Latanoprost for open-angle glaucoma (UKGTS): a randomised, multicentre, placebo-controlled trial.

BACKGROUND: Treatments for open-angle glaucoma aim to prevent vision loss through lowering of intraocular pressure, but to our knowledge no placebo-controlled trials have assessed visual function preservation, and the observation periods of previous (unmasked) trials have typically been at least 5 years. We assessed vision preservation in patients given latanoprost compared with those given placebo. METHODS: In this randomised, triple-masked, placebo-controlled trial, we enrolled patients with newly diagnosed open-angle glaucoma at ten UK centres (tertiary referral centres, teaching hospitals, and district general hospitals). Eligible patients were randomly allocated (1:1) with a website-generated randomisation schedule, stratified by centre and with a permuted block design, to receive either latanoprost 0·005% (intervention group) or placebo (control group) eye drops. Drops were administered from identical bottles, once a day, to both eyes. The primary outcome was time to visual field deterioration within 24 months. Analyses were done in all individuals with follow-up data. The Data and Safety Monitoring Committee (DSMC) recommended stopping the trial on Jan 6, 2011 (last patient visit July, 2011), after an interim analysis, and suggested a change in primary outcome from the difference in proportions of patients with incident progression between groups to time to visual field deterioration within 24 months. This trial is registered, number ISRCTN96423140. FINDINGS: We enrolled 516 individuals between Dec 1, 2006, and March 16, 2010. Baseline mean intraocular pressure was 19·6 mm Hg (SD 4·6) in 258 patients in the latanoprost group and 20·1 mm Hg (4·8) in 258 controls. At 24 months, mean reduction in intraocular pressure was 3·8 mm Hg (4·0) in 231 patients assessed in the latanoprost group and 0·9 mm Hg (3·8) in 230 patients assessed in the placebo group. Visual field preservation was significantly longer in the latanoprost group than in the placebo group: adjusted hazard ratio (HR) 0·44 (95% CI 0·28-0·69; p=0·0003). We noted 18 serious adverse events, none attributable to the study drug. INTERPRETATION: This is the first randomised placebo-controlled trial to show preservation of the visual field with an intraocular-pressure-lowering drug in patients with open-angle glaucoma. The study design enabled significant differences in vision to be assessed in a relatively short observation period. FUNDING: Pfizer, UK National Institute for Health Research Biomedical Research Centre.

Biomechanical parameters of the cornea measured with the Ocular Response Analyzer in normal eyes.

BACKGROUND: To evaluate the relationships between Reichert Ocular Response Analyzer (ORA) parameters corneal hysteresis (CH) and corneal response factor (CRF) and ocular dimensions, age and intraocular pressure. METHODS: Two hundred and twelve eyes of 212 participants with no ocular pathology had CH and CRF measured with the ORA. Intraocular pressure (IOP) was measured with the Dynamic Contour tonometer and central corneal thickness (CCT) was also evaluated. Partial least squares linear regression (PLSLR) analyses were performed to examine the relationships between each response variable, CH and CRF, and the predictor variables age, corneal curvature (CC), axial length (AL), CCT and IOP. RESULTS: CH was positively associated with CCT and negatively associated with age (scaled coefficients: CCT 0.62, p < 0.0001; age -0.55, p <0.0001; r2 = 0.25). CRF was positively associated with CCT and DCT IOP and negatively associated with age and AL (scaled coefficients: CCT 0.89, p < 0.0001; DCT IOP 0.46, p < 0.01; age - 0.60, p < 0.0001; AL -0.37, p < 0.01; r2 = 0.43). There was no significant association between CC and CH or CRF. CONCLUSIONS: The study suggests that age and CCT are strongly associated with CH and CRF, and that the latter is also influenced by AL and IOP. However, the variables studied could explain only 25% and 43% of the measured variation in CH and CRF, respectively, suggesting other factors also affect the values of these measurements.

The United Kingdom Glaucoma Treatment Study: a multicenter, randomized, placebo-controlled clinical trial: design and methodology.

OBJECTIVE: 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. DESIGN: The UKGTS is a randomized, double-masked, placebo-controlled, multicenter treatment trial for OAG. PARTICIPANTS: Five hundred sixteen newly diagnosed (previously untreated) patients with OAG were recruited prospectively at 10 centers between 2007 and 2010. METHODS: 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. MAIN OUTCOME MEASURES: 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. RESULTS: 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. CONCLUSIONS: 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. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

The United Kingdom Glaucoma Treatment Study: a multicenter, randomized, double-masked, placebo-controlled trial: baseline characteristics.

OBJECTIVE: 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. DESIGN: The UKGTS is a randomized, double-masked, placebo-controlled, multicenter treatment trial for OAG. PARTICIPANTS: A total of 516 patients with newly diagnosed (previously untreated) OAG were prospectively recruited at 10 UK centers between 2007 and 2010. METHODS: 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. MAIN OUTCOME MEASURES: The primary outcome measure is time to VF deterioration within 24 months. Secondary outcomes include the deterioration velocity of VF and quantitative imaging measures. RESULTS: 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). CONCLUSIONS: 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.

Five-year forecasts of the Visual Field Index (VFI) with binocular and monocular visual fields.

BACKGROUND: In clinical care, visual field (VF) damage is assessed using monocular VF testing, yet patients perceive the world binocularly. This study was conducted to compare 5-year forecasts for the Visual Field Index (VFI) generated from series of binocular and monocular VFs. METHODS: Series of ten consecutive VFs (Humphrey 24-2 Full-threshold) spanning on average 3.7 (SD: ±0.8) years from 60 eyes of 30 glaucomatous patients were retrospectively examined. The VFs of both eyes were merged to produce the integrated VF and its VFI score (Binocular VFI) was estimated. Forecasts of binocular and monocular VFIs were calculated for each patient by projecting the fitted linear regression 5 years ahead from the last VF following the method on the Humphrey Guided Progression Analysis (GPA) print-out. The precisions of the forecasts were calculated as the width of the 95% prediction limit (PL). RESULTS: The mean 5 year forecast for binocular VFIs was 92% (SD: 11%), which was significantly higher than forecasts from right and left eyes (79% [SD: 19%] and 82% [SD: 16%] respectively; P < 0.05). The width of the 95% PL for 5-year predictions with monocular VFIs (mean right eye: 29% [SD: 19%] and mean left eye: 27% [SD: 16%]) were significantly larger than that of the binocular VFI (mean: 12% [SD: 7%]; P < 0.05). CONCLUSIONS: Five year forecasted VFI values using binocular measures return significantly better values, and can be made with greater confidence than those based on monocular measures. In turn, forecasts of a patient's binocular VFI might be more relevant to estimating the patient's future functional VF.

Segmentation of fluorescence microscopy images for quantitative analysis of cell nuclear architecture.

Considerable advances in microscopy, biophysics, and cell biology have provided a wealth of imaging data describing the functional organization of the cell nucleus. Until recently, cell nuclear architecture has largely been assessed by subjective visual inspection of fluorescently labeled components imaged by the optical microscope. This approach is inadequate to fully quantify spatial associations, especially when the patterns are indistinct, irregular, or highly punctate. Accurate image processing techniques as well as statistical and computational tools are thus necessary to interpret this data if meaningful spatial-function relationships are to be established. Here, we have developed a thresholding algorithm, stable count thresholding (SCT), to segment nuclear compartments in confocal laser scanning microscopy image stacks to facilitate objective and quantitative analysis of the three-dimensional organization of these objects using formal statistical methods. We validate the efficacy and performance of the SCT algorithm using real images of immunofluorescently stained nuclear compartments and fluorescent beads as well as simulated images. In all three cases, the SCT algorithm delivers a segmentation that is far better than standard thresholding methods, and more importantly, is comparable to manual thresholding results. By applying the SCT algorithm and statistical analysis, we quantify the spatial configuration of promyelocytic leukemia nuclear bodies with respect to irregular-shaped SC35 domains. We show that the compartments are closer than expected under a null model for their spatial point distribution, and furthermore that their spatial association varies according to cell state. The methods reported are general and can readily be applied to quantify the spatial interactions of other nuclear compartments.

Molecular recognition of DNA by rigid [N]-polynorbornane-derived bifunctional intercalators: synthesis and evaluation of their binding properties.

We have exploited the concept of multivalency in the context of DNA recognition, using novel chemistry to synthesize a new type of bis-intercalator with unusual sequence-selectivity. Bis-intercalation has been observed previously, but design principles for de novo construction of such molecules are not known. Our compounds feature two aromatic moieties projecting from a rigid, polynorbornane-based scaffold. The length and character of the backbone as well as the identity of the intercalators were varied, resulting in mono- or divalent recognition of the double helix with varying affinity. Our lead compound proved to be a moderately sequence-selective bis-intercalator with an unwinding angle of 27 degrees and a binding constant of about 8 microM. 9-aminoacridine rings were preferred over acridine carboxamides or naphthalimides, and a rigid [3]-polynorbornane scaffold was superior to a [5]-polynorbornane. The flexibility of the linker connecting the rings to the scaffold, although less influential, could affect the strength and character of the DNA binding.

Measurement precision in a series of visual fields acquired by the standard and fast versions of the Swedish interactive thresholding algorithm: analysis of large-scale data from clinics.

IMPORTANCE: Swedish Interactive Thresholding Algorithm (SITA) testing strategies for the Humphrey Field Analyzer have become a clinical standard. Measurements from SITA Fast are thought to be more variable than SITA Standard, yet some clinics routinely use SITA Fast because it is quicker. OBJECTIVE: To examine the measurement precision of the 2 SITA strategies across a range of sensitivities using a large number of visual field (VF) series from 4 glaucoma clinics in England. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study at Moorfields Eye Hospital in London, England; Gloucestershire Eye Unit at Cheltenham General Hospital; Queen Alexandra Hospital in Portsmouth, England; and the Calderdale and Huddersfield National Health Service Foundation Trust that included 66,974 Humphrey 24-2 SITA Standard VFs (10,124 eyes) and 19,819 Humphrey 24-2 SITA Fast VFs (3654 eyes) recorded between May 20, 1997, and September 20, 2012. Pointwise ordinary least squares linear regression of measured sensitivity over time was conducted using VF series of 1 random eye from each patient. Residuals from the regression were pooled according to fitted sensitivities. For each sensitivity (decibel) level, the standard deviation of the residuals was used to estimate measurement precision and were compared for SITA Standard and SITA Fast. Simulations of progression from different VF baselines were used to evaluate how different levels of precision would affect time to detect VF progression. MAIN OUTCOME AND MEASURE: Median years required to detect progression. RESULTS: Median (interquartile range) patient age, follow-up, and series lengths for SITA Standard were 64 (53-72) years, 6.0 (4.0-8.5) years, and 6 (4-8) VFs, respectively; for SITA Fast, medians (interquartile range) were 70 (61-78) years, 5.1 (3.2-7.3) years, and 5 (4-6) VFs. Measurement precision worsened as sensitivity decreased for both test strategies. In the 20 to 5 dB range, SITA Fast was less precise than SITA Standard; this difference was largest between 15 to 10 dB, where variability in both methods peaked. Translated to median time to detection, differences in measurement precision were negligible, suggesting minimal effects on time to detect progression. CONCLUSIONS AND RELEVANCE: Although SITA Standard is a more precise testing algorithm than SITA Fast at lower VF sensitivities, it is unlikely to make a sizeable difference to improving the time to detect VF progression.

New quantitative approaches reveal the spatial preference of nuclear compartments in mammalian fibroblasts.

The nuclei of higher eukaryotic cells display compartmentalization and certain nuclear compartments have been shown to follow a degree of spatial organization. To date, the study of nuclear organization has often involved simple quantitative procedures that struggle with both the irregularity of the nuclear boundary and the problem of handling replicate images. Such studies typically focus on inter-object distance, rather than spatial location within the nucleus. The concern of this paper is the spatial preference of nuclear compartments, for which we have developed statistical tools to quantitatively study and explore nuclear organization. These tools combine replicate images to generate 'aggregate maps' which represent the spatial preferences of nuclear compartments. We present two examples of different compartments in mammalian fibroblasts (WI-38 and MRC-5) that demonstrate new knowledge of spatial preference within the cell nucleus. Specifically, the spatial preference of RNA polymerase II is preserved across normal and immortalized cells, whereas PML nuclear bodies exhibit a change in spatial preference from avoiding the centre in normal cells to exhibiting a preference for the centre in immortalized cells. In addition, we show that SC35 splicing speckles are excluded from the nuclear boundary and localize throughout the nucleoplasm and in the interchromatin space in non-transformed WI-38 cells. This new methodology is thus able to reveal the effect of large-scale perturbation on spatial architecture and preferences that would not be obvious from single cell imaging.

Examining visual field loss in patients in glaucoma clinics during their predicted remaining lifetime.

PURPOSE: To evaluate the proportion of patients in glaucoma clinics progressing at rates that would result in visual disability within their expected lifetime. METHODS: This retrospective study used visual field (VF) series of at least 3 years' duration from 3790 UK patients in glaucoma clinics calculating rates of loss for each eye using linear regression of mean deviation (MD) over time. Residual life expectancies derived from the UK Office of National Statistics actuarial tables for each patient were combined with these rates to estimate predicted MDs at end of expected lifetime. The proportion of patients projected to progress to visual impairment (MD: -14 dB or worse) or statutory blindness (MD: -22 dB or worse) in both eyes before end of expected lifetime was calculated. RESULTS: Only 3.0% (95% confidence interval [CI] 2.7%-3.4%) of patient eyes progressed at faster than -1.5 dB/year (n = 7149 eyes). Of those patients with both eyes followed, 5.2% (CI 4.5%-6.0%) were predicted to progress to statutory blindness, with a further 10.4% (CI 9.4%-11.4%) reaching visual impairment in their lifetime. More than 90% (CI 85.7%-94.3%) of patients predicted to progress to statutory blindness, had an MD worse than -6 dB in at least one eye at presentation. CONCLUSIONS: This modeling exercise indicates that most patients in glaucoma clinics are not at high risk of progressing to statutory blindness. The likelihood of patients suffering impairment in their lifetimes is linked to VF loss at presentation, which illuminates the importance of reliably detecting significant VF defects in primary care.

Detecting changes in retinal function: Analysis with Non-Stationary Weibull Error Regression and Spatial enhancement (ANSWERS).

Visual fields measured with standard automated perimetry are a benchmark test for determining retinal function in ocular pathologies such as glaucoma. Their monitoring over time is crucial in detecting change in disease course and, therefore, in prompting clinical intervention and defining endpoints in clinical trials of new therapies. However, conventional change detection methods do not take into account non-stationary measurement variability or spatial correlation present in these measures. An inferential statistical model, denoted 'Analysis with Non-Stationary Weibull Error Regression and Spatial enhancement' (ANSWERS), was proposed. In contrast to commonly used ordinary linear regression models, which assume normally distributed errors, ANSWERS incorporates non-stationary variability modelled as a mixture of Weibull distributions. Spatial correlation of measurements was also included into the model using a Bayesian framework. It was evaluated using a large dataset of visual field measurements acquired from electronic health records, and was compared with other widely used methods for detecting deterioration in retinal function. ANSWERS was able to detect deterioration significantly earlier than conventional methods, at matched false positive rates. Statistical sensitivity in detecting deterioration was also significantly better, especially in short time series. Furthermore, the spatial correlation utilised in ANSWERS was shown to improve the ability to detect deterioration, compared to equivalent models without spatial correlation, especially in short follow-up series. ANSWERS is a new efficient method for detecting changes in retinal function. It allows for better detection of change, more efficient endpoints and can potentially shorten the time in clinical trials for new therapies.

New insights into measurement variability in glaucomatous visual fields from computer modelling.

OBJECTIVE: To develop a model to simulate visual fields (VFs) in glaucoma patients, and to characterize variability of the Mean Deviation (MD) VF summary measurement using real VFs and simulations. METHODS: Pointwise VF variability was previously approximated using longitudinal VF data (24-2 SITA Standard, Humphrey Field Analyzer) from 2,736 patients; these data were used to build a non-parametric model to simulate VFs. One million VF simulations were generated from 1,000 VFs (1,000 simulations per 'ground-truth' VF), and the variability of simulated MDs was characterized as a function of ground-truth MD and Pattern Standard Deviation (PSD). RESULTS: The median (interquartile range, IQR) patient age and MD was 66 (56 to 75) years and -3.5 (-8.3 to -1.1) decibels, respectively. The inferred variability as a function of ground-truth MD and PSD indicated that variability, on average, increased rapidly as glaucoma worsened. However, the pattern of VF damage significantly affects the level of MD variability, with more than three-fold differences between patients with approximately the same levels of MD but different patterns of loss. CONCLUSIONS: A novel approach for simulating VFs is introduced. A better understanding of VF variability will help clinicians to differentiate real VF progression from measurement variability. This study highlights that, overall, MD variability increases as the level of damage increases, but variability is highly dependent on the pattern of VF damage. Future research, using VF simulations, could be employed to provide benchmarks for measuring the performance of VF progression detection algorithms and developing new strategies for measuring VF progression.

A survey of attitudes of glaucoma subspecialists in England and Wales to visual field test intervals in relation to NICE guidelines.

OBJECTIVES: To establish the attitudes of glaucoma specialists to the frequency of visual field (VF) testing in the UK, using the NICE recommendations as a standard for ideal practice. DESIGN: Interview and postal survey. SETTING: UK and Eire Glaucoma Society national meeting 2011 in Manchester, UK, with a second round of surveys administered by post. PARTICIPANTS: All consultant glaucoma specialists in England and Wales were invited to complete the survey. PRIMARY AND SECONDARY OUTCOME MEASURES: (1) Compliance of assigned follow-up VF intervals with NICE guidelines for three hypothetical patient scenarios, with satisfactory treated intraocular pressure and (a) no evidence of VF progression; (b) evidence of VF progression and (c) uncertainty about VF progression, and respondents were asked to provide typical follow-up intervals representative of their practice; (2) attitudes to research recommendations for six VF in the first 2 years for newly diagnosed patients with glaucoma. RESULTS: 70 glaucoma specialists completed the survey. For each of the clinical scenarios a, b and c, 14 (20%), 33 (47%) and 28 (40%) responses, respectively, fell outside the follow-up interval recommended by NICE. Nearly half of the specialists (46%) agreed that 6 VF tests in the first 2 years was ideal practice, while 16 (28%) said this was practice 'not possible', with many giving resources within the NHS setting as a limiting factor. CONCLUSIONS: The results from this survey suggest that there is a large variation in attitudes to follow-up intervals for patients with glaucoma in the UK, with assigned intervals for VF testing which are, in many cases, inconsistent with the guidelines from NICE.

Relating retinal nerve fiber layer thickness and functional estimates of ganglion cell sampling density in healthy eyes and in early glaucoma.

PURPOSE: To investigate the relationship between retinal nerve fiber layer (RNFL) thickness and peripheral grating resolution acuity (PGRA) as well as differential light sensitivity (DLS) in healthy subjects and patients with early glaucoma. The agreement between estimates of retinal ganglion cell (GC) density from each functional test is explored. METHODS: PGRA was measured in 24 patients with early glaucoma (mean deviation [MD] > -8 dB) and 26 healthy subjects using achromatic Gabor stimuli in 4 diagonal visual field locations at 10° eccentricity. DLS for a Goldmann size III equivalent was obtained from individual spatial summation functions and expressed in Humphrey Field Analyzer-equivalent decibel values. RNFL thickness was measured around the optic nerve head using Zeiss Stratus optical coherence tomography and related to functional measures using a retinotopic map. Functional GC density was estimated using structure/function models for both tests. Passing-Bablok regression was used to investigate the structure/function relationships. RESULTS: A positive and statistically significant association was found between PGRA and RNFL thickness, and separately between DLS and RNFL thickness, for combined glaucoma and healthy data (both P < 0.05). The slope of the structure/function association in healthy subjects was not significantly different to that in glaucoma patients using either functional measure (both P > 0.05). Agreement between estimates of GC density from psychophysical data was moderate. CONCLUSIONS: The relationship between PGRA and RNFL thickness is at least as great in magnitude as that between DLS and RNFL thickness; a significant structure/function association is also observed in healthy subjects alone.

Are practical recommendations practiced? A national multi-centre cross-sectional study on frequency of visual field testing in glaucoma.

AIM: To estimate current clinical practice for frequency of visual field (VF) monitoring in glaucoma in England. METHODS: A cross-sectional review of all patients with chronic open angle glaucoma (COAG) attending specialist glaucoma clinics at six hospitals in England was performed. The number of VF tests undertaken prior to the study date and during the first 2 years since diagnosis were recorded and compared with European Glaucoma Society (EGS) guidelines for newly-diagnosed patients. Clinician-requested monitoring intervals were compared with intervals from the National Institute of Clinical Excellence (NICE) guidelines, and the relationships with disease severity, intraocular pressure (IOP) and glaucoma progression status were reviewed. RESULTS: One-hundred and four patients with COAG were included. 73 patients had at least 2 years of follow-up. Median (IQR) total number of VF tests and in the first 2 years of diagnosis were 4 (2-7) and 2 (2-3), respectively. No patients met EGS guidelines, but 87% of patients had their monitoring intervals requested in accordance with NICE guidelines. These intervals were not related to disease severity or VF stability (Kruskal-Wallis test, p=0.25) but shortened significantly when IOP control was inadequate or when the overall clinical impression was disease progression (p<0.001). CONCLUSIONS: Most newly-diagnosed COAG patients receive less than three VFs in the first 2 years following diagnosis and an average of 0.7 VF per year over the duration of follow-up.

The influence of intersubject variability in ocular anatomical variables on the mapping of retinal locations to the retinal nerve fiber layer and optic nerve head.

PURPOSE: To investigate the influence of intersubject variation in ocular parameters on the mapping of retinal locations to the retinal nerve fiber layer and optic nerve head. METHODS: One hundred retinal nerve fiber layer (RNFL) bundle photographs from 100 subjects were optimized digitally and single RNFL bundles manually traced back to the ONH where their entry point was noted. A 24-2 visual field (VF) grid pattern was superimposed onto the photographs in order to relate VF test points to intersecting RNFL bundles and their entry angles into the ONH. Axial length, spherical equivalent, the position of the ONH in relation to the fovea, size, orientation, tilt, and shape of the ONH were assessed. Multilevel linear models were generated for predicting the entry angle of RNFL bundles, based on ocular parameters. RESULTS: A total of 6388 RNFL bundles were traced. The influence of ocular parameters could be evaluated for 33 out of 52 VF locations. The position of the ONH in relation to the fovea was the most prominent predictor for variations in the mapping of retinal locations to the ONH, followed by disc area, axial length, spherical equivalent, disc shape, disc orientation, and disc tilt. CONCLUSIONS: Mapping of retinal locations to the optic nerve head varies between patients according to a given patient's ocular parameters. By considering these parameters, patient-tailored, structure-function maps can be built and structural and functional measurements can be correlated more accurately. Individualized maps may assist clinicians detecting glaucoma and monitoring glaucomatous progression.

Practical landmarks for visual field disability in glaucoma.

BACKGROUND/AIMS: To assess whether mean deviation (MD) from automated perimetry is related to the visual field (VF) component for legal fitness to drive (LFTD) in glaucoma patients. METHODS: Monocular 24-2 VFs of 2604 patients with bilateral VF damage were retrospectively investigated. Integrated visual fields were calculated and used as a surrogate to assess LFTD according to current UK driving licence criteria. The better eye MD (BEMD), worse eye MD (WEMD) and a measure utilising MD of both eyes were compared, to assess respective diagnostic capabilities to predict LFTD (using the integrated visual field surrogate test as the gold standard) and a 'Probability of Failure' (PoF) for various defect levels was calculated. RESULTS: BEMD appears to be a good predictor of the VF component for a patient's LFTD (receiver operating characteristic area under the curve: 96.2%); MDs from both eyes offered no significant extra diagnostic power (area under the curve: 96.4%). PoF for BEMD thresholds of ≤-10 dB and ≤-14 dB were 70 (95% CI 66% to 74%) and 92% (87% to 95%), respectively. CONCLUSION: There is a strong relationship between BEMD and a patient's LFTD. PoF values for LFTD associated with readily available MD values provide practical landmarks for VF disability in glaucoma.

A novel distribution of visual field test points to improve the correlation between structure-function measurements.

PURPOSE: To create a new visual field (VF) test grid centered at the optic disc (disc-centered field [DCF]) and to infer the combination of VF test points (structure-function field [SFF]), taken from the DCF and the conventional fovea-centered 24-2 grid (24-2) of standard automated perimetry, which yields the strongest sectorial correlation between structure-function measurements of retinal nerve fiber layer (RNFL) thickness and VF sensitivity. METHODS: In 50 eyes with ocular hypertension or open angle glaucoma, the DCF and 24-2 VF were measured with a humphrey field analyzer II (Full Threshold strategy) and RNFL thickness was measured with Stratus optical coherence tomography. test points from the DCF and 24-2 VF Were combined and divided into 12 sectors according to the spatial distribution of the RNFL. A novel VF for structure-function studies was established using the following criteria: each sector must contain at least one or two test points (depending on the sector's location), and the combination of test points which yields the strongest structure-function correlation is selected. RESULTS: The SFF consisted of 40 test points. The structure-function correlation for the SFF was compared with the standard 24-2 VF; a multiple-comparison test for dependent groups was carried out using a percentile bootstrap method, which indicated that the sector correlation coefficients in the SFF were significantly higher than those in the 24-2 VF. CONCLUSIONS: The SFF, with fewer test locations, has a stronger structure-function correlation than the 24-2 VF. This improved correlation may help clinicians to better interpret functional measurements in relation to structural measurements.

The relationship between variability and sensitivity in large-scale longitudinal visual field data.

PURPOSE: Evaluation of progressive visual field (VF) damage is often based on pointwise sensitivity data from standard automated perimetry; however, frequency-of seeing and test-retest studies demonstrate that these measurements can be highly variable, especially in areas of damage. The aim of this study was to characterize VF variability by the level of sensitivity using a statistical method to quantify heteroscedasticity. METHODS: A total of 14,887 Humphrey 24-2 SITA Standard VFs from 2736 patients (2736 eyes) attending Moorfields Eye Hospital from 1997 to 2009 were studied retrospectively. The VF series of each eye was analyzed using pointwise linear regression of sensitivity over time, with residuals (difference from fitted-value) from each regression pooled according to both observed and fitted sensitivities. RESULTS: The median (interquartile range) patient age, follow-up, and series length was 64 (54-71) years, 5.5 (3.9-7.0) years, and 6 (5-7) VFs, respectively. The inferred variability as a function of fitted-sensitivity was in good agreement with previous estimates. Variability was also described as a function of measured sensitivity, which confirmed that variability increased rapidly as the observed sensitivity decreased. CONCLUSIONS: This study highlights a new approach for characterizing VF variability by the level of sensitivity. A considerable strength of the method is that inference is based on thousands of clinic patients rather than the tens of subjects in test-retest studies. The results can help distinguish real VF progression from measurement variability and will be used in models for glaucoma progression detection.