Opthalmology & Visual Sciences publications

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Open Access
A polygenic risk score predicts functional progression in early primary open-angle glaucoma
(Association for Research in Vision & Ophthalmology, 2022) Siggs, O.; Qassim, A.; Han, X.; Marshall, H.; Mullany, S.; Souzeau, E.; Galanopoulos, A.; Agar, A.; Landers, J.; Casson, R.; Hewitt, A.W.; Healey, P.; Graham, S.L.; MacGregor, S.; Craig, J.; The Association for Research in Vision & Ophthalmology Annual Meeting (ARVO) (1 May 2022 - 5 May 2022 : Denver, CO, USA & online)
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A polygenic risk score predicts intraocular pressure readings outside office hours and early morning spikes as measured by home tonometry
(Elsevier, 2020) Qassim, A.; Mullany, S.; Awadalla, M.S.; Hassall, M.M.; Nguyen, T.; Marshall, H.; Kolovos, A.; Schulz, A.M.; Han, X.; Gharahkhani, P.; Galanopoulos, A.; Agar, A.; Healey, P.R.; Hewitt, A.W.; Landers, J.; Casson, R.J.; Graham, S.L.; MacGregor, S.; Souzeau, E.; Siggs, O.M.; et al.
OBJECTIVE: Intraocular pressure (IOP) elevations may occur in early morning or outside office hours and can be missed during routine in-clinic IOP measurements. Such fluctuations or peaks likely contribute to glaucoma progression. We sought to investigate the relationship between an IOP polygenic risk score (PRS) and short-term IOP profile. DESIGN: Cross-sectional study. PARTICIPANTS: 473 eyes from 239 participants with suspected or established primary open angle glaucoma sampled from the PROGRESSA study from four outpatient ophthalmology clinics in Australia between August 2016 and December 2019. METHODS: Participants underwent Icare HOME tonometer measurements to record IOP four times a day for five days. Unreliable measurements were excluded. A minimum of two days with at least three reliable measurements were required. We used a previously-validated IOP PRS derived from 146 common IOP-associated variants in a linear regression model with adjustment for central corneal thickness and age. MAIN OUTCOME MEASURES: Highest recorded early-morning IOP, and mean IOP within and outside office hours. Early-morning IOP spikers were defined as eyes with a higher early-morning IOP than the highest recorded IOP during office hours. RESULTS: 334 eyes from 176 participants (mean age 64 years, SD 9) generated reliable measurements for inclusion. Eyes in the highest IOP PRS quintile had an early-morning IOP increase by 4.3 mmHg (95% confidence interval [CI] 1.4-7.3; P = 0.005) and mean IOP outside office hours increase of 2.7 mmHg (95% CI 0.61-4.7; P = 0.013) than the lowest quintile, which were independently significant after accounting for a recent in-clinic IOP measured by Goldmann applanation tonometry. Eyes in the highest PRS quintile were 5.4-fold more likely to be early-morning IOP spikers than the lowest quintile (odds ratio 95% CI 1.3-23.6; P = 0.023) CONCLUSION: A previously validated IOP PRS was associated with higher early-morning IOP, and mean IOP outside office hours. These findings support a role for genetic risk prediction of susceptibility to elevated IOP that may not be apparent in-clinic hours, requiring more detailed clinical phenotyping using home tonometry, the results of which may guide additional interventions to improve IOP control.
Open Access
An intraocular pressure polygenic risk score stratifies multiple primary open-angle glaucoma parameters including treatment intensity
(Elsevier, 2020) Qassim, A.; Souzeau, E.; Siggs, O.M.; Hassall, M.M.; Han, X.; Griffiths, H.L.; Frost, N.A.; Vallabh, N.A.; Kirwan, J.F.; Menon, G.; Cree, A.J.; Galanopoulos, A.; Agar, A.; Healey, P.R.; Graham, S.L.; Landers, J.; Casson, R.J.; Gharahkhani, P.; Willoughby, C.E.; Hewitt, A.W.; et al.
Abstract not available.
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Association between Body Mass Index and Primary Open-Angle Glaucoma in Three Cohorts
(Elsevier, 2023) Marshall, H.; Berry, E.C.; Torres, S.D.; Mullany, S.; Schmidt, J.; Thomson, D.; Nguyen, T.T.; Knight, L.S.W.; Hollitt, G.; Qassim, A.; Kolovos, A.; Ridge, B.; Schulz, A.; Lake, S.; Mills, R.A.; Agar, A.; Galanopoulos, A.; Landers, J.; Healey, P.R.; Graham, S.L.; et al.
Purpose: To evaluate the relationship between body mass index (BMI) and glaucoma progression. DESIGN: Multicohort observational study Methods: This study combined a retrospective longitudinal analysis of suspect and early manifest primary open-angle glaucoma cases from the Progression Risk of Glaucoma: RElevant SNPs with Significant Association (PROGRESSA) study, with two replication cohorts from the UK Biobank and the Canadian Longitudinal Study of Ageing (CLSA). In the PROGRESSA study, multivariate analysis correlated BMI with longitudinal visual field progression in 471 participants. BMI was then associated with glaucoma diagnosis and cross-sectional VCDR measurements in the UK Biobank, and finally prospectively associated with longitudinal change in VCDR in the CLSA study, and with Results: In the PROGRESSA study, a lower BMI conferred a faster rate of visual field progression (Mean duration of monitoring (5.28±1.80years (10.6±3.59 visits) (beta: 0.04dB/year/SD [0.005, 0.069] P=0.013). In the UK Biobank a 1 standard deviation lower BMI was associated with a worse cross-sectional VCDR (beta: -0.048/SD [-0.056, 0.96] P<0.001), and with a 10% greater likelihood of glaucoma diagnosis, as per specialist grading of retinal fundus imaging (OR: 0.90 [0.84, 0.98] P=0.011). Similarly, a lower BMI was associated with a greater risk of glaucoma diagnosis as per International Classification of Disease data (OR: 0.94/SD 95% CI: [0.91, 0.98] P=0.002). BMI was also positively correlated with IOP (beta: 0.11/SD 95% CI: [0.06, 0.15] P<0.001). Finally, a lower BMI was then associated with greater VCDR change in the CLSA (beta: -0.007/SD 95% CI: [-0.01, -0.001] P=0.023). Conclusions: Body mass index was correlated with longitudinal and cross-sectional glaucomatous outcomes. This supports previous work illustrating a correlation between BMI and glaucoma.
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Association of High Polygenic Risk With Visual Field Worsening Despite Treatment in Early Primary Open-Angle Glaucoma
(American Medical Association, 2023) Siggs, O.M.; Qassim, A.; Han, X.; Marshall, H.N.; Mullany, S.; He, W.; Souzeau, E.; Galanopoulos, A.; Agar, A.; Landers, J.; Casson, R.J.; Hewitt, A.W.; Healey, P.R.; Graham, S.L.; MacGregor, S.; Craig, J.E.
Importance: Irreversible vision loss from primary open-angle glaucoma (POAG) can be prevented through timely diagnosis and treatment, although definitive diagnosis can be difficult in early-stage disease. As a consequence, large numbers of individuals with suspected glaucoma require regular monitoring, even though many of these may never develop disease and other high-risk individuals with suspected glaucoma may have delayed or inadequate treatment. POAG is one of the most heritable common diseases, and this provides an opportunity to use genetic instruments in risk-stratified screening, diagnosis, and treatment of early glaucoma. Objective: To assess the association of glaucoma polygenic risk with glaucoma progression in early-stage disease. Design, Setting, and Participants: This cohort study used clinical and genetic data obtained from a longitudinal cohort study, Progression Risk of Glaucoma: Relevant SNPs With Significant Association (PROGRESSA). Participants of European ancestry with characteristic optic nerve head changes suggestive of glaucoma were included. Data were collected between February 2012 and June 2020. Analysis took place between July 2020 and April 2022. Main Outcomes and Measures: The association of a glaucoma polygenic risk score (PRS) (2673 uncorrelated variants) with rate of peripapillary retinal nerve fiber layer thinning on optical coherence tomography and progression of visual field loss on 24-2 Humphrey visual fields. Results: A total of 1777 eyes from 896 individuals had sufficient data for structural progression analyses and 1563 eyes from 808 individuals for functional progression analyses. The mean (SD) age was 62.1 (9.9) years, 488 (44%) were male, and 1087 of 1103 individuals (98.5%) had European ancestry. An ancestrally matched normative population cohort (n = 17 642) was used for PRS reference. Individuals in the top 5% PRS risk group were at a higher risk of visual field progression compared with the remaining 95% after 5 years (hazard ratio, 1.5; 95% CI, 1.13-1.97; P = .005). Conversely, those in the bottom 20% PRS risk group were at a lower risk of visual field progression compared with an intermediate risk group over 3 years (hazard ratio, 0.52; 95% CI, 0.28-0.96; P = .04). Conclusions and Relevance: In this study, high polygenic risk was associated with more rapid structural and functional progression in early POAG, despite more intensive treatment. A PRS may serve as a valuable adjunct to identify individuals who stand to benefit the most from more frequent surveillance and earlier or more intensive treatment.
Open Access
Cardiovascular disease predicts structural and functional progression in early glaucoma
(Elsevier, 2021) Marshall, H.; Mullany, S.; Qassim, A.; Hassall, M.; Siggs, O.; Ridge, B.; Nguyen, T.; Awadalla, M.; Andrew, N.; Healey, P.; Agar, A.; Galanopoulos, A.; Hewitt, A.; Macgregor, S.; Graham, S.; Mills, R.; Landers, J.; Casson, R.; Craig, J.
Purpose: To investigate the association between cardiovascular disease and baseline structural defects and disease progression in glaucoma. Design: Prospective, longitudinal study of preperimetric and perimetric glaucoma. Participants: Two thousand six hundred twenty-eight eyes from 1314 participants recruited to the Progression Risk of Glaucoma: Relevant SNPs with Significant Association (PROGRESSA) study were evaluated for baseline and longitudinal structural thinning using spectral-domain OCT and for visual field progression on Humphrey visual field (HVF) assessment. Methods: Patients were classified as either predominantly macula ganglion cell–inner plexiform layer (mGCIPL), predominantly peripapillary retinal nerve fiber layer (pRNFL), or both mGCIPL and pRNFL structural change at enrollment, and then evaluated for longitudinal OCT or HVF progression. Cardiovascular disease and medication characteristics of the participants were compared with a reference group of stable patients. Main Outcome Measures: OCT and HVF baseline status and longitudinal progression. Results: After accounting for age and cardiovascular characteristics, patients with predominantly mGCIPL thinning at baseline showed a higher prevalence of hypertension (odds ratio [OR], 2.70; 95% confidence interval [CI], 1.66–4.41; P < 0.001), antihypertensive use (OR, 2.03; 95% CI, 1.20–3.46; P = 0.008), and statin use (OR, 1.98; 95% CI, 1.07–3.66; P = 0.029) than reference patients. Patients with predominantly pRNFL thinning exhibited a comparable prevalence of cardiovascular disease or medication with reference patients. Review of longitudinal OCT and HVF data (mean follow-up, 5.34 ± 1.29 years) showed that hypertension was associated with an increased risk of both OCT (OR, 1.79; 95% CI, 1.17–2.75; P = 0.006) and HVF progression (OR, 1.92; 95% CI, 1.18–3.15; P = 0.013). A 1-standard deviation (approximately 21 mmHg) increase in systolic blood pressure at baseline was associated with a greater risk of OCT progression (OR, 1.27; 95% CI, 1.01–1.63; P = 0.041) and HVF progression (OR, 1.32; 95% CI, 1.01–1.73; P = 0.043). The association between systolic blood pressure and structural progression was comparable to that observed between intraocular pressure and structural progression (OR, 1.30; 95% CI, 1.01–1.67; P = 0.039). Conclusions: Cardiovascular disease is an important risk factor for glaucoma progression.
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Corneal stiffness parameters are predictive of structural and functional progression in glaucoma suspect eyes
(Elsevier, 2020) Qassim, A.; Mullany, S.; Abedi, F.; Marshall, H.; Hassall, M.M.; Kolovos, A.; Knight, L.S.W.; Nguyen, T.; Awadalla, M.S.; Chappell, A.; Schulz, A.M.; Galanopoulos, A.; Agar, A.; Healey, P.R.; Hewitt, A.W.; Graham, S.L.; Landers, J.; Casson, R.J.; Siggs, O.M.; Craig, J.E.
Purpose: To investigate corneal stiffness parameters (SPs) as predictors of future progression risk in glaucoma suspect eyes. Design: Prospective, longitudinal study. Participants: Three hundred seventy-one eyes from 228 primary open-angle glaucoma suspects, based on optic disc appearance, with normal baseline Humphrey Visual Field (HVF; Carl Zeiss Meditec) results. Methods: Baseline corneal SPs were measured using Corvis ST (Oculus Optikgeräte GmbH). Participants were followed up every 6 months with clinical examination, HVF testing, and OCT. The baseline SP at first applanation (SP-A1) and highest concavity predicted the prospective outcome measures. Main Outcome Measures: Structural progression was measured by the OCT rate of thinning of the retinal nerve fiber layer (RNFL) and ganglion cell–inner plexiform layer (GCIPL). Functional progression was assessed by permutation analysis of pointwise linear regression criteria on HVF testing. Results: Stiffness parameters correlated positively with central corneal thickness (CCT), which was adjusted for in all analyses. A higher SP-A1, suggestive of a stiffer cornea, was associated with a faster rate of RNFL thinning (P < 0.001), synergistic with thinner CCT (P = 0.004) over a mean follow-up of 4.2 years. Eyes with higher SP-A1 and thinner CCT (thin and stiff corneas) showed accelerated RNFL thinning by 0.72 μm/year relative to eyes with lower SP-A1 and thicker CCT (95% confidence interval [CI], 0.17–1.28; P = 0.011) and were at 2.9-fold higher likelihood of fast RNFL progression of more than 1 μm/year (95% CI, 1.4–6.1; P = 0.006). Consistent results also were observed with GCIPL thinning. Furthermore, a higher SP-A1 was associated with a greater risk of visual field progression (P = 0.002), synergistic with thinner CCT (P = 0.010). Eyes with higher SP-A1 and thinner CCT were at 3.7-fold greater risk of visual field progression relative to eyes with thicker CCT and lower SP-A1 (95% CI, 1.3–10.5; P = 0.014). Conclusions: Glaucoma suspect eyes with higher corneal SPs and lower CCT, suggestive of thin and stiff corneas, are at greater risk of progression. Corneal SPs seem to act synergistically with CCT as risk factors for glaucoma progression.
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High Polygenic Risk is Associated with Earlier Initiation and Escalation of Treatment in Early Primary Open Angle Glaucoma
(Elsevier, 2023) Marshall, H.N.; Mullany, S.; Han, X.; Qassim, A.; He, W.; Hassall, M.M.; Schmidt, J.; Thomson, D.; Nguyen, T.T.; Berry, E.C.; Knight, L.S.; Hollitt, G.L.; Ridge, B.; Schulz, A.; Mills, R.A.; Healey, P.R.; Agar, A.; Galanopoulos, A.; Landers, J.; Graham, S.L.; et al.
Purpose: To assess the association between a glaucoma polygenic risk score (PRS) and treatment outcomes in primary open-angle glaucoma. Design: Prospective, observational cohort study. Participants: Participants from the Progression Risk of Glaucoma: Relevant SNPs with Significant Association Study were divided into a cohort with suspect glaucoma who were treatment naive at enrollment and one with early manifest and suspect glaucoma receiving treatment at enrollment. Methods: A per-allele weighted glaucoma PRS was calculated for 1107 participants. Multivariable mixedeffects Cox proportional regression analysis assessed the association between PRS and time to commencement of intraocular pressure (IOP)-lowering therapy in 416 patients with suspect glaucoma who were treatment naive at study enrollment. Secondary analysis evaluated the association between PRS and escalation of IOPlowering therapy among 691 patients with suspect and early manifest glaucoma who were receiving IOPlowering therapy at enrollment. Main Outcome Measures: Commencement or escalation of IOP-lowering therapy. Results: A higher PRS was associated with a greater risk of commencing IOP-lowering therapy within 5 years (hazard ratio [HR], 1.45 per 1 standard deviation [/SD]; 95% confidence interval [CI], 1.27e1.62; P < 0.001). Participants in the upper population-based quintile showed a 3.3 times greater risk of commencing therapy by 5 years than those in the lowest quintile (HR, 3.30; 95% CI, 1.63e6,70; P < 0.001) and a 5.4 times greater risk of commencing IOP-lowering therapy by 2 years than the those in the lowest quintile (HR, 5.45; 95% CI, 2.08e14.25; P < 0.001). A higher PRS was associated with a greater risk of treatment escalation among patients receiving treatment at enrollment (HR, 1.19/SD; 95% CI, 1.09e1.31; P < 0.001). In combined analysis of all participants, participants in the top population-based quintile were at 2.3 times greater risk of requiring initiation or escalation of IOP-lowering therapy than those in the lowest quintile (HR, 2.33; 95% CI, 1.75e3.01; P < 0.001). Conclusions: This study demonstrated novel associations between glaucoma polygenic risk and risk of commencement or escalation of IOP-lowering therapy, building on previous work highlighting the potential clinical usefulness of genetic risk stratification in glaucoma.
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High-speed cannula detachment into the eye during hydrodissection
(Slack, 2014) McPherson, Z.E.; Lau, O.C.; Chen, T.S.; Kam, A.W.; Amjadi, S.; Zhang, M.G.; Playfair, T.J.; Agar, A.; Francis, I.C.
Detachment of a hydrodissection cannula during a phacoemulsification procedure appeared to produce no adverse sequelae during surgery. Day 1 postoperatively, two nonpenetrating hemorrhagic retinal lesions were identified; there was no evidence of posterior capsular perforation. Day 6 postoperatively, the pupil was temporally peaked by a fine vitreous strand running to the main-port incision in the superotemporal cornea. This was divided with Nd:YAG laser, and argon laser was applied to encircle the two retinal lesions. Postoperative uncorrected visual acuity remained 6/4 at day 1, day 6, and week 4 (3 weeks after laser application) follow-up visits. Surgeons must accept responsibility for confirming the integrity of the cannula and syringe connection before beginning hydrodissection, which can be highly destructive to intracameral structures.
Open Access
The APOE E4 allele is associated with faster rates of mGCIPL thinning in the PROGRESSA cohort
(Association for Research in Vision & Ophthalmology, 2022) Mullany, S.; Marshall, H.; Souzeau, E.; Hassall, M.; Agar, A.; Galanopoulos, A.; Landers, J.; Mitchell, P.; Healey, P.; Graham, S.L.; Hewitt, A.W.; MacGregor, S.; Gharahkhani, P.; Casson, R.; Siggs, O.; Craig, J.E.; The Association for Research in Vision & Ophthalmology Annual Meeting (ARVO) (1 May 2022 - 5 May 2022 : Denver, CO, USA & online)

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