The Myopia Research Group at SERI, in conjunction with the SNEC and National University of Singapore, has been involved in various aspects of myopia research over the last 20 years. Our group’s research is focused on five sub-themes: genetics, animal experimental models, epidemiology and community-based interventions, treatments to retard myopia progression and visually-disabling pathologic myopia.
The aims of our group are to better understand the epidemiology, genetics, pathogenesis and public health implications of myopia and to develop and evaluate novel interventions to prevent or slow myopia progression in young children. We are also focused on formulating better management strategies for myopia-related complications in older adulthood. Our multi-disciplinary team will address key questions to tackle the epidemic of myopia.
The Epidemiology Studies
Several large population-based studies have helped determine the prevalence of myopia in children, including the School Cohort of Refraction Myopia cohort (SCORM), which followed children aged 7-9 years for a period of 10 years, and the Strabismus Amblyopia and Refractive Error Singaporean preschool children (STARS), a cross-sectional study of children aged six months to six years. Data is also available from several adult studies, including the Singapore Malay, Indian and Chinese eye studies (SiMES, SINDI, SCES) which provide information of myopic prevalence in Singaporeans aged above 40 years. Early life data is also available from the GUSTO birth cohort involving 1,200 children where their refractive status was measured when they were 3 and 6 years old.
GUSTO light / FitSight study
One of the most important modifiable environmental risk factors for myopia is the lack of outdoor time in children. However, the patterns and precise duration of outdoor light exposure to prevent myopia are still not fully understood yet. To understand this better, our team has developed a novel FitSight watch that aims to track and quantify light levels and outdoor time continuously. The watch will be used in the Growing Up In Singapore Towards Healthy Outcomes (GUSTO) study.
GUSTO is a large, multi-disciplinary cohort study which consists of the children of all pregnant women aged 18 years and above who attended the first trimester antenatal clinic at National University Hospital (NUH) and KK Hospital (KKH). The children have been followed up yearly since birth. Our involvement in the GUSTO Cohort study will look into determining new light exposure patterns, using our FitSight watch in 900 myopic and non-myopic children.
Myopia measurements of these children were taken at their 6th year visit, and at their 7th year visit. The FitSight watch, along with an activity diary to track outdoor time, was piloted by 500 children. A new and improved prototype of the FitSight watch will be developed and administered to 900 children during their 9th year visit. Eye examination to evaluate myopia will also be measured by cycloplegic autorefraction and axial length (AL). The prevention or delay of early-onset myopia in young children by increasing time outdoors will prevent the progression of myopia in childhood to High Myopia (HM) in adulthood.
Light illuminance levels experienced by child on a typical weekday and weekend day
The rate of high myopia is linked to the prevalence of myopia. Adults with high myopia (SE worse than -5.0 D) may have pathologic myopia (PM) complications that could result in visual impairment. The SEED High Myopia (SEED-HM) study aims to determine the 10-year changes in PM and its effects on visual function and health-related quality of life in adults with high myopia. The SEED older adult cohort comprises of 700 highly myopic adults from 4 Singapore studies: SP2, SiMES, SINDI, and SCES, while there are 120 from the SCORM young adult cohort. The adults will be recalled to the SERI clinic in 10 years and the fundus photographs/OCT will be graded for all PM lesions. Some of the tests performed include visual acuity (VA) for distance, biometry measurements, and fundus photographs.
We will also assess eye shape, choroidal thickness and choroidal vasculature using novel SS-OCT Angiogram imaging approaches and scleral rigidity with a novel adaption of B-scan ultrasound machine to compare high myopia with and without PM. The changing natural history of progression from high myopia to PM across age groups and generations in SEED and SCORM will provide valuable information on early and late predictors of PM.
Novel Wide-field OCT/SS-OCTFundus photographs based on the International Classification of Myopia Maculopathy in SEED-HM study
Category 3: Patchy atrophy
Category 4: Macula atrophy
Together, these studies provide us with great detail of the size of the myopic problem in Singapore, and an opportunity to study risk factors associated with myopia.
Myopia and Genetics
Genetic studies in myopia show a complex interaction of multiple genetic influences. Our work with the international Consortium for Refractive Errors and Myopia (CREAM) has uncovered several novel genetics variants by meta-analyzing genome-wide association studies (GWAS) from more than 30 population-based studies in Europe, Asia, the United States and Australia. The challenge now is to consolidate information to see if we can identify high risk children with genetic susceptibility for extreme myopia within the Singaporean Chinese population who will benefit from early interventions to slow down the progression of myopia.
The Biology of Myopia
Over the years, we have also studied the factors that influence myopia in our mouse and chick models. Our studies show that atropine reduces myopia progression in both pigmented and non-pigmented mice eyes. Atropine may also act on one or more muscarinic receptors to differentially regulate expression levels of specific receptors which in turn influence axial length and vitreous depth, the main morphological parameters associated with myopia.
Our muscarinic receptor knockout mouse study has provided in vivo evidence to support an important role for the M2/M3 muscarinic receptor in myopia development. The data indicates that the actions of the M2 receptor are mediated by changes in the expression of key extracellular matrix proteins, linking the functional role of M2 with scleral remodeling in myopia. The study also highlights the utility of the mouse as a model for myopia, particularly in conjunction with our new technologies that can measure ocular dimensions and optical properties with high precision. Further mouse studies are needed to pinpoint and validate the downstream targets of M2, as well as to investigate the role of the M3 receptor subtype in myopia development.
More recently, we have also shown that manipulation of the chromaticity of light can also influence myopia progression. Chicks raised in red/green environment become more myopic, while those in blue/green light became more hyperopic. We intend to see if similar chromatic manipulation could also slow myopic progression in children.
Interventional Studies: Slowing, Stopping and Reversing Myopia
Researchers at SERI/SNEC have been exploring ways of slowing or stopping myopia using optical (e.g. progressive add, bifocal and myopic defocus glasses) and pharmacological (e.g. pirenzepine and atropine) interventions. Of these, results from the Atropine Treatment of Myopia (ATOM) studies have been most promising. There are two major ATOM studies, ATOM1 and ATOM2, involving a total of 800 subjects and testing a variety of doses of atropine over a three to five year periods. These studies suggest that even a low dose of atropine (0.01%) could slow myopia progression by 60% with minimal to no side effects.
This has translated into clinical practice with many clinicians locally and worldwide now converting to lower doses. More work still needs to be done to better understand the exact pharmacological mechanism of the medication, and to determine the best possible treatment regime. Low-dose atropine, however, has been one of the more exciting new developments in myopia management for some time.
There are, however, other novel optical (e.g. peripheral defocus optics or corneal modifying contact lenses) and pharmacological treatments which need to be explored. The role of different treatment modalities (either on its own or in combination) is still unclear and much work still needs to be done on the subject.
We also know that environmental factors, such as a lack of outdoor activity, may influence myopia onset and progression. Reasons for this are uncertain, but it is believed that levels of light intensity, chromatics and frequency may be important. The FIT outdoor trial evaluated a weekend park outdoor programme. There was a significant increase in mean outdoor time during the intervention “weekend park programme” (14.75 hours/week) compared with the control (12.40 hours/week). Besides, a novel fitness tracker (FitSight) has been developed to record light levels and encourage children to increase time they spend outdoors.
The tracker has been evaluated in the FitSight study of 23 children, STARS study of 60 children and pilot GUSTO study of 285 children. The data of outdoor activity was collected using a one-week outdoor activity diary. Interestingly, children in Singapore go outdoors in episodes or spurts of about 20 minutes six to eight times per day. The top outdoor activities from the diaries were walking, playing at a park and running for younger children. For teenage children, the top outdoor activities were walking, running and ball games.
Myopia, HM rates and associated visual impairment have been reduced in the population of Singapore by increasing outdoor time for children and preventing or delaying early-onset of myopia. Steps have been made to undertake an exploratory randomised controlled study both locally and in conjunction with collaborators overseas. Combined outdoor preventive measures and myopia treatment control are expected to be beneficial with added additive efficacy.
The importance in this research is how it can be used clinically to prevent or slow myopia in childhood, minimise the subsequent impact on quality-of-life and quality-of-vision in adulthood (e.g. through optical and surgical correction) and to manage any myopia-related complications which may occur in mid to late adulthood.
The myopic epidemic in Singapore started in the 1980s, and individuals from that generation of Singaporeans, with a prevalence of high myopia of 20 to 30%, are now entering their 5th decade when myopic complications (such as retinal detachment, macula neovascularisation, schisis or atrophy, early cataracts and glaucoma) are likely to start manifesting.
Directions of Myopia Research
Our plans for the future include programmes encompassing five sub themes: genetics, animal experimental models, epidemiology and community-based interventions, treatments to retard myopia progression and visually-disabling pathologic myopia. These cover different aspects of myopia research. The epidemiological studies have already led to the modification of behavior in the community and changes in national policies.
1. ATOM StudyThe ATOM studies have led to changes in our clinical management of children with progressive myopia.
2. GUSTO light/FitSight studyOur GUSTO Fitsight study will determine new light exposure patterns using our invention the FitSight watch in myopic and non-myopic children. The light data from Fitsight watch will provide valuable information on the development of outdoor programs in different settings, such as school and communities. Our proposed outdoor physical activity programme will be integrated into schools and rolled out nationwide in conjunction with the Ministries of Education and Health (Health Promotion Board). Our prevention strategy in healthy children will prevent or delay the early onset of myopia and reduce HM in later adult life.
3. SEED-HM StudyOur SEED-HM study will determine the 10-year changes in PM and effects on visual function and health-related quality of life in adults with high myopia and PM. Our proposal offers a new means of characterising disease phenotypes in PM, detailed evaluations of the impact on quality of life and new knowledge on imaging biomarkers that will provide baseline data for the development of new clinical treatments.
Saw SM, Katz J, Schein OD, Chew SJ, Chan TK. Epidemiology of myopia.
Saw SM, Hong CY, Chia KS, Stone RA, Tan Dd. Nearwork and myopia in young children. Lancet. 2001; 357:390Chong YS, Liang Y, Gazzard G, Stone RA, Saw SM. Association between breastfeeding and likelihood of myopia in children. JAMA Journal of the American Medical Association. 2005; 293:3001-2.
Saw SM, Tong L, Chua WH, Koh D, Tan DTH, Katz J. Incidence and progression of myopia in Singapore school children. Invest Ophthalmol Vis Sci 2005;46:51-57.
Tan DT, Lam DS, Chua WH, Shu-Ping DF, Crockett RS; Asian Pirenzepine Study Group. One-year multicenter, double-masked, placebo-controlled, parallel safety and efficacy study of 2% pirenzepine ophthalmic gel in children with myopia. Ophthalmol 2005;112(1):84-91.
Luu CD, Lau AM, Koh AH, Tan D. Multifocal electroretinogram in children on atropine treatment for myopia. Br J Ophthalmol. 2005;89(2):151-3.
Chua WH, Balakrishnan V, Chan YH, Tong L, Ling Y, Quah BL, Tan D. Atropine for the treatment of childhood myopia. Ophthalmology. 2006;113(12):2285-91.
Tong L, Huang XL, Koh AL, Zhang X, Tan DT, Chua WH. Atropine for the treatment of childhood myopia. effect on myopia progression after cessation of atropine. Ophthalmol 2009;116(3):572-9.
Samarawickrama C, Mitchell P, Tong L, Gazzard G, Lim L, Wong TY, Saw SM. Myopia-related optic disc and retinal changes in adolescent children from Singapore. Ophthalmol. 2011;118:2050-7.
Morgan IG, Ohno-Matsui K, Saw SM. Myopia. Lancet. 2012; 379(9827):1739-48.
Fan Q, Zhou X, Khor CC, Cheng CY, Goh LK, Sim X, Tay WT, Li YJ, Ong RT, Suo C, Cornes B, Ikram MK, Chia KS, Seielstad M, Liu J, Vithana E, Young TL, Tai ES, Wong TY, Aung T, Teo YY, Saw SM. Genome-wide meta-analysis of five Asian cohorts identifies PDGFRA as a susceptibility locus for corneal astigmatism. PLoS Genet. 2011; 7(12):e1002402.
Low W, Dirani M, Gazzard G, Chan YH, Zhou HJ, Selvaraj P, Au Eong KG, Young TL, Mitchell P, Wong TY, Saw SM. Family history, near work, outdoor activity, and myopia in Singapore Chinese preschool children. Br J Ophthalmol. 2010;94(8):1012-6.
Lim W, Kwan JL, Goh LK, Beuerman RW, Barathi VA. Evaluation of gene expression profiles and pathways underlying postnatal development in mouse sclera. Mol Vis. 2012;18:1436-48.
Barathi VA, Weon SR, Tan QS, Lin KJ, Tong L, Beuerman RW. Transglutaminases(TGs) in ocular and periocular tissues: effect of muscarinic agents on TGs in scleral fibroblasts. PLoS One. 2011;6(4):e18326.
Barathi VA, Beuerman RW. Molecular mechanisms of muscarinic receptors in mousescleral fibroblasts: Prior to and after induction of experimental myopia with atropine treatment. Mol Vis. 2011;17:680-92.
Verkicharla PK, Ramamurthy D, Nguyen QD, Zhang X, Pu SH, Malhotra R, Ostbye T, Lamoureux EL, Saw SM. Development of the fitsight fitness tracker to increase time outdoors to prevent myopia. Translational vision science & technology. 2017;6:20
Prof Saw Seang Mei
Assoc Prof Audrey Chia
Key Team Members
Clin Prof Donald Tan
Prof Roger Beuerman
Prof Wong Tien Yin
Prof Cheng Ching-Yu
Dr Velachamy Amutha Barathi
Prof Terri Young
Adj Prof Khor Chiea Chuen
Dr Victor Koh
Dr Qiao Fan
Dr Saiko Matsumura
Dr Carla Lanca
Dr Suan Pu
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