise global dos dados obtidos e a população portuguesa com 55 anos ou mais, os resultados deste estudo revelaram que 12,48% (95% CI: 11,61-13,33) da população apresentavam sinais de alguma forma de DMI, e que 1,16% destes casos (95% CI: 0,85-1,46) detinham uma das formas tardias da doença. A DMI-NV e a AG foram, respetivamente, encontradas em 0,55% (95% CI: 0,36-0,75) e 0,61% (95% CI: 0,37-0,84) dos casos de DMI avançada. Previsivelmente, e ajustando para os potenciais confundidores, a prevalência de DMI aumentou de forma significativa com a idade, quer para a forma precoce (OR=1,35; 95% CI: 1,23-1,99; p<0,001), quer para a tardia (OR=3,01; 95% CI: 2,22-4,08; p<0,001). A análise multivariada da coorte revelou que, para além da idade, a localização geográfica da população em estudo consistiu numa variável significativa e independente associada às formas tardia (OR=2,06; 95% CI: 1,07-3,95; p=0,029) e precoce (OR=2,57; 95% CI: 2,12-3,12; p<0,001) de DMI. A comparação das estimativas de prevalência entre as duas populações analisadas revelou valores significativamente superiores para a população do interior, no que concerne às formas precoce (6,99% versus 15,39%, respetivamente para a população costeira e do interior; p<0,001) e tardia (0,67% versus 1,29%, respetivamente para as duas subpopulações; p<0,001) desta patologia. Considerando que a localização geográfica da população em estudo foi objetivada como variável preditiva associada às formas tardia e precoce de DMI, podemos admitir que esta variável represente uma medida de perfis comportamentais e dos hábitos de vida, incluindo diferentes padrões dietéticos e genéticos que o presente estudo não permitiu avaliar. Atualmente, e tendo em consideração a relevância dos padrões alimentares e dos estilos de vida como fatores de risco ou protetores no desenvolvimento e progressão da DMI, encontra-se em curso um estudo, no qual se pretende avaliar os hábitos alimentares e os estilos de vida das duas subpopulações estudadas e a sua potencial influência nas já objetivadas estimativas de prevalência para a DMI. O papel de fatores de risco nutricionais e associados ao estilo de vida na génese da DMI foi analisado numa extensão do presente estudo, conduzida na população da Lousã e que incluiu 449 participantes com sinais fundoscópicos de DMI precoce e 434 sem sinais da doença. Os resultados desta análise sugeriram que a prática de exercício físico pode ter um papel protetor na DMI (OR=0,69; CI 95%: 0,51-0,93; p=0,018) e que a alta adesão à dieta Mediterrânica poderá ter, também, um papel protetor marginalmente significativo (OR=0,64; CI 95%: 0,41-1,01; p=0,057). A análise por grupos alimentares e por micronutrientes revelou que o elevado consumo de fruta, cafeína, fibras, betacarotenos, vitamina E e C constituía um fator protetor no desenvolvimento desta patologia.Age-related macular degeneration (AMD) is considered to be the third major cause of blindness in the world and it is first in rank in the developed countries when it comes to the population of 55 years of age or older. Furthermore, the overall aging of the world population puts it in a position of primary importance as a public health problem. Clinical funduscopic early disease signs are the presence of drusen with or without retinal pigment alterations, which are important markers of progression for late forms of the disease. Late AMD is responsible for severe and irreversible vision loss and it includes two morphologically distinct types: neovascular age-related macular degeneration (NV-AMD) and geographic atrophy (GA). The former accounts for about two thirds of the cases of late AMD and it is responsible for 90% of blindness cases related to this pathology. The use of anti- vascular endothelial growth factor drugs has revolutionized the treatment of NV-AMD inasmuch as they have been able to prevent the evolution of the disease in more than 90% of cases. The early diagnosis of individuals at risk of developing late AMD is of paramount importance. Multiple risk factors for AMD, which go beyond the ocular signs, have been taken into consideration. Thus, risk factors that have to do with genetics, demography, nutrition, the environment as well as personal habits and lifestyles have become important study areas. However, the evidence and the estimated association between disease and risk factors are sometimes inconsistent. There was no data available regarding the prevalence rates of AMD among the Portuguese population before the study underlying the present thesis. Therefore, the main objective of this study has consisted of gathering significant information on those rates; as secondary objectives, one aimed at assessing risk factors associated with the disease, as well as doing a comparative analysis on prevalence rates and risk factors in two subpopulations of central Portugal, with different geographical location and with potentially different lifestyles. The first estimate of AMD prevalence, adjusted for sex and age, was obtained in the coastal population from the centre of the country. Of the 4341 individuals that were contacted, 3000 were included and of these, 2975 were incorporated in the final analysis. The prevalence of early and late AMD, adjusted for sex and age, was 6,99% and 0,67%, respectively. The primary results revealed a prevalence of late stage AMD lower than previously reported in other international studies [NV-AMD – 0,44% (95% CI: 0,23 to 0,75); AG – 0,27% (95% CI: 0,12 to 0,53)]. Bearing in mind the main objective to estimate, sex and age adjusted prevalence for early and late AMD, in a broader population sample, we have included in this study a second Summary 14 population coming from the inner centre of the country. In this population subgroup, of the 4999 individuals contacted, 3023 were included, of which 3021 were submitted to final analysis. The estimated prevalence of early and late stage AMD, for this subpopulation, was of 15,39% and 1,29%, respectively. Considering the overall analysis of the gathered data and the Portuguese population aged 55 or older, the results of this study revealed that in 12,48% (95% CI: 11,61 to 13,33) of the total population, signs of some form of AMD were found, and also that 1,16% of these cases (95% CI: 0,85 to 1,46) showed one of the late stages of the disease. The NV-AMD and the GA were found, respectively, in 0,55% (95% CI: 0,36 to 0,75) and 0,61% (95% CI: 0,37 to 0,84) of the cases of late AMD. Unsurprisingly, and adjusting for major confounding factors, the prevalence of AMD increased significantly with age both for the early (OR=1,35; 95% CI: 1,23 to 1,99; p<0,001), and the late stage (OR=3,01; 95% CI: 2,22 to 4,08; p<0,001) of the disease. Multivariate cohort analysis revealed that, in addition to age, the geographical location of the study population proved to be an independent and significant variable associated with the late stage (OR=2,06; 95% CI: 1,07 to 3,95; p=0,029) and the early stage (OR=2,57; 95% CI: 2,12 to 3,12; p<0,001) of AMD. The comparison of prevalence estimates between the two populations revealed significantly higher values for the population of the interior, in what concerns both early and late stages of this pathological condition (6,99% versus 15,39; 0,67% versus 1,29%, respectively, p<0,001). Considering that geographic location of the study population was objectified as a predictor variable associated with late and early stages of AMD, we can assume that this variable may represent a measure of behavioural profiles and lifestyle habits, including different eating and genetic patterns, which were not possible to be assessed by the present study. At the moment, and taking into account the relevance of eating habits and lifestyles either as risk or protective factors in the development and progression of AMD, a study is taking place, which is intended to evaluate the eating habits and lifestyles of the two subpopulations studied, and their likely influence on the already objectified prevalence estimates for AMD. The role of nutritional and lifestyle risk factors associated with the development of AMD was taken into account in an extension of the present study held in the population of Lousã, which included 449 participants with fundoscopic signs of early AMD and 434 who didn’t present any signs of the disease. The analized results suggested that physical exercise could have a protective role against AMD (OR=0,69; 95% CI: 0,51 to 0,93; p=0,018). Furthermore, eating habits agreeing with the Mediterranean diet may also have a marginally significant protective role (OR=0,64; 95% CI: 0,41 to 1,01; p=0,057). The analysis of food groups and micronutrients revealed that the high consumption of fruit, caffeine, fibre, beta-carotene, vitamins E and C constitute a protective factor against the development of this clinical condition

Ocular Risk Factors for Exudative AMD: A Novel Semiautomated Grading System

Purpose. To evaluate the contribution of the ocular risk factors in the conversion of the fellow eye of patients with unilateral exudative AMD, using a novel semiautomated grading system. Materials and Methods. Single-center, retrospective study including 89 consecutive patients with unilateral exudative AMD and ≥3 years of followup. Baseline color fundus photographs were graded using an innovative grading software, RetmarkerAMD (Critical Health SA). Results. The follow-up period was 60.9 ± 31.3 months. The occurrence of CNV was confirmed in 42 eyes (47.2%). The cumulative incidence of CNV was 23.6% at 2 years, 33.7% at 3 years, 39.3% at 5 years, and 47.2% at 10 years, with a mean annual incidence of 12.0% (95% CI = 0.088-0.162). The absolute number of drusen in the central 1000 and 3000  μ m (P < 0.05) and the absolute number of drusen ≥125 µm in the central 3000 and 6000 µm (P < 0.05) proved to be significant risk factors for CNV. Conclusion. The use of quantitative variables in the determination of the OR of developing CNV allowed the establishment of significant risk factors for neovascularization. The long follow-up period and the innovative methodology reinforce the value of our results. This trial is registered with ClinicalTrials.gov NCT00801541

Common and rare genetic risk variants in age-related macular degeneration and genetic risk score in the Coimbra eye study

Purpose: To determine the contribution of common and rare genetic variants in age-related macular degeneration (AMD) in a Portuguese population from the Coimbra Eye Study (CES), and the genetic risk score (GRS). Methods: Participants underwent ophthalmologic examination and imaging. A centralized reading centre performed AMD staging. Genetic sequencing was carried out with the EYE-RISK assay. Sixty-nine single nucleotide polymorphisms (SNPs) were genotyped and tested for association with AMD. Case–control and progression-to- AMD analyses were performed using logistic regression to assess allelic odds ratio (OR) at a 95% confidence interval (CI) for each variant. GRS was calculated for cases/controls and progressors/non-progressors. Cumulative impact of rare variants was compared between cases/controls using logistic regression. Results: In case–control analysis (237 cases/640 controls) variants associated with risk of disease were: ARMS2 rs10490924, ARMS2_HTRA1 rs3750846, CFH rs35292876, SLC16A8 rs8135665, TGFBR1 rs1626340. Major risk variants ARMS2/ HTRA1 rs3750846, CFH rs570618 and C3 rs2230199 had unexpected lower allele frequency (AF), and the highest risk-conferring variant was a rare variant, CFH rs35292876 (OR, 2.668; p-value = 0.021). In progression-to- AMD analysis (137 progressors/ 630 non-progressors), variants associated with risk of progression were ARMS2 rs10490924, ARMS2_HTRA1 rs3750846, CFH rs35292876. GRS of cases/ controls was 1.124 ± 1.187 and 0.645 ± 1.124 (p-value < 0.001), and of progressors/non-progressors was 1.190 ± 1.178 and 0.669 ± 1.141 (p-value < 0.001). Higher proportion of pathogenic rare CFH variants was observed in cases (OR, 9.661; p-value < 0.001). Conclusions: Both common and rare variants were associated with AMD, but a CFH rare variant conferred the highest risk of disease while three major risk variants had a lower-than- expected AF in our population originary from a geographic region with lower prevalence of AMD. GRS was still significantly higher in AMD patients. Damaging CFH rare variants were cumulatively more common in AMD cases

Age-Related Macular Degeneration Staging by Color Fundus Photography vs. Multimodal Imaging-Epidemiological Implications (The Coimbra Eye Study-Report 6)

Epidemiology of age-related macular degeneration (AMD) is based on staging systems relying on color fundus photography (CFP). We aim to compare AMD staging using CFP to multimodal imaging with optical coherence tomography (OCT), infra-red (IR), and fundus autofluorescence (FAF), in a large cohort from the Epidemiologic AMD Coimbra Eye Study. All imaging exams from the participants of this population-based study were classified by a central reading center. CFP images were graded according to the International Classification and Grading System for AMD and staged with Rotterdam classification. Afterward, CFP images were reviewed with OCT, IR, and FAF and stage update was performed if necessary. Early and late AMD prevalence was compared in a total of 1616 included subjects. In CFP-based grading, the prevalence was 14.11% for early AMD (n = 228) and 1.05% (n = 17) for late AMD, nine cases (0.56%) had neovascular AMD (nAMD) and eight (0.50%) geographic atrophy (GA). Using multimodal grading, the prevalence increased to 14.60% for early AMD (n = 236) and 1.61% (n = 26) for late AMD, with 14 cases (0.87%) of nAMD and 12 (0.74%) of GA. AMD staging was more accurate with the multimodal approach and this was especially relevant for late AMD. We propose that multimodal imaging should be adopted in the future to better estimate and compare epidemiological data in different populations

Automated Brightness and Contrast Adjustment of Color Fundus Photographs for the Grading of Age-Related Macular Degeneration

Purpose The purpose of this study was to develop an algorithm to automatically standardize the brightness, contrast, and color balance of digital color fundus photographs used to grade AMD and to validate this algorithm by determining the effects of the standardization on image quality and disease grading. Methods: Seven-field color photographs of patients (>50 years) with any stage of AMD and a control group were acquired at two study sites, with either the Topcon TRC-50DX or Zeiss FF-450 Plus cameras. Field 2 photographs were analyzed. Pixel brightness values in the red, green, and blue (RGB) color channels were adjusted in custom-built software to make the mean brightness and contrast of the images equal to optimal values determined by the Age-Related Eye Disease Study (AREDS) 2 group. Results: Color photographs of 370 eyes were analyzed. We found a wide range of brightness and contrast values in the images at baseline, even for those taken with the same camera. After processing, image brightness variability (brightest image–dimmest image in a color channel) was reduced 69-fold, 62-fold, and 96-fold for the RGB channels. Contrast variability was reduced 6-fold, 8-fold, and 13-fold, respectively, after adjustment. Of the 23% images considered nongradable before adjustment, only 5.7% remained nongradable. Conclusions: This automated software enables rapid and accurate standardization of color photographs for AMD grading. Translational Relevance This work offers the potential to be the future of assessing and grading AMD from photos for clinical research and teleimaging