Publications by authors named "David A Mackey"

382 Publications

Association of Monogenic and Polygenic Risk With the Prevalence of Open-Angle Glaucoma.

JAMA Ophthalmol 2021 Jul 15. Epub 2021 Jul 15.

Department of Ophthalmology, Flinders University, Bedford Park, Australia.

Importance: Early diagnosis of open-angle glaucoma can lead to vision-saving treatment, and genetic variation is an increasingly powerful indicator in disease risk stratification.

Objective: To compare polygenic and monogenic variants in risk of glaucoma.

Design, Setting, And Participants: Clinical and genetic data were obtained for 2507 individuals from the Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG) and 411 337 individuals in cross-sectional cohort studies including individuals of European ancestry in the UK Biobank. Recruitment to the UK Biobank occurred between 2006 and 2010, and data analysis occurred between September 2019 and August 2020.

Main Outcomes And Measures: Association of monogenic and polygenic variants with glaucoma risk.

Results: Individuals at high polygenic risk, defined as those in the top 5% of an unselected population, had a glaucoma risk (odds ratio [OR], 2.77; 95% CI, 2.58-2.98) comparable with the risk among individuals heterozygous for the MYOC p.Gln368Ter variant (OR 4.19; 95% CI, 3.25-5.31), which is the most common single-gene variant known to cause primary open-angle glaucoma. High polygenic risk was more than 6 times more common than MYOC p.Gln368Ter heterozygosity in ANZRAG (15.7% vs 2.6%) and more than 15 times more common in the general population (5.0% vs 0.32%). Within ANZRAG, high polygenic risk was associated with a mean (SD) age at glaucoma diagnosis that did not differ from the age at glaucoma diagnosis among individuals heterozygous for MYOC p.Gln368Ter (57.2 [14.2] vs 54.8 [13.6] years; P > .99).

Conclusions And Relevance: Monogenic and high polygenic risk were each associated with a more than 2.5-fold increased odds of developing glaucoma and an equivalent mean age at glaucoma diagnosis, with high polygenic risk more than 15 times more common in the general population.
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http://dx.doi.org/10.1001/jamaophthalmol.2021.2440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8283675PMC
July 2021

Clinical Evidence for the Importance of the Wild-Type Allele in the Phenotypic Expression of RP11.

Genes (Basel) 2021 Jun 14;12(6). Epub 2021 Jun 14.

Centre for Ophthalmology and Visual Science, The University of Western Australia, Perth, WA 6009, Australia.

-associated retinopathy (RP11) is a common form of autosomal dominant retinitis pigmentosa (adRP) that exhibits wide variation in phenotype ranging from non-penetrance to early-onset RP. Herein, we report inter-familial and intra-familial variation in the natural history of RP11 using multimodal imaging and microperimetry. Patients were recruited prospectively. The age of symptom onset, best-corrected visual acuity, microperimetry mean sensitivity (MS), residual ellipsoid zone span and hyperautofluorescent ring area were recorded. Genotyping was performed using targeted next-generation and Sanger sequencing and copy number variant analysis. mutations were found in 14 individuals from seven unrelated families. Four disease patterns were observed: (A) childhood onset with rapid progression ( = 4), (B) adult-onset with rapid progression ( = 4), (C) adult-onset with slow progression ( = 4) and (D) non-penetrance ( = 2). Four different patterns were observed in a family harbouring c.267del; patterns B, C and D were observed in a family with c.772_773delins16 and patterns A, B and C were observed in 3 unrelated individuals with large deletions. Our findings suggest that the RP11 phenotype may be related to the wild-type allele rather than the type of mutation. Further studies that correlate in vitro wild-type allele expression level with the disease patterns are required to investigate this association.
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http://dx.doi.org/10.3390/genes12060915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232116PMC
June 2021

Classifying ABCA4 mutation severity using age-dependent ultra-widefield fundus autofluorescence-derived total lesion size.

Retina 2021 Jun 4. Epub 2021 Jun 4.

Centre for Ophthalmology and Visual Science (incorporating Lions Eye Institute), The University of Western Australia, Australia Australian Inherited Retinal Disease Registry and DNA Bank, Department of Medical Technology and Physics, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia Department of Ophthalmology, Royal Perth Hospital, Perth, Western Australia, Australia Department of Ophthalmology, Perth Children's Hospital, Nedlands, Western Australia, Australia.

Purpose: To establish a mutation-specific age-dependent ultra-widefield fundus autofluorescence (UWF-FAF) trajectory in a large Stargardt disease (STGD1) cohort using total lesion size (TLS) and to develop a clinical method for variant classification.

Methods: A retrospective study of patients with biallelic ABCA4 mutations were evaluated with UWF-FAF. Boundaries of TLS, defined by stippled hyper/hypoautofluorescence, were outlined manually. Pathogenicity was assessed according to ACMG/AMP criteria and mutation severities were classified based on current literature. Age-dependent trajectories in TLS were examined in patients with nullizygous, mild and intermediate mutations. Mutations of uncertain severities were classified using a clinical criterion based on age of symptom onset and TLS.

Results: Eighty-one STGD1 patients (mean age=42±20; mean visual acuity=20/200) were recruited from 65 unrelated families. Patients with biallelic null/severe variants (n=6) demonstrated an increase in TLS during their second decade reaching a mean±SD of 796±29mm2 by age 40. Those harbouring mild mutations c.5882G>A or c.5603A>T had lesions confined to the posterior pole with a mean±SD TLS of 30±39mm2. Intermediate mutations c.6079C>T or c.[2588G>C;5603A>T] in trans with a null/severe mutation had a mean±SD TLS of 397±29mm2. Thirty-two mutations were predicted to cause severe (n=22), intermediate (n=6) and mild (n=5) impairment of ABCA4 function based on age of symptom onset and TLS.

Conclusion: Age-dependent TLS showed unique ABCA4 mutation-specific trajectories. Our novel clinical criterion using age of symptom onset and TLS to segregate ABCA4 mutations into three severity groups requires further molecular studies in order to confirm its validity.
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http://dx.doi.org/10.1097/IAE.0000000000003227DOI Listing
June 2021

Physical Activity and Cardiovascular Fitness During Childhood and Adolescence: Association With Retinal Nerve Fibre Layer Thickness in Young Adulthood.

J Glaucoma 2021 May 11. Epub 2021 May 11.

Centre for Ophthalmology and Visual Science (incorporating Lions Eye Institute) School of Human Sciences (Exercise and Sport Science), The University of Western Australia School of Allied Health, Curtin University, Perth, WA Garvan-Weizmann Centre for Cellular Genomics, Garvan Institute of Medical Research, Sydney, NSW School of Medicine, Menzies Research Institute Tasmania, University of Tasmania, Hobart, TAS Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, East Melbourne, Vic., Australia Department of Health, Human Performance and Recreation, University of Arkansas, Fayetteville, AR.

Precis: Higher physical working capacity (PWC) at age 17 was associated with thicker peripapillary retinal nerve fiber layer (pRNFL) at age 20, suggesting a mechanistic link between cardiovascular fitness and neuroretinal integrity.

Purpose: Physical activity and cardiovascular fitness has been linked with lower odds of developing glaucoma. We tested the hypothesis that early beneficial effects of physical activity and cardiovascular fitness can be observed by measuring the pRNFL thickness in young healthy adults.

Methods: The Raine Study is a longitudinal study that has followed a cohort since before their births in 1989-1992. Parent-reported physical activity was collected between 8 and 17 years, and latent class analysis was used to identify the participants' physical activity trajectories. At the 20-year follow-up (participants' mean age=20.1±0.4 y), participants' metabolic equivalent of task-minutes/week was determined using self-reported physical activity data. Participants' PWC was assessed at the 14- and 17-year follow-ups to estimate their level of cardiovascular fitness. An eye examination, which included spectral-domain optical coherence tomography imaging, was conducted at the 20-year follow-up for 1344 participants.

Results: Parent-reported or participant-reported physical activity was not associated with pRNFL thickness. However, higher PWC at 17 years was associated with thicker pRNFL globally [by 0.3 µm; 95% confidence interval (CI)=0.2-0.6; P<0.001], superotemporally (by 0.4 µm; 95% CI=0.1-0.7; P=0.013), inferonasally (by 0.7 µm; 95% CI=0.1-0.9; P=0.002), and nasally (by 0.4 µm; 95% CI=0.1-0.7; P=0.006) per 10 Watt increase in PWC.

Conclusions: The association between estimated cardiovascular fitness and pRNFL thickness suggests there may be overlapping mechanisms for cardiovascular health and retinal ganglion cell integrity. While the effect sizes were small, it is possible that larger effects and clinically significant associations may arise as we follow this cohort of participants through their later adulthood.
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http://dx.doi.org/10.1097/IJG.0000000000001865DOI Listing
May 2021

Genetic variation affects morphological retinal phenotypes extracted from UK Biobank optical coherence tomography images.

PLoS Genet 2021 May 12;17(5):e1009497. Epub 2021 May 12.

School of Life Course Sciences, Section of Ophthalmology, King's College London, London, United Kingdom.

Optical Coherence Tomography (OCT) enables non-invasive imaging of the retina and is used to diagnose and manage ophthalmic diseases including glaucoma. We present the first large-scale genome-wide association study of inner retinal morphology using phenotypes derived from OCT images of 31,434 UK Biobank participants. We identify 46 loci associated with thickness of the retinal nerve fibre layer or ganglion cell inner plexiform layer. Only one of these loci has been associated with glaucoma, and despite its clear role as a biomarker for the disease, Mendelian randomisation does not support inner retinal thickness being on the same genetic causal pathway as glaucoma. We extracted overall retinal thickness at the fovea, representative of foveal hypoplasia, with which three of the 46 SNPs were associated. We additionally associate these three loci with visual acuity. In contrast to the Mendelian causes of severe foveal hypoplasia, our results suggest a spectrum of foveal hypoplasia, in part genetically determined, with consequences on visual function.
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http://dx.doi.org/10.1371/journal.pgen.1009497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143408PMC
May 2021

Associations of sleep apnoea with glaucoma and age-related macular degeneration: an analysis in the United Kingdom Biobank and the Canadian Longitudinal Study on Aging.

BMC Med 2021 May 11;19(1):104. Epub 2021 May 11.

Centre for Ophthalmology and Visual Science, Lions Eye Institute, University of Western Australia, Nedlands, Western Australia, Australia.

Background: Sleep apnoea, a common sleep-disordered breathing condition, is characterised by upper airway collapse during sleep resulting in transient hypoxia, hypoperfusion of the optic nerve, and spike in intracranial pressure. Previous studies have reported conflicting findings on the association of sleep apnoea with glaucoma, and there are limited reports on the link between sleep apnoea and age-related macular degeneration (AMD).

Methods: Middle-aged and older participants from the longitudinal United Kingdom (UK) Biobank (n = 502,505) and the Canadian Longitudinal Study on Aging (CLSA; n = 24,073) were included in this analysis. Participants in the UK Biobank and the CLSA were followed for 8 and 3 years, respectively. Participants with diagnosed glaucoma or AMD at baseline were excluded from the analysis. In the UK Biobank, sleep apnoea and incident cases of glaucoma and AMD were identified through hospital inpatient admission, primary care records, and self-reported data. Multivariable Cox proportional hazards models were used to explore associations of sleep apnoea with incidence of glaucoma or AMD.

Results: During the 8-year follow-up in the UK Biobank, glaucoma incidence rates per 1000 person-years were 2.46 and 1.59 for participants with and without sleep apnoea, and the AMD incidence rates per 1000 person-years were 2.27 and 1.42 for participants with and without sleep apnoea, respectively. Multivariable adjusted hazard ratios of glaucoma and AMD risk for sleep apnoea were 1.33 (95% confidence interval [CI] 1.10-1.60, P = 0.003) and 1.39 (95% CI 1.15-1.68, P <  0.001) relative to participants without sleep apnoea. In the CLSA cohort, disease information was collected through in-person interview questionnaires. During the 3-year follow-up, glaucoma incidence rates per 1000 person-years for those with and without sleep apnoea were 9.31 and 6.97, and the AMD incidence rates per 1000 person-years were 8.44 and 6.67, respectively. In the CLSA, similar associations were identified, with glaucoma and AMD odds ratios of 1.43 (95% CI 1.13-1.79) and 1.39 (95% CI 1.08-1.77), respectively, in participants with sleep apnoea compared to those without sleep apnoea (both P <  0.001).

Conclusions: In two large-scale prospective cohort studies, sleep apnoea is associated with a higher risk of both glaucoma and AMD. These findings indicate that patients with sleep apnoea might benefit from regular ophthalmologic examinations.
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http://dx.doi.org/10.1186/s12916-021-01973-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111909PMC
May 2021

Inherited retinal diseases are the most common cause of blindness in the working-age population in Australia.

Ophthalmic Genet 2021 Aug 3;42(4):431-439. Epub 2021 May 3.

Centre for Ophthalmology and Visual Science (Incorporating Lions Eye Institute), The University of Western Australia, Nedlands, Australia.

This study examined the frequency of inherited retinal diseases (IRDs) as the reason for blindness registrations over the last two decades and the demographic and clinical phenotypes of inherited retinal disease (IRD)-related registrations. Retrospective, observational study of individuals registered with a state-wide blind and vision-impaired registry. Low-vision or blindness-only (≤20/200 or ≤20°) certificates issued to children (0-15 years), working-age (16-64 years) and older-age (65 and older) adults were assessed. Sex and age distributions were examined for the top 20 reasons for certification. Demographic and clinical features of specific phenotypes of IRDs listed in the registry were examined. Amongst 11824 low-vision certificates issued between July 1995 and January 2017, 679 (5.7%) listed an IRD as the reason for registration. In individuals with blindness-only certification (N=4919), IRDs was the second most common diagnosis (8.3%), overtaking glaucoma (8.1%) and diabetic retinopathy (5.4%). IRD was the second most common reason for low-vision certification amongst children (11.6%) and the most common reason amongst working-age population (23.3%). The mean±SD age for IRD-related blindness-only certification was 46±20 years. The top three phenotypes of IRD-related low-vision certification were non-syndromic retinitis pigmentosa (54%), Stargardt disease (12%) and macular dystrophy (8%). Our findings of IRDs as a common cause of blindness in all ages justify continued funding for providing low-vision services and developing treatments for these conditions.
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http://dx.doi.org/10.1080/13816810.2021.1913610DOI Listing
August 2021

IMI 2021 Yearly Digest.

Invest Ophthalmol Vis Sci 2021 Apr;62(5)

College of Optometry, University of Houston, Houston, Texas, United States.

Purpose: The International Myopia Institute (IMI) Yearly Digest highlights new research considered to be of importance since the publication of the first series of IMI white papers.

Methods: A literature search was conducted for articles on myopia between 2019 and mid-2020 to inform definitions and classifications, experimental models, genetics, interventions, clinical trials, and clinical management. Conference abstracts from key meetings in the same period were also considered.

Results: One thousand articles on myopia have been published between 2019 and mid-2020. Key advances include the use of the definition of premyopia in studies currently under way to test interventions in myopia, new definitions in the field of pathologic myopia, the role of new pharmacologic treatments in experimental models such as intraocular pressure-lowering latanoprost, a large meta-analysis of refractive error identifying 336 new genetic loci, new clinical interventions such as the defocus incorporated multisegment spectacles and combination therapy with low-dose atropine and orthokeratology (OK), normative standards in refractive error, the ethical dilemma of a placebo control group when myopia control treatments are established, reporting the physical metric of myopia reduction versus a percentage reduction, comparison of the risk of pediatric OK wear with risk of vision impairment in myopia, the justification of preventing myopic and axial length increase versus quality of life, and future vision loss.

Conclusions: Large amounts of research in myopia have been published since the IMI 2019 white papers were released. The yearly digest serves to highlight the latest research and advances in myopia.
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http://dx.doi.org/10.1167/iovs.62.5.7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088231PMC
April 2021

Childhood and Early Onset Glaucoma Classification and Genetic Profile in a Large Australasian Disease Registry.

Ophthalmology 2021 Apr 20. Epub 2021 Apr 20.

Department of Ophthalmology, Flinders University, Flinders Medical Centre, Adelaide, Australia.

Purpose: To report the relative frequencies of childhood and early onset glaucoma subtypes and their genetic findings in a large single cohort.

Design: Retrospective clinical and molecular study.

Participants: All individuals with childhood glaucoma (diagnosed 0 to <18 years) and early onset glaucoma (diagnosed 18 to <40 years) referred to a national disease registry.

Methods: We retrospectively reviewed the referrals of all individuals with glaucoma diagnosed at <40 years of age recruited to the Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG). Subtypes of glaucoma were determined using the Childhood Glaucoma Research Network (CGRN) classification system. DNA extracted from blood or saliva samples underwent sequencing of genes associated with glaucoma.

Main Outcome Measures: The phenotype and genotype distribution of glaucoma diagnosed at <40 years of age.

Results: A total of 290 individuals (533 eyes) with childhood glaucoma and 370 individuals (686 eyes) with early onset glaucoma were referred to the ANZRAG. Primary glaucoma was the most prevalent condition in both cohorts. In the childhood cohort, 57.6% of individuals (167/290, 303 eyes) had primary congenital glaucoma (PCG), and 19.3% (56/290, 109 eyes) had juvenile open-angle glaucoma. Juvenile open-angle glaucoma constituted 73.2% of the early onset glaucoma cohort (271/370, 513 eyes). Genetic testing in probands resulted in a diagnostic yield of 24.7% (125/506) and a reclassification of glaucoma subtype in 10.4% of probands (13/125). The highest molecular diagnostic rate was achieved in probands with glaucoma associated with nonacquired ocular anomalies (56.5%). Biallelic variants in CYP1B1 (n = 29, 23.2%) and heterozygous variants in MYOC (n = 24, 19.2%) and FOXC1 (n = 21, 16.8%) were most commonly reported among probands with a molecular diagnosis. Biallelic CYP1B1 variants were reported in twice as many female individuals as male individuals with PCG (66.7% vs. 33.3%, P = 0.02).

Conclusions: We report on the largest cohort of individuals with childhood and early onset glaucoma from Australasia using the CGRN classification. Primary glaucoma was most prevalent. Genetic diagnoses ascertained in 24.7% of probands supported clinical diagnoses and genetic counseling. International collaborative efforts are required to identify further genes because the majority of individuals still lack a clear molecular diagnosis.
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http://dx.doi.org/10.1016/j.ophtha.2021.04.016DOI Listing
April 2021

A 127 kb truncating deletion of PGRMC1 is a novel cause of X-linked isolated paediatric cataract.

Eur J Hum Genet 2021 Apr 19. Epub 2021 Apr 19.

Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia.

Inherited paediatric cataract is a rare Mendelian disease that results in visual impairment or blindness due to a clouding of the eye's crystalline lens. Here we report an Australian family with isolated paediatric cataract, which we had previously mapped to Xq24. Linkage at Xq24-25 (LOD = 2.53) was confirmed, and the region refined with a denser marker map. In addition, two autosomal regions with suggestive evidence of linkage were observed. A segregating 127 kb deletion (chrX:g.118373226_118500408del) in the Xq24-25 linkage region was identified from whole-genome sequencing data. This deletion completely removed a commonly deleted long non-coding RNA gene LOC101928336 and truncated the protein coding progesterone receptor membrane component 1 (PGRMC1) gene following exon 1. A literature search revealed a report of two unrelated males with non-syndromic intellectual disability, as well as congenital cataract, who had contiguous gene deletions that accounted for their intellectual disability but also disrupted the PGRMC1 gene. A morpholino-induced pgrmc1 knockdown in a zebrafish model produced significant cataract formation, supporting a role for PGRMC1 in lens development and cataract formation. We hypothesise that the loss of PGRMC1 causes cataract through disrupted PGRMC1-CYP51A1 protein-protein interactions and altered cholesterol biosynthesis. The cause of paediatric cataract in this family is the truncating deletion of PGRMC1, which we report as a novel cataract gene.
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http://dx.doi.org/10.1038/s41431-021-00889-8DOI Listing
April 2021

Evaluation of Shared Genetic Susceptibility to High and Low Myopia and Hyperopia.

JAMA Ophthalmol 2021 Jun;139(6):601-609

Cardiff University School of Optometry and Vision Sciences, Cardiff, United Kingdom.

Importance: Uncertainty currently exists about whether the same genetic variants are associated with susceptibility to low myopia (LM) and high myopia (HM) and to myopia and hyperopia. Addressing this question is fundamental to understanding the genetics of refractive error and has clinical relevance for genotype-based prediction of children at risk for HM and for identification of new therapeutic targets.

Objective: To assess whether a common set of genetic variants are associated with susceptibility to HM, LM, and hyperopia.

Design, Setting, And Participants: This genetic association study assessed unrelated UK Biobank participants 40 to 69 years of age of European and Asian ancestry. Participants 40 to 69 years of age living in the United Kingdom were recruited from January 1, 2006, to October 31, 2010. Of the total sample of 502 682 participants, 117 279 (23.3%) underwent an ophthalmic assessment. Data analysis was performed from December 12, 2019, to June 23, 2020.

Exposures: Four refractive error groups were defined: HM, -6.00 diopters (D) or less; LM, -3.00 to -1.00 D; hyperopia, +2.00 D or greater; and emmetropia, 0.00 to +1.00 D. Four genome-wide association study (GWAS) analyses were performed in participants of European ancestry: (1) HM vs emmetropia, (2) LM vs emmetropia, (3) hyperopia vs emmetropia, and (4) LM vs hyperopia. Polygenic risk scores were generated from GWAS summary statistics, yielding 4 sets of polygenic risk scores. Performance was assessed in independent replication samples of European and Asian ancestry.

Main Outcomes And Measures: Odds ratios (ORs) of polygenic risk scores in replication samples.

Results: A total of 51 841 unrelated individuals of European ancestry and 2165 unrelated individuals of Asian ancestry were assigned to a specific refractive error group and included in our analyses. Polygenic risk scores derived from all 4 GWAS analyses were predictive of all categories of refractive error in both European and Asian replication samples. For example, the polygenic risk score derived from the HM vs emmetropia GWAS was predictive in the European sample of HM vs emmetropia (OR, 1.58; 95% CI, 1.41-1.77; P = 1.54 × 10-15) as well as LM vs emmetropia (OR, 1.15; 95% CI, 1.07-1.23; P = 8.14 × 10-5), hyperopia vs emmetropia (OR, 0.83; 95% CI, 0.77-0.89; P = 4.18 × 10-7), and LM vs hyperopia (OR, 1.45; 95% CI, 1.33-1.59; P = 1.43 × 10-16).

Conclusions And Relevance: Genetic risk variants were shared across HM, LM, and hyperopia and across European and Asian samples. Individuals with HM inherited a higher number of variants from among the same set of myopia-predisposing alleles and not different risk alleles compared with individuals with LM. These findings suggest that treatment interventions targeting common genetic risk variants associated with refractive error could be effective against both LM and HM.
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http://dx.doi.org/10.1001/jamaophthalmol.2021.0497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033508PMC
June 2021

Response to Letter to the Editor: Optic Disc Measures in Obstructive Sleep Apnea: A Community-based Study of Middle-aged and Older Adults.

J Glaucoma 2021 Jun;30(6):e312-e313

Centre for Ophthalmology and Visual Science (Incorporating Lions Eye Institute) The University of Western Australia Perth, WA.

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http://dx.doi.org/10.1097/IJG.0000000000001850DOI Listing
June 2021

Functional benefits of a chorioretinal anastomosis at 2 years in eyes with a central retinal vein occlusion treated with ranibizumab compared with ranibizumab monotherapy.

BMJ Open Ophthalmol 2021 8;6(1):e000728. Epub 2021 Mar 8.

Centre for Eye Research Australia, Melbourne, Victoria, Australia.

Objective: To evaluate the functional benefits (best corrected visual acuity (BCVA), central subfield thickness, injection loads, central venous pressure (CVP)) of a laser-induced chorioretinal anastomosis (L-CRA) in patients with central retinal vein occlusion (CRVO) treated with ranibizumab compared with ranibizumab monotherapy.

Methods And Analysis: This is a post-hoc analysis of the 2-year randomised ranibizumab plus L-CRA for CRVO trial. Twenty-four patients (82.5%) developed a functioning or successful L-CRA; outcome effects were monitored in the monthly as-needed ranibizumab phase from months 7 to 24 and compared with the ranibizumab monotherapy group (n=29).

Results: From months 7 to 24, the mean (95% CI) injection load for the functioning L-CRA group was 2.18 (1.57 to 2.78) compared with 7.07 (6.08 to 8.06) for the control group (p<0.0001). The mean BCVA was averaged across all timepoints between the control and functioning L-CRA groups (average difference=11.46 (3.16 to 19.75) letters, p=0.01). At 2 years, there was an 82.5% reduction in the odds of high CVP (greater or equal to central retinal artery diastolic pressure) for those with a successful L-CRA compared with controls (p<0.0001).

Conclusion: For patients with CRVO, adding L-CRA as a causal-based treatment to conventional therapy reduced CVP and injection loads and offered improved BCVA. ACTRN12612000004864.
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http://dx.doi.org/10.1136/bmjophth-2021-000728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7942268PMC
March 2021

Time spent outdoors in childhood is associated with reduced risk of myopia as an adult.

Sci Rep 2021 Mar 18;11(1):6337. Epub 2021 Mar 18.

Centre for Ophthalmology and Visual Science (Incorporating Lions Eye Institute), The University of Western Australia, Perth, Australia.

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.
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http://dx.doi.org/10.1038/s41598-021-85825-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973740PMC
March 2021

Associations between seven-year C-reactive protein trajectory or pack-years smoked with choroidal or retinal thicknesses in young adults.

Sci Rep 2021 Mar 17;11(1):6147. Epub 2021 Mar 17.

Centre for Ophthalmology and Visual Science (Incorporating Lions Eye Institute), University of Western Australia, 2 Verdun St, Nedlands, WA, 6009, Australia.

Inflammation and cigarette smoking predispose to macular diseases, and choroidal and retinal thinning. We explored the choroidal and retinal thicknesses in young adults against their 7-year C-reactive protein (CRP) level trajectory and pack-years smoked. Participants from the Raine study, a longitudinal cohort study, had serum CRP levels analysed at the 14-, 17-, and 20-year follow-ups. Group-based trajectory modelling was used to classify participants according to their 7-year CRP levels. At the 20-year follow-up (at 18-22 years old), participants completed questionnaires on their smoking history, and underwent optical coherence tomography imaging to obtain their choroidal and retinal thicknesses at the macula. Three CRP trajectories were identified: consistently low CRP levels (78% of sample), increasing (11%), or consistently high (11%). 340 and 1035 participants were included in the choroidal and retinal thickness analyses, respectively. Compared to those in the "Low" trajectory group, participants in the "Increasing" and "High" groups had 14-21 μm thinner choroids at most macular regions. Every additional pack-year smoked was linked with a 0.06-0.10 μm thinner retina at the inner and outer macular rings, suggesting a dose-dependent relationship between smoking and thinner retinas. These associations may suggest that an increased risk of future visual impairment or eye disease associated with these risk factors may be present since young adulthood.
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http://dx.doi.org/10.1038/s41598-021-85626-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969753PMC
March 2021

Genome-wide association study in almost 195,000 individuals identifies 50 previously unidentified genetic loci for eye color.

Sci Adv 2021 Mar 10;7(11). Epub 2021 Mar 10.

Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.

Human eye color is highly heritable, but its genetic architecture is not yet fully understood. We report the results of the largest genome-wide association study for eye color to date, involving up to 192,986 European participants from 10 populations. We identify 124 independent associations arising from 61 discrete genomic regions, including 50 previously unidentified. We find evidence for genes involved in melanin pigmentation, but we also find associations with genes involved in iris morphology and structure. Further analyses in 1636 Asian participants from two populations suggest that iris pigmentation variation in Asians is genetically similar to Europeans, albeit with smaller effect sizes. Our findings collectively explain 53.2% (95% confidence interval, 45.4 to 61.0%) of eye color variation using common single-nucleotide polymorphisms. Overall, our study outcomes demonstrate that the genetic complexity of human eye color considerably exceeds previous knowledge and expectations, highlighting eye color as a genetically highly complex human trait.
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http://dx.doi.org/10.1126/sciadv.abd1239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946369PMC
March 2021

Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries.

Nat Commun 2021 02 24;12(1):1258. Epub 2021 Feb 24.

Faculty of Medicine, University of Southampton, Southampton, UK.

Primary open-angle glaucoma (POAG), is a heritable common cause of blindness world-wide. To identify risk loci, we conduct a large multi-ethnic meta-analysis of genome-wide association studies on a total of 34,179 cases and 349,321 controls, identifying 44 previously unreported risk loci and confirming 83 loci that were previously known. The majority of loci have broadly consistent effects across European, Asian and African ancestries. Cross-ancestry data improve fine-mapping of causal variants for several loci. Integration of multiple lines of genetic evidence support the functional relevance of the identified POAG risk loci and highlight potential contributions of several genes to POAG pathogenesis, including SVEP1, RERE, VCAM1, ZNF638, CLIC5, SLC2A12, YAP1, MXRA5, and SMAD6. Several drug compounds targeting POAG risk genes may be potential glaucoma therapeutic candidates.
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http://dx.doi.org/10.1038/s41467-020-20851-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904932PMC
February 2021

Time spent outdoors through childhood and adolescence - assessed by 25-hydroxyvitamin D concentration - and risk of myopia at 20 years.

Acta Ophthalmol 2021 Jan 10. Epub 2021 Jan 10.

Lions Eye Institute, Centre for Ophthalmology and Visual Science, University of Western Australia, Perth, Australia.

Purpose: To investigate the relationship between time spent outdoors, at particular ages in childhood and adolescence, and myopia status in young adulthood using serum 25-hydroxyvitamin D [25(OH)D] concentration as a biomarker of time spent outdoors.

Methods: Participants of the Raine Study Generation 2 cohort had 25(OH)D concentrations measured at the 6-, 14-, 17- and 20-year follow-ups. Participants underwent cycloplegic autorefraction at age 20 years, and myopia was defined as a mean spherical equivalent -0.50 dioptres or more myopic. Logistic regression was used to analyse the association between risk of myopia at age 20 years and age-specific 25(OH)D concentrations. Linear mixed-effects models were used to analyse trajectory of 25(OH)D concentrations from 6 to 20 years.

Results: After adjusting for sex, race, parental myopia, body mass index and studying status, myopia at 20 years was associated with lower 25(OH)D concentration at 20 years (per 10 nmol/L decrease, odds ratio (aOR)=1.10, 95% CI: 1.02, 1.18) and a low vitamin D status [25(OH)D < 50 nmol/L] at 17 years (aOR = 1.71, 95% CI: 1.06, 2.76) and 20 years (aOR = 1.71, 95% CI: 1.14, 2.56), compared to those without low vitamin D status. There were no associations between 25(OH)D at younger ages and myopia. Individuals who were myopic at 20 years had a 25(OH)D concentration trajectory that declined, relative to non-myopic peers, with increasing age. Differences in 25(OH)D trajectory between individuals with and without myopia were greater among non-Caucasians compared to Caucasians.

Conclusions: Myopia in young adulthood was most strongly associated with recent 25(OH)D concentrations, a marker of time spent outdoors.
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http://dx.doi.org/10.1111/aos.14709DOI Listing
January 2021

Associations Between Fetal Growth Trajectories and the Development of Myopia by 20 Years of Age.

Invest Ophthalmol Vis Sci 2020 12;61(14):26

Centre for Ophthalmology and Visual Science, Lions Eye Institute, University of Western Australia, Perth, Western Australia, Australia.

Purpose: To evaluate the contribution of genetic and early life environmental factors, as reflected by fetal anthropometric growth trajectories, toward the development of myopia during childhood and adolescence.

Methods: This analysis included 498 singleton Caucasian participants from the Raine Study, a pregnancy cohort study based in Western Australia. Serial fetal biometric measurements of these participants were collected via ultrasound scans performed at 18, 24, 28, 34, and 38 weeks' gestation. At a 20-year follow-up, the participants underwent a comprehensive ophthalmic examination, including cycloplegic autorefraction and ocular biometry measurements. Using a group-based trajectory modeling approach, we identified groups of participants with similar growth trajectories based on measurements of fetal head circumference (HC), abdominal circumference, femur length (FL), and estimated fetal weight (EFW). Differences between trajectory groups with respect to prevalence of myopia, axial length (AL), and corneal radius of curvature measured at the 20-year follow-up were evaluated via logistic regression and analysis of variance.

Results: Prevalence of myopia was highest among participants with consistently short or consistently long FLs (P = 0.04). There was also a trend toward increased prevalence with larger HC in late gestation, although not at a statistically significant level. Trajectory groups reflecting faster HC, FL, or EFW growth correlated with significantly flatter corneas (P = 0.03, P = 0.04, and P = 0.01, respectively) and a general, but not statistically significant, increase in AL.

Conclusions: Environmental or genetic factors influencing intrauterine skeletal growth may concurrently affect ocular development, with effects persisting into adulthood.
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http://dx.doi.org/10.1167/iovs.61.14.26DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774062PMC
December 2020

Expanding the genetic spectrum of choroideremia in an Australian cohort: report of five novel variants.

Hum Genome Var 2020 23;7:35. Epub 2020 Oct 23.

Australian Inherited Retinal Disease Registry and DNA Bank, Department of Medical Technology and Physics, Sir Charles Gairdner Hospital, Hospital Avenue, Nedlands, Western Australia Australia.

Choroideremia is an X-linked chorioretinal dystrophy caused by mutations in the gene. Several gene replacement clinical trials are in advanced stages. In this study, we report the molecular confirmation of choroideremia in 14 Australian families sourced from the Australian Inherited Retinal Disease Registry and DNA Bank. Sixteen males (14 symptomatic) and 18 females (4 symptomatic; 14 obligate carriers) were identified for analysis. Participants' DNA was analyzed for disease-causing variants by Sanger sequencing, TaqMan qPCR and targeted NGS. We report phenotypic and genotypic data for the 14 symptomatic males and four females manifesting disease symptoms. A pathogenic or likely pathogenic variant was detected in all families. Eight variants were previously reported, and five were novel. Two variants were identified. We previously reported the molecular confirmation of choroideremia in 11 Australian families. This study expands the genetically confirmed Australian cohort to 32 males and four affected carrier females.
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http://dx.doi.org/10.1038/s41439-020-00122-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584600PMC
October 2020

Improving parents' knowledge of early signs of paediatric eye disease: A double-blind randomized controlled trial.

Clin Exp Ophthalmol 2020 12 26;48(9):1250-1260. Epub 2020 Oct 26.

Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia.

Importance: Educating parents to recognize signs of eye disease and consult a healthcare professional is critical to timely diagnosis, intervention and outcomes.

Background: We evaluate the effectiveness of an eye-health information pamphlet on parents' level of concern and help-seeking intention should they hypothetically observe leukocoria or strabismus in their child.

Design: Double-blind, randomized controlled trial conducted at a metropolitan antenatal outpatient clinic.

Participants: In total, 518 pregnant women were enrolled in the study.

Methods: After completing a study-specific, pre-test survey describing hypothetical clinical scenarios at baseline, participants were randomly assigned to receive a pamphlet on either paediatric eye health (intervention) or infant play (control). The post-test survey was sent by email 2 weeks after baseline.

Main Outcome Measures: A change in the parents' level of concern if they observed leukocoria or strabismus and a change in their help-seeking intention if they hypothetically observed leukocoria or strabismus in their child.

Results: Of the 518 women, 382 (73.7%) completed the post-test survey. At follow-up, women who received the intervention were more likely to report a higher level of concern if they observed leukocoria (OR 1.711 [CI: 1.176-2.497] P = .005]) and were less likely to delay help-seeking (OR 0.560 [CI 0.382-0.817] P = .003). No change in the level of concern for strabismus was identified between the groups; however, at follow-up, women who received the intervention were less likely to delay help-seeking (OR 0.318 [CI 0.125-0.806] P = .016).

Conclusion And Relevance: Providing parents with relevant, evidence-based information can significantly improve their knowledge and positively influence help-seeking intentions if leukocoria or strabismus are observed.
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http://dx.doi.org/10.1111/ceo.13866DOI Listing
December 2020

Deep learning segmentation of hyperautofluorescent fleck lesions in Stargardt disease.

Sci Rep 2020 10 5;10(1):16491. Epub 2020 Oct 5.

Centre for Ophthalmology and Visual Science (Incorporating Lions Eye Institute), The University of Western Australia, 2 Verdun Street, Nedlands, WA, Australia.

Stargardt disease is one of the most common forms of inherited retinal disease and leads to permanent vision loss. A diagnostic feature of the disease is retinal flecks, which appear hyperautofluorescent in fundus autofluorescence (FAF) imaging. The size and number of these flecks increase with disease progression. Manual segmentation of flecks allows monitoring of disease, but is time-consuming. Herein, we have developed and validated a deep learning approach for segmenting these Stargardt flecks (1750 training and 100 validation FAF patches from 37 eyes with Stargardt disease). Testing was done in 10 separate Stargardt FAF images and we observed a good overall agreement between manual and deep learning in both fleck count and fleck area. Longitudinal data were available in both eyes from 6 patients (average total follow-up time 4.2 years), with both manual and deep learning segmentation performed on all (n = 82) images. Both methods detected a similar upward trend in fleck number and area over time. In conclusion, we demonstrated the feasibility of utilizing deep learning to segment and quantify FAF lesions, laying the foundation for future studies using fleck parameters as a trial endpoint.
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http://dx.doi.org/10.1038/s41598-020-73339-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536408PMC
October 2020

Exploring microperimetry and autofluorescence endpoints for monitoring disease progression in -associated retinopathy.

Ophthalmic Genet 2021 02 27;42(1):1-14. Epub 2020 Sep 27.

Centre for Ophthalmology and Visual Science, The University of Western Australia , Perth, Australia.

Background: Mutations in the splicing factor pre-messenger RNA processing factor 31 () gene cause autosomal dominant retinitis pigmentosa 11 (RP11) through a haplo-insufficiency mechanism. We describe the phenotype and progression of microperimetry and autofluorescence endpoints in an Indigenous Australian RP11 family.

Patients And Methods: Ophthalmic examination, optical coherence tomography, fundus autofluorescence and microperimetry were performed at baseline and every 6-12 months. Baseline and annual change in best-corrected visual acuity (BCVA), microperimetry mean sensitivity (MS) and number of scotoma loci, residual ellipsoid zone (EZ) span and hyperautofluorescent ring (HAR) area were reported. Next-generation and Sanger sequencing were performed in available members.

Results: 12 affected members from three generations were examined. Mean (SD, range) age at onset of symptoms was 11 (4.5, 4-19) years. MS declined steadily from the third decade and EZ span and HAR area declined rapidly during the second decade. Serial microperimetry showed negligible change in MS over 2-3 years. However, mean EZ span, near-infrared and short-wavelength HAR area reduction was 203 (6.4%) µm/year, 1.8 (8.7%) mm/year and 1.1 (8.6%) mm/year, respectively. Genetic testing was performed on 11 affected and 10 asymptomatic members and c.1205 C > A (p.Ser402Ter) mutation was detected in all affected and two asymptomatic members (non-penetrant carriers).

Conclusions: Our findings suggest that in the studied cohort, the optimal window for therapeutic intervention is the second decade of life and residual EZ span and HAR area can be considered as efficacy outcome measures. Further studies on larger samples with different  mutations and longer follow-up duration are recommended.
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http://dx.doi.org/10.1080/13816810.2020.1827442DOI Listing
February 2021

Edge of Scotoma Sensitivity as a Microperimetry Clinical Trial End Point in Retinopathy.

Transl Vis Sci Technol 2020 09 9;9(10). Epub 2020 Sep 9.

Centre of Ophthalmology and Visual Science (incorporating Lions Eye Institute), The University of Western Australia, Western Australia, Australia.

Purpose: Microperimetry is commonly used to assess retinal function. We perform cross-sectional and longitudinal analysis on microperimetry parameters in retinopathy and explore end points suitable for future clinical trials.

Methods: Microperimetry was performed using two grids, Grid 1 (18° diameter) and Grid 2 (6° diameter). In Grid 1, four parameters (number of nonscotomatous loci, mean sensitivity [MS], responding point sensitivity [RPS], and edge of scotoma sensitivity [ESS]) were analyzed. In Grid 2, number of nonscotomatous loci and MS were examined. Interocular symmetry was also examined. Longitudinal analysis was conducted in a subset of eyes.

Results: Microperimetry could be performed in 16 of 21 patients. In Grid 1 ( = 15; average age, 35.6 years), average number of nonscotomatous loci, MS, RPS, and ESS were 46.6 loci, 10.0 dB, 14.7 and 9.6 dB, respectively. In Grid 2 ( = 13; average age, 37.4 years), 12 eyes had measurable sensitivity across the entire grid. Average MS was 23.8 dB. Interocular analysis revealed large 95% confidence intervals for all parameters. Longitudinally, Grid 1 ( = 12, average follow-up 2.6 years) ESS showed the fastest rate of decline (-1.84 dB/y) compared with MS (-0.34 dB/y) and RPS (-0.90 dB/y).

Conclusions: Our data suggest that ESS may be more useful than MS and RPS in test grids that cover a large extent of the macula. We caution the use of contralateral eye as an internal control.

Translational Relevance: ESS may decrease the duration or sample size of treatment trials in retinopathy.
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http://dx.doi.org/10.1167/tvst.9.10.9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488629PMC
September 2020

Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity.

Diabetes 2020 12 11;69(12):2806-2818. Epub 2020 Sep 11.

Department of Biostatistics, Boston University School of Public Health, Boston, MA.

Leptin influences food intake by informing the brain about the status of body fat stores. Rare mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in , , , and , and one intergenic variant near The missense variant Val94Met (rs17151919) in was common in individuals of African ancestry only, and its association with lower leptin concentrations was specific to this ancestry ( = 2 × 10, = 3,901). Using in vitro analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting that leptin regulates early adiposity.
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http://dx.doi.org/10.2337/db20-0070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7679778PMC
December 2020

Prevalence of Keratoconus Based on Scheimpflug Imaging: The Raine Study.

Ophthalmology 2021 04 26;128(4):515-521. Epub 2020 Aug 26.

Centre for Ophthalmology and Visual Science (incorporating Lions Eye Institute), University of Western Australia, Perth, Australia; Garvan Institute of Medical Research, Sydney, Australia.

Purpose: To describe the prevalence and systemic associations of keratoconus in young adults in Perth, Western Australia.

Design: Cross-sectional study.

Participants: One thousand two hundred fifty-nine participants 20 years of age.

Methods: The Raine Study is a multigenerational, longitudinal cohort study based in Perth, Western Australia. This study represents a cross-sectional analysis of the birth cohort on returning for a 20-year follow-up. Participants underwent a detailed ophthalmic examination, including visual acuity assessment and Scheimpflug imaging using the Pentacam (Oculus, Wetzlar, Germany), and completed a health questionnaire. Keratoconus was defined as a Belin/Ambrόsio enhanced ectasia display score of 2.6 or more in either eye based on Pentacam imaging.

Main Outcome Measures: Prevalence of keratoconus in this cohort.

Results: Of the 1259 participants, 50.8% were women and 85.7% were White. Fifteen participants had keratoconus in at least 1 eye, giving a prevalence of 1.2% (95% confidence interval, 0.7%-1.9%), or 1 in 84. A significant difference was found in best-corrected visual acuity (0.01 logarithm of the minimum angle of resolution vs. -0.05 logarithm of the minimum angle of resolution; P = 0.007), cylinder (1.25 diopters [D] vs. 0.25 D cylinder; P < 0.001) and spherical equivalent (-1.42 D vs. -0.50 D sphere; P = 0.02) on objective refraction, mean keratometry of the steep meridian (45.19 D vs. 43.76 D; P < 0.001), and mean corneal thickness at the thinnest point (475 μm vs. 536 μm; P < 0.001) between those with and without keratoconus. Keratoconus was associated with regular cigarette smoking (38.5% vs. 14.6%; P = 0.04), but showed no association with gender, race, body mass index, use of spectacles or contact lenses, history of allergic eye disease, or pregnancy.

Conclusions: The prevalence of keratoconus in this Australian population-based study of 20-year-old adults was 1.2% (95% confidence interval, 0.7%-1.9%), or 1 in 84, which is one of the highest reported in the world. This has important implications for screening individuals at a younger age so that treatment can be initiated before disease progression.
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http://dx.doi.org/10.1016/j.ophtha.2020.08.020DOI Listing
April 2021

Interpreting MAIA Microperimetry Using Age- and Retinal Loci-Specific Reference Thresholds.

Transl Vis Sci Technol 2020 06 18;9(7):19. Epub 2020 Jun 18.

Centre of Ophthalmology and Visual Science (incorporating Lions Eye Institute), The University of Western Australia, Perth, Western Australia.

Purpose: Macular Integrity Assessment (MAIA) microperimetry is used widely in clinical trials and routine practice to assess paracentral scotoma. Current interpretation of MAIA is based on an assumed uniform 25 decibel (dB) cutoff for normal function irrespective of subject age and retinal location. We examined this convention by establishing an age- and loci-specific reference in healthy eyes and comparing this to the <25 dB cutoff.

Methods: Retrospective MAIA results from healthy eyes were analyzed for prevalence of loci with <25 dB. At each locus, a new reference cutoff was derived from quantile regression of sensitivity against age at the 2.5th percentile. Two clinical cases of serial MAIA testing were analyzed using the new approach and compared to the <25 dB cutoff.

Results: Fifty-four and 56 age-matched (range: 16-75 years) healthy eyes underwent small (37 loci) and large (68 loci) grid testing, respectively. Retinal sensitivity <25 dB was found in 5% of the small grid (1998 data points) and 10% of the large grid (3808 data points). These were found predominantly in older subjects and at the central point or in the perifoveal region. Quantile regression at each individual locus showed age-related decline with a median gradient of 0.6 dB/decade.

Conclusions: We caution against using <25 dB cutoff in MAIA interpretation and advocate an age- and loci-specific cutoff criterion.

Translational Relevance: Our study suggests that MAIA interpretation is influenced by the criterion used for defining abnormal pointwise measurement.
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http://dx.doi.org/10.1167/tvst.9.7.19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414638PMC
June 2020

Is Dietary Vitamin A Associated with Myopia from Adolescence to Young Adulthood?

Transl Vis Sci Technol 2020 05 28;9(6):29. Epub 2020 May 28.

Department of Genetics and Epidemiology, Lions Eye Institute, Perth, Western Australia, Australia.

Purpose: Potential links may exist between vitamin A intake and myopia via various pathways. In this study, we examined the association between dietary vitamin A intake during adolescence and myopia in early adulthood.

Methods: We performed a prospective analysis utilizing data collected from participants of the Raine Study Gen2. Dietary vitamin A intake, determined via food frequency questionnaires completed at ages 14, 17, and 20 years, was compared with ophthalmic measurements collected at year 20. Low vitamin A levels were defined as <600 µg/day. Regression models were used to adjust for ocular sun exposure level, educational level, and parental myopia as potential confounders.

Results: A total of 642 subjects were analyzed. Although those with adequate vitamin A intakes were less likely to be myopic ( = 0.03), this association became insignificant when adjusted for potential confounding factors in logistic regression modeling (odds ratio, 0.59; 95% confidence interval, 0.98-2.52; = 0.06).

Conclusions: There were no significant associations between total vitamin A intakes during adolescence and year 20 refractive errors after adjustment for confounders. Replication of this finding and further investigations are essential to rule out the suggestion that sufficient vitamin A intake during adolescence is associated with lower risk of myopia in early adulthood.

Translational Relevance: Our findings are not definitive that ingesting foods high in vitamin A during childhood and adolescence does not have a role for preventing myopia in early adulthood.
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http://dx.doi.org/10.1167/tvst.9.6.29DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408804PMC
May 2020

Cataract surgical patients as a candidate sentinel population for SARS-CoV-2 surveillance.

Clin Exp Ophthalmol 2020 12 11;48(9):1316-1318. Epub 2020 Sep 11.

Department of Surgery, Ophthalmology, University of Melbourne, Melbourne, Victoria, Australia.

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http://dx.doi.org/10.1111/ceo.13844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461235PMC
December 2020

Recurrent Rare Copy Number Variants Increase Risk for Esotropia.

Invest Ophthalmol Vis Sci 2020 08;61(10):22

Department of Ophthalmology, Boston Children's Hospital, Boston, Massachusetts, United States.

Purpose: To determine whether rare copy number variants (CNVs) increase risk for comitant esotropia.

Methods: CNVs were identified in 1614 Caucasian individuals with comitant esotropia and 3922 Caucasian controls from Illumina SNP genotyping using two Hidden Markov model (HMM) algorithms, PennCNV and QuantiSNP, which call CNVs based on logR ratio and B allele frequency. Deletions and duplications greater than 10 kb were included. Common CNVs were excluded. Association testing was performed with 1 million permutations in PLINK. Significant CNVs were confirmed with digital droplet polymerase chain reaction (ddPCR). Whole genome sequencing was performed to determine insertion location and breakpoints.

Results: Esotropia patients have similar rates and proportions of CNVs compared with controls but greater total length and average size of both deletions and duplications. Three recurrent rare duplications significantly (P = 1 × 10-6) increase the risk of esotropia: chromosome 2p11.2 (hg19, 2:87428677-87965359), spanning one long noncoding RNA (lncRNA) and two microRNAs (OR 14.16; 95% confidence interval [CI] 5.4-38.1); chromosome 4p15.2 (hg19, 4:25554332-25577184), spanning one lncRNA (OR 11.1; 95% CI 4.6-25.2); chromosome 10q11.22 (hg19, 10:47049547-47703870) spanning seven protein-coding genes, one lncRNA, and four pseudogenes (OR 8.96; 95% CI 5.4-14.9). Overall, 114 cases (7%) and only 28 controls (0.7%) had one of the three rare duplications. No case nor control had more than one of these three duplications.

Conclusions: Rare CNVs are a source of genetic variation that contribute to the genetic risk for comitant esotropia, which is likely polygenic. Future research into the functional consequences of these recurrent duplications may shed light on the pathophysiology of esotropia.
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http://dx.doi.org/10.1167/iovs.61.10.22DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443120PMC
August 2020
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