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Abstract Background Myopia, commonly known as near-sightedness, has emerged as a global epidemic, impacting almost one in three individuals across the world. The increasing prevalence of myopia during early childhood has heightened the risk of developing high myopia and related sight-threatening eye conditions in adulthood. This surge in myopia rates, occurring within a relatively stable genetic framework, underscores the profound influence of environmental and lifestyle factors on this condition. In this comprehensive narrative review, we shed light on both established and potential environmental and lifestyle contributors that affect the development and progression of myopia. Main body Epidemiological and interventional research has consistently revealed a compelling connection between increased outdoor time and a decreased risk of myopia in children. This protective effect may primarily be attributed to exposure to the characteristics of natural light (i.e., sunlight) and the release of retinal dopamine. Conversely, irrespective of outdoor time, excessive engagement in near work can further worsen the onset of myopia. While the exact mechanisms behind this exacerbation are not fully comprehended, it appears to involve shifts in relative peripheral refraction, the overstimulation of accommodation, or a complex interplay of these factors, leading to issues like retinal image defocus, blur, and chromatic aberration. Other potential factors like the spatial frequency of the visual environment, circadian rhythm, sleep, nutrition, smoking, socio-economic status, and education have debatable independent influences on myopia development. Conclusion The environment exerts a significant influence on the development and progression of myopia. Improving the modifiable key environmental predictors like time spent outdoors and engagement in near work can prevent or slow the progression of myopia. The intricate connections between lifestyle and environmental factors often obscure research findings, making it challenging to disentangle their individual effects. This complexity underscores the necessity for prospective studies that employ objective assessments, such as quantifying light exposure and near work, among others. These studies are crucial for gaining a more comprehensive understanding of how various environmental factors can be modified to prevent or slow the progression of myopia.

Abstract Background Pubertal growth patterns correlate with future health outcomes. However, the genetic mechanisms mediating growth trajectories remain largely unknown. Here, we modeled longitudinal height growth with Super-Imposition by Translation And Rotation (SITAR) growth curve analysis on ~ 56,000 trans-ancestry samples with repeated height measurements from age 5 years to adulthood. We performed genetic analysis on six phenotypes representing the magnitude, timing, and intensity of the pubertal growth spurt. To investigate the lifelong impact of genetic variants associated with pubertal growth trajectories, we performed genetic correlation analyses and phenome-wide association studies in the Penn Medicine BioBank and the UK Biobank. Results Large-scale growth modeling enables an unprecedented view of adolescent growth across contemporary and 20th-century pediatric cohorts. We identify 26 genome-wide significant loci and leverage trans-ancestry data to perform fine-mapping. Our data reveals genetic relationships between pediatric height growth and health across the life course, with different growth trajectories correlated with different outcomes. For instance, a faster tempo of pubertal growth correlates with higher bone mineral density, HOMA-IR, fasting insulin, type 2 diabetes, and lung cancer, whereas being taller at early puberty, taller across puberty, and having quicker pubertal growth were associated with higher risk for atrial fibrillation. Conclusion We report novel genetic associations with the tempo of pubertal growth and find that genetic determinants of growth are correlated with reproductive, glycemic, respiratory, and cardiac traits in adulthood. These results aid in identifying specific growth trajectories impacting lifelong health and show that there may not be a single “optimal” pubertal growth pattern.

Abstract Our study aims to identify children at risk of developing high myopia for timely assessment and intervention, preventing myopia progression and complications in adulthood through the development of a deep learning system (DLS). Using a school-based cohort in Singapore comprising of 998 children (aged 6–12 years old), we train and perform primary validation of the DLS using 7456 baseline fundus images of 1878 eyes; with external validation using an independent test dataset of 821 baseline fundus images of 189 eyes together with clinical data (age, gender, race, parental myopia, and baseline spherical equivalent (SE)). We derive three distinct algorithms – image, clinical and mix (image + clinical) models to predict high myopia development (SE ≤ −6.00 diopter) during teenage years (5 years later, age 11–17). Model performance is evaluated using area under the receiver operating curve (AUC). Our image models (Primary dataset AUC 0.93–0.95; Test dataset 0.91–0.93), clinical models (Primary dataset AUC 0.90–0.97; Test dataset 0.93–0.94) and mixed (image + clinical) models (Primary dataset AUC 0.97; Test dataset 0.97–0.98) achieve clinically acceptable performance. The addition of 1 year SE progression variable has minimal impact on the DLS performance (clinical model AUC 0.98 versus 0.97 in primary dataset, 0.97 versus 0.94 in test dataset; mixed model AUC 0.99 versus 0.97 in primary dataset, 0.95 versus 0.98 in test dataset). Thus, our DLS allows prediction of the development of high myopia by teenage years amongst school-going children. This has potential utility as a clinical-decision support tool to identify “at-risk” children for early intervention.

A multi-ethnic meta-analysis of exome array data from over 27,000 participants identifies several rare variants that could contribute to risk of ocular refractive error.

Abstract Myopia (near-sightedness) is an important public health issue. Spending more time outdoors can prevent myopia but the long-term association between this exposure and myopia has not been well characterised. We investigated the relationship between time spent outdoors in childhood, adolescence and young adulthood and risk of myopia in young adulthood. The Kidskin Young Adult Myopia Study (KYAMS) was a follow-up of the Kidskin Study, a sun exposure-intervention study of 1776 children aged 6–12 years. Myopia status was assessed in 303 (17.6%) KYAMS participants (aged 25–30 years) and several subjective and objective measures of time spent outdoors were collected in childhood (8–12 years) and adulthood. Index measures of total, childhood and recent time spent outdoors were developed using confirmatory factor analysis. Logistic regression was used to assess the association between a 0.1-unit change in the time outdoor indices and risk of myopia after adjusting for sex, education, outdoor occupation, parental myopia, parental education, ancestry and Kidskin Study intervention group. Spending more time outdoors during childhood was associated with reduced risk of myopia in young adulthood (multivariable odds ratio [OR] 0.82, 95% confidence interval [CI] 0.69, 0.98). Spending more time outdoors in later adolescence and young adulthood was associated with reduced risk of late-onset myopia (≥ 15 years of age, multivariable OR 0.79, 95% CI 0.64, 0.98). Spending more time outdoors in both childhood and adolescence was associated with less myopia in young adulthood.

PurposeTo evaluate the associations of sleep factors with myopia, spherical equivalent (SE), and axial length (AL) in elementary school-aged children from the Growing Up in Singapore Towards healthy Outcomes (GUSTO) birth cohort.MethodsThis cross-sectional study included multi-ethnic children who participated in the GUSTO prospective birth cohort and were delivered in two major tertiary hospitals in Singapore (2009–2010). Sleep factors and myopia outcomes were assessed at the 8- and 9-year study visits, respectively. Parent-reported sleep quality was assessed with the Children's Sleep Habits Questionnaire (CSHQ) total scores. Additionally, each child's sleep duration, timing (bedtime; waketime), and the consistency of sleep duration or timing (i.e., the difference between weekends and weekdays) were parent-reported. Outcomes included cycloplegic SE, myopia (SE ≤ −0.5 D) and AL. Eye measurements from both eyes were included in the analyses. Multivariable linear or logistic regression with Generalized Estimating Equations were used to account for the correlation between paired eyes and confounders in the associations of sleep factors at age 8 and myopia at age 9.ResultsA total of 572 multi-ethnic children (49.5% boys; 56.1% Chinese) aged 9 years were included in the analyses. Overall, 37.3% of eyes were myopic. Children reported a mean total CSHQ score of 46 [standard deviation (SD) = 6]. The mean duration of sleep was 9.2 (SD = 1.0) hours per day (h/day), with 59.9% of children reporting sufficient sleep (≥9 h/day) based on guidelines recommended by the National Sleep Foundation, USA. The mean bedtime and wake time were 22:00 (SD = 00:53) and 07:08 (SD = 00:55), respectively. In multivariable regression models, total CSHQ scores, the duration of sleep, bedtime and wake time were not significantly associated with myopia, SE, or AL (p ≥ 0.05 for all), adjusting for gender, ethnicity, time outdoors, near-work, parental myopia, maternal education levels (and additionally the child's height when the outcome was AL). Similarly, the consistency of both the duration and timing of sleep (across weekends and weekdays) were not significantly associated with myopia, SE, or AL (p ≥ 0.05 for all).ConclusionIn this cross-sectional study, sleep quality, duration, timing, and the consistency of specific sleep factors were not independently associated with myopia, SE, or AL among elementary school-aged children in Singapore. Large longitudinal studies are warranted to corroborate these results.

Abstract Background Due to high prevalence myopia has gained importance in epidemiological studies. Children with early onset are at particular risk of complications associated with myopia, as progression over time might result in high myopia and myopic macular degeneration. Both genetic and environmental factors play a role in the increasing prevalence of myopia. The aim of this study is to review the current literature on epidemiology and risk factors for myopia in school children (aged 6–19 years) around the world. Main body PubMed and Medline were searched for the following keywords: prevalence, incidence, myopia, refractive error, risk factors, children and visual impairment. English language articles published between Jan 2013 and Mar 2019 were included in the study. Studies were critically reviewed for study methodology and robustness of data. Eighty studies were included in this literature review. Myopia prevalence remains higher in Asia (60%) compared with Europe (40%) using cycloplegic refraction examinations. Studies reporting on non-cycloplegic measurements show exceptionally high myopia prevalence rates in school children in East Asia (73%), and high rates in North America (42%). Low prevalence under 10% was described in African and South American children. In recent studies, risk factors for myopia in schoolchildren included low outdoor time and near work, dim light exposure, the use of LED lamps for homework, low sleeping hours, reading distance less than 25 cm and living in an urban environment. Conclusion Low levels of outdoor activity and near work are well-established risk factors for myopia; this review provides evidence on additional environmental risk factors. New epidemiological studies should be carried out on implementation of public health strategies to tackle and avoid myopia. As the myopia prevalence rates in non-cycloplegic studies are overestimated, we recommend considering only cycloplegic measurements.

Myopia is one of the leading causes of visual impairment globally. Despite increasing prevalence and incidence, the associated cost of treatment remains unclear. Health care spending is a major concern in many countries and understanding the cost of myopia correction is the first step eluding to the overall cost of myopia treatment. As cost of treatment will reduce the burden of cost of illness, this will aid in future cost-benefit analysis and the allocation of healthcare resources, including considerations in integrating eye care (refractive correction with spectacles) into universal health coverage (UHC). We performed a systematic review to determine the economic costs of myopia correction. However, there were few studies for direct comparison. Costs related to myopia correction were mainly direct with few indirect costs. Annual prevalence-based direct costs for myopia ranged from $14-26 (USA), $56 (Iran) and $199 (Singapore) per capita, respectively (population: 274.63 million, 75.15 million and 3.79 million, respectively). Annually, the direct costs of contact lens were $198.30-$378.10 while spectacles and refractive surgeries were $342.50 and $19.10, respectively. This review provides an insight to the cost of myopia correction. Myopia costs are high from nation-wide perspectives because of the high prevalence of myopia, with contact lenses being the more expensive option. Without further interventions, the burden of illness of myopia will increase substantially with the projected increase in prevalence worldwide. Future studies will be necessary to generate more homogenous cost data and provide a complete picture of the global economic cost of myopia.

Abstract Purpose A recent meta-analysis revealed PAX6 as a risk gene for myopia. There is a link between PAX6 and HOXA9. Furthermore, HOXA9 has been reported to activate TGF-β that is a risk factor for myopia. We speculate HOXA9 may participate in myopia development. Methods The Singapore GUSTO birth cohort provides data on children’s cycloplegic refraction measured at age of 3 years and their methylation profile based on the umbilical cord DNA. The HOXA9 expression levels were measured in the eyes of mono-ocular form deprivation myopia in mice. The plasmid with the mouse HOXA9 cDNA was constructed and then transfected to mouse primary retinal pigment epithelial (RPE) cells. The expression levels of myopia-related genes and cell proliferation were measured in the HOXA9-overexpressed RPE cells. Results A total of 519 children had data on methylation profile and cycloplegic refraction. The mean spherical equivalent refraction (SE) was 0.90D. Among 8 SE outliers (worse than -2D), 7 children had HOXA9 hypomethylation. The HOXA9 levels in the retina of myopic eyes was 2.65-fold (p = 0.029; paired t-test) higher than the uncovered fellow eyes. When HOXA9 was over-expressed in the RPE cells, TGF-β, MMP2, FGF2 and IGF1R expression levels were dose-dependently increased by HOXA9. However, over-expression of HOXA9 had no significant influence on IGF1 or HGF expression. In addition, HOXA9 also increased RPE proliferation. Conclusion Based on the human, animal and cellular data, the transcription factor HOXA9 may promote the expression of pro-myopia genes and RPE proliferation, which eventually contribute to myopia development.

Summary: Background: By 2050, almost 5 billion people globally are projected to have myopia, of whom 20% are likely to have high myopia with clinically significant risk of sight-threatening complications such as myopic macular degeneration. These are diagnoses that typically require specialist assessment or measurement with multiple unconnected pieces of equipment. Artificial intelligence (AI) approaches might be effective for risk stratification and to identify individuals at highest risk of visual loss. However, unresolved challenges for AI medical studies remain, including paucity of transparency, auditability, and traceability. Methods: In this retrospective multicohort study, we developed and tested retinal photograph-based deep learning algorithms for detection of myopic macular degeneration and high myopia, using a total of 226 686 retinal images. First we trained and internally validated the algorithms on datasets from Singapore, and then externally tested them on datasets from China, Taiwan, India, Russia, and the UK. We also compared the performance of the deep learning algorithms against six human experts in the grading of a randomly selected dataset of 400 images from the external datasets. As proof of concept, we used a blockchain-based AI platform to demonstrate the real-world application of secure data transfer, model transfer, and model testing across three sites in Singapore and China. Findings: The deep learning algorithms showed robust diagnostic performance with areas under the receiver operating characteristic curves [AUC] of 0·969 (95% CI 0·959–0·977) or higher for myopic macular degeneration and 0·913 (0·906–0·920) or higher for high myopia across the external testing datasets with available data. In the randomly selected dataset, the deep learning algorithms outperformed all six expert graders in detection of each condition (AUC of 0·978 [0·957–0·994] for myopic macular degeneration and 0·973 [0·941–0·995] for high myopia). We also successfully used blockchain technology for data transfer, model transfer, and model testing between sites and across two countries. Interpretation: Deep learning algorithms can be effective tools for risk stratification and screening of myopic macular degeneration and high myopia among the large global population with myopia. The blockchain platform developed here could potentially serve as a trusted platform for performance testing of future AI models in medicine. Funding: None.

Background: The risk of pathologic myopia (PM) increases with worsening myopia and may be related to retinal microvasculature alterations. To evaluate this, we analyzed the macular microvasculature of myopes with swept source-optical coherence tomographic angiography (SS-OCTA) in adolescent and young adult Singaporeans.Methods: This is a prevalent case-control study including 93 young Chinese from the Strabismus, Amblyopia and Refractive error in Singaporean children (STARS, N = 45) study and the Singapore Cohort Study of Risk Factors for Myopia (SCORM, N = 48) studies. Macular vessel density (VD) measurements were obtained from 3 × 3 mm SS-OCTA scans and independently assessed using ImageJ. These measurements were compared between individuals with non-high myopia [non-HM, N = 40; SE >-5.0 diopter (D)] and HM (SE ≤-5.0D, N = 53).Results: The mean macular VD was 40.9 ± 0.6% and 38.2 ± 0.5% in the non-HM and HM, groups, respectively (p = 0.01 adjusted for age and gender). Mean FAZ area in the superficial layer was 0.22 ± 0.02 mm2 in the HM group, which was smaller compared to non-HM group (0.32 ± 0.03 mm2, p = 0.04). Mean deep FAZ area was similar between the two groups (0.45 ± 0.03 mm2 and 0.48 ± 0.04 mm2 in the HM and non-HM groups, respectively, p = 0.70).Conclusions: VD was lower and superficial FAZ area was smaller, in adolescents and young adults with HM compared to non-HM. These findings require validation in prospective studies to assess their impact on the subsequent development of PM.

Abstract We investigated body mass index (BMI) trajectories in the first 2 years of life in 1170 children from an Asian mother-offspring cohort in Singapore, and examined their predictors and associations with childhood cardio-metabolic risk measures at 5 years. Latent class growth mixture modelling analyses were performed to identify distinct BMI z-score (BMIz) trajectories. Four trajectories were identified: 73.2%(n = 857) of the children showed a normal BMIz trajectory, 13.2%(n = 155) a stable low-BMIz trajectory, 8.6%(n = 100) a stable high-BMIz trajectory and 5.0%(n = 58) a rapid BMIz gain after 3 months trajectory. Predictors of the stable high-BMIz and rapid BMIz gain trajectories were pre-pregnancy BMI, gestational weight gain, Malay and Indian ethnicity, while predictors of stable low-BMIz trajectory were preterm delivery and Indian ethnicity. At 5 years, children with stable high-BMIz or rapid BMIz gain trajectories had increased waist-to-height ratios [B(95%CI) 0.02(0.01,0.03) and 0.03(0.02,0.04)], sum of skinfolds [0.42(0.19,0.65) and 0.70(0.36,1.03)SD units], fat-mass index [0.97(0.32,1.63)SD units] and risk of obesity [relative risk 3.22(1.73,6.05) and 2.56 (1.19,5.53)], but not higher blood pressure. BMIz trajectories were more predictive of adiposity at 5 years than was BMIz at 2 years. Our findings on BMIz trajectories in the first 2 years suggest important ethnic-specific differences and impacts on later metabolic outcomes.

Abstract Background The association between early weight gain and later allergic outcomes has not been well studied. We examined the relation between weight gain and the subsequent development of allergic outcomes in the first 36 months of life in a Singapore birth cohort. Methods In repeated visits in the first 15 months, we measured infant weight and administered questionnaires ascertaining allergic outcomes. At ages 18 and 36 months, we administered skin prick tests (SPTs) to inhalant and food allergens. Results At 18 months, 13.5% had a positive SPT, 3.5% had wheeze and a positive SPT, 3.9% had rhinitis and a positive SPT, and 6.1% had eczema and a positive SPT. Higher weight gain from 6 to 9 months, 9 to 12 months and 12 to 15 months were independently associated with a reduced risk of developing a positive SPT at 18 months (p-trend ≤0.03). At 36 months, 23.5% had a positive SPT, 11.9% had wheeze and a positive SPT, 12.2% rhinitis and a positive SPT, and 11.5% eczema and a positive SPT. Higher weight gain from 12 to 15 months was associated with a reduced risk of developing a positive SPT at 36 months (p-trend

[This corrects the article DOI: 10.1371/journal.pone.0220143.].

PurposeTo evaluate the roles of known myopia-associated genetic variants for development of myopic macular degeneration (MMD) in individuals with high myopia (HM), using case-control studies from the Consortium of Refractive Error and Myopia (CREAM).MethodsA candidate gene approach tested 50 myopia-associated loci for association with HM and MMD, using meta-analyses of case-control studies comprising subjects of European and Asian ancestry aged 30 to 80 years from 10 studies. Fifty loci with the strongest associations with myopia were chosen from a previous published GWAS study. Highly myopic (spherical equivalent [SE] ≤ -5.0 diopters [D]) cases with MMD (N = 348), and two sets of controls were enrolled: (1) the first set included 16,275 emmetropes (SE ≤ -0.5 D); and (2) second set included 898 highly myopic subjects (SE ≤ -5.0 D) without MMD. MMD was classified based on the International photographic classification for pathologic myopia (META-PM).ResultsIn the first analysis, comprising highly myopic cases with MMD (N = 348) versus emmetropic controls without MMD (N = 16,275), two SNPs were significantly associated with high myopia in adults with HM and MMD: (1) rs10824518 (P = 6.20E-07) in KCNMA1, which is highly expressed in human retinal and scleral tissues; and (2) rs524952 (P = 2.32E-16) near GJD2. In the second analysis, comprising highly myopic cases with MMD (N = 348) versus highly myopic controls without MMD (N = 898), none of the SNPs studied reached Bonferroni-corrected significance.ConclusionsOf the 50 myopia-associated loci, we did not find any variant specifically associated with MMD, but the KCNMA1 and GJD2 loci were significantly associated with HM in highly myopic subjects with MMD, compared to emmetropes.

Table of contents O1 Changes in peripheral refraction associated with decreased ocular axial growth rate in marmosets Alexandra Benavente-Perez, Ann Nour, Tobin Ansel, Kathleen Abarr, Luying Yan, Keisha Roden, David Troilo O2 PPARα activation suppresses myopia development by increasing scleral collagen synthesis--a new drug target to suppress myopia development Chanyi Lu, Miaozhen Pan, Min Zheng, Jia Qu, Xiangtian Zhou O3 Evidence and possibilities for local ocular growth regulating signal pathways Christine F Wildsoet O4 Myopia researches at Eye Hospital of Wenzhou Medical University Fan Lu, Xiangtian Zhou, Jie Chen, Jinhua Bao, Liang Hu, Qinmei Wang, Zibing Jin, Jia Qu O5 Color, temporal contrast and myopia Frances Rucker, Stephanie Britton, Stephan Hanowsky, Molly Spatcher O6 The impact of atropine usage on visual function and reading performance in myopic school children in Taiwan Hui-Ying Kuo, Ching-Hsiu Ke, I-Hsin Kuo, Chien-Chun Peng, Han-Yin Sun O7 Increased time outdoors prevents the onset of myopia: evidence from randomised clinical trials Ian G Morgan O8 Environmental risk factors and gene-environment interactions for myopia in the ALSPAC cohort Jeremy A. Guggenheim, Rupal L. Shah, Cathy Williams O9 Retinal metabolic profiling identifies declines in FP receptor-linked signaling as contributors to form-deprived myopic development in guinea pigs Jinglei Yang, Peter S. Reinach, Sen Zhang, Miaozhen Pan, Wenfeng Sun, Bo Liu, Xiangtian Zhou O10 The study of peripheral refraction in moderate and high myopes after one month of wearing orthokeratology lens Jun Jiang, Haoran Wu, Fan Lu O11 Axial length of school children around the earth’s equatorial area and factors affecting the axial length Kazuo Tsubota, Hiroko Ozawa, Hidemasa Torii, Shigemasa Takamizawa, Toshihide Kurihara, Kazuno Negishi O12 Processing of defocus in the chicken retina by retinal ganglion cells Klaus Graef, Daniel Rathbun, Frank Schaeffel O13 Blue SAD light protects against form deprivation myopia in chickens, by local signaling within the retina Ladan Ghodsi, William K. Stell O14 Contributions of ON and OFF pathways to emmetropization and form deprivation myopia in mice Machelle T. Pardue, Ranjay Chakraborty, Han na Park, Curran S. Sidhu, P. Michael Iuvone O15 Response of the human choroid to defocus Michael J Collins O16 What can RNA sequencing tell us about myopic sclera? Nethrajeith Srinvasalu, Sally A McFadden, Paul N Baird O17 Overview of dopamine, retinal function, and myopia P. Michael Iuvone O18 The eye as a "robust" optical system and myopia Pablo Artal O19 Effect of discontinuation of orthokeratology lens wear on axial elongation in children Pauline Cho, SW Cheung O20 Myopia prevention in Taiwan Pei-Chang Wu O21 Alternatives to ultraviolet light and riboflavin for in vivo crosslinking of scleral collagen Quan V. Hoang, Sally A. McFadden O22 Absence of intrinsically photosensitive retinal ganglion cells (ipRGC) alters normal refractive development in mice Ranjay Chakraborty, Duk C. Lee, Erica G. Landis, Michael A. Bergen, Curran Sidhu, Samer Hattar, P. Michael Iuvone, Richard A. Stone, Machelle T. Pardue O23 Scleral micro-RNAs in myopia development and their potential as therapeutic targets Ravi Metlapally O24 Effects of the long-wavelength filtered continuous spectrum on emmetropization in juvenile guinea pigs Ruiqin Li, Qinglin Xu, Hong Zhon, Chenglin Pan, Weizhon Lan, Xiaoning Li, Ling Chen, Zhikuan Yang O25 Ocular and environmental factors associated with eye growth in childhood Scott A. Read O26 Overview- prevention and prediction of myopia and pathologic myopia Seang-Mei Saw O27 New insights into the roles of retinal dopamine in form-deprivation myopia and refractive development in C57BL/6 mice Shi-Jun Weng, Xiao-Hua Wu, Kang-Wei Qian, Yun-Yun Li, Guo-Zhong Xu, Furong Huang, Xiangtian Zhou, Jia Qu, Xiong-Li Yang, Yong-Mei Zhong O28 The effects of the adenosine antagonist, 7-methylxanthine, on refractive development in rhesus monkeys Earl L Smith III, Baskar Arumugam, Li-Fang Hung, Lisa A. Ostrin, Klaus Trier, Monica Jong, Brien A. Holden O29 Application of SWATH™ based next generation proteomics (NGP) in studying eye growth: opportunities and challenges Thomas Chuen Lam, Bing Zuo, Samantha Shan, Sally A. McFadden, Dennis Yan-yin Tse, Jingfang Bian, King-Kit Li, Quan Liu, Chi-ho To O30 How could emmetropization make use of longitudinal chromatic aberration? Timothy J. Gawne, John T. Siegwart Jr., Alexander H. Ward, Thomas T. Norton O31 Balance effect of dopamine D1 and D2 receptor subtype activation on refraction development Xiangtian Zhou O32 BMP gene expression changes in chick rpe in response to visual manipulations Yan Zhang, Yue Liu, Carol Ho, Eileen Phan, Abraham Hang, Emily Eng, Christine Wildsoet

This report by the Consortium for Refractive Error and Myopia uses gene-environment-wide interaction study (GEWIS) to identify genetic loci that affect environmental influence in myopia development, and identifies ethnic specific genetic loci that attribute to eye refractive errors.

Lutein and zeaxanthin play important roles in visual functions, but their influence on early visual development is unclear. We related maternal lutein and zeaxanthin concentrations during pregnancy to offspring visual acuity (VA) in 471 mother−child pairs from the Growing Up in Singapore Towards healthy Outcomes (GUSTO) cohort. Maternal concentrations of plasma lutein and zeaxanthin were determined at delivery. We measured uncorrected distance of VA in 3-year old children using a LEA Symbols chart; readings were converted to the logarithm of Minimum Angle of Resolution (logMAR), with >0.3 logMAR indicating poor VA. Associations were examined using linear or Poisson regression adjusted for confounders. The median (inter-quartile range) of maternal lutein and zeaxanthin concentrations were 0.13 (0.09, 0.18) and 0.09 (0.07, 0.12) µmol/L, respectively. A total of 126 children had poor VA. The highest tertile of maternal zeaxanthin concentration was associated with 38% lower likelihood of poor VA in children (95% CI: 0.42, 0.93, p-Trends = 0.02). Higher maternal lutein concentrations were associated with a lower likelihood of poor VA in children (RR 0.60 (95% CI: 0.40, 0.88) for middle tertile; RR 0.78 (95% CI: 0.51, 1.19) for highest tertile (p-Quadratic = 0.02)). In conclusion, lutein and zeaxanthin status during pregnancy may influence offspring early visual development; but the results require confirmation with further studies, including more comprehensive measurements of macular functions.

This study investigated the relationships between pre- and early post-natal maternal depression and their changes with frontal electroencephalogram (EEG) activity and functional connectivity in 6- and 18-month olds, as well as externalizing and internalizing behaviors in 24-month olds (n = 258). Neither prenatal nor postnatal maternal depressive symptoms independently predicted neither the frontal EEG activity nor functional connectivity in 6- and 18-month infants. However, increasing maternal depressive symptoms from the prenatal to postnatal period predicted greater right frontal activity and relative right frontal asymmetry amongst 6-month infants but these finding were not observed amongst 18-month infants after adjusted for post-conceptual age on the EEG visit day. Subsequently increasing maternal depressive symptoms from the prenatal to postnatal period predicted lower right frontal connectivity within 18-month infants but not among 6-month infants after controlling for post-conceptual age on the EEG visit day. These findings were observed in the full sample and the female sample but not in the male sample. Moreover, both prenatal and early postnatal maternal depressive symptoms independently predicted children's externalizing and internalizing behaviors at 24 months of age. This suggests that the altered frontal functional connectivity in infants born to mothers whose depressive symptomatology increases in the early postnatal period compared to that during pregnancy may reflect a neural basis for the familial transmission of phenotypes associated with mood disorders, particularly in girls.

ObjectiveWe aimed to study the maternal retinal microvasculature at mid-trimester and its relationship with subsequent fetal growth and birth size.MethodsWe recruited 732 pregnant women aged 18-46 years in the first trimester with singleton pregnancies. All had retinal photography and fetal scan performed at 26-28 weeks gestation, and subsequent fetal scan at 32-34 weeks gestation. Infant anthropometric measurements were done at birth. Retinal microvasculature was measured using computer software from the retinal photographs.ResultsIn multiple linear regression models, each 10 μm narrowing in maternal retinal arteriolar caliber was associated with decreases of 1.36 mm in fetal head circumference at 32-34 weeks gestation, as well as decreases of 1.50 mm and 2.30 mm in infant head circumference and birth length at delivery, respectively. Each standard deviation decrease in maternal retinal arteriolar fractal dimension was associated with decreases of 1.55 mm in fetal head circumference at 32-34 weeks gestation, as well as decreases of 1.08 mm and 46.42 g in infant head circumference and birth weight at delivery, respectively.ConclusionsNarrower retinal arteriolar caliber and a sparser retinal vascular network in mothers, reflecting a suboptimal uteroplacental microvasculature during mid-pregnancy, were associated with poorer fetal growth and birth size.

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

Most studies linking maternal diet with offspring adiposity have focused on single nutrients or foods, but a dietary pattern approach is more representative of the overall diet. We thus aimed to investigate the relations between maternal dietary patterns and offspring adiposity in a multi-ethnic Asian mother–offspring cohort in Singapore. We derived maternal dietary patterns using maternal dietary intake information at 26–28 weeks of gestation, of which associations with offspring body mass index (BMI), abdominal circumference (AC), subscapular skinfold (SS), and triceps skinfold (TS) were assessed using longitudinal data analysis (linear mixed effects (LME)) and multiple linear regression at ages 0, 3, 6, 9, 12, 15, 18, 24, 36, 48, and 54 months. Three dietary patterns were derived: (1) vegetables-fruit-and-white rice (VFR); (2) seafood-and-noodles (SfN); and (3) pasta-cheese-and-bread (PCB). In the LME model adjusting for potential confounders, each standard deviation (SD) increase in maternal VFR pattern score was associated with 0.09 mm lower offspring TS. Individual time-point analysis additionally revealed that higher VFR score was generally associated with lower postnatal offspring BMI z-score, TS, SS, and sum of skinfolds (SS + TS) at ages 18 months and older. Maternal adherence to a dietary pattern characterized by higher intakes of fruit and vegetables and lower intakes of fast food was associated with lower offspring adiposity.

BackgroundOverweight and obesity are thought to significantly influence a person's risk of cardiovascular disease, possibly via its effect on the microvasculature. Retinal vascular caliber is a surrogate marker of microvascular disease and a predictor of cardiovascular events. The aim of this systematic review and meta-analysis was to determine the association between body mass index (BMI) and retinal vascular caliber.Methods and findingsRelevant studies were identified by searches of the MEDLINE and EMBASE databases from 1966 to August 2011. Standardized forms were used for data extraction. Among over 44,000 individuals, obese subjects had narrower arteriolar and wider venular calibers when compared with normal weight subjects, independent of conventional cardiovascular risk factors. In adults, a 1 kg/m(2) increase in BMI was associated with a difference of 0.07 μm [95% CI: -0.08; -0.06] in arteriolar caliber and 0.22 μm [95% CI: 0.21; 0.23] in venular caliber. Similar results were found for children.ConclusionsHigher BMI is associated with narrower retinal arteriolar and wider venular calibers. Further prospective studies are needed to examine whether a causative relationship between BMI and retinal microcirculation exists.

Pathological myopia is one of the leading causes of blindness worldwide. The condition is particularly prevalent in Asia. Unlike myopia, pathological myopia is accompanied by degenerative changes in the retina, which if left untreated can lead to irrecoverable vision loss. The accurate diagnosis of pathological myopia will enable timely intervention and facilitate better disease management to slow down the progression of the disease. Current methods of assessment typically consider only one type of data, such as that from retinal imaging. However, different kinds of data, including that of genetic, demographic and clinical information, may contain different and independent information, which can provide different perspectives on the visually observable, genetic or environmental mechanisms for the disease. The combination of these potentially complementary pieces of information can enhance the understanding of the disease, providing a holistic appreciation of the multiple risks factors as well as improving the detection outcomes. In this study, we propose a computer-aided diagnosis framework for Pathological Myopia diagnosis through Biomedical and Image Informatics(PM-BMII). Through the use of multiple kernel learning (MKL) methods, PM-BMII intelligently fuses heterogeneous biomedical information to improve the accuracy of disease diagnosis. Data from 2,258 subjects of a population-based study, in which demographic and clinical information, retinal fundus imaging data and genotyping data were collected, are used to evaluate the proposed framework. The experimental results show that PM-BMII achieves an AUC of 0.888, outperforming the detection results from the use of demographic and clinical information 0.607 (increase 46.3%, p

BACKGROUND:Mild retinopathy (microaneurysms or dot-blot hemorrhages) is observed in persons without diabetes or hypertension and may reflect microvascular disease in other organs. We conducted a genome-wide association study (GWAS) of mild retinopathy in persons without diabetes. METHODS:A working group agreed on phenotype harmonization, covariate selection and analytic plans for within-cohort GWAS. An inverse-variance weighted fixed effects meta-analysis was performed with GWAS results from six cohorts of 19,411 Caucasians. The primary analysis included individuals without diabetes and secondary analyses were stratified by hypertension status. We also singled out the results from single nucleotide polymorphisms (SNPs) previously shown to be associated with diabetes and hypertension, the two most common causes of retinopathy. RESULTS:No SNPs reached genome-wide significance in the primary analysis or the secondary analysis of participants with hypertension. SNP, rs12155400, in the histone deacetylase 9 gene (HDAC9) on chromosome 7, was associated with retinopathy in analysis of participants without hypertension, -1.3±0.23 (beta ± standard error), p = 6.6×10(-9). Evidence suggests this was a false positive finding. The minor allele frequency was low (∼2%), the quality of the imputation was moderate (r(2) ∼0.7), and no other common variants in the HDAC9 gene were associated with the outcome. SNPs found to be associated with diabetes and hypertension in other GWAS were not associated with retinopathy in persons without diabetes or in subgroups with or without hypertension. CONCLUSIONS:This GWAS of retinopathy in individuals without diabetes showed little evidence of genetic associations. Further studies are needed to identify genes associated with these signs in order to help unravel novel pathways and determinants of microvascular diseases.

Gestational Diabetes Mellitus (GDM) is associated with an increased risk of perinatal morbidity and long term health issues for both the mother and offspring. Previous research has demonstrated associations between maternal diet and GDM development, but evidence in Asian populations is limited. The objective of our study was to examine the cross-sectional relationship between maternal dietary patterns during pregnancy and the risk of GDM in a multi-ethnic Asian cohort. Maternal diet was ascertained using 24-h dietary recalls from participants in the Growing up in Singapore towards healthy outcomes (GUSTO) study—a prospective mother-offspring cohort, and GDM was diagnosed according to 1999 World Health Organisation guidelines. Dietary patterns were identified using factor analysis, and multivariate regression analyses performed to assess the association with GDM. Of 909 participants, 17.6% were diagnosed with GDM. Three dietary patterns were identified: a vegetable-fruit-rice-based-diet, a seafood-noodle-based-diet and a pasta-cheese-processed-meat-diet. After adjusting for confounding variables, the seafood-noodle-based-diet was associated with a lower likelihood of GDM (Odds Ratio (95% Confidence Interval)) = 0.74 (0.59, 0.93). The dietary pattern found to be associated with GDM in our study was substantially different to those reported previously in Western populations.

The optimal introduction of complementary foods provides infants with nutritionally balanced diets and establishes healthy eating habits. The documentation of infant feeding practices in multi-ethnic Asian populations is limited. In a Singapore cohort study (GUSTO), 842 mother-infant dyads were interviewed regarding their feeding practices when the infants were aged 9 and 12 months. In the first year, 20.5% of infants were given dietary supplements, while 5.7% took probiotics and 15.7% homeopathic preparations. At age 9 months, 45.8% of infants had seasonings added to their foods, increasing to 56.3% at 12 months. At age 12 months, 32.7% of infants were given blended food, although 92.3% had begun some form of self-feeding. Additionally, 87.4% of infants were fed milk via a bottle, while a third of them had food items added into their bottles. At both time points, more than a third of infants were provided sweetened drinks via the bottle. Infants of Indian ethnicity were more likely to be given dietary supplements, have oil and seasonings added to their foods and consumed sweetened drinks from the bottle (p < 0.001). These findings provide a better understanding of variations in infant feeding practices, so that healthcare professionals can offer more targeted and culturally-appropriate advice.

Impaired fetal development, reflected by low birth weight or prematurity, predicts an increased risk for psychopathology, especially attention deficit hyperactivity disorder (ADHD). Such effects cut across the normal range of birth weight and gestation. Despite the strength of existing epidemiological data, cognitive pathways that link fetal development to mental health are largely unknown. In this study we examined the relation of birth weight (>2500 g) and gestational age (37-41 weeks) within the normal range with specific executive functions in 195 Singaporean six-year-old boys of Chinese ethnicity. Birth weight adjusted for gestational age was used as indicator of fetal growth while gestational age was indicative of fetal maturity. Linear regression revealed that increased fetal growth within the normal range is associated with an improved ability to learn rules during the intra/extra-dimensional shift task and to retain visual information for short period of time during the delayed matching to sample task. Moreover, faster and consistent reaction times during the stop-signal task were observed among boys born at term, but with higher gestational age. Hence, even among boys born at term with normal birth weight, variations in fetal growth and maturity showed distinct effects on specific executive functions.

We studied a sample of 75 Chinese, 73 Malay, and 29 Indian healthy neonates taking part in a cohort study to examine potential differences in neonatal brain morphology and white matter microstructure as a function of ethnicity using both structural T2-weighted magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI). We first examined the differences in global size and morphology of the brain among the three groups. We then constructed the T2-weighted MRI and DTI atlases and employed voxel-based analysis to investigate ethnic differences in morphological shape of the brain from the T2-weighted MRI, and white matter microstructure measured by fractional anisotropy derived from DTI. Compared with Malay neonates, the brains of Indian neonates' tended to be more elongated in anterior and posterior axis relative to the superior-inferior axis of the brain even though the total brain volume was similar among the three groups. Although most anatomical regions of the brain were similar among Chinese, Malay, and Indian neonates, there were anatomical variations in the spinal-cerebellar and cortical-striatal-thalamic neural circuits among the three populations. The population-related brain regions highlighted in our study are key anatomical substrates associated with sensorimotor functions.

As one of the leading causes of visual impairment and blindness, myopia poses a significant public health burden in Asia. The primary determinant of myopia is an elongated ocular axial length (AL). Here we report a meta-analysis of three genome-wide association studies on AL conducted in 1,860 Chinese adults, 929 Chinese children, and 2,155 Malay adults. We identified a genetic locus on chromosome 1q41 harboring the zinc-finger 11B pseudogene ZC3H11B showing genome-wide significant association with AL variation (rs4373767, β = -0.16 mm per minor allele, P(meta) =2.69 × 10(-10)). The minor C allele of rs4373767 was also observed to significantly associate with decreased susceptibility to high myopia (per-allele odds ratio (OR) =0.75, 95% CI: 0.68-0.84, P(meta) =4.38 × 10(-7)) in 1,118 highly myopic cases and 5,433 controls. ZC3H11B and two neighboring genes SLC30A10 and LYPLAL1 were expressed in the human neural retina, retinal pigment epithelium, and sclera. In an experimental myopia mouse model, we observed significant alterations to gene and protein expression in the retina and sclera of the unilateral induced myopic eyes for the murine genes ZC3H11A, SLC30A10, and LYPLAL1. This supports the likely role of genetic variants at chromosome 1q41 in influencing AL variation and high myopia.

Corneal astigmatism refers to refractive abnormalities and irregularities in the curvature of the cornea, and this interferes with light being accurately focused at a single point in the eye. This ametropic condition is highly prevalent, influences visual acuity, and is a highly heritable trait. There is currently a paucity of research in the genetic etiology of corneal astigmatism. Here we report the results from five genome-wide association studies of corneal astigmatism across three Asian populations, with an initial discovery set of 4,254 Chinese and Malay individuals consisting of 2,249 cases and 2,005 controls. Replication was obtained from three surveys comprising of 2,139 Indians, an additional 929 Chinese children, and an independent 397 Chinese family trios. Variants in PDGFRA on chromosome 4q12 (lead SNP: rs7677751, allelic odds ratio = 1.26 (95% CI: 1.16-1.36), P(meta) = 7.87×10(-9)) were identified to be significantly associated with corneal astigmatism, exhibiting consistent effect sizes across all five cohorts. This highlights the potential role of variants in PDGFRA in the genetic etiology of corneal astigmatism across diverse Asian populations.

Aims To determine axial length (AL) elongation profiles in children aged 3-6 years in an Asian population. Methods Eligible subjects were recruited from the Growing Up in Singapore Towards Healthy Outcomes birth cohort. AL measurement was performed using IOLMaster (Carl Zeiss Meditec, Jena, Germany) at 3 and 6 years. Anthropometric measurements at birth, cycloplegic refraction at 3 and 6 years, questionnaires on the children's behavioural habits at 2 years and parental spherical equivalent refraction were performed. Multivariable linear regression model with generalised estimating equation was performed to determine factors associated with AL elongation. Results 273 eyes of 194 children were included. The mean AL increased from 21.72±0.59 mm at 3 years to 22.52±0.66 mm at 6 years (p<0.001). Myopic eyes at 6 years had greater AL elongation (1.02±0.34 mm) compared with emmetropic eyes (0.85±0.25 mm, p=0.008) and hyperopic eyes (0.74±0.16 mm, p<0.001). The 95th percentile limit of AL elongation was 1.59 mm in myopes, 1.34 mm in emmetropes and 1.00 mm in hyperopes. Greater birth weight (per 100 g, ß=0.010, p=0.02) was significantly associated with greater AL elongation from 3 to 6 years, while parental and other behavioural factors assessed at 2 years were not (all p=0.08). Conclusion In this preschool cohort, AL elongates at an average length of 0.80 mm from 3 to 6 years, with myopes demonstrating the greatest elongation. The differences in 95th percentile limits for AL elongation between myopes, emmetropes and hyperopes can be valuable information in identifying myopia development in preschool children. [ABSTRACT FROM AUTHOR]

Purpose To evaluate factors influencing stabilisation of myopia in the Singapore Cohort of Risk factors for Myopia. Methods We evaluated the longitudinal natural history of 424 myopic participants from 1999 to 2022. The outcome was the change in myopia from the adolescence follow-up visit (aged 12-19 years) to the adulthood follow-up visit (aged 26-33 years). Association of predictive factors, including baseline spherical error, gender, ethnicity, parental myopia, time outdoor, near work and age at adolescence, was examined with the dichotomous outcome of adult myopia progression (= -1.00 dioptres (D) over 10 years) using multiple logistic regression and progression in linear regression models. Results For the primary outcome, the mean rate of progression of the outcome was found to be -0.04±0.09 D per year from the adolescent to the adulthood follow-up visits. 82.3% (95% CI 78.3% to 85.8%) had myopia stabilisation, with progression of less than 1.00 D over 10 years while 61.3% (95% CI 56.5% to 66.0%) of the subjects had progression of less than 0.50 D. In logistic regression models, both male gender (p=0.035) and non-Chinese ethnicity (p=0.032) were more likely to achieve myopia stabilisation while in linear multivariate regression models, males had a significantly slower degree of myopia progression (p=0.021). Conclusion 5 in 6 Singaporean young adults had myopia stabilisation. Male gender is 2 times and non-Chinese ethnicities are 2.5 times more likely to achieve myopia stabilisation. However, a proportion of myopes continue to exhibit a clinically significant degree of progression in adulthood. [ABSTRACT FROM AUTHOR]

Purpose To investigate the predictive factors for myopic macular degeneration (MMD) and progression in adults with myopia. Methods We examined 828 Malay and Indian adults (1579 myopic eyes) with myopia (spherical equivalent (SE) ≤-0.5 dioptres) at baseline who participated in both baseline and 12-year follow-up visits of the Singapore Malay Eye Study and the Singapore Indian Eye Study. Eye examinations, including subjective refraction and axial length (AL) measurements, were performed. MMD was graded from fundus photographs following the Meta-Analysis for Pathologic Myopia classification. The predictive factors for MMD development and progression were assessed in adults without and with MMD at baseline, respectively as risk ratios (RR) using multivariable modified Poisson regression models. The receiver operating characteristic curve was used to visualise the performance of the predictive models for the development of MMD, with performance quantified by the area under the curve (AUC). Results The 12-year cumulative MMD incidence was 10.3% (95% CI 8.9% to 12.0%) among 1504 myopic eyes without MMD at baseline. Tessellated fundus was a major predictor of MMD (RR=2.50, p<0.001), among other factors including age, worse SE and longer AL (all p<0.001). The AUC for prediction of MMD development was found to be 0.78 (95% CI 0.76 to 0.80) for tessellated fundus and increased significantly to an AUC of 0.86 (95% CI 0.84 to 0.88) with the combination of tessellated fundus with age, race, gender and SE (p<0.001). Older age (p=0.02), worse SE (p<0.001) and longer AL (p<0.001) were found to be predictors of MMD progression. Conclusions In adults with myopia without MMD, tessellated fundus, age, SE and AL had good predictive value for incident MMD. In adults with MMD, 1 in 10 eyes experienced progression over the same period. Older age, more severe myopia and longer AL were independent risk factors for progression. [ABSTRACT FROM AUTHOR]