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PurposeData on myopia progression during its entire course are scarce. The aim of this study is to investigate myopia progression in Europeans as a function of age and degree of myopia from first prescription to final refractive error.MethodsThe Drentse Refractive Error and Myopia Study assessed data from a branch of opticians in the Netherlands from 1985 onwards in a retrospective study. First pair of glasses prescribed was defined as a spherical equivalent of refraction (SER) ≤−0.5 D to ≥−3.0 D. Subjects with prescriptions at an interval of at least 1 year were included in the analysis.ResultsA total of 2555 persons (57.3% female) met the inclusion criteria. Those with first prescription before the age of 10 years showed the strongest progression (−0.50 D; IQR: −0.75 to −0.19) and a significantly (pConclusionOur trajectories of the natural course of myopia progression may serve as a guide for myopia management in European children. SER at 10 years is an important prognostic indicator and will help determine treatment intensity.

Purpose To describe the natural course, phenotype and genotype of patients with X-linked retinoschisis (XLRS). Design Retrospective cohort study. Participants Three hundred forty patients with XLRS from 178 presumably unrelated families. Methods This multicenter, retrospective cohort study reviewed medical records of XLRS patients for medical history, symptoms, visual acuity (VA), ophthalmoscopy, full-field electroretinography and retinal imaging (fundus photography, spectral-domain optical coherence tomography (SD-OCT), fundus autofluorescence). Main Outcome Measures Age at onset, age of diagnosis, severity of visual impairment, annual visual decline, electroretinogram and imaging findings. Results In total, 340 patients were included with a mean follow-up time of 13.2 years (range, 0–50.1 years). The median age to reach mild visual impairment and low vision was 12 and 25 years, respectively. Severe visual impairment and blindness were predominantly observed in patients above 40 years old, with a predicted prevalence of 35% and 25% at the age of 60, respectively. The VA increased slightly in the first two decades of life, and subsequently transitioned in to an average annual decline of 0.44% (P A (p.(Glu72Lys) (101 subjects, 29.7%) and a deletion of exon 3 (38 subjects, 11.2%). Conclusion A large variability in phenotype and natural course of XLRS was seen in this study. In most patients, XLRS showed a slow deterioration starting in the second decade of life, suggesting an optimal window of opportunity for treatment within the first three decades of life. The integrity of EZ as well as the PROS length on SD-OCT may be important in choosing optimal candidates for treatment, and as potential structural endpoints in future therapeutic studies. No clear genotype-phenotype correlation was found.

PURPOSE: To investigate the natural disease course of retinal dystrophies associated with crumbs cell polarity complex component 1 (CRB1) and identify clinical end points for future clinical trials. DESIGN: Single-center, prospective case series. METHODS: An investigator-initiated nationwide collaborative study that included 22 patients with CRB1-associated retinal dystrophies. Patients underwent ophthalmic assessment at baseline and 2 years after baseline. Clinical examination included best-corrected visual acuity (BCVA) using Early Treatment Diabetic Retinopathy Study charts, Goldmann kinetic perimetry (V4e isopter seeing retinal areas), microperimetry, full-field electroretinography, full-field stimulus threshold (FST), fundus photography, spectral-domain optical coherence tomography, and fundus autofluorescence imaging. RESULTS: Based on genetic, clinical, and electrophysiological data, patients were diagnosed with retinitis pigmentosa (19 [86%]), cone-rod dystrophy (2 [9%]), or isolated macular dystrophy (1 [5%]). Analysis of the entire cohort at 2 years showed no significant changes in BCVA (P = .069) or V4e isopter seeing retinal areas (P = .616), although signs of clinical progression were present in individual patients. Macular sensitivity measured on microperimetry revealed a significant reduction at the 2-year follow-up (P < .001). FST responses were measurable in patients with nonrecordable electroretinograms. On average, FST responses remained stable during follow-up. CONCLUSION: In CRB1-associated retinal dystrophies, visual acuity and visual field measures remain relatively stable over the course of 2 years. Microperimetry showed a significant decrease in retinal sensitivity during follow-up and may be a more sensitive progression marker. Retinal sensitivity on microperimetry may serve as a functional clinical end point in future human treatment trials for CRB1-associated retinal dystrophies.

Supplemental digital content is available in the text., SIGNIFICANCE Our findings show that non-Dutch background, lower maternal education, and lower net household income level may be new risk factors for myopia development in the Netherlands. Newly introduced physical activity spaces may not be effective enough in increasing outdoor exposure in children to reduce eye growth. PURPOSE The aims of this study were to evaluate socioeconomic inequalities in myopia incidence, eye growth, outdoor exposure, and computer use and to investigate if newly introduced physical activity spaces can reduce eye growth in school-aged children. METHODS Participants (N = 2643) from the Dutch population–based birth cohort Generation R were examined at ages 6 and 9 years. Socioeconomic inequalities in myopia incidence, eye growth, and lifestyle were determined using regression analyses. Information on physical activity spaces located in Rotterdam was obtained. Differences in eye growth between those who became exposed to new physical activity spaces (n = 230) and those nonexposed (n = 1866) were evaluated with individual-level fixed-effects models. RESULTS Myopia prevalence was 2.2% at age 6 years and 12.2% at age 9 years. Outdoor exposure was 11.4 h/wk at age 6 years and 7.4 h/wk at age 9 years. Computer use was 2.1 h/wk at age 6 years and 5.2 h/wk at age 9 years. Myopia incidence was higher in children with non-Dutch background, and families with lower household income and lower maternal education (odds ratio [OR], 1.081 [95% confidence interval, 1.052 to 1.112]; OR, 1.035 [95% confidence interval, 1.008 to 1.063]; OR, 1.028 [95% confidence interval, 1.001 to 1.055], respectively). Children living

Purpose To investigate the association between smartphone use and refractive error in teenagers using the Myopia app. Design Cross-sectional population-based study. Participants A total of 525 teenagers 12 to 16 years of age from 6 secondary schools and from the birth cohort study Generation R participated. Methods A smartphone application (Myopia app; Innovattic) was designed to measure smartphone use and face-to-screen distance objectively and to pose questions about outdoor exposure. Participants underwent cycloplegic refractive error and ocular biometry measurements. Mean daily smartphone use was calculated in hours per day and continuous use as the number of episodes of 20 minutes on screen without breaks. Linear mixed models were conducted with smartphone use, continuous use, and face-to-screen distance as determinants and spherical equivalent of refraction (SER) and axial length-to-corneal radius (AL:CR) ratio as outcome measures stratified by median outdoor exposure. Main Outcome Measures Spherical equivalent of refraction in diopters and AL:CR ratio. Results The teenagers on average were 13.7 ± 0.85 years of age, and myopia prevalence was 18.9%. During school days, total smartphone use on average was 3.71 ± 1.70 hours/day and was associated only borderline significantly with AL:CR ratio (β = 0.008; 95% confidence interval [CI], –0.001 to 0.017) and not with SER. Continuous use on average was 6.42 ± 4.36 episodes of 20-minute use without breaks per day and was associated significantly with SER and AL:CR ratio (β = –0.07 [95% CI, –0.13 to –0.01] and β = 0.004 [95% CI, 0.001–0.008], respectively). When stratifying for outdoor exposure, continuous use remained significant only for teenagers with low exposure (β = –0.10 [95% CI, –0.20 to –0.01] and β = 0.007 [95% CI, 0.001–0.013] for SER and AL:CR ratio, respectively). Smartphone use during weekends was not associated significantly with SER and AL:CR ratio, nor was face-to-screen distance. Conclusions Dutch teenagers spent almost 4 hours per day on their smartphones. Episodes of 20 minutes of continuous use were associated with more myopic refractive errors, particularly in those with low outdoor exposure. This study suggested that frequent breaks should become a recommendation for smartphone use in teenagers. Future large longitudinal studies will allow more detailed information on safe screen use in youth.

Contains fulltext : 243957.pdf (Publisher’s version ) (Open Access) PURPOSE: Primary open-angle glaucoma (POAG) has been reported to occur more frequently in Africans, and to follow a more severe course compared to Europeans. We aimed to describe characteristics of POAG presentation and treatment across three ethnic groups from Africa and one from Europe. METHODS: We ascertained 151 POAG patients from South African Coloured (SAC) and 94 South African Black (SAB) ethnicity from a university hospital in South Africa. In Tanzania, 310 patients were recruited from a university hospital and a referral hospital. In the Netherlands, 241 patients of European ancestry were included. All patients were over 35 years old and had undergone an extensive ophthalmic examination. Patients were diagnosed according to the ISGEO criteria. A biogeographic ancestry analysis was performed to estimate the proportion of genetic African ancestry (GAA). RESULTS: The biogeographic ancestry analysis showed that the median proportion of GAA was 97.6% in Tanzanian, 100% in SAB, 34.2% in SAC and 1.5% in Dutch participants. Clinical characteristics at presentation for Tanzanians, SAB, SAC and Dutch participants, respectively: mean age: 63, 57, 66, 70 years (p

Applying deep learning in population genomics is challenging because of computational issues and lack of interpretable models. Here, we propose GenNet, a novel open-source deep learning framework for predicting phenotypes from genetic variants. In this framework, interpretable and memory-efficient neural network architectures are constructed by embedding biologically knowledge from public databases, resulting in neural networks that contain only biologically plausible connections. We applied the framework to seventeen phenotypes and found well-replicated genes such as HERC2 and OCA2 for hair and eye color, and novel genes such as ZNF773 and PCNT for schizophrenia. Additionally, the framework identified ubiquitin mediated proteolysis, endocrine system and viral infectious diseases as most predictive biological pathways for schizophrenia. GenNet is a freely available, end-to-end deep learning framework that allows researchers to develop and use interpretable neural networks to obtain novel insights into the genetic architecture of complex traits and diseases., van Hilten and colleagues present GenNet, a deep-learning framework for predicting phenotype from genetic data. This framework generates interpretable neural networks that provide insight into the genetic basis of complex traits and diseases.

Contains fulltext : 238066.pdf (Publisher’s version ) (Open Access) PURPOSE: To compare treatment outcomes of treatment-naïve eyes with neovascular age-related macular degeneration (nAMD) with bevacizumab as the first-line treatment, according to the guidelines of the Dutch Ophthalmological Society, with those treated first with either ranibizumab or aflibercept, as used in many other countries, all treated using a treat-and-extend strategy. METHODS: Data were obtained from the prospectively designed Fight Retinal Blindness! outcomes registry. The primary outcome was the mean change from baseline in visual acuity of all treated eyes, after 12, 24 and 36 months of treatment. Secondary outcomes were the number of injections, the number of visits and the rate of switching to a second anti-VEGF drug. RESULTS: The study included 703 treatment-naïve eyes with nAMD with 12 months follow-up, 373 eyes with 24 months follow-up, and 171 eyes with 36 months follow-up in the Netherlands, and 1131, 652, and 303 treatment-naïve eyes with respectively 12, 24, and 36 months of follow-up in all other countries. The change in visual acuity from baseline did not differ between the Netherlands and the other countries at any follow-up time. The median number of injections, visits and the proportion of eyes switching treatment was significantly higher in the Netherlands than in the other countries. CONCLUSION: Starting anti-VEGF treatment for nAMD with bevacizumab, as is mandatory in the Netherlands, delivers outcomes similar to those starting treatment with either ranibizumab or aflibercept, but at a cost of more frequent injections, and visits, and more frequent switching treatment to a second drug.

Purpose Age-related macular degeneration (AMD) is a common multifactorial disease in the elderly with a prominent genetic basis. Many risk variants have been identified, but the interpretation remains challenging. We investigated the genetic distribution of AMD-associated risk variants in a large European consortium, calculated attributable and pathway-specific genetic risks, and assessed the influence of lifestyle on genetic outcomes. Design Pooled analysis of cross-sectional data from the European Eye Epidemiology Consortium. Participants Seventeen thousand one hundred seventy-four individuals 45 years of age or older participating in 6 population-based cohort studies, 2 clinic-based studies, and 1 case-control study. Methods Age-related macular degeneration was diagnosed and graded based on fundus photographs. Data on genetics, lifestyle, and diet were harmonized. Minor allele frequencies and population-attributable fraction (PAF) were calculated. A total genetic risk score (GRS) and pathway-specific risk scores (complement, lipid, extra-cellular matrix, other) were constructed based on the dosage of SNPs and conditional β values; a lifestyle score was constructed based on smoking and diet. Main Outcome Measures Intermediate and late AMD. Results The risk variants with the largest difference between late AMD patients and control participants and the highest PAFs were located in ARMS2 (rs3750846) and CHF (rs570618 and rs10922109). Combining all genetic variants, the total genetic risk score ranged from –3.50 to 4.63 and increased with AMD severity. Of the late AMD patients, 1581 of 1777 (89%) showed a positive total GRS. The complement pathway and ARMS2 were by far the most prominent genetic pathways contributing to late AMD (positive GRS, 90% of patients with late disease), but risk in 3 pathways was most frequent (35% of patients with late disease). Lifestyle was a strong determinant of the outcome in each genetic risk category; unfavorable lifestyle increased the risk of late AMD at least 2-fold. Conclusions Genetic risk variants contribute to late AMD in most patients. However, lifestyle factors have a strong influence on the outcome of genetic risk and should be a strong focus in patient management. Genetic risks in ARMS2 and the complement pathway are present in most late AMD patients but are mostly combined with risks in other pathways.

Previously, variation in retinal vascular caliber has been reported in association with chronic kidney disease (CKD) but findings remain inconsistent. To help clarify this we conducted individual participant data meta-analysis and aggregate data meta-analysis on summary estimates to evaluate cross-sectional associations between retinal vascular caliber and CKD. A systematic review was performed using Medline and EMBASE for articles published until October 2018. The aggregate analysis used a two-stage approach combining summary estimates from eleven studies (44,803 patients) while the individual participant analysis used a one-stage approach combining raw data from nine studies (33,222 patients). CKD stages 3-5 was defined as an estimated glomerular filtration rate under 60 mL/min/1.73m2. Retinal arteriolar and venular caliber (central retinal arteriolar and venular equivalent) were assessed from retinal photographs using computer-assisted methods. Logistic regression estimated relative risk of CKD stages 3-5 associated with a 20 μm decrease (approximately one standard deviation) in central retinal arteriolar and venular equivalent. Prevalence of CKD stages 3-5 was 11.2% of 33,222 and 11.3% of 44,803 patients in the individual participant and aggregate data analysis, respectively. No significant associations were detected in adjusted analyses between central retinal arteriolar and venular equivalent and CKD stages 3-5 in the aggregate analysis for central retinal arteriolar relative risk (0.98, 95% confidence interval 0.94-1.03); venular equivalent (0.99, 0.95-1.04) or individual participant central retinal arteriolar (0.99, 0.95-1.04) or venular equivalent (1.01, 0.97-1.05). Thus, meta-analysis provided little evidence to suggest that cross sectional direct measurements of retinal vascular caliber was associated with CKD stages 3-5 in the general population. Hence, meta-analyses of longitudinal studies evaluating the association between retinal parameters and CKD stages 3-5 may be warranted.

Purpose Geographic atrophy (GA) secondary to age-related macular degeneration is considered a single entity. This study aimed to determine whether GA subgroups exist that can be defined by their genotype and phenotype. Design Retrospective analysis of cross-sectional data. Participants Individuals (196 eyes of 196 patients) 50 years of age or older with GA from the EYE-RISK database. Methods Participants were graded for the presence of each of the following fundus features on color fundus photography: large soft drusen, reticular pseudodrusen (RPD), refractile drusen, hyperpigmentation, location of atrophy (foveal vs. extrafoveal), and multifocal lesions. Genotypes of 33 single nucleotide polymorphisms previously assigned to the complement, lipid metabolism, or extracellular matrix (ECM) pathways and ARMS2 also were included, and genetic risk scores (GRSs) for each of those 3 pathways were calculated. Hierarchical cluster analysis was used to determine subgroups of participants defined by these features. The discriminative ability of genotype, phenotype, or both for each subgroup was determined with 10-fold cross-validated areas under the receiver operating characteristic curve (cvAUCs), and the agreement between predicted and actual subgroup membership was assessed with calibration plots. Main Outcome Measures Identification and characterization of GA subgroups based on their phenotype and genotype. Results Cluster analyses identified 3 subgroups of GA. Subgroup 1 was characterized by high complement GRS, frequently associated with large soft drusen and foveal atrophy; subgroup 2 generally showed low GRS, foveal atrophy, and few drusen (any type); and subgroup 3 showed a high ARMS2 and ECM GRS, RPD, and extrafoveal atrophy. A high discriminative ability existed between subgroups for the genotype (cvAUC, ≥0.94), and a modest discriminative ability existed for the phenotype (cvAUC, Conclusions We identified 3 GA subgroups that differed mostly by their genotype. Atrophy location and drusen type were the most relevant phenotypic features.

Nuclear cataract is the most common type of age-related cataract and a leading cause of blindness worldwide. Age-related nuclear cataract is heritable (h2 = 0.48), but little is known about specific genetic factors underlying this condition. Here we report findings from the largest to date multi-ethnic meta-analysis of genome-wide association studies (discovery cohort N = 14,151 and replication N = 5299) of the International Cataract Genetics Consortium. We confirmed the known genetic association of CRYAA (rs7278468, P = 2.8 × 10−16) with nuclear cataract and identified five new loci associated with this disease: SOX2-OT (rs9842371, P = 1.7 × 10−19), TMPRSS5 (rs4936279, P = 2.5 × 10−10), LINC01412 (rs16823886, P = 1.3 × 10−9), GLTSCR1 (rs1005911, P = 9.8 × 10−9), and COMMD1 (rs62149908, P = 1.2 × 10−8). The results suggest a strong link of age-related nuclear cataract with congenital cataract and eye development genes, and the importance of common genetic variants in maintaining crystalline lens integrity in the aging eye., Here, the authors report a multi-ethnic genome wide association meta-analysis of 12 studies from the International Cataract Genetics Consortium. They find six new loci associated with age-related nuclear cataract, in addition to replicating the association at CRYAA, and suggest a strong genetic link between age-related nuclear and congenital cataracts.

Purpose A trend that myopia is becoming gradually more common is shown in studies worldwide. Highest frequencies have been found in East Asian urban populations (96.5%) but also a study in Europe shows that nearly half of the 25-29 year olds has myopia. With the increase in prevalence, high myopia, i.e. a spherical equivalent of -6 or more and an axial length of 26 mm or more is also on the rise. High myopia particularly carries a significant risk of ocular pathology related to the long axial length. This highlights the need for myopia management in children with progressive myopia, in particular progression to high myopia. Recent findings During the last decade, many intervention studies for myopia progression have emerged. Although lifestyle adjustments are effective, pharmacological and optical interventions have shown the highest efficacy on reduction of eye growth. High concentration atropine (0.5%-1.0%) shows the most reduction in axial length progression, but has drawbacks of light sensitivity and loss of accommodation. Nevertheless, when these side effects are mitigated by multifocal photochromatic glasses, the long-term adherence to high dose atropine is high. Lower concentrations of atropine are less effective, but have less side effects. Studies on optical interventions have reported reduction of progression for Ortho-K and multifocal contact lenses, but are in need for replication in larger studies with longer duration. Summary The field of myopia management is rapidly evolving, and a position on the best approach for daily clinics is desirable. Over the last 10 years, our team of clinical researchers has developed a strategy which involves decision-making based on age, axial length, position on the axial length growth chart, progression rate, risk of high myopia, risk profile based on lifestyle and familial risk, side effects, and individual preference. This personalised approach ensures the most optimal long-term myopia control, and helps fight against visual impairment and blindness in the next generations of elderly.

Aims The contribution of sex hormones to micro- and macrovascular damage might differ among women and men. In particular, little is known about the association between sex hormones and small vessel disease. Therefore, we examined the association of total oestradiol, total testosterone, free-androgen index (FAI), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), and androstenedione levels with micro- and macrovascular diseases. Methods and results This cross-sectional study included 2950 women and 2495 men from the population-based Rotterdam Study. As proxy of microvascular damage, we measured diameters of retinal arterioles and venules. Markers of macrovascular damage included carotid intima-media thickness and carotid plaque, coronary artery calcification (CAC), and peripheral artery disease. Linear and logistic regression models were used and adjusted for age, cardiovascular risk factors, and years since menopause. Associations with microvasculature: In women, total testosterone [mean difference per 1-unit increase in natural-log transformed total testosterone (95% confidence interval, CI): 2.59 (0.08–5.09)] and androstenedione [4.88 (1.82–7.95)] and in men DHEAS [2.80 (0.23–5.37)] and androstenedione [5.83 (2.19–9.46)] were associated with larger venular caliber. Associations with markers of large vessel disease: In women, higher total testosterone [−0.29 (−0.56 to −0.03)], FAI [−0.33 (−0.56 to −0.10)], and androstenedione levels [−0.33 (−0.64 to −0.02)] were associated with lower CAC burden and FAI [odds ratio (95% CI): 0.82 (0.71–0.94)] was associated with lower prevalence of plaque. Conclusion A more androgenic profile was associated with more microvascular damage in both women and men. Among women, however, higher androgen levels were also associated with less macrovascular damage. Our findings suggest that androgens might have distinct effects on the vasculature, depending on the vascular bed and stages of the atherosclerosis process.

Purpose: To increase insight into the myopic presentation of central serous chorioretinopathy (CSC) by comparing a large group of myopic patients with CSC with reference groups with only one of the diagnoses. Methods: Myopic patients with CSC (spherical equivalent

Background: Early identification of AMD can lead to prompt and more effective treatment, better outcomes, and better final visual acuity, several risk scores have been devised to determine the individual level of risk for developing AMD. Herein, the Delphi method was used to provide recommendations for daily practice regarding preventive measures and follow-up required for subjects at low, moderate, and high risk of AMD evaluated with the Simplified Test AMD Risk-assessment Scale (STARS®) questionnaire. Methods: A steering committee of three experts drafted and refined 25 statements on the approach to be recommended in different clinical situations [general recommendations (n = 2), use of evaluation tools (n = 4), general lifestyle advice (n = 3), and AREDS-based nutritional supplementation (n = 5)] with the help of a group of international experts, all co-authors of this paper. Thirty retinal specialists from Europe and the US were chosen based on relevant publications, clinical expertise, and experience in AMD, who then provided their level of agreement with the statements. Statements for which consensus was not reached were modified and voted upon again. Results: In the first round of voting, consensus was reached for 24 statements. After modification, consensus was then reached for the remaining statement. Conclusion: An interprofessional guideline to support preventive measures in patients at risk of AMD based on STARS® scoring has been developed to aid clinicians in daily practice, which will help to optimize preventive care of patients at risk of AMD.

Item does not contain fulltext PURPOSE: To study the relatively high effect of the refractive error gene GJD2 in human myopia, and to assess its relationship with refractive error, ocular biometry and lifestyle in various age groups. METHODS: The population-based Rotterdam Study (RS), high myopia case-control study MYopia STudy, and the birth-cohort study Generation R were included in this study. Spherical equivalent (SER), axial length (AL), axial length/corneal radius (AL/CR), vitreous depth (VD), and anterior chamber depth (ACD) were measured using standard ophthalmologic procedures. Biometric measurements were compared between GJD2 (rs524952) genotype groups; education and environmental risk score (ERS) were calculated to estimate gene-environment interaction effects, using the Synergy index (SI). RESULTS: RS adults carrying two risk alleles had a lower SER and longer AL, ACD and VD (AA versus TT, 0.23D vs. 0.70D; 23.79 mm vs. 23.52 mm; 2.72 mm vs. 2.65 mm; 16.12 mm vs. 15.87 mm; all P < 0.001). Children carrying two risk alleles had larger AL/CR at ages 6 and 9 years (2.88 vs. 2.87 and 3.00 vs. 2.96; all P < 0.001). Education and ERS both negatively influenced myopia and the biometric outcomes, but gene-environment interactions did not reach statistical significance (SI 1.25 [95% confidence interval {CI}, 0.85-1.85] and 1.17 [95% CI, 0.55-2.50] in adults and children). CONCLUSIONS: The elongation of the eye caused by the GJD2 risk genotype follows a dose-response pattern already visible at the age of 6 years. These early effects are an example of how a common myopia gene may drive myopia.

Retinal swelling due to the accumulation of fluid is associated with the most vision-threatening retinal diseases. Optical coherence tomography (OCT) is the current standard of care in assessing the presence and quantity of retinal fluid and image-guided treatment management. Deep learning methods have made their impact across medical imaging, and many retinal OCT analysis methods have been proposed. However, it is currently not clear how successful they are in interpreting the retinal fluid on OCT, which is due to the lack of standardized benchmarks. To address this, we organized a challenge RETOUCH in conjunction with MICCAI 2017, with eight teams participating. The challenge consisted of two tasks: fluid detection and fluid segmentation. It featured for the first time: all three retinal fluid types, with annotated images provided by two clinical centers, which were acquired with the three most common OCT device vendors from patients with two different retinal diseases. The analysis revealed that in the detection task, the performance on the automated fluid detection was within the inter-grader variability. However, in the segmentation task, fusing the automated methods produced segmentations that were superior to all individual methods, indicating the need for further improvements in the segmentation performance.

To identify risk factors for axial length (AL) elongation and incident school myopia.Population-based prospective birth-cohort study.Four thousand seven hundred thirty-four children examined at 6 and 9 years of age from the Generation R Study in Rotterdam, The Netherlands.Axial length and corneal radius (CR) were measured with an IOLMaster 500 and daily life activities and demographic characteristics were obtained by questionnaire. Three thousand three hundred sixty-two children (71%) were eligible for cycloplegic refractive error measurements. Linear regression models on AL elongation were used to create a risk score based on the regression coefficients resulting from environmental and ocular factors. The predictive value of the prediction score for myopia (≤-0.5 diopter) was estimated using receiver operating characteristic curves. To test if regression coefficients differed for baseline AL-to-CR ratio, interaction terms were calculated with baseline AL-to-CR ratio and environmental factors.Axial length elongation and incident myopia.From 6 to 9 years of age, average AL elongation was 0.21±0.009 mm/year and myopia developed in 223 of 2136 children (10.4%), leading to a myopia prevalence at 9 years of age of 12.0%. Seven parameters were associated independently (P0.05) with faster AL elongation: parental myopia, 1 or more books read per week, time spent reading, no participation in sports, non-European ethnicity, less time spent outdoors, and baseline AL-to-CR ratio. The discriminative accuracy for incident myopia based on these risk factors was 0.78. Axial length-to-CR ratio at baseline showed statistically significant interaction with number of books read per week (P0.01) and parental myopia (P0.01). Almost all predictors showed the highest association with AL elongation in the highest quartile of AL-to-CR ratio; incidental myopia in this group was 24% (124/513).Determination of a risk score can help to identify school children at high risk of myopia. Our results suggest that behavioral changes can offer protection particularly in these children.

Contains fulltext : 205478.pdf (Publisher’s version ) (Open Access) PURPOSE: Ocular biometry varies within groups of emmetropic, hyperopic or myopic children. The aim of this study was to quantify the effect of foetal and infant growth on ocular biometry in early childhood, to determine the most important period for this association, and to examine genetic overlap with height and birth weight. METHODS: 5931 children (50.1% girls) from a population-based prospective birth cohort study underwent intra-uterine and infant growth measurements at second and third trimester, and from birth to 72 months. An ophthalmic examination including axial length (mm) and corneal radius of curvature (mm) was performed at 6 years of age. The associations between prenatal and postnatal growth variables and axial length and corneal radius of curvature were assessed with conditional linear regression analyses. Weighted genetic risk scores for birth weight and height were calculated and causality was tested with Mendelian randomisation. RESULTS: Weight and length from mid-pregnancy to 2 years of age were most important prognostic factors for axial length and corneal radius of curvature at age 4.9-9 years (mean 6.2 years S.D. 0.5). For height (Standard deviation score), the association with axial length and corneal radius of curvature was highest for the measurement at 12 months (beta 0.171 p < 0.001 and 0.070 p < 0.001). The genetic height and birth weight risk scores were both significantly associated with ocular biometry. CONCLUSIONS: Larger neonates had longer axial length and greater corneal radius of curvature. Growth during pregnancy and 2 years postnatally is the most important period underlying this association and may be partly genetically determined by genes associated with height.

PURPOSE: To assess the age-specific proportion of visual impairment in patients with pseudoxanthoma elasticum (PXE) and to compare this with foveal abnormality and similar data of late age-related macular degeneration patients. METHODS: Cross-sectional data of 195 patients with PXE were reviewed, including best-corrected visual acuity and imaging. The World Health Organisation criteria were used to categorize bilateral visual impairment. These results were compared with similar data of 131 patients with late age-related macular degeneration from the Rotterdam study. RESULTS: Overall, 50 PXE patients (26.0%) were visually impaired, including 21 (11%) with legal blindness. Visual functioning declined with increasing age. In patients older than 50 years, 37% was visually impaired and 15% legally blind. Foveal choroidal neovascularization was found in 84% of eyes with a best-corrected visual acuity lower than 20/70 (0.30) and macular atrophy in the fovea in 16%. In late age-related macular degeneration patients, 40% were visually impaired and 13% legally blind. Visual impairment started approximately 20 years later as compared with PXE patients. CONCLUSION: Visual impairment and blindness are frequent in PXE, particularly in patients older than 50 years. Although choroidal neovascularization is associated with the majority of vision loss, macular atrophy is also common. The proportion of visual impairment in PXE is comparable with late age-related macular degeneration but manifests earlier in life.

With the growing prevalence of myopia, already at epidemic levels in some countries, there is an urgent need for new management approaches. However, with the increasing number of research publications on the topic of myopia control, there is also a clear necessity for agreement and guidance on key issues, including on how myopia should be defined and how interventions, validated by well-conducted clinical trials, should be appropriately and ethically applied. The International Myopia Institute (IMI) reports the critical review and synthesis of the research evidence to date, from animal models, genetics, clinical studies, and randomized controlled trials, by more than 85 multidisciplinary experts in the field, as the basis for the recommendations contained therein. As background to the need for myopia control, the risk factors for myopia onset and progression are reviewed. The seven generated reports are summarized: (1) Defining and Classifying Myopia, (2) Experimental Models of Emmetropization and Myopia, (3) Myopia Genetics, (4) Interventions for Myopia Onset and Progression, (5) Clinical Myopia Control Trials and Instrumentation, (6) Industry Guidelines and Ethical Considerations for Myopia Control, and (7) Clinical Myopia Management Guidelines.

textabstractPURPOSE. To assess the phenotypic variability and natural course of inherited retinal diseases (IRDs) caused by EYS mutations. METHODS. Multiethnic cohort study (N ¼ 30) with biallelic EYS variants from a clinical IRD database (retinitis pigmentosa [RP], N ¼ 27; cone-rod dystrophy [CRD], N ¼ 1; and macular dystrophy, N ¼ 2). In vitro minigene splice assay was performed to determine the effect on EYS pre-mRNA splicing of the c.1299þ5_1299þ8del variant in macular dystrophy patients. RESULTS. We found 27 different EYS variants in RP patients and 7 were novel. The rate of visual field loss of the V4e isopter area was 0.84 6 0.44 ln(deg2 ) per year, and the rate of visual acuity loss was 0.75 Early Treatment Diabetic Retinopathy Study letters per year. Ellipsoid zone width was correlated with area of the hyperautofluorescent ring, with rs ¼ 0.78 and P < 0.001. Rate of decline in ellipsoid zone width was 57 6 17 lm per year (P < 0.01) (n ¼ 14) or 3.69% 6 0.51% from baseline per year (P < 0.001). An isolated CRD patient carried a homozygous EYS variant (c.9405T>A), previously identified in RP patients. Two siblings with macular dystrophy carried compound heterozygous EYS variants: c.1299þ5_1299þ8del and c.6050G>T. The former was novel and shown to result in skipping of exon 8, and the latter was a known RP variant. CONCLUSIONS. We report on EYS-associated macular dystrophy, extending the spectrum of EYSassociated IRDs. We observed heterogeneity between RP patients in age of onset and disease progression. Identical EYS variants were found in cases with RP, CRD, and macular dystrophy. Screening for EYS variants in CRD and macular dystrophy patients might increase the diagnostic yield in previously unsolved cases.

Importance: Primary open-angle glaucoma presents with increased prevalence and a higher degree of clinical severity in populations of African ancestry compared with European or Asian ancestry. Despite this, individuals of African ancestry remain understudied in genomic research for blinding disorders.Objectives: To perform a genome-wide association study (GWAS) of African ancestry populations and evaluate potential mechanisms of pathogenesis for loci associated with primary open-angle glaucoma.Design, Settings, and Participants: A 2-stage GWAS with a discovery data set of 2320 individuals with primary open-angle glaucoma and 2121 control individuals without primary open-angle glaucoma. The validation stage included an additional 6937 affected individuals and 14 917 unaffected individuals using multicenter clinic- and population-based participant recruitment approaches. Study participants were recruited from Ghana, Nigeria, South Africa, the United States, Tanzania, Britain, Cameroon, Saudi Arabia, Brazil, the Democratic Republic of the Congo, Morocco, Peru, and Mali from 2003 to 2018. Individuals with primary open-angle glaucoma had open iridocorneal angles and displayed glaucomatous optic neuropathy with visual field defects. Elevated intraocular pressure was not included in the case definition. Control individuals had no elevated intraocular pressure and no signs of glaucoma.Exposures: Genetic variants associated with primary open-angle glaucoma.Main Outcomes and Measures: Presence of primary open-angle glaucoma. Genome-wide significance was defined as P < 5 × 10−8 in the discovery stage and in the meta-analysis of combined discovery and validation data.Results: A total of 2320 individuals with primary open-angle glaucoma (mean [interquartile range] age, 64.6 [56-74] years; 1055 [45.5%] women) and 2121 individuals without primary open-angle glaucoma (mean [interquartile range] age, 63.4 [55-71] years; 1025 [48.3%] women) were included in the discovery GWAS. The GWAS discovery meta-analysis demonstrated association of variants at amyloid-β A4 precursor protein-binding family B member 2 (APBB2; chromosome 4, rs59892895T>C) with primary open-angle glaucoma (odds ratio [OR], 1.32 [95% CI, 1.20-1.46]; P = 2 × 10−8). The association was validated in an analysis of an additional 6937 affected individuals and 14 917 unaffected individuals (OR, 1.15 [95% CI, 1.09-1.21]; P < .001). Each copy of the rs59892895*C risk allele was associated with increased risk of primary open-angle glaucoma when all data were included in a meta-analysis (OR, 1.19 [95% CI, 1.14-1.25]; P = 4 × 10−13). The rs59892895*C risk allele was present at appreciable frequency only in African ancestry populations. In contrast, the rs59892895*C risk allele had a frequency of less than 0.1% in individuals of European or Asian ancestry.Conclusions and Relevance: In this genome-wide association study, variants at the APBB2 locus demonstrated differential association with primary open-angle glaucoma by ancestry. If validated in additional populations this finding may have implications for risk assessment and therapeutic strategies.

Objective Reticular pseudodrusen (RPD), a key feature of age-related macular degeneration (AMD), are poorly detected by human experts on standard color fundus photography (CFP) and typically require advanced imaging modalities such as fundus autofluorescence (FAF). The objective was to develop and evaluate the performance of a novel multimodal, multitask, multiattention (M3) deep learning framework on RPD detection. Materials and Methods A deep learning framework (M3) was developed to detect RPD presence accurately using CFP alone, FAF alone, or both, employing >8000 CFP-FAF image pairs obtained prospectively (Age-Related Eye Disease Study 2). The M3 framework includes multimodal (detection from single or multiple image modalities), multitask (training different tasks simultaneously to improve generalizability), and multiattention (improving ensembled feature representation) operation. Performance on RPD detection was compared with state-of-the-art deep learning models and 13 ophthalmologists; performance on detection of 2 other AMD features (geographic atrophy and pigmentary abnormalities) was also evaluated. Results For RPD detection, M3 achieved an area under the receiver-operating characteristic curve (AUROC) of 0.832, 0.931, and 0.933 for CFP alone, FAF alone, and both, respectively. M3 performance on CFP was very substantially superior to human retinal specialists (median F1 score = 0.644 vs 0.350). External validation (the Rotterdam Study) demonstrated high accuracy on CFP alone (AUROC, 0.965). The M3 framework also accurately detected geographic atrophy and pigmentary abnormalities (AUROC, 0.909 and 0.912, respectively), demonstrating its generalizability. Conclusions This study demonstrates the successful development, robust evaluation, and external validation of a novel deep learning framework that enables accessible, accurate, and automated AMD diagnosis and prognosis.

Importance: Treatments for geographic atrophy (GA), a late stage of age-related macular degeneration (AMD), are currently under development. Understanding the natural course is needed for optimal trial design. Although enlargement rates of GA and visual acuity (VA) in the short term are known from clinical studies, knowledge of enlargement in the long term, life expectancy, and visual course is lacking. Objective: To determine long-term enlargement of GA. Design, Setting, and Participants: In this study, participant data were collected from 4 population-based cohort studies, with up to 25 years of follow-up and eye examinations at 5-year intervals: the Rotterdam Study cohorts 1, 2, and 3 and the Blue Mountains Eye Study. Data were collected from 1990 to 2015, and data were analyzed from January 2019 to November 2020. Main Outcomes and Measures: Area of GA was measured pixel by pixel using all available imaging. Area enlargement and enlargement of the square root-transformed area, time until GA reached the central fovea, and time until death were assessed, and best-corrected VA, smoking status, macular lesions according to the Three Continent AMD Consortium classification, a modified version of the Wisconsin age-related maculopathy grading system, and AMD genetic variants were covariates in Spearman, Pearson, or Mann-Whitney analyses. Results: Of 171 included patients, 106 (62.0%) were female, and the mean (SD) age at inclusion was 82.6 (7.1) years. A total of 147 of 242 eyes with GA (60.7%) were newly diagnosed in our study. The mean area of GA at first presentation was 3.74 mm2(95% CI, 3.11-4.67). Enlargement rate varied widely between persons (0.02 to 4.05 mm2per year), with a mean of 1.09 mm2per year (95% CI, 0.89-1.30). Stage of AMD in the other eye was correlated with GA enlargement (Spearman ρ = 0.34; P =.01). Foveal involvement was already present in incident GA in 55 of 147 eyes (37.4%); 23 of 42 eyes (55%) developed this after a mean (range) period of 5.6 (3-12) years, and foveal involvement did not develop before death in 11 of 42 eyes (26%). After first diagnosis, 121 of 171 patients with GA (70.8%) died after a mean (SD) period of 6.4 (5.4) years. Visual function was visually impaired (less than 20/63) in 47 of 107 patients (43.9%) at last visit before death. Conclusions and Relevance: In this study, enlargement of GA appeared to be highly variable in the general population. More than one-third of incident GA was foveal at first presentation; those with extrafoveal GA developed foveal GA after a mean of 5.6 years. Future intervention trials should focus on recruiting those patients who have a high chance of severe visual decline within their life expectancy..

Importance The incidence of rhegmatogenous retinal detachment (RRD) is partly determined by its risk factors, such as age, sex, cataract surgery, and myopia. Changes in the prevalence of these risk factors could change RRD incidence in the population. Objective To determine whether the incidence of RRD in the Netherlands has changed over recent years and whether this change is associated with an altered prevalence of RRD risk factors. Design, Setting, and Participants This cohort study included data from all 14 vitreoretinal clinics in the Netherlands, as well as a large Dutch population-based cohort study. All patients who underwent surgical repair for a primary RRD in the Netherlands from January 1 to December 31, 2009, and January 1 to December 31, 2016, were analyzed, in addition to all participants in the population-based Rotterdam Study who were examined during these years. Analysis began February 2018 and ended November 2019. Exposures RRD risk factors, including age, male sex, cataract extraction, and myopia. Main Outcomes and Measures Age-specific RRD incidence rate in the Dutch population, as well as change in RRD incidence and risk factor prevalence between 2009 and 2016. Results In 2016, 4447 persons (median [range] age, 61 [3-96] years) underwent surgery for a primary RRD within the Netherlands, resulting in an RRD incidence rate of 26.2 per 100 000 person-years (95% CI, 25.4-27.0). The overall RRD incidence rate had increased by 44% compared with similar data from 2009. The increase was observed in both phakic (1994 in 2009 to 2778 in 2016 [increase, 39%]) and pseudophakic eyes (1004 in 2009 to 1666 in 2016 [increase, 66%]), suggesting that cataract extraction could not solely account for the overall rise. Over the same period, the prevalence of mild, moderate, and severe myopia among persons aged 55 to 75 years had increased by 15.6% (881 of 4561 [19.3%] vs 826 of 3698 [22.3%]), 20.3% (440 of 4561 [9.6%] vs 429 of 3698 [11.6%]), and 26.9% (104 of 4561 [2.3%] vs 107 of 3698 [2.9%]), respectively, within the population-based Rotterdam Study. Conclusions and Relevance In this study, an increase was observed in primary RRD incidence in the Netherlands over a 7-year period, which could not be explained by a different age distribution or cataract surgical rate. A simultaneous myopic shift in the Dutch population may be associated, warranting further population-based studies on RRD incidence and myopia prevalence. This cohort study assesses whether the incidence of rhegmatogenous retinal detachment has changed over recent years and whether this change is associated with an altered prevalence of rhegmatogenous retinal detachment risk factors in the Netherlands. Question What is the incidence of primary rhegmatogenous retinal detachment (RRD) in the Netherlands and has it changed over recent years? Findings In this cohort study, 4447 individuals in the Netherlands underwent surgery for RRD in 2016, resulting in an incidence of 26.2 per 100 000 inhabitants, an increase of 44% compared with similar data from 2009. Over the same period, an increase in myopia prevalence in a Dutch population-based cohort study was observed. Meaning In the Netherlands, an increase in RRD incidence may be associated with a simultaneous myopic shift in the population.

PURPOSE: To investigate the natural history of RHO-associated retinitis pigmentosa (RP). METHODS: A multicenter, medical chart review of 100 patients with autosomal dominant RHO-associated RP. RESULTS: Based on visual fields, time-to-event analysis revealed median ages of 52 and 79 years to reach low vision (central visual field

Contains fulltext : 235455.pdf (Publisher’s version ) (Open Access) PURPOSE: To determine the long-term longitudinal axial length changes in myopic and hyperopic adults with an iris-fixated phakic intraocular lens (pIOL). METHODS: The medical records of patients aged ≥18 years with myopia or hyperopia who were treated with pIOL implantation between 1996 and 2011 for refractive correction with a minimum follow-up of 5 years after pIOL implantation were analyzed. The main outcome measure was change in ocular axial length over time. RESULTS: 149 eyes of 149 myopic patients and 27 hyperopic eyes of 27 patients were included in this study. Mean patient age was 37.1 ± 10.4 years (35% male) in the myopic group and 39.4 ± 9.4 years (4% male) in the hyperopic group. The eyes of the myopic patients showed a significant mean increase in axial length of 0.45 ± 0.61 mm after a mean follow-up time of 144 ± 38 months (p

Deep learning is rarely used in population genomics because of the computational burden and challenges in interpreting neural networks. Here, we propose GenNet, a novel open-source deep learning framework for predicting phenotypes from genetic variants. In this framework, interpretable and memory-efficient neural network architectures are constructed by embedding biological knowledge from public databases, resulting in neural networks that contain only biological plausible connections.We applied the framework to seventeen phenotypes from a case-control study, a population-based study and the UK Biobank. Interpreting the networks revealed well-replicated genes such as HERC2 and OCA2 for hair and eye color and novel genes such as ZNF773 and PCNT for schizophrenia. Additionally, the framework obtained an AUC of 0.74 in the held-out test set and identified ubiquitin mediated proteolysis, endocrine system and viral infectious diseases as most predictive biological pathways for schizophrenia.GenNet is a freely available, end-to-end deep learning framework that allows researchers to develop and use interpretable neural networks to obtain novel insights into the genetic architecture of complex traits and diseases.

Purpose: To test the hypothesis that emmetropization buffers against genetic and environmental risk factors for myopia by investigating whether risk factor effect sizes vary depending on children's position in the refractive error distribution.Methods: Refractive error was assessed in participants from two birth cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC) (noncycloplegic autorefraction) and Generation R (cycloplegic autorefraction). A genetic risk score for myopia was calculated from genotypes at 146 loci. Time spent reading, time outdoors, and parental myopia were ascertained from parent-completed questionnaires. Risk factors were coded as binary variables (0 = low, 1 = high risk). Associations between refractive error and each risk factor were estimated using either ordinary least squares (OLS) regression or quantile regression.Results: Quantile regression: effects associated with all risk factors (genetic risk, parental myopia, high time spent reading, low time outdoors) were larger for children in the extremes of the refractive error distribution than for emmetropes and low ametropes in the center of the distribution. For example, the effect associated with having a myopic parent for children in quantile 0.05 vs. 0.50 was as follows: ALSPAC: age 15, -1.19 D (95% CI -1.75 to -0.63) vs. -0.13 D (-0.19 to -0.06), P = 0.001; Generation R: age 9, -1.31 D (-1.80 to -0.82) vs. -0.19 D (-0.26 to -0.11), P < 0.001. Effect sizes for OLS regression were intermediate to those for quantiles 0.05 and 0.50.Conclusions: Risk factors for myopia were associated with much larger effects in children in the extremes of the refractive error distribution, providing indirect evidence that emmetropization buffers against both genetic and environmental risk factors.

Learning Objectives Upon completion of this activity, participants will be able to:Distinguish the most salient pathological feature of high myopia.Evaluate the long-term tolerability of atropine eye drops for myopia.Analyze the long-term efficacy of atropine eye drops for myopia.Assess variables that might alter the efficacy of atropine eye drops for myopia. Continuing Medical Education In support of improving patient care, this activity has been planned and implemented by Medscape, LLC and Springer Nature. Medscape, LLC is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team. Medscape, LLC designates this Journal-based CME activity for a maximum of 1.00 AMA PRA Category 1 Credit(s). Physicians should claim only the credit commensurate with the extent of their participation in the activity. All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 75% minimum passing score and complete the evaluation at www.medscape.org/journal/eye; (4) view/print certificate. Credit hours 1.0 Release date: Expiration date: 21 September 2021 Post-test link: https://medscape.org/eye/posttest934752 Authors/Editors disclosure information Sobha Sivaprasad, MD, has disclosed the following relevant financial relationships: served as an advisor or consultant for: Allergan, Inc.; Apellis; Bayer AG; Boehringer Ingelheim Pharmaceuticals, Inc.; Heidelberg Pharma GmbH; Novartis; Oculis; Optos; Oxurion; Roche. Served as a speaker or a member of a speakers bureau for: Allergan, Inc.; Bayer AG; Novartis Pharmaceuticals Corporation; Optos. Received grants for clinical research from: Allergan, Inc.; Bayer AG; Boehringer Ingelheim Pharmaceuticals, Inc.; Novartis Pharmaceuticals Corporation; Optos. Jan Roelof Polling, MD, has disclosed the following relevant financial relationships: served as an advisor or consultant for: Théa Laboratories; Nevakar, Inc. Emily Tan, MD, has disclosed no relevant financial relationships. Sjoerd Driessen, MD, has disclosed no relevant financial relationships. Sjoukje E. Loudon, MD, has disclosed no relevant financial relationships. Hoi-Lam Wong, MD, has disclosed no relevant financial relationships. Astrid van der Schans, MD, PhD, has disclosed no relevant financial relationships. J. Willem Tideman, MD, has disclosed no relevant financial relationships. Caroline C. W. Klaver, MD, PhD, has disclosed the following relevant financial relationships: served as an advisor or consultant for: Bayer AG; Nevakar, Inc.; Novartis Pharmaceuticals Corporation; Théa Laboratories. Journal CME author disclosure information Charles P. Vega, MD, has disclosed the following relevant financial relationships: served as an advisor or consultant for: GlaxoSmithKline; Johnson & Johnson Pharmaceutical Research & Development, L.L.C. Served as a speaker or a member of a speakers bureau for: Genentech, Inc.; GlaxoSmithKline., Background Atropine is the most powerful treatment for progressive myopia in childhood. This study explores the 3-year effectiveness of atropine in a clinical setting. Methods In this prospective clinical effectiveness study, children with progressive myopia ≥ 1D/year or myopia ≤ −2.5D were prescribed atropine 0.5%. Examination, including cycloplegic refraction and axial length (AL), was performed at baseline, and follow-up. Outcome measures were spherical equivalent (SER) and AL; annual progression of SER on treatment was compared with that prior to treatment. Adjustments to the dose were made after 1 year in case of low (AL ≥ 0.3 mm/year) or high response (AL

Contains fulltext : 220949.pdf (Publisher’s version ) (Open Access) The Rotterdam Study is an ongoing prospective cohort study that started in 1990 in the city of Rotterdam, The Netherlands. The study aims to unravel etiology, preclinical course, natural history and potential targets for intervention for chronic diseases in mid-life and late-life. The study focuses on cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric, dermatological, otolaryngological, locomotor, and respiratory diseases. As of 2008, 14,926 subjects aged 45 years or over comprise the Rotterdam Study cohort. Since 2016, the cohort is being expanded by persons aged 40 years and over. The findings of the Rotterdam Study have been presented in over 1700 research articles and reports. This article provides an update on the rationale and design of the study. It also presents a summary of the major findings from the preceding 3 years and outlines developments for the coming period.

Contains fulltext : 225467.pdf (Publisher’s version ) (Closed access) PURPOSE: To study the disease course of RPE65-associated inherited retinal degenerations (IRDs) as a function of the genotype, define a critical age for blindness, and identify potential modifiers. METHODS: Forty-five patients with IRD from 33 families with biallelic RPE65 mutations, 28 stemming from a genetic isolate. We collected retrospective data from medical charts. Coexisting variants in 108 IRD-associated genes were identified with Molecular Inversion Probe analysis. RESULTS: Most patients were diagnosed within the first years of life. Daytime visual function ranged from near-normal to blindness in the first four decades and met WHO criteria for blindness for visual acuity and visual field in the fifth decade. p.(Thr368His) was the most common variant (54%). Intrafamilial variability and interfamilial variability in disease severity and progression were observed. Molecular Inversion Probe analysis confirmed all RPE65 variants and identified one additional variant in LRAT and one in EYS in two separate patients. CONCLUSION: All patients with RPE65-associated IRDs developed symptoms within the first year of life. Visual function in childhood and adolescence varied but deteriorated inevitably toward blindness after age 40. In this study, genotype was not predictive of clinical course. The variance in severity of disease could not be explained by double hits in other IRD genes.

Purpose: To develop and validate a deep learning model for automatic segmentation of geographic atrophy (GA) in color fundus images (CFIs) and its application to study growth rate of GA. Participants: 409 CFIs of 238 eyes with GA from the Rotterdam Study (RS) and the Blue Mountain Eye Study (BMES) for model development, and 5,379 CFIs of 625 eyes from the Age-Related Eye Disease Study (AREDS) for analysis of GA growth rate. Methods: A deep learning model based on an ensemble of encoder-decoder architectures was implemented and optimized for the segmentation of GA in CFIs. Four experienced graders delineated GA in CFIs from RS and BMES. These manual delineations were used to evaluate the segmentation model using 5-fold cross-validation. The model was further applied to CFIs from the AREDS to study the growth rate of GA. Linear regression analysis was used to study associations between structural biomarkers at baseline and GA growth rate. A general estimate of the progression of GA area over time was made by combining growth rates of all eyes with GA from the AREDS set. Results: The model obtained an average Dice coefficient of 0.72 $\pm$ 0.26 on the BMES and RS. An intraclass correlation coefficient of 0.83 was reached between the automatically estimated GA area and the graders' consensus measures. Eight automatically calculated structural biomarkers (area, filled area, convex area, convex solidity, eccentricity, roundness, foveal involvement and perimeter) were significantly associated with growth rate. Combining all growth rates indicated that GA area grows quadratically up to an area of around 12 mm$^{2}$, after which growth rate stabilizes or decreases. Conclusion: The presented deep learning model allowed for fully automatic and robust segmentation of GA in CFIs. These segmentations can be used to extract structural characteristics of GA that predict its growth rate., Comment: 22 pages, 3 tables, 4 figures, 1 supplemental figure

Contains fulltext : 219120.pdf (Publisher’s version ) (Open Access) Environmental factors are important in the development of myopia. There is still limited evidence as to whether computer use is a risk factor. The aim of this study is to investigate the association between computer use and myopia in the context of other near work activities. Within the birth cohort study Generation R, we studied 5074 children born in Rotterdam between 2002 and 2006. Refractive error and axial length was measured at ages 6 and 9. Information on computer use and outdoor exposure was obtained at age 3, 6 and 9 years using a questionnaire, and reading time and reading distance were assessed at age 9 years. Myopia prevalence (spherical equivalent 10 h/wk) and OR = 1.072; 95% CI = 1.048-1.097 respectively). The combined effect of near work (computer use, reading time and reading distance) showed an increased odds ratio for myopia at age 9 (OR = 1.072; 95% CI = 1.047-1.098), while outdoor exposure showed a decreased odds ratio (OR = 0.996; 95% CI = 0.994-0.999) and the interaction term was significant (P = 0.036). From our results, we can conclude that within our sample of children, increased computer use is associated with myopia development. The effect of combined near work was decreased by outdoor exposure. The risks of digital devices on myopia and the protection by outdoor exposure should become widely known. Public campaigns are warranted.

Contains fulltext : 225990.pdf (Publisher’s version ) (Open Access) PURPOSE: To compare frequently used classification systems for age-related macular degeneration (AMD) in their abilty to predict late AMD. METHODS: In total, 9066 participants from the population-based Rotterdam Study were followed up for progression of AMD during a study period up to 30 years. AMD lesions were graded on color fundus photographs after confirmation on other image modalities and grouped at baseline according to six classification systems. Late AMD was defined as geographic atrophy or choroidal neovascularization. Incidence rate (IR) and cumulative incidence (CuI) of late AMD were calculated, and Kaplan-Meier plots and area under the operating characteristics curves (AUCs) were constructed. RESULTS: A total of 186 persons developed incident late AMD during a mean follow-up time of 8.7 years. The AREDS simplified scale showed the highest IR for late AMD at 104 cases/1000 py for ages 75 years. The 3-Continent harmonization classification provided the most stable progression. Drusen area >10% ETDRS grid (hazard ratio 30.05, 95% confidence interval [CI] 19.25-46.91) was most prognostic of progression. The highest AUC of late AMD (0.8372, 95% CI: 0.8070-0.8673) was achieved when all AMD features present at baseline were included. CONCLUSIONS: Highest turnover rates from intermediate to late AMD were provided by the AREDS simplified scale and the Rotterdam classification. The 3-Continent harmonization classification showed the most stable progression. All features, especially drusen area, contribute to late AMD prediction. TRANSLATIONAL RELEVANCE: Findings will help stakeholders select appropriate classification systems for screening, deep learning algorithms, or trials.

Contains fulltext : 196646.pdf (Publisher’s version ) (Open Access) Retinitis pigmentosa (RP) encompasses a group of inherited retinal dystrophies characterized by the primary degeneration of rod and cone photoreceptors. RP is a leading cause of visual disability, with a worldwide prevalence of 1:4000. Although the majority of RP cases are non-syndromic, 20-30% of patients with RP also have an associated non-ocular condition. RP typically manifests with night blindness in adolescence, followed by concentric visual field loss, reflecting the principal dysfunction of rod photoreceptors; central vision loss occurs later in life due to cone dysfunction. Photoreceptor function measured with an electroretinogram is markedly reduced or even absent. Optical coherence tomography (OCT) and fundus autofluorescence (FAF) imaging show a progressive loss of outer retinal layers and altered lipofuscin distribution in a characteristic pattern. Over the past three decades, a vast number of disease-causing variants in more than 80 genes have been associated with non-syndromic RP. The wide heterogeneity of RP makes it challenging to describe the clinical findings and pathogenesis. In this review, we provide a comprehensive overview of the clinical characteristics of RP specific to genetically defined patient subsets. We supply a unique atlas with color fundus photographs of most RP subtypes, and we discuss the relevant considerations with respect to differential diagnoses. In addition, we discuss the genes involved in the pathogenesis of RP, as well as the retinal processes that are affected by pathogenic mutations in these genes. Finally, we review management strategies for patients with RP, including counseling, visual rehabilitation, and current and emerging therapeutic options.

Purpose To assess joint effects of genetic and modifiable factors on the 10-year progression of age-related macular degeneration (AMD). Design Individual and pooled data analyses of 2 population-based cohorts. Participants Blue Mountains Eye Study (BMES) and Rotterdam Study (RS) participants (n = 835). Methods Participants of the BMES and RS were followed up over 10 years or more. At baseline and follow-up visits, interviews using questionnaires and eye examinations with retinal photography were performed. Age-related macular degeneration was assessed by trained photographic graders and verified by retinal specialists. Genetic susceptibility to AMD meant carrying 2 or more risk alleles of the CFH or ARMS2 SNPs, or both (rs1061170 and rs10490924), relative to 0 or 1 risk allele. Discrete logistic regression models were used to investigate the joint associations of genetic susceptibility and either smoking, fish consumption, dietary intake of lutein–zeaxanthin, or combined environmental risk scores from the 3 modifiable factors with the risk of AMD progression. Odds ratios (ORs) with 95% confidence intervals (CIs) and synergy indexes are reported. Main Outcome Measure Ten-year progression of AMD, categorized as any (≥1 step) or 2-step (≥2 steps) progression on the Three Continent AMD Consortium 5-step severity scale. Results Older age, the presence of AMD genetic susceptibility, and baseline AMD status were associated strongly with AMD progression (P Conclusions Among persons with AMD genetic susceptibility and pre-existing early AMD lesions, presenting with high environmental risk scores from 3 modifiable factors (smoking, infrequent consumption of fish, low lutein–zeaxanthin intake) were associated with an increased risk of 2-step progression over 10 years.

PURPOSE. The purpose of this study was to investigate the phenotype and long-term clinical course of female carriers of RPGR mutations. METHODS. This was a retrospective cohort study of 125 heterozygous RPGR mutation carriers from 49 families. RESULTS. Eighty-three heterozygotes were from retinitis pigmentosa (RP) pedigrees, 37 were from cone-/cone-rod dystrophy (COD/CORD) pedigrees, and 5 heterozygotes were from pedigrees with mixed RP/CORD or unknown diagnosis. Mutations were located in exon 1-14 and in ORF15 in 42 of 125 (34%) and 83 of 125 (66%) subjects, respectively. The mean age at the first examination was 34.4 years (range, 2.1 to 86.0 years). The median follow-up time in heterozygotes with longitudinal data (n = 62) was 12.2 years (range, 1.1 to 52.2 years). Retinal pigmentary changes were present in 73 (58%) individuals. Visual symptoms were reported in 51 (40%) cases. Subjects with both symptoms and pigmentary fundus changes were older than the other heterozygotes (P = 0.01) and had thinner foveal outer retinas (P = 0.006). Complete expression of the RP or CORD phenotype was observed in 29 (23%) heterozygotes, although usually in milder forms than in affected male relatives. Best-corrected visual acuity (BCVA) was < 20/40 and < 20/400 in at least one eye in 45 of 116 (39%) and 11 of 116 (9%) heterozygotes, respectively. Myopia was observed in 74 of 101 (73%) subjects and was associated with lower BCVA (P = 0.006). Increasing age was associated with lower BCVA (P = 0.002) and decreasing visual field size (P = 0.012; I4e isopter). CONCLUSIONS. RPGR mutations lead to a phenotypic spectrum in female carriers, with myopia as a significantly aggravating factor. Complete disease expression is observed in some individuals, who may benefit from future (gene) therapeutic options.

Contains fulltext : 200463.pdf (Publisher’s version ) (Open Access) A potential mechanism by which smoking affects ischemic stroke is through wider venules, but this mediating role of wider venules has never been quantified. Here, we aimed to estimate to what extent the effect of smoking on ischemic stroke is possibly mediated by the venules via the recently developed four-way effect decomposition. This study was part of a population-based study including 9109 stroke-free persons participated in the study in 1990, 2004, or 2006 (mean age: 63.7 years; 58% women). Smoking behavior (smoking versus non-smoking) was identified by interview. Retinal venular calibers were measured semi-automatically on retinal photographs. Incident strokes were assessed until January 2016. A regression-based approach was used with venular calibers as mediator to decompose the total effect of smoking compared to non-smoking into four components: controlled direct effect (neither mediation nor interaction), pure indirect effect (mediation only), reference interaction effect (interaction only) and mediated interaction effect (both mediation and interaction). During a mean follow-up of 12.5 years, 665 persons suffered an ischemic stroke. Smoking increased the risk of developing ischemic stroke compared to non-smoking with an excess risk of 0.41 (95% confidence interval 0.10; 0.67). With retinal venules as a potential mediator, the excess relative risk could be decomposed into 77% controlled direct effect, 4% mediation only, 4% interaction only, and 15% mediated interaction. To conclude, in the pathophysiology of ischemic stroke, the effect of smoking on ischemic stroke may partly explained by changes in the venules, where there is both pure mediation and mediated interaction.

Contains fulltext : 193421.pdf (Publisher’s version ) (Open Access) PURPOSE: To generate percentile curves of axial length (AL) for European children, which can be used to estimate the risk of myopia in adulthood. METHODS: A total of 12 386 participants from the population-based studies Generation R (Dutch children measured at both 6 and 9 years of age; N = 6934), the Avon Longitudinal Study of Parents and Children (ALSPAC) (British children 15 years of age; N = 2495) and the Rotterdam Study III (RS-III) (Dutch adults 57 years of age; N = 2957) contributed to this study. Axial length (AL) and corneal curvature data were available for all participants; objective cycloplegic refractive error was available only for the Dutch participants. We calculated a percentile score for each Dutch child at 6 and 9 years of age. RESULTS: Mean (SD) AL was 22.36 (0.75) mm at 6 years, 23.10 (0.84) mm at 9 years, 23.41 (0.86) mm at 15 years and 23.67 (1.26) at adulthood. Axial length (AL) differences after the age of 15 occurred only in the upper 50%, with the highest difference within the 95th percentile and above. A total of 354 children showed accelerated axial growth and increased by more than 10 percentiles from age 6 to 9 years; 162 of these children (45.8%) were myopic at 9 years of age, compared to 4.8% (85/1781) for the children whose AL did not increase by more than 10 percentiles. CONCLUSION: This study provides normative values for AL that can be used to monitor eye growth in European children. These results can help clinicians detect excessive eye growth at an early age, thereby facilitating decision-making with respect to interventions for preventing and/or controlling myopia.

Contains fulltext : 200479.pdf (Publisher’s version ) (Open Access) There is an urgency to find new treatment strategies that could prevent or delay the onset or progression of AMD. Different classes of lipids and lipoproteins metabolism genes have been associated with AMD in a multiple ways, but despite the ever-increasing knowledge base, we still do not understand fully how circulating lipids or local lipid metabolism contribute to AMD. It is essential to clarify whether dietary lipids, systemic or local lipoprotein metabolismtrafficking of lipids in the retina should be targeted in the disease. In this article, we critically evaluate what has been reported in the literature and identify new directions needed to bring about a significant advance in our understanding of the role for lipids in AMD. This may help to develop potential new treatment strategies through targeting the lipid homeostasis.

Purpose: To describe the phenotypic spectrum of retinal disease caused by the c.2991+1655A>G mutation in CEP290 and to compare disease severity between homozygous and compound heterozygous patients. Methods: Medical records were reviewed for best-corrected visual acuity (BCVA), age of onset, fundoscopy descriptions. Foveal outer nuclear layer (ONL) and ellipsoid zone (EZ) presence was assessed using spectral-domain optical coherence tomography (SD-OCT). Differences between compound heterozygous and homozygous patients were analyzed based on visual performance and visual development. Results: A total of 66 patients were included. The majority of patients had either light perception or no light perception. In the remaining group of 14 patients, median BCVA was 20/195 Snellen (0.99 LogMAR; range 0.12-1.90) for the right eye, and 20/148 Snellen (0.87 LogMAR; range 0.22-1.90) for the left. Homozygous patients tended to be more likely to develop light perception compared to more severely affected compound heterozygous patients (P = 0.080) and are more likely to improve from no light perception to light perception (P = 0.022) before the age of 6 years. OCT data were available in 12 patients, 11 of whom had retained foveal ONL and EZ integrity up to 48 years (median 23 years) of age. Conclusions: Homozygous patients seem less severely affected compared to their compound-heterozygous peers. Improvement of visual function may occur in the early years of life, suggesting a time window for therapeutic intervention up to the approximate age of 17 years. This period may be extended by an intact foveal ONL and EZ on OCT.

Importance Advanced age-related macular degeneration (AMD) is a leading cause of blindness in Western countries. Causal, modifiable risk factors need to be identified to develop preventive measures for advanced AMD. Objective To assess whether smoking, alcohol consumption, blood pressure, body mass index, and glycemic traits are associated with increased risk of advanced AMD. Design, Setting, Participants This study used 2-sample mendelian randomization. Genetic instruments composed of variants associated with risk factors at genome-wide significance (P

Key Points Question What are the genotypic and phenotypic characteristics of patients with early-onset drusen maculopathy? Findings In this case-control study, patients with early-onset drusen maculopathy were frequently carriers of rare genetic variants in the complement factor H gene and were characterized by the presence of a large macular drusen area and lower genetic risk scores compared with patients with age-related macular degeneration. Meaning Sequencing of the complement factor H gene is important in considering future treatments targeting the complement system in patients with early-onset drusen maculopathy. Furthermore, the presence of a large macular drusen area supports the severe phenotype in these patients, who may be at high risk of developing geographic atrophy or choroidal neovascularization., This case-control study evaluates genotypic and phenotypic characteristics of patients with early-onset drusen maculopathy., Importance Early-onset drusen maculopathy (EODM) is a severe disease and can lead to advanced macular degeneration early in life; however, genetic and phenotypic characteristics of individuals with EODM are not well studied. Objective To identify genotypic and phenotypic characteristics of individuals with EODM. Design, Setting, and Participants This case-control study collected data from the European Genetic Database from September 2004 to October 2019. A total of 89 patients with EODM diagnosed at 55 years or younger and 91 patients with age-related macular degeneration (AMD) diagnosed at 65 years or older were included. Exposures Coding regions of CFH, CFI, C3, C9, CFB, ABCA4, PRPH2, TIMP3, and CTNNA1 genes were sequenced, genetic risk scores (GRS) were calculated based on 52 AMD-associated variants, and phenotypic characteristics on color fundus photographs were analyzed comparing patients with EODM and AMD. Main Outcomes and Measures GRS, frequency of rare genetic complement variants, and phenotypic characteristics. Results This case-control study included 89 patients with EODM (mean [SD] age, 51.8 [8.7] years; 58 [65.2%] were female) and 91 patients with AMD (mean [SD] age, 77.6 [6.1] years; 45 [49.5%] female). At a mean (SD) age of 56.4 (7.3) years, 40 of 89 patients with EODM (44.9%) were affected by geographic atrophy or choroidal neovascularization. A lower GRS was observed in patients with EODM compared with patients with AMD (1.03 vs 1.60; P = .002), and 27 of 89 patients with EODM (30.3%) carried rare variants in the CFH gene compared with 7 of 91 patients with AMD (7.7%). Carriership of a rare CFH variant was associated with EODM (odds ratio, 7.2; 95% CI, 2.7-19.6; P

PURPOSE: It is unknown which retinal cells are involved in the retina-to-sclera signaling cascade causing myopia. As inherited retinal dystrophies (IRD) are characterized by dysfunction of a single retinal cell type and have a high risk of refractive errors, a study investigating the affected cell type, causal gene, and refractive error in IRDs may provide insight herein. DESIGN: Case-control study. METHODS: STUDY POPULATION: Total of 302 patients with IRD. from 2 ophthalmogenetic centers in the Netherlands. REFERENCE POPULATION: Population-based Rotterdam Study-III and Erasmus Rucphen Family Study (N = 5550). Distributions and mean spherical equivalent (SE) were calculated for main affected cell type and causal gene; and risks of myopia and hyperopia were evaluated using logistic regression. RESULTS: Bipolar cell-related dystrophies were associated with the highest risk of SE high myopia 239.7; odds ratio (OR) mild hyperopia 263.2, both P

Contains fulltext : 182318.pdf (Publisher’s version ) (Open Access) To determine the incidence of glaucomatous visual field loss (GVFL) two decades after the start of the Rotterdam Study, and to compare known risk factors for open-angle glaucoma (OAG) between different clinical manifestations of OAG. Of 6806 participants aged 55 years and older from the population-based Rotterdam Study, 3939 underwent visual field testing at baseline and at least one follow-up round. The ophthalmic examinations included optic disc assessment and measurements of intraocular pressure (IOP), refractive error, diastolic blood pressure (DBP), and height and weight. The incidence rate of GVFL was calculated. Associations with the risk factors age, gender, baseline IOP, family history, myopia, DBP, and body-mass index [BMI] were assessed using Cox regression, with different clinical manifestations of OAG as outcome measure (glaucomatous optic neuropathy (GON), GVFL, GVFL and GON, GVFL without GON, and GON without GVFL). Median follow-up was 11.1 (IQR 6.8-17.2; range 5.0-20.3) years. The incidence rate of GVFL was 2.9 (95% confidence interval 2.4-3.4) per 1000 person years (140 cases with incident GVFL in one (n = 113) or both (n = 27) eyes). Baseline IOP and age were significantly associated with all OAG outcomes (all p < 0.001); BMI showed a non-significant protective effect in all outcomes (p = 0.01 to p = 0.09). Gender, myopia, and DBP were not associated with any outcome. Our study provides an estimate of the long-term incidence of GVFL in a predominantly white population. The development of GVFL was strongly associated with baseline IOP and age. Risk factor profiles were similar for the different outcomes.

Purpose To describe the phenotype, long-term clinical course, clinical variability, and genotype of patients with CRB1 -associated retinal dystrophies. Design Retrospective cohort study. Participants Fifty-five patients with CRB1 -associated retinal dystrophies from 16 families. Methods A medical record review of 55 patients for age at onset, medical history, initial symptoms, best-corrected visual acuity, ophthalmoscopy, fundus photography, full-field electroretinography (ffERG), Goldmann visual fields (VFs), and spectral-domain optical coherence tomography. Main Outcome Measures Age at onset, visual acuity survival time, visual acuity decline rate, and electroretinography and imaging findings. Results A retinitis pigmentosa (RP) phenotype was present in 50 patients, 34 of whom were from a Dutch genetic isolate (GI), and 5 patients had a Leber congenital amaurosis phenotype. The mean follow-up time was 15.4 years (range, 0–55.5 years). For the RP patients, the median age at symptom onset was 4.0 years. In the RP group, median ages for reaching low vision, severe visual impairment, and blindness were 18, 32, and 44 years, respectively, with a visual acuity decline rate of 0.03 logarithm of the minimum angle of resolution per year. The presence of a truncating mutation did not alter the annual decline rate significantly ( P = 0.75). Asymmetry in visual acuity was found in 31% of patients. The annual VF decline rate was 5% in patients from the genetic isolate, which was significantly faster than in non-GI patients ( P Conclusions Mutations in the CRB1 gene are associated with a spectrum of progressive retinal degeneration. Visual acuity survival analyses indicate that the optimal intervention window for subretinal gene therapy is within the first 2 to 3 decades of life.

Item does not contain fulltext BACKGROUND: Parkinsonism is a common neurodegenerative syndrome in middle-aged and elderly persons. The etiology is multifactorial with a possible vascular contribution, but this has not been comprehensively studied. OBJECTIVE: To determine whether selected markers of subclinical vascular pathology are associated with the risk of all-cause parkinsonism in the general population. METHODS: We assessed a range of markers of subclinical vascular pathology (ankle-brachial index, carotid plaques and intima media thickness, retinal arteriolar and venular calibers) in 6199 persons from the population-based Rotterdam Study, who were free of parkinsonism and dementia at baseline. We followed these persons up till onset of parkinsonism, dementia, and death for 89,387 person-years until January 1, 2013. Hazard ratios (HRs) for all-cause parkinsonism and separately for Parkinson disease (PD) versus non-PD were estimated from competing risk regression models adjusting for potential confounders. RESULTS: During follow-up, we identified 211 cases of parkinsonism (110 had PD). None of the five markers of subclinical pathology was associated with all-cause parkinsonism. Only low ankle-brachial index was associated with a higher risk of non-PD parkinsonism (HR = 0.79, 95%CI: 0.68-0.92), but not with the risk of PD. CONCLUSION: We did not find a consistent pattern of associations between systemic vascular pathology markers with parkinsonism, suggesting that the potential involvement of vascular pathology is not prominent or needs further evaluation in studies with an even larger sample size.