Improving statistical power of glaucoma clinical trials using an ensemble of cyclical generative adversarial networks

Albeit spectral-domain OCT (SDOCT) is now in clinical use for glaucoma management, published clinical trials relied on time-domain OCT (TDOCT) which is characterized by low signal-to-noise ratio, leading to low statistical power. For this reason, such trials require large numbers of patients observed over long intervals and become more costly. We propose a probabilistic ensemble model and a cycle-consistent perceptual loss for improving the statistical power of trials utilizing TDOCT. TDOCT are converted to synthesized SDOCT and segmented via Bayesian fusion of an ensemble of GANs. The final retinal nerve fibre layer segmentation is obtained automatically on an averaged synthesized image using label fusion. We benchmark different networks using i) GAN, ii) Wasserstein GAN (WGAN) (iii) GAN + perceptual loss and iv) WGAN + perceptual loss. For training and validation, an independent dataset is used, while testing is performed on the UK Glaucoma Treatment Study (UKGTS), i.e. a TDOCT-based trial. We quantify the statistical power of the measurements obtained with our method, as compared with those derived from the original TDOCT. The results provide new insights into the UKGTS, showing a significantly better separation between treatment arms, while improving the statistical power of TDOCT on par with visual field measurements

Aligning scan acquisition circles in optical coherence tomography images of the retinal nerve fibre layer

Optical coherence tomography (OCT) is widely used in the assessment of retinal nerve fibre layer thickness (RNFLT) in glaucoma. Images are typically acquired with a circular scan around the optic nerve head. Accurate registration of OCT scans is essential for measurement reproducibility and longitudinal examination. This study developed and evaluated a special image registration algorithm to align the location of the OCT scan circles to the vessel features in the retina using probabilistic modelling that was optimised by an expectation-maximization algorithm. Evaluation of the method on 18 patients undergoing large numbers of scans indicated improved data acquisition and better reproducibility of measured RNFLT when scanning circles were closely matched. The proposed method enables clinicians to consider the RNFLT measurement and its scan circle location on the retina in tandem, reducing RNFLT measurement variability and assisting detection of real change of RNFLT in the longitudinal assessment of glaucoma

Hierarchical Censored Bayesian Analysis of Visual Field Progression

Purpose: To develop a Bayesian model (BM) for visual field (VF) progression accounting for the hierarchical, censored and heteroskedastic nature of the data. Methods: Three versions of a hierarchical BM were developed: a simple linear (Hi-linear); censored at 0 dB (Hi-censored); heteroskedastic censored (Hi-HSK). For the latter, we modeled the test variability according to VF sensitivity using a large test-retest cohort (1396 VFs, 146 eyes with glaucoma). We analyzed a large cohort of 44,371 VF tests from 3352 eyes from five glaucoma clinics. We quantified the bias in the estimated rate-of-progression, the detection of progression (Hit-rate [HR]), the median time-to-progression and the prediction error of future observations (mean absolute error [MAE]). HR and time-to-progression were compared at matched false-positive-rate (FPR), quantified using permutations of a separate test-retest cohort (360 tests, 30 eyes with glaucoma). BMs were compared to simple linear regression and Permutation-Analyses-of Pointwise-Linear-Regression. Differences in time-to-progression were tested using survival analysis. Results: Censored models showed the smallest bias in the rate-of-progression. The three BMs performed very similarly in terms of HR and time-to-progression and always better than the other methods. The average reduction in time-to-progression was 37% with the BMs (P < 0.001) at 5% FPR. MAE for prediction was very similar among methods. Conclusions: Bayesian hierarchical models improved the detection of VF progression. Accounting for censoring improves the precision of the estimates, but minimal effect is provided by accounting for heteroskedasticity. Translational Relevance: These results are relevant for quantification of VF progression in practice and for clinical trials

Exploring Eye Movements in Patients with Glaucoma When Viewing a Driving Scene

Background: Glaucoma is a progressive eye disease and a leading cause of visual disability. Automated assessment of the visual field determines the different stages in the disease process: it would be desirable to link these measurements taken in the clinic with patient's actual function, or establish if patients compensate for their restricted field of view when performing everyday tasks. Hence, this study investigated eye movements in glaucomatous patients when viewing driving scenes in a hazard perception test (HPT). Methodology/Principal Findings: The HPT is a component of the UK driving licence test consisting of a series of short film clips of various traffic scenes viewed from the driver's perspective each containing hazardous situations that require the camera car to change direction or slow down. Data from nine glaucomatous patients with binocular visual field defects and ten age-matched control subjects were considered (all experienced drivers). Each subject viewed 26 different films with eye movements simultaneously monitored by an eye tracker. Computer software was purpose written to pre-process the data, co-register it to the film clips and to quantify eye movements and point-of-regard (using a dynamic bivariate contour ellipse analysis). On average, and across all HPT films, patients exhibited different eye movement characteristics to controls making, for example, significantly more saccades (P<0.001; 95% confidence interval for mean increase: 9.2 to 22.4%). Whilst the average region of ‘point-of-regard’ of the patients did not differ significantly from the controls, there were revealing cases where patients failed to see a hazard in relation to their binocular visual field defect. Conclusions/Significance: Characteristics of eye movement patterns in patients with bilateral glaucoma can differ significantly from age-matched controls when viewing a traffic scene. Further studies of eye movements made by glaucomatous patients could provide useful information about the definition of the visual field component required for fitness to drive

Efficacy of Repeat Selective Laser Trabeculoplasty in Medication-Naïve Open Angle Glaucoma and Ocular Hypertension during the LiGHT Trial

PURPOSE: To determine the efficacy of repeat selective laser trabeculoplasty (SLT) in medication-naïve open angle glaucoma (OAG) and ocular hypertensive (OHT) patients requiring repeat treatment for early to medium-term failure during the Laser in Glaucoma and Ocular Hypertension (LiGHT) trial. // DESIGN: Post-hoc analysis of SLT treatment arm of a multicentre prospective randomised-controlled-trial. // PARTICIPANTS: Treatment-naïve OAG or OHT requiring repeat 360-degree SLT within 18 months. Re-treatment was triggered by pre-defined IOP and disease-progression criteria (using objective individualised target IOPs) // METHODS: After SLT at baseline, patients were followed for a minimum of 18 months after second (‘repeat’) SLT. A mixed model analysis was performed with the eye as the unit of analysis, with crossed random-effects to adjust for correlation between fellow eyes and repeated measures within eyes. Kaplan-Meier curves plot the duration of effect. // OUTCOME MEASURES: Initial (‘early’) IOP lowering at 2-months and duration of effect following initial and Repeat SLT. // RESULTS: 115 eyes of 90 patients received Repeat SLT during first 18 months of the trial. Pre-treatment IOP prior to Initial SLT was significantly higher than that prior to pre-retreatment IOP of Repeat SLT (mean difference: 3.4, 95% confidence interval (CI) 2.6 to 4.3, mmHg; p<0.001). Absolute IOP reduction at 2-months was greater following Initial, compared to Repeat, SLT (mean difference: 1.0, 95% CI 0.2 to 1.8, mmHg; p=0.02). Adjusted absolute IOP reduction at 2-months (adjusting for IOP prior to initial or repeat laser) was greater following Repeat SLT (adjusted mean difference: -1.1, 95% CI -1.7 to -0.5, mmHg; p=0.001). 34 eyes were ‘early failures’ (retreated 2-months after Initial SLT) vs 81 ‘later failures’ (retreatment beyond 2-months following Initial SLT). No significant difference in early absolute IOP reduction at 2-months following Repeat SLT was noted between ‘early’ vs ‘later’ failures’ (mean difference: 0.3, 95% CI, -1.1 to 1.8,mmHg; p=0.655). Repeat SLT maintained drop-free IOP control in 67% of 115 eyes at 18 months, with no clinically-relevant adverse events. // CONCLUSION: These exploratory analyses demonstrate Repeat SLT can maintain IOP at or below Target IOP in medication-naive OAG and OHT eyes requiring retreatment with atleast an equivalent duration of effect to initial laser

Predicting visual function from the measurements of retinal nerve fiber layer structure

Purpose: To develop and validate a method for predicting visual function from retinal nerve fibre layer (RNFL) structure in glaucoma. Methods: RNFL thickness (RNFLT) measurements from GDxVCC scanning laser polarimetry (SLP) and visual field (VF) sensitivity from standard automated perimetry were made available from 535 eyes from three centres. In a training dataset, structure-function relationships were characterized using linear regression and a type of neural network: Radial Basis Function customised under a Bayesian framework (BRBF). These two models were used in a test dataset to 1) predict sensitivity values at individual VF locations from RNFLT measurements and 2) predict the spatial relationship between VF locations and positions at a peripapillary RNFLT measurement annulus. Predicted spatial relationships were compared with a published anatomical structure-function map. Results: Compared with linear regression, BRBF yielded a nearly two-fold improvement (P<0.001; paired t-test) in performance of predicting VF sensitivity in the test dataset (mean absolute prediction error of 2.9dB (standard deviation (SD) 3.7dB) versus 4.9dB (SD 4.0dB)). The predicted spatial structure-function relationship accorded better (P<0.001; paired t-test) with anatomical prior knowledge when the BRBF was compared with the linear regression (median absolute angular difference of 15° versus 62°). Conclusions: The BRBF generates clinically useful relationships that relate topographical maps of RNFL measurement to VF locations and allows the VF sensitivity to be predicted from structural measurements. This method may allow clinicians to evaluate structural and functional measures in the same domain. It could also be generalized to use other structural measures

Estimating the Distribution of True Rates of Visual Field Progression in Glaucoma

Purpose: The purpose of this study was to estimate the distribution of the true rates of progression (RoP) of visual field (VF) loss. . Methods: We analyzed the progression of mean deviation over time in series of ≥ 10 tests from 3352 eyes (one per patient) from 5 glaucoma clinics, using a novel Bayesian hierarchical Linear Mixed Model (LMM); this modeled the random-effect distribution of RoPs as the sum of 2 independent processes following, respectively, a negative exponential distribution (the "true" distribution of RoPs) and a Gaussian distribution (the "noise"), resulting in a skewed exGaussian distribution. The exGaussian-LMM was compared to a standard Gaussian-LMM using the Watanabe-Akaike Information Criterion (WAIC). The random-effect distributions were compared to the empirical cumulative distribution function (eCDF) of linear regression RoPs using a Kolmogorov-Smirnov test. Results: The WAIC indicated a better fit with the exGaussian-LMM (estimate [standard error]: 192174.4 [721.2]) than with the Gaussian-LMM (192595 [697.4], with a difference of 157.2 [22.6]). There was a significant difference between the eCDF and the Gaussian-LMM distribution (P < 0.0001), but not with the exGaussian-LMM distribution (P = 0.108). The estimated mean (95% credible intervals, CIs) "true" RoP (-0.377, 95% CI = -0.396 to -0.359 dB/year) was more negative than the observed mean RoP (-0.283, 95% CI = -0.299 to -0.268 dB/year), indicating a bias likely due to learning in standard LMMs. Conclusions: The distribution of "true" RoPs can be estimated with an exGaussian-LMM, improving model accuracy. Translational Relevance: We used these results to develop a fast and accurate analytical approximation for sample-size calculations in clinical trials using standard LMMs, which was integrated in a freely available web application

Two-year visual field outcomes of the treatment for advanced glaucoma study (TAGS)

Purpose to compare visual field (VF) progression between the two arms of the Treatment of Advanced Glaucoma Study (TAGS) Design post-hoc analysis of VF data from a two-arm multicenter randomized controlled clinical trial Methods 453 patients with newly diagnosed advanced open-angle glaucoma in at least one eye from 27 centers in the United Kingdom were randomized to either trabeculectomy (N = 227) or medications in their index eye (N = 226) and followed-up for two years with two 24-2 VF tests at baseline, 4, 12 and 24 months. We analyzed data for participants with a reliable VF (False positive rate < 15%) at baseline and at least two other time-points. Main Outcome Measures Average difference in rate of progression (RoP) was analyzed using a hierarchical Bayesian model. Time for each eye to progress from baseline beyond specific cut-offs (0.5, 1, 1.5 and 2 dB) was compared using survival analysis. Results 211 eyes in the trabeculectomy-first arm and 203 eyes in the medications-first arm were analyzed. The average RoPs (Estimate [95% Credible Intervals]) were -0.59 [-0.88, -0.31] dB/year in the medications-first arm and -0.40 [-0.67, -0.13] dB/year in the trabeculectomy-first arm. The difference was not significant (Bayesian p-value = 0.353). More eyes progressed in the medications-first arm: ≥0.5 dB (p = 0.001), ≥1dB (p = 0.014), ≥1.5dB (p = 0.071) and ≥2dB (p = 0.061). Conclusions there was no significant difference in the average RoP at two years. Initial trabeculectomy significantly reduced the proportion of progressing eyes