Optometry and Vision Sciences - Research Publications
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ItemNo Preview AvailableGenetic testing and gene therapy in retinal diseases: Knowledge and perceptions of optometrists in Australia and New Zealand(WILEY, 2024-01)With advances in gene-based therapies for heritable retinal diseases, primary eye care clinicians should be informed on ocular genetics topics. This cross-sectional survey evaluated knowledge, attitudes, and concerns regarding genetic testing and gene therapy for retinal diseases among optometrists in Australia and New Zealand. Survey data included practitioner background, attitudes and practices towards genetic testing for monogenic inherited retinal disease (IRDs) and age-related macular degeneration, and knowledge of ocular genetics and gene therapy. Responses were received from 516 optometrists between 1 April and 31 December 2022. Key perceived barriers to accessing genetic testing were lack of clarity on referral pathways (81%), cost (65%), and lack of treatment options if a genetic cause is identified (50%). Almost all respondents (98%) believed that ophthalmologists should initiate genetic testing for IRDs and fewer understood the role of genetic counsellors and clinical geneticists. This study found that optometrists in Australia and New Zealand have a high level of interest in ocular genetics topics. However, knowledge gaps include referral pathways and awareness of genetic testing and gene therapy outcomes. Addressing perceived barriers to access and promoting sharing of knowledge between interdisciplinary networks can set the foundation for genetic education agendas in primary eye care.
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ItemNo Preview AvailableCharacterising the diagnosis of genetic maculopathies in a real-world private tertiary retinal practice in Australia: protocol for a retrospective clinical audit(TAYLOR & FRANCIS LTD, 2023-12-12)PURPOSE: Accurate diagnosis of macular atrophy is paramount to enable appropriate treatment when novel treatments for geographic atrophy and macular dystrophies become available. Genetic testing is useful in distinguishing between the two conditions but is not feasible for the majority of patients in real-world clinical practice. Therefore, we aimed to investigate the potential misdiagnosis of inherited macular dystrophy as age-related macular degeneration (AMD) in real-world ophthalmic practice to assist in the development of guidelines to improve diagnostic accuracy while minimizing genetic testing for targeted patients. METHODS: Retrospective review of the medical records of patients diagnosed with AMD, which included imaging, between 1995 and 2023 from a large multidisciplinary private ophthalmic practice in Australia. We will use a stepwise method to screen for probable cases of macular dystrophy, followed by a consensus review by an expert panel. The outcomes are (1) to determine the potential misdiagnosis rate of macular dystrophy as atrophic AMD by retinal specialists and general ophthalmologists; (2) to identify clinical imaging modalities that are most useful for differentiating macular dystrophy from atrophic AMD; and (3) to establish preliminary guidance for clinicians to improve the diagnosis of macular atrophy from AMD in practice, and thereby target cost-efficient genetic testing. DISCUSSION: Improving the diagnostic accuracy of both AMD and macular dystrophy, while ensuring cost-efficient genetic testing, will improve the targeted treatment of macular diseases when emerging treatments become available.
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ItemNo Preview AvailableAdaptive optics imaging in inherited retinal diseases: A scoping review of the clinical literature(ELSEVIER SCIENCE INC, 2024)Adaptive optics (AO) imaging enables direct, objective assessments of retinal cells. Applications of AO show great promise in advancing our understanding of the etiology of inherited retinal disease (IRDs) and discovering new imaging biomarkers. This scoping review systematically identifies and summarizes clinical studies evaluating AO imaging in IRDs. Ovid MEDLINE and EMBASE were searched on February 6, 2023. Studies describing AO imaging in monogenic IRDs were included. Study screening and data extraction were performed by 2 reviewers independently. This review presents (1) a broad overview of the dominant areas of research; (2) a summary of IRD characteristics revealed by AO imaging; and (3) a discussion of methodological considerations relating to AO imaging in IRDs. From 140 studies with AO outcomes, including 2 following subretinal gene therapy treatments, 75% included fewer than 10 participants with AO imaging data. Of 100 studies that included participants' genetic diagnoses, the most common IRD genes with AO outcomes are CNGA3, CNGB3, CHM, USH2A, and ABCA4. Confocal reflectance AO scanning laser ophthalmoscopy was the most reported imaging modality, followed by flood-illuminated AO and split-detector AO. The most common outcome was cone density, reported quantitatively in 56% of studies. Future research areas include guidelines to reduce variability in the reporting of AO methodology and a focus on functional AO techniques to guide the development of therapeutic interventions.
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ItemNo Preview AvailableAssessment of photoreceptor function with ultrafast retinal densitometry(Optica Publishing Group, 2022-10-01)The optical density of visual pigment can be measured by imaging the dark-adapted eye while bleaching with visible light. This measurement can be made for individual photoreceptor cells using adaptive optics; however, activation of the phototransduction cascade imparts rapid changes in phase that modulate the signal via optical interference. This limits utility because data must be averaged over many experimental runs. Here we used a "flood" illuminated adaptive optics system at 4000 fps, bright light to achieve rapid bleaching, and broad illumination bandwidth to mitigate interference effects. Data were super-resolved using the natural motion of the eye to overcome the reduced pixel resolution of the ultrafast camera. This approach was applied to classify the trichromatic cone photoreceptor mosaic at a single fixation locus within the foveal region of 3 healthy subjects. Subjects were dark adapted for 6 minutes to replenish cone photopigment. This was followed either directly by imaging at 555 ± 50 nm, or by first pre-adapting the retina to 700 nm light to preferentially deplete "L" cone pigment. A total of 3,252 cones were classified as either "S", "M", or "L" type based on clustering of the intensity data observed under these two conditions. Mean classification probability ranged from 99.3 to 99.8%, with individual cell probabilities exceeding 95% in 97.0 to 99.2% of cones. Accuracy of cone classification peaked when using the first 10-30 ms of data, with significant reductions in accuracy noted with the inclusion of data from later times. Our results show that rapid bleaching and data acquisition significantly improve the robustness of cell-resolved densitometry.
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ItemThe Diagnostic Yield of Next Generation Sequencing in Inherited Retinal Diseases: A Systematic Review and Meta-analysis(Elsevier, 2023-05)PURPOSE: Accurate genotyping of individuals with inherited retinal diseases (IRD) is essential for patient management and identifying suitable candidates for gene therapies. This study evaluated the diagnostic yield of next generation sequencing (NGS) in IRDs. DESIGN: Systematic review and meta-analysis. METHODS: This systematic review was prospectively registered (CRD42021293619). Ovid MEDLINE and Ovid Embase were searched on 6 June 2022. Clinical studies evaluating the diagnostic yield of NGS in individuals with IRDs were eligible for inclusion. Risk of bias assessment was performed. Studies were pooled using a random...effects inverse variance model. Sources of heterogeneity were explored using stratified analysis, meta-regression, and sensitivity analysis. RESULTS: This study included 105 publications from 28 countries. Most studies (90 studies) used targeted gene panels. The diagnostic yield of NGS was 61.3% (95% confidence interval: 57.8-64.7%; 51 studies) in mixed IRD phenotypes, 58.2% (51.6-64.6%; 41 studies) in rod-cone dystrophies, 57.7% (46.8-68.3%; eight studies) in macular and cone/cone-rod dystrophies, and 47.6% (95% CI: 41.0-54.3%; four studies) in familial exudative vitreoretinopathy. For mixed IRD phenotypes, a higher diagnostic yield was achieved pooling studies published between 2018-2022 (64.2% [59.5-68.7%]), studies using exome sequencing (73.5% [58.9-86.1%]), and studies using the American College of Medical Genetics variant interpretation standards (65.6% [60.8-70.4%]). CONCLUSION: The current diagnostic yield of NGS in IRDs is between 52-74%. The certainty of the evidence was judged as low or very low. A key limitation of the current evidence is the significant heterogeneity between studies. Adoption of standardized reporting guidelines could improve confidence in future meta-analyses.
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ItemVictorian evolution of inherited retinal diseases natural history registry (VENTURE study): Rationale, methodology and initial participant characteristics(WILEY, 2022-09)BACKGROUND: Emerging treatments are being developed for inherited retinal diseases, requiring a clear understanding of natural progression and a database of potential participants for clinical trials. This article describes the rationale, study design and methodology of the Victorian Evolution of inherited retinal diseases NaTUral history REgistry (VENTURE), including data from the first 150 participants enrolled. METHODS: VENTURE collects retrospective and prospective data from people with inherited retinal diseases. Following registration, participants are asked to attend a baseline examination using a standardised protocol to confirm their inherited retinal disease diagnosis. Examination procedures include (i) retinal function, using visual acuity and perimetry; (ii) retinal structure, using multimodal imaging and (iii) patient-reported outcomes. Participants' molecular diagnoses are obtained from their clinical records or through targeted-panel genetic testing by an independent laboratory. Phenotype and genotype data are used to enrol participants into disease-specific longitudinal cohort sub-studies. RESULTS: From 7 July 2020 to 30 December 2021, VENTURE enrolled 150 registrants (138 families) and most (63%) have a rod-cone dystrophy phenotype. From 93 participants who have received a probable molecular diagnosis, the most common affected genes are RPGR (13% of all registrants), USH2A (10%), CYP4V2 (7%), ABCA4 (5%), and CHM (5%). Most participants have early to moderate vision impairment, with over half (55%) having visual acuities of better than 6/60 (20/200) at registration. CONCLUSIONS: The VENTURE study will complement existing patient registries and help drive inherited retinal disease research in Australia, facilitating access to research opportunities for individuals with inherited retinal diseases.
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ItemSurvey of perspectives of people with inherited retinal diseases on ocular gene therapy in Australia(SPRINGERNATURE, 2023-04-01)Many gene therapies are in development for treating people with inherited retinal diseases (IRD). We hypothesized that potential recipients of gene therapy would have knowledge gaps regarding treatment. We aimed to assess knowledge, attitudes, and perceptions of genetic therapies among potential recipients with IRD, using a novel instrument we designed (Attitudes to Gene Therapy-Eye (AGT-Eye)) and their associations with demographic data, self-reported visual status, and tools assessing quality of life and attitudes toward clinical trials using a community-based cross-sectional survey of Australian adults with IRD. AGT-Eye, overall quality of life EQ-5D-5L, National Eye Institute Visual Functioning Questionnaire (NEI-VFQ-25) and Patient Attitudes to Clinical Trials (PACT-22) instruments were administered. Six hundred and eighty-one people completed the study, 51.7% women of mean age 53.5 years (SD ± 15.8). Most participants (91.6%) indicated they would likely accept gene therapy if it was available to them or family members. However, only 28.3% agreed that they had good knowledge of gene therapy. Most obtained information about gene therapy from the internet (49.3%). Respondents with post-graduate degrees scored highest compared to other educational levels on methods (p < 0.001) and outcomes (p = 0.003) and were more likely to see economic value of treatment (p = 0.043). Knowledge gaps were present regarding methods and outcomes of gene therapy. This survey has shown high level of interest in the IRD community for gene therapies, and highlights areas for improved clinician and patient education.
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ItemAssociation between systemic omega-3 polyunsaturated fatty acid levels, and corneal nerve structure and function(SPRINGERNATURE, 2023-06)BACKGROUND: Omega-3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have anti-inflammatory and neuroprotective properties. This study sought to determine the relationship between corneal parameters and systemic omega-3 fatty acid levels. METHODS: Forty-seven participants with no/mild peripheral neuropathy (26 with diabetes and 21 without) underwent comprehensive ocular surface and systemic PUFA assessments. Corneal anatomical parameters were assessed using in vivo confocal microscopy. Corneal sensitivity was measured using non-contact esthesiometry. Relationships between systemic PUFA levels and corneal parameters were evaluated with multiple linear regression, adjusted for age, sex, neuropathy symptom score, and presence of diabetes and dry eye disease. The relationship between corneal nerve fibre length (CNFL) and corneal sensitivity threshold was evaluated. RESULTS: The median Omega-3 Index, a measure of erythrocyte EPA and DHA, was 5.21% (interquartile range: 4.44-5.94%) in the study population. Mean ( ± SD) CNFL was 13.53 ± 3.37 mm/mm2. Multiple linear regression showed that Omega-3 Index (β = 0.33; p = 0.02), age (β = -0.46; p = 0.001) and diabetes (β = -0.30; p = 0.03) were independently associated with CNFL (R2 = 0.39, p = 0.002). In a separate model, DHA (β = 0.32; p = 0.027) and age (β = -0.41; p = 0.003) were associated with CNFL (R2 = 0.37, p = 0.003). Neither systemic EPA nor omega-6 fatty acid levels correlated with CNFL. There was no association between PUFA levels and corneal sensitivity or corneal immune cell density. A negative correlation was found between CNFL and corneal sensation thresholds to a cooled stimulus in diabetes participants, in the central (ρ = -0.50; p = 0.009) and peripheral (ρ = -0.50; p = 0.01) cornea. CONCLUSIONS: A positive relationship between the systemic Omega-3 Index and corneal nerve parameters suggests omega-3 PUFA intake may influence corneal nerve architecture.
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ItemGenetic Testing of Inherited Retinal Disease in Australian Private Tertiary Ophthalmology Practice(DOVE MEDICAL PRESS LTD, 2022)BACKGROUND: To assess the prevalence of genetic testing for inherited retinal diseases (IRDs) in a tertiary practice setting. METHODS: Single-centre retrospective analysis of patients with diagnosed or suspected IRD. RESULTS: Four hundred and sixty-four patient records were analysed. Patients had received care for different IRDs grouped as follows: panretinal pigmentary retinopathies (283, 61%), macular dystrophies (136, 29.3%), stationary diseases (23, 5%), hereditary vitreoretinopathies (14, 3%), and other IRDs (8, 1.7%). The suspected pattern of inheritance of patients' IRD was predominantly autosomal recessive (205, 44.2%). Genetic testing was performed with the corresponding results available for 44 patients (9.5%). Diagnostic yield was 65.9% for the results received. Genetic test results were available mostly for younger patients (13.1% for <45 years vs 6.2% ≥45 years of age, p = 0.01) and those who received greater than 12 months of care (16% for ≥12 months vs 4% for <12 months, p < 0.01). For patients without genetic testing results, reasons include awaiting a geneticist consultation (17.9%), awaiting test results (4.5%), or patient refusal (8.4%). Most clinical records (69.2%) did not document genetic testing status. CONCLUSION: Genetic testing is increasingly being utilised in the work-up for patients with IRD worldwide. This large Australian private practice IRD cohort shows a low uptake of testing (around 10%), reflecting historical management patterns and accessibility of genetic counselling and testing. The results show that younger patients and those with a longer duration of care were more likely to have received genetic testing. As the importance of IRD genetic testing continues to increase, we expect to see a change in patient management within the Australian private ophthalmology system and testing rates to increase. Further research is required to identify and address clinician and patient barriers to improving genetic testing rates for IRD.
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ItemMeasurement Properties of the Attitudes to Gene Therapy for the Eye (AGT-Eye) Instrument for People With Inherited Retinal Diseases(ASSOC RESEARCH VISION OPHTHALMOLOGY INC, 2022-02)PURPOSE: To assess the measurement properties of the Attitudes to Gene Therapy for the Eye (AGT-Eye) instrument among Australian adults with inherited retinal diseases (IRDs) and parents/caregivers of people with IRDs. Constructs of interest included sources of information, knowledge of treatment methods, awareness of treatment outcomes, and perceived value of gene therapy for IRDs. METHODS: A cross-sectional, self-reported, 30-item questionnaire was administered in English from January to June 2021. It was predominantly conducted online with phone and paper alternatives available. Rating scale models were generated separately for each of the four subscales to assess fit, discrimination, and differential item functioning of the items, as well as targeting, reliability, and precision of the subscales. Principal components analysis was used to assess dimensionality. RESULTS: Responses from 681 participants (87.1% online, 12.9% phone/mail) were included (ages 18-93 years; 51.7% female). Removal of two poorly performing items slightly improved subscale properties. Item reliability was high for each of the subscales; however, person reliability was suboptimal, with limited ability to stratify participants according to traits (person separation coefficient < 1.8 for each subscale). There was no evidence of differential item functioning by gender, online completion, or patient/caregiver status. Evidence of multidimensionality was detected for two subscales. CONCLUSIONS: Four subscales of the AGT-Eye will be used to analyze operational knowledge and perceived value of ocular gene therapy in Australia. Measurement properties may be improved with the generation of additional items. TRANSLATIONAL RELEVANCE: Physicians can use the AGT-Eye to assess knowledge and expectations of potential recipients of ocular gene therapy for IRDs.