Special Issue Biomarkers and Surrogate Endpoints: Lessons Learned From Glaucoma

With the recent progress in imaging technologies for assessment of structural damage in glaucoma, a debate has emerged on whether these measurements can be used as valid surrogate endpoints in clinical trials evaluating new therapies for the disease. A discussion of surrogates should be grounded on knowledge acquired from their use in other areas of medicine as well as regulatory requirements. This article reviews the conditions for valid surrogacy in the context of glaucoma clinical trials and critically evaluates the role of biomarkers such as IOP and imaging measurements as potential surrogates for clinically relevant outcomes. Valid surrogate endpoints must be able to predict a clinically relevant endpoint, such as loss of vision or decrease in quality of life. In addition, the effect of a proposed treatment on the surrogate must capture the effect of the treatment on the clinically relevant endpoint. Despite its widespread use in clinical trials, no proper validation of IOP as a surrogate endpoint has yet been conducted for any class of IOP-lowering treatments. Although strong evidence has accumulated about imaging measurements as predictors of relevant functional outcomes in glaucoma, there is still insufficient evidence to support their use as valid surrogate endpoints. However, imaging biomarkers could potentially be used as part of composite endpoints in glaucoma trials, overcoming weaknesses of the use of structural or functional endpoints in isolation. Efforts should be taken to properly design and conduct studies that can provide proper validation of potential biomarkers in glaucoma clinical trials

Estimating the Risk of Developing Glaucoma

The issue of risk assessment in glaucoma has received increasing attention in the past few years since the publication of results from the Ocular Hypertension Treatment Study. Predictive models have been developed in order to estimate the risk that patients with ocular hypertension will develop glaucoma if left untreated. The purpose of this article is to review issues on the development and validation of predictive models to estimate risk of glaucoma development. Current models are reviewed and details about their development and validation are provided

Structural Change Can Be Detected in Advanced-Glaucoma Eyes.

PurposeTo compare spectral-domain optical coherence tomography (SD-OCT) standard structural measures and a new three-dimensional (3D) volume optic nerve head (ONH) change detection method for detecting change over time in severely advanced-glaucoma (open-angle glaucoma [OAG]) patients.MethodsThirty-five eyes of 35 patients with very advanced glaucoma (defined as a visual field mean deviation < -21 dB) and 46 eyes of 30 healthy subjects to estimate aging changes were included. Circumpapillary retinal fiber layer thickness (cpRNFL), minimum rim width (MRW), and macular retinal ganglion cell-inner plexiform layer (GCIPL) thicknesses were measured using the San Diego Automated Layer Segmentation Algorithm (SALSA). Progression was defined as structural loss faster than 95th percentile of healthy eyes. Three-dimensional volume ONH change was estimated using the Bayesian-kernel detection scheme (BKDS), which does not require extensive retinal layer segmentation.ResultsThe number of progressing glaucoma eyes identified was highest for 3D volume BKDS (13, 37%), followed by GCPIL (11, 31%), cpRNFL (4, 11%), and MRW (2, 6%). In advanced-OAG eyes, only the mean rate of GCIPL change reached statistical significance, -0.18 μm/y (P = 0.02); the mean rates of cpRNFL and MRW change were not statistically different from zero. In healthy eyes, the mean rates of cpRNFL, MRW, and GCIPL change were significantly different from zero. (all P < 0.001).ConclusionsGanglion cell-inner plexiform layer and 3D volume BKDS show promise for identifying change in severely advanced glaucoma. These results suggest that structural change can be detected in very advanced disease. Longer follow-up is needed to determine whether changes identified are false positives or true progression

Wayfinding and Glaucoma: A Virtual Reality Experiment.

PurposeWayfinding, the process of determining and following a route between an origin and a destination, is an integral part of everyday tasks. The purpose of this study was to investigate the impact of glaucomatous visual field loss on wayfinding behavior using an immersive virtual reality (VR) environment.MethodsThis cross-sectional study included 31 glaucomatous patients and 20 healthy subjects without evidence of overall cognitive impairment. Wayfinding experiments were modeled after the Morris water maze navigation task and conducted in an immersive VR environment. Two rooms were built varying only in the complexity of the visual scene in order to promote allocentric-based (room A, with multiple visual cues) versus egocentric-based (room B, with single visual cue) spatial representations of the environment. Wayfinding tasks in each room consisted of revisiting previously visible targets that subsequently became invisible.ResultsFor room A, glaucoma patients spent on average 35.0 seconds to perform the wayfinding task, whereas healthy subjects spent an average of 24.4 seconds (P = 0.001). For room B, no statistically significant difference was seen on average time to complete the task (26.2 seconds versus 23.4 seconds, respectively; P = 0.514). For room A, each 1-dB worse binocular mean sensitivity was associated with 3.4% (P = 0.001) increase in time to complete the task.ConclusionsGlaucoma patients performed significantly worse on allocentric-based wayfinding tasks conducted in a VR environment, suggesting visual field loss may affect the construction of spatial cognitive maps relevant to successful wayfinding. VR environments may represent a useful approach for assessing functional vision endpoints for clinical trials of emerging therapies in ophthalmology

Retinal Nerve Fiber Layer Features Identified by Unsupervised Machine Learning on Optical Coherence Tomography Scans Predict Glaucoma Progression.

Purpose:To apply computational techniques to wide-angle swept-source optical coherence tomography (SS-OCT) images to identify novel, glaucoma-related structural features and improve detection of glaucoma and prediction of future glaucomatous progression. Methods:Wide-angle SS-OCT, OCT circumpapillary retinal nerve fiber layer (cpRNFL) circle scans spectral-domain (SD)-OCT, standard automated perimetry (SAP), and frequency doubling technology (FDT) visual field tests were completed every 3 months for 2 years from a cohort of 28 healthy participants (56 eyes) and 93 glaucoma participants (179 eyes). RNFL thickness maps were extracted from segmented SS-OCT images and an unsupervised machine learning approach based on principal component analysis (PCA) was used to identify novel structural features. Area under the receiver operating characteristic curve (AUC) was used to assess diagnostic accuracy of RNFL PCA for detecting glaucoma and progression compared to SAP, FDT, and cpRNFL measures. Results:The RNFL PCA features were significantly associated with mean deviation (MD) in both SAP (R2 = 0.49, P < 0.0001) and FDT visual field testing (R2 = 0.48, P < 0.0001), and with mean circumpapillary RNFL thickness (cpRNFLt) from SD-OCT (R2 = 0.58, P < 0.0001). The identified features outperformed each of these measures in detecting glaucoma with an AUC of 0.95 for RNFL PCA compared to an 0.90 for mean cpRNFLt (P = 0.09), 0.86 for SAP MD (P = 0.034), and 0.83 for FDT MD (P = 0.021). Accuracy in predicting progression was also significantly higher for RNFL PCA compared to SAP MD, FDT MD, and mean cpRNFLt (P = 0.046, P = 0.007, and P = 0.044, respectively). Conclusions:A computational approach can identify structural features that improve glaucoma detection and progression prediction

Macular Pigment and Visual Function in Patients With Glaucoma: The San Diego Macular Pigment Study.

PurposeAlthough recent studies have shown that macular pigment (MP) is significantly lower in glaucoma patients, this relationship merits further investigation.MethodsThis cross-sectional study included 85 glaucoma patients and 22 controls. All subjects had standard automated perimetry (SAP) and retinal nerve fiber layer (RNFL) thickness measurements. Intake of lutein (L) and zeaxanthin (Z) was estimated using a novel dietary screener. The Heidelberg Spectralis dual-wavelength autofluorescence (AF) technology was employed to study the relationship between MP and glaucoma. The association between MP volume and glaucoma was investigated using linear regression models accounting for potential confounding factors.ResultsGlaucoma patients had significantly worse SAP mean deviation (MD) and lower RNFL thickness in the study eye compared to control subjects (P < 0.001 for both). MP (volume) was comparable between groups (P = 0.436). In the univariable model, diagnosis of glaucoma was not associated with MP volume (R2 = 1.22%; P = 0.257). Dietary intake of L and Z was positively and significantly related to MP in the univariable (P = 0.022) and multivariable (P = 0.020) models.ConclusionsThese results challenge previous studies that reported that glaucoma is associated with low MP. Dietary habits were found to be the main predictor of MP in this sample. Further research is merited to better understand the relationship between glaucoma, MP, and visual performance in these patients

The Relative Odds of Progressing by Structural and Functional Tests in Glaucoma.

PurposeThe purpose of this study was to evaluate the effect of disease severity and number of tests acquired during follow-up on the relative odds of identifying progression by structural or functional tests in glaucoma.MethodsThis was an observational cohort study involving 462 eyes of 305 patients with glaucoma and 62 eyes of 49 healthy subjects. Glaucoma patients and healthy subjects were followed for an average of 3.6 ± 0.9 and 3.8 ± 0.9 years, with a median (interquantile range) of 8 (6-9) and 7 (6-8) visits, respectively. At each visit, subjects underwent visual field assessment with standard automated perimetry (SAP) and retinal nerve fiber layer (RNFL) evaluation by spectral-domain optical coherence tomography (SD-OCT). Slopes of change in SAP mean sensitivity and OCT RNFL thickness over time were estimated by linear regression using progressively cumulative visits over time. Cutoff values for age-related expected rates of change for each test were obtained from the healthy group. Progression by SD-OCT and/or SAP was determined if the slope of change was statistically significant and also lower (faster) than the fifth percentile cutoff calculated from the healthy group. A generalized estimating equation logistic regression model was used to evaluate the relative odds of progressing by OCT versus SAP in glaucoma eyes.ResultsEyes with less severe disease at baseline had a higher chance of being detected as progressing by SD-OCT but not by SAP, whereas an increase in disease severity at baseline increased the chance that the eye would be detected as progressing by SAP but not SD-OCT. Each 1 dB higher MD was associated with a 5% increase in the odds of detecting progression by SD-OCT versus SAP (odds ratio = 1.05 per 1 dB; 95% confidence interval: 1.01-1.09; P = 0.005).ConclusionsThe ability to detect glaucoma progression by SAP versus SD-OCT is significantly influenced by the stage of disease. Our results may provide useful information for guiding clinicians on the relative utility of these tests for detecting change throughout the disease continuum