United Kingdom Glaucoma Treatment Study Research Articles

Does the Visual Field Improve After Initiation of Intraocular Pressure Lowering in the United Kingdom Glaucoma Treatment Study?

PurposeEvidence to support the hypothesis that visual field (VF) status can improve after initiation of intraocular pressure (IOP) reducing treatment is controversial. We take advantage of participant eligibility data from the United Kingdom Glaucoma Treatment Study (UKGTS) to test this hypothesis in newly diagnosed glaucomatous patients randomised to IOP lowering therapy or placebo. DesignMulticentre, randomised, triple-masked, placebo-controlled trial. ParticipantsNewly diagnosed open-angle glaucoma patients in the UKGTS with eligibility and baseline data (n = 202 and n = 205 participants from the treatment and placebo groups, respectively). MethodsUKGTS eligibility data, including two reliable VFs (Humphrey 24-2 SITA Standard) and IOP measurements were compared to UKGTS trial baseline data acquired after allocation to treatment (topical prostaglandin analog) or placebo eye drops. Mean change in VF mean deviation (MD) and proportion of eyes that improved MD by more than different thresholds were compared across this interval in the treatment and placebo groups. Secondary analyses included stratifying the groups by level of IOP, level of VF loss and age along with pointwise analyses including change in subsets of VF locations. Main outcome measureMean change in VF MD. ResultsMean (standard deviation [SD]) time between eligibility/baseline visits and reduction in IOP was 12 (3) weeks and 4.8 (4.2) and 1.0 (3.6) mmHg for the treated and placebo eyes, respectively. Mean (SD) change in MD was almost the same for the treated (-0.03 (1.45) dB) and placebo groups (+0.08 (1.72) dB) (P=0.47). Proportion of participants with an MD improvement of 1 dB or more were similar for both groups (P=0.25). No association was found between MD improvement and magnitude of IOP lowering. Stratifying data by IOP, level of VF loss and age did not reveal any differences between the treated and placebo groups and neither did any of the pointwise VF analyses. ConclusionInitial short-term VF changes in the treatment and placebo arms of UKGTS were the same. In these newly diagnosed patients (non-advanced glaucoma) we found no evidence to support the hypothesis that VF status improves after initial lowering of IOP by medical therapy.

Relationship between Intraocular Pressure Fluctuation and Visual Field Progression Rates in the United Kingdom Glaucoma Treatment Study

To investigate whether intraocular pressure (IOP) fluctuation is associated independently with the rate of visual field (VF) progression in the United Kingdom Glaucoma Treatment Study. Randomized, double-masked, placebo-controlled multicenter trial. Participants with ≥5 VFs (213 placebo, 217 treatment). Associations between IOP metrics and VF progression rates (mean deviation [MD] and five fastest locations) were assessed with linear mixed models. Fluctuation variables were mean Pascal ocular pulse amplitude (OPA), standard deviation (SD) of diurnal Goldmann IOP (diurnal fluctuation), and SD of Goldmann IOP at all visits (long-term fluctuation). Fluctuation values were normalized for mean IOP to make them independent from the mean IOP. Correlated nonfluctuation IOP metrics (baseline, peak, mean, supine, and peak phasing IOP) were combined with principal component analysis, and principal component 1 (PC1) was included as a covariate. Interactions between covariates and time from baseline modeled the effect of the variables on VF rates. Analyses were conducted separately in the two treatment arms. Associations between IOP fluctuation metrics and rates of MD and the five fastest test locations. In the placebo arm, only PC1 was associated significantly with the MD rate (estimate, -0.19 dB/year [standard error (SE), 0.04 dB/year]; P < 0.001), whereas normalized IOP fluctuation metrics were not. No variable was associated significantly with MD rates in the treatment arm. For the fastest five locations in the placebo group, PC1 (estimate, -0.58 dB/year [SE, 0.16 dB/year]; P < 0.001), central corneal thickness (estimate, 0.26 dB/year [SE, 0.10 dB/year] for 10 μm thicker; P= 0.01) and normalized OPA (estimate, -3.50 dB/year [SE, 1.04 dB/year]; P= 0.001) were associated with rates of progression; normalized diurnal and long-term IOP fluctuations were not. In the treatment group, only PC1 (estimate, -0.27 dB/year [SE, 0.12 dB/year]; P= 0.028) was associated with the rates of progression. No evidence supports that either diurnal or long-term IOP fluctuation, as measured in clinical practice, are independent factors for glaucoma progression; other aspects of IOP, including mean IOP and peak IOP, may be more informative. Ocular pulse amplitude may be an independent factor for faster glaucoma progression. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Follow-up studies of the classical landmark studies in Glaucoma.

It was not until the nineteen nineties that there was scientific evidence for the primary treatment concept of glaucoma, lowering intraocular pressure. The treatment concept of lowering intraocular pressure is now proven by randomized controlled clinical trials (landmark studies). This review provides an overview of the follow-up studies to these landmark studies from the last 18 months. The 20-year data of the ocular hypertension treatment study showed a 49% incidence of primary open-angle glaucoma. The data of this landmark study was used for developing different machine learning algorithms. Bilateral disease, disc hemorrhages, and higher intraocular pressure (IOP) were risk factors for visual field deterioration in the United Kingdom Glaucoma Treatment Study. The Advanced Glaucoma Intervention Trial and the Collaborative Initial Glaucoma Treatment Study identified demographic factors, comorbidity, and clinical variables associated with visual field damage. Analysis was performed on Chinese subsets from the Laser in Glaucoma and Ocular Hypertension Study (LiGHT). Looking at all the follow-up studies to the tube shunt landmark studies, preoperative IOP, neovascular glaucoma, Ahmed implantation, and younger age were predictors of failure. A follow-up study to the Effectiveness in Angle-Closure Glaucoma in Lens Extraction Study showed that patients were ten times more likely to maintain a drop-free target IOP after lens extraction than after laser iridotomy. A superior location for iridotomy results in significantly more significant angle widening than temporal or nasal locations, as shown by a follow-up study to the Zhongshan Angle Closure Prevention Trial using OCT and gonioscopy. The number of published follow-up studies to the landmark studies in glaucoma show the ongoing development of clinical questions in management of glaucoma.

Comparing Five Criteria for Evaluating Glaucomatous Visual Fields

No consensus exists on the relative superiority among criteria for evaluating glaucomatous visual field (VF) damage. We compared the sensitivities and specificities of 5 criteria-Glaucoma Hemifield Test (GHT), Hoddap-Anderson-Parrish 2 (HAP2), Foster, United Kingdom Glaucoma Treatment Study (UKGTS), and Low-pressure Glaucoma Treatment Study (LoGTS)-across various levels of functional and structural glaucomatous damage. Retrospective cross-sectional study. This single-center study included patients with suspect or known glaucoma with reliable VF (Humphrey 24-2 Swedish Interactive Thresholding Algorithm) and optical coherence tomography (OCT; Spectralis, Heidelberg Engineering) examinations within a 4-month period. One eye per patient was included. The level of functional and structural damage was defined by mean deviation (MD) and by an OCT score, respectively. We created the OCT score by counting the number of abnormal (MD percentile [P] <1%) global and sectoral averages of optic nerve head MRW, circumpapillary RNFL thickness, and macular GCL thickness. We inferred specificities and sensitivities from positive rates of the criteria in patients with low glaucomatous damage (MD at P ≥ 10% or OCT score = 0) and with higher damage (MD at P < 10% or OCT score > 0), respectively. We included 1230 patients. In patients with low glaucomatous damage, HAP2 and UKGTS had higher positive rates, suggesting lower specificities, whereas GHT, Foster, and LoGTS had lower positive rates, suggesting higher specificities. In patients with higher glaucomatous damage, HAP2 and UKGTS had higher positive rates, indicating higher sensitivities, whereas GHT, Foster, and LoGTS had lower positive rates, indicating lower sensitivities. No criteria had uniformly superior performance. Selection of criteria should consider the degree of damage anticipated and the desire for either higher sensitivity or specificity.

Structure/function/treatment in glaucoma: progress over the last 10years

Since the 1990s several so-called landmark studies were carried out, which played an important role in the management of glaucoma patients due to their multicenter, randomized and masked structure. The Ocular Hypertension Treatment Study (OHTS) and the Collaborative Initial Treatment Glaucoma Study (CIGTS) and their follow-up studies are especially important in the conservative glaucoma management and in the evaluation of structure and function. The OHTS examined if lowering of the intraocular pressure (IOP) treatment reduces the progression from ocular hypertension to primary open angle glaucoma and what risk factors influence the progression. The CIGTS examined the progression of glaucoma in patients treated either with pharmacotherapy or with surgery. The recent studies, the United Kingdom Glaucoma Treatment Study (UKGTS) and Glaucoma Automated Test Evaluation (GATE) investigated the influence of treatment with latanoprost on the development of visual field defects and examination of different screening tests in glaucoma, respectively. The OHTS provided results that justify prophylactic treatment as well as watchful waiting. The results of CIGTS showed that under certain conditions surgical treatment of a newly discovered glaucoma can be recommended for moderate to advanced glaucoma. In the UKGTS treatment with latanoprost reduced the intraocular pressure and also the progression of visual field defects in beginning and moderate glaucoma damage. The GATE study found no clear-cut advantage of screening examinations, with cost effectiveness and without a substantial proportion of diagnoses being missed.

OCT Signal Enhancement with Deep Learning

To establish whether deep learning methods are able to improve the signal-to-noise ratio of time-domain (TD) OCT images to approach that of spectral-domain (SD) OCT images. Method agreement study and progression detection in a randomized, double-masked, placebo-controlled, multicenter trial for open-angle glaucoma (OAG), the United Kingdom Glaucoma Treatment Study (UKGTS). The training and validation cohort comprised 77 stable OAG participants with TD OCT and SD OCT imaging at up to 11 visits within 3 months. The testing cohort comprised 284 newly diagnosed OAG patients with TD OCT images from a cohort of 516 recruited at 10 United Kingdom centers between 2007 and2010. An ensemble of generative adversarial networks (GANs) was trained on TD OCT and SD OCT image pairs from the training dataset and applied to TD OCT images from the testing dataset. Time-domain OCT images were converted to synthesized SD OCT images and segmented via Bayesian fusion on the output of the GANs. Bland-Altman analysis assessed agreement between TD OCT and synthesized SD OCT average retinal nerve fiber layer thickness (RNFLT) measurements and the SD OCT RNFLT. Analysis of the distribution of the rates of RNFLT change in TD OCT and synthesized SD OCT in the two treatment arms of the UKGTS was compared. A Cox model for predictors of time-to-incident visual field (VF) progression was computed with the TD OCT and the synthesized SD OCT images. The 95% limits of agreement were between TD OCT and SD OCT were 26.64 to -22.95; between synthesized SD OCT and SD OCT were 8.11 to -6.73; and between SD OCT and SD OCT were 4.16 to -4.04. The mean difference in the rate of RNFLT change between UKGTS treatment and placebo arms with TD OCT was 0.24 (P= 0.11) and with synthesized SD OCT was 0.43 (P= 0.0017). The hazard ratio for RNFLT slope in Cox regression modeling for time to incident VF progression was 1.09 (95% confidence interval [CI], 1.02-1.21; P=0.035) for TD OCT and 1.24 (95% CI, 1.08-1.39; P= 0.011) for synthesized SD OCT. Image enhancement significantly improved the agreement of TD OCT RNFLT measurements with SD OCT RNFLT measurements. The difference, and its significance, in rates of RNFLT change in the UKGTS treatment arms was enhanced and RNFLT change became a stronger predictor of VF progression.

Risk Factors for Visual Field Deterioration in the United Kingdom Glaucoma Treatment Study

The United Kingdom Glaucoma Treatment Study (UKGTS) investigated the visual field (VF)-preserving effect of medical treatment in open-angle glaucoma (OAG). The objective of this analysis was to identify risk factors associated with VF deterioration. Randomized, double-masked, placebo-controlled multicenter trial. Five hundred sixteen participants with previously untreated OAG were recruited prospectively in 10 United Kingdom centers. Eligibility criteria were modeled on those for the Early Manifest Glaucoma Trial. Study participants were randomized to either latanoprost 0.005% or placebo eye drops. The observation period was 2 years and involved, among other procedures, VF testing and intraocular pressure (IOP) measurement at 11 scheduled visits, with clustering of tests at baseline, 18 months, and 24 months. Guided progression analysis pattern deviation maps were used to determine VF deterioration. Cox regression was used to compute the hazard ratios (HRs) and respective 95% confidence intervals (CIs) while accounting for the correlation within sites. Model selection was guided by backward stepwise selection conducted on the model containing all variables that were significant at the 0.2 level in the univariate analysis. Follow-up variables that showed collinearity with baseline values were not retained in the final model. Time to VF deterioration. Treatment with latanoprost reduced the HR, for VF deterioration by 58% (HR, 0.42; 95% CI, 0.27-0.67; P= 0.001). Factors associated with deterioration were bilateral disease (HR, 1.59 for yes vs. no; 95% CI, 1.02-2.50; P= 0.041), higher baseline IOP (HR, 1.07 per mmHg; 95% CI, 1.02-1.12; P= 0.008), and disc hemorrhage at visit 1 (HR, 2.08; 95% CI, 1.07-4.04; P= 0.030). Smoking (current or previous) was associated with a reduced HR, for VF deterioration (HR, 0.59; 95% CI, 0.37-0.93; P= 0.023). No other evaluated factors were found to be statistically significant in the multivariable analysis. In the UKGTS, treatment with latanoprost halved VF deterioration risk. Bilateral disease, higher IOP, and disc hemorrhage were confirmed as risk factors for deterioration; smoking history seemed to be protective against VF deterioration.

Cost-Utility Analysis of Glaucoma Medication Adherence

The majority of patients with glaucoma do not take their medications as prescribed. Estimates of the cost-utility value of adherence to prescribed glaucoma medication are vital to implement potentially effective interventions. Cost-utility analysis using Monte Carlo microsimulations incorporating a series of Markov cycles (10 000 iterations per strategy). Patients with glaucoma aged ≥40 years with a full lifetime horizon (up to 60 years). The analysis estimated glaucomatous progression on the basis of data from the United Kingdom Glaucoma Treatment Study. Participants with glaucoma entered the model at age 40 years with a mean deviation in the better-seeing eye of-1.4±-1.9 decibels (dB) and-4.3±-3.4 dB in the worse-seeing eye. Participants whose glaucoma worsened each year accumulate-0.8 dB loss compared with-0.1 dB loss for those who remained stable. Data from the Glaucoma Laser Trial and the Tube versus Trabeculectomy Studies were used to assign probabilities of worsening disease among treated patients. Claims data estimating rates of glaucoma medication adherence over 4 years were used to assign probability of adherence. Those with poor adherence were modeled as having outcomes similar to the placebo arm of the clinical trials. As patients' mean deviation deteriorated, they transitioned between health states from mild (≥-6 dB), to moderate (<-6 to ≥-12 dB), to severe glaucoma (<-12 to ≥23 dB), to unilateral (<-20 dB) and bilateral blindness. At each health state, patients incurred the costs of treatment and established health utilities; ultimately, societal costs of low vision and blindness were included. Cost and quality-adjusted life year (QALY) of glaucoma medication adherence. Beginning at an initial glaucoma diagnosis at age 40 years, patients proceeded to single-eye blindness as early as 19 years among those who were nonadherent and 23 years for those remaining adherent. Total healthcare costs for adherent patients averaged $62 782 (standard deviation [SD], 34 107), and those for nonadherent patients averaged $52 722 (SD, 38 868). Nonadherent patients had a mean loss of 0.34 QALYs, resulting in a cost-effectiveness ratio of $29 600 per QALY gained. At a conservative willingness to pay of $50 000/QALY, there is room to expand services to improve patient adherence.

Are Patient Self-Reported Outcome Measures Sensitive Enough to Be Used as End Points in Clinical Trials?: Evidence from the United Kingdom Glaucoma Treatment Study

The United Kingdom Glaucoma Treatment Study (UKGTS) demonstrated the effectiveness of an intraocular pressure-lowering drug in patients with glaucoma using visual field progression as a primary outcome. The present study tested the hypothesis that responses on patient-reported outcome measures (PROMs; secondary outcome measure) differ between patients receiving a topical prostaglandin analog (latanoprost) or placebo eye drops in UKGTS. Multicenter, randomized, triple-masked, placebo-controlled trial. Newly diagnosed glaucoma patients in the UKGTS with baseline and exit PROMs (n= 182 and n= 168 patients from the treatment and placebo groups, respectively). In the UKGTS (trial registration number, ISRCTN96423140), patients with open-angle glaucoma were allocated to receive latanoprost (treatment) or placebo; the observation period was 24months. Patients completed general health PROMs (European Quality of Life in 5 Dimensions [EQ-5D] and 36-item Short Form [SF-36]) and PROMs specific to glaucoma (15-item Glaucoma Quality of Life [GQL-15] and 9-item Glaucoma Activity Limitation [GAL-9]) at baseline and exit from the trial. Percentage changes between measurement on PROMs were calculated for each patient and compared between treatment arms. In addition, differences between stable patients (n= 272) and those with glaucomatous progression (n=78), as determined by visual field change (primary outcome), were assessed. PROMs on health-related and vision-related quality of life. Average percentage change on PROMs was similar for patients in both arms of the trial, with no statistically significant differences between treatment and placebo groups (EQ-5D, P= 0.98; EQ-5D visual analog scale, P= 0.88; SF-36, P= 0.94, GQL-15, P= 0.66; GAL-9, P= 0.87). There were statistically significant differences between stable and progressing patients on glaucoma-specific PROMs (GQL-15, P= 0.02; GAL-9, P= 0.02), but not on general health PROMs (EQ-5D, P= 0.62; EQ-5D visual analog scale, P= 0.23; SF-36, P= 0.65). Average change in PROMs on health-related and vision-related quality of life was similar forthe treatment and placebo groups in the UKGTS. The PROMs used may not be sensitive enough to functionasprimary end points in clinical trials when participants have newly diagnosed early-stage glaucoma.

Impact of Different Visual Field Testing Paradigms on Sample Size Requirements for Glaucoma Clinical Trials

Visual field testing is an important endpoint in glaucoma clinical trials, and the testing paradigm used can have a significant impact on the sample size requirements. To investigate this, this study included 353 eyes of 247 glaucoma patients seen over a 3-year period to extract real-world visual field rates of change and variability estimates to provide sample size estimates from computer simulations. The clinical trial scenario assumed that a new treatment was added to one of two groups that were both under routine clinical care, with various treatment effects examined. Three different visual field testing paradigms were evaluated: a) evenly spaced testing, b) United Kingdom Glaucoma Treatment Study (UKGTS) follow-up scheme, which adds clustered tests at the beginning and end of follow-up in addition to evenly spaced testing, and c) clustered testing paradigm, with clusters of tests at the beginning and end of the trial period and two intermediary visits. The sample size requirements were reduced by 17–19% and 39–40% using the UKGTS and clustered testing paradigms, respectively, when compared to the evenly spaced approach. These findings highlight how the clustered testing paradigm can substantially reduce sample size requirements and improve the feasibility of future glaucoma clinical trials.

Combining optical coherence tomography with visual field data to rapidly detect disease progression in glaucoma: a diagnostic accuracy study.

Progressive optic nerve damage in glaucoma results in vision loss, quantifiable with visual field (VF) testing. VF measurements are, however, highly variable, making identification of worsening vision ('progression') challenging. Glaucomatous optic nerve damage can also be measured with imaging techniques such as optical coherence tomography (OCT). To compare statistical methods that combine VF and OCT data with VF-only methods to establish whether or not these allow (1) more rapid identification of glaucoma progression and (2) shorter or smaller clinical trials. Method 'hit rate' (related to sensitivity) was evaluated in subsets of the United Kingdom Glaucoma Treatment Study (UKGTS) and specificity was evaluated in 72 stable glaucoma patients who had 11 VF and OCT tests within 3 months (the RAPID data set). The reference progression detection method was based on Guided Progression Analysis™ (GPA) Software (Carl Zeiss Meditec Inc., Dublin, CA, USA). Index methods were based on previously described approaches [Analysis with Non-Stationary Weibull Error Regression and Spatial enhancement (ANSWERS), Permutation analyses Of Pointwise Linear Regression (PoPLR) and structure-guided ANSWERS (sANSWERS)] or newly developed methods based on Permutation Test (PERM), multivariate hierarchical models with multiple imputation for censored values (MaHMIC) and multivariate generalised estimating equations with multiple imputation for censored values (MaGIC). Ten university and general ophthalmology units (UKGTS) and a single university ophthalmology unit (RAPID). UKGTS participants were newly diagnosed glaucoma patients randomised to intraocular pressure-lowering drops or placebo. RAPID participants had glaucomatous VF loss, were on treatment and were clinically stable. 24-2 VF tests with the Humphrey Field Analyzer and optic nerve imaging with time-domain (TD) Stratus OCT™ (Carl Zeiss Meditec Inc., Dublin, CA, USA). Criterion hit rate and specificity, time to progression, future VF prediction error, proportion progressing in UKGTS treatment groups, hazard ratios (HRs) and study sample size. Criterion specificity was 95% for all tests; the hit rate was 22.2% for GPA, 41.6% for PoPLR, 53.8% for ANSWERS and 61.3% for sANSWERS (all comparisons p ≤ 0.042). Mean survival time (weeks) was 93.6 for GPA, 82.5 for PoPLR, 72.0 for ANSWERS and 69.1 for sANSWERS. The median prediction errors (decibels) when the initial trend was used to predict the final VF were 3.8 (5th to 95th percentile 1.7 to 7.6) for PoPLR, 3.0 (5th to 95th percentile 1.5 to 5.7) for ANSWERS and 2.3 (5th to 95th percentile 1.3 to 4.5) for sANSWERS. HRs were 0.57 [95% confidence interval (CI) 0.34 to 0.90; p = 0.016] for GPA, 0.59 (95% CI 0.42 to 0.83; p = 0.002) for PoPLR, 0.76 (95% CI 0.56 to 1.02; p = 0.065) for ANSWERS and 0.70 (95% CI 0.53 to 0.93; p = 0.012) for sANSWERS. Sample size estimates were not reduced using methods including OCT data. PERM hit rates were between 8.3% and 17.4%. Treatment effects were non-significant in MaHMIC and MaGIC analyses; statistical significance was altered little by incorporating imaging. TD OCT is less precise than current imaging technology; current OCT technology would likely perform better. The size of the RAPID data set limited the precision of criterion specificity estimates. The sANSWERS method combining VF and OCT data had a higher hit rate and identified progression more quickly than the reference and other VF-only methods, and produced more accurate estimates of the progression rate, but did not increase treatment effect statistical significance. Similar studies with current OCT technology need to be undertaken and the statistical methods need refinement. Current Controlled Trials ISRCTN96423140. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 4. See the NIHR Journals Library website for further project information. Data analysed in the study were from the UKGTS. Funding for the UKGTS was provided through an unrestricted investigator-initiated research grant from Pfizer Inc. (New York, NY, USA), with supplementary funding from the NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK. Imaging equipment loans were made by Heidelberg Engineering, Carl Zeiss Meditec and Optovue (Fremont, CA, USA). Pfizer, Heidelberg Engineering, Carl Zeiss Meditec and Optovue had no input into the design, conduct, analysis or reporting of any of the UKGTS findings or this work. The sponsor for both the UKGTS and RAPID data collection was Moorfields Eye Hospital NHS Foundation Trust. David F Garway-Heath, Tuan-Anh Ho and Haogang Zhu are partly funded by the NIHR Biomedical Research Centre based at Moorfields Eye Hospital and UCL Institute of Ophthalmology. David F Garway-Heath's chair at University College London (UCL) is supported by funding from the International Glaucoma Association.

Using perimetric data to estimate ganglion cell loss for detecting progression of glaucoma: a comparison of models.

PurposeModels relating perimetric sensitivities to ganglion cell numbers have been proposed for combining structural and functional measures from patients with glaucoma. Here we compared seven models for ability to differentiate progressing and stable patients, testing the hypothesis that the model incorporating local spatial scale would have the best performance.MethodsThe models were compared for the United Kingdom Glaucoma Treatment Study (UKGTS) data for the right eyes of 489 patients recently diagnosed with glaucoma. The SITA 24‐2 program was utilised for perimetry and Stratus OCT fast scanning protocol for thickness of circumpapillary retinal nerve fibre layer (RNFL). The first analysis defined progression in terms of decline in RNFL thickness. The highest and lowest quintiles (22 subjects per group) were identified for change in thickness of inferior temporal (IT), superior temporal (ST), and global RNFL (μm year−1); a two‐way anova was used to look for differences between the models in ability to discriminate the two quintiles. The second analysis defined a ‘progression group’ as those who were flagged by the UKGTS criteria as having progressive loss in perimetric sensitivity, and a ‘no progression’ group as those with rate of change in Mean Deviation (MD) closest to 0 dB year−1 (87 subjects per group). The third analysis characterised variability of retinal ganglion cell (RGC) models for the two groups in the second analysis, using the standard deviation of residuals from linear regression of ganglion cell number over time to compute Coefficient of Variation (CoV).ResultsThe first analysis produced a negative result because the three anovas found no effect of model or interaction of model and group (F 6,294 < 3.1, p > 0.08). There was an effect of group only for the anova with the ST sector (F 6,294 = 12.2, p < 0.001). The second analysis also produced a negative result, because ROC areas were in the range 0.69–0.72 for all models. The third analysis found that even when variability in MD was low, the CoV was so large that test‐retest variation could include 100% loss of ganglion cells.ConclusionsTwo very different approaches for testing the hypothesis both gave a negative result. For all seven ganglion cell models, rates of ganglion cell loss were highly affected by fluctuations in height of the hill of vision. Methods for reducing effects of between‐visit variability are needed in order to assess progression by relating perimetric sensitivities and ganglion cell numbers.

Between-Subject Variability in Healthy Eyes as a Primary Source of Structural-Functional Discordance in Patients With Glaucoma.

PurposeTo test with an independent data set the finding that between-subject variability in healthy eyes is the primary source of structural–functional discordance in patients with glaucoma.MethodsNeuroretinal rim area, retinal nerve fiber layer thickness, and perimetric data were analyzed for one eye in each of 55 control subjects and for 245 right eyes of patients in the United Kingdom Glaucoma Treatment Study. Data were gathered with the Heidelberg Retina Tomograph (HRT), Stratus Optical Coherence Tomograph (OCT), and Humphrey Field Analyzer (HFA). Discordance was quantified as width of the limits of agreement from a Bland-Altman analysis of depth of defect. The ratio of variances (F test) for the patient and control groups was computed for comparisons of HFA-OCT, HFA-HRT, and OCT-HRT. Bonferroni adjustment required P less than 0.017 for statistical significance. The discordance in the patients was also quantified as the 95% prediction interval computed from the discordance in controls using the Hood-Kardon model for the HFA-OCT comparison.ResultsThe F ratio comparing discordance in patients and controls was 0.77, 1.43, and 1.32 for the HFA-OCT, HFA-HRT, and OCT-HRT comparisons with P values 0.88, 0.06, and 0.11, respectively. For the Hood-Kardon model, 4.7% of the patients had discordance outside the 95% prediction interval computed from the discordance in controls. Similar results were obtained when all comparisons were repeated for left eyes of patients.ConclusionsThese results confirm previous findings that between-subject variability in healthy eyes is the primary source of structural–functional discordance in patients with glaucoma, and extends this finding to a structural–structural comparison.

More Accurate Modeling of Visual Field Progression in Glaucoma: ANSWERS.

To validate a method for visual field (VF) progression analysis, called ANSWERS (Analysis with Non-Stationary Weibull Error Regression and Spatial Enhancement), which takes into account increasing measurement variability as glaucoma progresses and spatial correlation among test locations. ANSWERS outputs both a global index of progression and a pointwise estimate of rate of change at each VF location. ANSWERS was compared with linear regression of mean deviation (MD) and permutation of pointwise linear regression (PoPLR). Visual field series of up to 2 years from the United Kingdom Glaucoma Treatment Study were used. This consists of 9104 Swedish Interactive Thresholding Algorithm Standard 24-2 VFs. ANSWERS and PoPLR rate of change were used to predict the VF at the next visit using subseries that were within 7, 13, 18, or 22 months from the baseline. The comparison was carried out on the statistical sensitivity, specificity, and accuracy of predicting future VF. Across all subseries, statistical sensitivity of ANSWERS in detecting VF deterioration was significantly better than the linear regression of MD and PoPLR, especially in short time series. Prediction accuracy of ANSWERS was better than PoPLR at all series lengths, and the improvement was particularly marked in shorter series. Seventy-five percent of VF series were better predicted by ANSWERS compared with PoPLR. The average prediction error of ANSWERS was 15% lower than that of PoPLR. ANSWERS is more sensitive to detect VF progression and predicts future VF loss better than linear regression of MD and PoPLR, especially over short observation periods. (http://www.isrctn.com number, ISRCTN96423140.).

The United Kingdom Glaucoma Treatment Study: A Multicenter, Randomized, Double-masked, Placebo-controlled Trial: Baseline Characteristics

The United Kingdom Glaucoma Treatment Study (UKGTS) tests the hypothesis that treatment with a topical prostaglandin analog, compared with placebo, reduces the frequency of visual field (VF) deterioration events in patients with open-angle glaucoma (OAG) by 50% over a 2-year period. Additional goals are to evaluate study power with novel clinical trial outcomes: (1) VF deterioration velocity and (2) VF and quantitative imaging measurements modeled as joint outcomes. The UKGTS is a randomized, double-masked, placebo-controlled, multicenter treatment trial for OAG. A total of 516 patients with newly diagnosed (previously untreated) OAG were prospectively recruited at 10 UK centers between 2007 and 2010. Eligible patients were randomly assigned to treatment with latanoprost 0.005% or placebo. The observation period was 2 years, with subjects monitored by VF testing, quantitative imaging, optic disc photography, and tonometry at 11 visits. The primary outcome measure is time to VF deterioration within 24 months. Secondary outcomes include the deterioration velocity of VF and quantitative imaging measures. The main source of referrals was optometrists (88%). A total of 777 subjects were assessed for eligibility, and 261 were excluded because they did not meet the inclusion criteria or declined to participate. The mean age of the 516 participants was 66 years, and 52.9% were male; 90.1% of the participants were white, and approximately one third (32.2%) reported a family history of glaucoma. A total of 777 eyes were eligible at initial assessment. Both eyes were eligible for 265 participants. Mean (standard deviation) intraocular pressure (IOP) at baseline for the eyes with better versus worse mean deviation (MD) was 18.9 (4.1) and 19.9 (4.7) mmHg, respectively (P = 0.0053). Some 56.1% of all eligible eyes had IOP <20 mmHg at baseline. The median (interquartile range) VF MD for all eligible eyes was -2.9 dB (-1.6 to -4.8 dB). This is the first randomized, placebo-controlled trial to evaluate the efficacy of medical treatment in reducing VF deterioration in OAG. The baseline characteristics for eligible patients and eyes from this cohort are presented and compared with those of previous trials. The baseline characteristics are similar to those of the largely population-based Early Manifest Glaucoma Trial. The early stage of the glaucoma and relatively low IOP at diagnosis suggest remarkably sensitive case findings by community optometrists in the United Kingdom.

The United Kingdom Glaucoma Treatment Study: A Multicenter, Randomized, Placebo-Controlled Clinical Trial: Design and Methodology

Elevated intraocular pressure (IOP) is a major risk factor for the deterioration of open-angle glaucoma (OAG); medical IOP reduction is the standard treatment, yet no randomized placebo-controlled study of medical IOP reduction has been undertaken previously. The United Kingdom Glaucoma Treatment Study (UKGTS) tests the hypothesis that treatment with a topical prostaglandin analog, compared with placebo, reduces the frequency of visual field (VF) deterioration events in OAG patients by 50% over a 2-year period. The UKGTS is a randomized, double-masked, placebo-controlled, multicenter treatment trial for OAG. Five hundred sixteen newly diagnosed (previously untreated) patients with OAG were recruited prospectively at 10 centers between 2007 and 2010. Patients were assigned by concealed telephone allocation to treatment with a prostaglandin analog (latanoprost 0.005%) or placebo. The observation period was 2 years, with subjects monitored by VF testing, quantitative imaging, optic disc photography, and tonometry at 11 visits. Data were acquired according to novel protocols optimized for the analysis of deterioration velocity. The sample size was determined for a 2-sided error of α=0.05 to detect the difference between 24% and 11% in incident deterioration over a 24-month follow-up at 90% power and assuming a 25% attrition rate. The primary outcome was time to VF deterioration within 24 months. Secondary outcomes included the deterioration velocity of VF and quantitative imaging measures and the relationship between these velocities and risk factors for deterioration. The study design enabled a short trial with a 2-year observation period and provided data that can be used to assess the feasibility of further shortening trial duration with the progression velocity of VF and structural imaging measurements as outcomes. The UKGTS is the first randomized, placebo-controlled trial to evaluate the efficacy of medical treatment in reducing VF deterioration in OAG. The measurement of deterioration velocity and inclusion of quantitative imaging has the potential to reduce the number of patients and duration required for subsequent clinical trials. This trial also will quantify risk factors for deterioration, enabling more precise risk profiling of patients and the development of patient management protocols. The author(s) have no proprietary or commercial interest in any materials discussed in this article.