Diagnostic assessment of glaucoma and non-glaucomatous optic neuropathies via optical texture analysis of the retinal nerve fibre layer.

The clinical diagnostic evaluation of optic neuropathies relies on the analysis of the thickness of the retinal nerve fibre layer (RNFL) by optical coherence tomography (OCT). However, false positives and false negatives in the detection of RNFL abnormalities are common. Here we show that an algorithm integrating measurements of RNFL thickness and reflectance from standard wide-field OCT scans can be used to uncover the trajectories and optical texture of individual axonal fibre bundles in the retina and to discern distinctive patterns of loss of axonal fibre bundles in glaucoma, compressive optic neuropathy, optic neuritis and non-arteritic anterior ischaemic optic neuropathy. Such optical texture analysis can detect focal RNFL defects in early optic neuropathy, as well as residual axonal fibre bundles in end-stage optic neuropathy that were indiscernible by conventional OCT analysis and by red-free RNFL photography. In a diagnostic-performance study, optical texture analysis of the RNFL outperformed conventional OCT in the detection of glaucoma, as defined by visual-field testing or red-free photography. Our findings show that optical texture analysis of the RNFL for the detection of optic neuropathies is highly sensitive and specific.

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

BACKGROUND: 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). OBJECTIVE: 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. DESIGN: 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). SETTING: Ten university and general ophthalmology units (UKGTS) and a single university ophthalmology unit (RAPID). PARTICIPANTS: 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. INTERVENTIONS: 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). MAIN OUTCOME MEASURES: 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. RESULTS: 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. LIMITATIONS: 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. CONCLUSIONS: 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. TRIAL REGISTRATION: Current Controlled Trials ISRCTN96423140. FUNDING: 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.

Accuracy of matching optic discs with visual fields: the European Structure and Function Assessment Trial (ESAFAT).

PURPOSE: To determine the ability of ophthalmologists across Europe to match stereoscopic optic disc photographs to visual fields of varying severity. DESIGN: Evaluation and comparison of 2 diagnostic tests. PARTICIPANTS: A total of 109 of 260 invited ophthalmologists in 11 European countries. These had participated in the previous European Optic Disc Assessment Trial (EODAT), a trial on glaucoma diagnostic accuracy based on optic discs only. METHODS: Each participant matched stereo optic disc photographs of 40 healthy and 48 glaucomatous eyes to a visual field chosen from 4 options per disc. The 4 presented visual fields included the corresponding one and 3 other visual fields, varying in severity. The matching accuracy and any inaccuracy per disease severity were calculated. Classification accuracy (as glaucomatous or healthy) was compared with EODAT data. Duplicate slides allowed for the assessment of intraobserver agreement. MAIN OUTCOME MEASURES: Accuracy of matching optic discs with their corresponding visual field and of classifying them as healthy or glaucomatous; intraobserver agreement (κ). RESULTS: The overall accuracy of ophthalmologists for correctly matching stereoscopic optic disc photographs to their visual fields was 58.7%. When incorrectly matched, the observers generally overestimated the visual field severity (P<0.001), notably in eyes with early glaucoma. The intraobserver agreement was, on average, moderate (0.52). CONCLUSIONS: European ophthalmologists correctly matched stereoscopic optic disc photographs to their corresponding visual field in only approximately 59% of cases. In most mismatches, the clinicians overestimated the visual field damage.

Assessment of optic disc photographs for glaucoma by UK optometrists: the Moorfields Optic Disc Assessment Study (MODAS).

PURPOSE: To assess the ability of UK optometrists to accurately discriminate between stereoscopic photographs of healthy and glaucomatous optic discs. METHODS: An online survey, including questions relating to qualification, practice environment, and diagnostic methods was completed by 1256 optometrists. Based on their responses, 208 (17%) were selected to undertake an online disc assessment exercise. Optometrists evaluated the same disc images previously assessed by European ophthalmologists as part of the European Optic Disc Assessment Trial (EODAT); the task was to state if the disc appeared healthy or glaucomatous. There were 110 stereoscopic disc images, of which 40 were healthy, 48 glaucomatous, and six ocular hypertensive, with 16 duplicates images. Sensitivity, specificity and overall accuracy were calculated and compared between optometrist groups and with the EODAT ophthalmologists using permutation analysis. RESULTS: Median sensitivity was 0.92 (95% CI: 0.70, 1.00) and median specificity was 0.74 (95% CI: 0.62, 0.88). Median overall accuracy was 80% (95% CI: 67%, 88%). Agreement between optometrists was moderate (Fleiss' κ: 0.57). Optometrists with higher qualifications did not have overall higher sensitivity than those without (p = 0.23), but had higher specificity (p = 0.001) and higher overall accuracy (p < 0.001). Optometrists displayed higher sensitivity but lower specificity than the EODAT ophthalmologists. CONCLUSION: UK optometrists displayed a high sensitivity and moderate specificity when assessing optic discs for the presence of glaucoma, in the context of this study.

Physical activity and ocular perfusion pressure: the EPIC-Norfolk eye study.

PURPOSE: To examine the relationship between physical activity and ocular perfusion pressure (OPP), a consistent risk factor for glaucoma. METHODS: The relationship between previous physical activity and current OPP in 5650 participants aged 48 to 90 who attended the first (1993-1997) and third (2006-2010) health check as part of the European Prospective Investigation into Cancer (EPIC)-Norfolk study was examined. Usual combined physical activity at work and leisure was assessed using a validated instrument. Individuals were categorized as inactive, moderately inactive, moderately active, or active. Three IOP measurements were obtained (Ocular Response Analyzer [ORA]; Reichert, Inc., Depew, NY). Mean Goldmann correlated IOP (IOPg) from one eye was used in the analysis. Systolic and diastolic blood pressure (BP) were recorded as the mean of two measurements taken with a sphygmomanometer. Associations between physical activity and low (≤40 mm Hg) mean OPP (2/3 mean arterial pressure - IOP) and low (≤50 mm Hg) diastolic OPP (diastolic BP - IOP) were tested using logistic regression, adjusting for age, sex, body mass index, social class, IOP, and BP. RESULTS: Active people had a lower risk of mean OPP ≤ 40 mm Hg and diastolic OPP ≤ 50 mm Hg after adjusting for age, sex, social class, and body mass index (odds ratio, 0.75; 95% confidence interval [CI], 0.60-0.93; P < 0.01) and (odds ratio, 0.73, 95% CI, 0.58-0.93; P = 0.01), respectively. The association between physical activity and perfusion pressure was independent of IOP, but largely mediated through diastolic BP. CONCLUSIONS: Lower levels of physical activity were associated with lower OPP. Further research is needed to investigate the potential benefit of increased physical activity as a safe and simple method of modifying glaucoma risk.

Quantifying discordance between structure and function measurements in the clinical assessment of glaucoma.

OBJECTIVE: To evaluate a new method of quantifying and visualizing discordance between structural and functional measurements in glaucomatous eyes by predicting the visual field (VF) from retinal nerve fiber layer thickness (RNFLT) using a bayesian radial basis function. METHODS: Five GDx VCC RNFLT scans and 5 Humphrey 24-2 Swedish Interactive Thresholding Algorithm VF tests were performed for 50 glaucomatous eyes from 50 patients. A best-available estimate (BAE) of the true VF was calculated as the pointwise median of these 5 replications. This BAE VF was compared with every RNFLT-predicted VF from the bayesian radial basis function and every measured VF. Predictability of VFs from RNFLT was established from previous data. A structure-function pattern discordance map and a structure-function discordance index (scores of 0-1) were established from the predictability limits for each structure-function measurement pair to quantify and visualize the discordance between the structure-predicted and measured VFs. RESULTS: The mean absolute difference between the structure-predicted and BAE VFs was 3.9 dB. The mean absolute difference between measured and BAE VFs was 2.6 dB. The mean (SD) structure-function discordance index score was 0.34 (0.11). Ninety-seven (39%) of the structure-predicted VFs showed significant discordance (structure-function discordance index score >0.3) from measured VFs. CONCLUSIONS: On average, the bayesian radial basis function predicts the BAE VF from RNFLT slightly less well than a measured VF from the 5 VFs composing the BAE VF. The pattern discordance map highlights locations with structure-function discordance, with the structure-function discordance index providing a summary index. These tools may help clinicians trust the mutually confirmatory structure-function measurements with good concordance or identify unreliable ones with poor concordance.

Clinical assessment of stereoscopic optic disc photographs for glaucoma: the European Optic Disc Assessment Trial.

PURPOSE: To determine the diagnostic accuracy of judging optic disc photographs for glaucoma by ophthalmologists. DESIGN: Evaluation of diagnostic test and technology. PARTICIPANTS: A total of 243 of 875 invited ophthalmologists in 11 European countries. METHODS: We determined how well each participant classified 40 healthy eyes and 48 glaucomatous eyes with varying severity of the disease on stereoscopic slides. Duplicate slides were provided for determining intraobserver agreement. All eyes were also imaged with the GDx with variable corneal compensation (GDx-VCC) (Carl Zeiss Meditec AG, Jena, Germany) and the Heidelberg Retina Tomograph (HRT) I (Heidelberg Engineering GmbH, Heidelberg, Germany). Diagnostic accuracies of clinicians were compared with those of the best machine classifiers. MAIN OUTCOME MEASURES: Accuracy of classification, expressed as sensitivity, specificity, and overall accuracy. Intraobserver agreement (kappa). RESULTS: The overall diagnostic accuracy of ophthalmologists was 80.5% (standard deviation [SD], 6.8; range, 61.4%-94.3%). The machine classifiers outperformed most observers in diagnostic accuracy; the GDx-VCC nerve fiber indicator and the HRT's best classifier correctly classified 93.2% and 89.8% of eyes, respectively. The intraobserver agreement (kappa) varied between -0.13 and 1.0 and was on average good (0.7). CONCLUSIONS: In general, ophthalmologists classify optic disc photographs moderately well for detecting glaucoma. There is, however, large variability in diagnostic accuracy among and agreement within clinicians. Common imaging devices outperform most clinicians in classifying optic discs. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Development and evaluation of a linear staircase strategy for the measurement of perimetric sensitivity.

Perimetric sensitivity of patients with glaucoma has traditionally been measured in logarithmic (dB) units, but linear sensitivity correlates better with conventional structural measures of glaucomatous damage. Monte Carlo simulations of perimetric algorithms were used to assess potential effects of logarithmic steps on bias and variability when perimetric sensitivity was represented in linear units, and to assess the potential benefits of algorithms using linear steps. Simulations predicted that linear staircases could reduce the sensitivity-dependence of bias, variability and efficiency. These predictions were supported by a perimetric study of 21 patients with glaucoma and 20 age-similar controls who made repeat visits over several weeks.