1,721,084 research outputs found
Estimating the Distribution of True Rates of Visual Field Progression in Glaucoma
Full text linkPurpose: The purpose of this study was to estimate the distribution of the true rates of progression (RoP) of visual field (VF) loss.Methods: We analyzed the progression of mean deviation over time in series of ≥ 10 tests from 3352 eyes (one per patient) from 5 glaucoma clinics, using a novel Bayesian hierarchical Linear Mixed Model (LMM); this modeled the random-effect distribution of RoPs as the sum of 2 independent processes following, respectively, a negative exponential distribution (the “true” distribution of RoPs) and a Gaussian distribution (the “noise”), resulting in a skewed exGaussian distribution. The exGaussian-LMM was compared to a standard Gaussian-LMM using the Watanabe-Akaike Information Criterion (WAIC). The random-effect distributions were compared to the empirical cumulative distribution function (eCDF) of linear regression RoPs using a Kolmogorov-Smirnov test. Results: The WAIC indicated a better fit with the exGaussian-LMM (estimate [standard error]: 192174.4 [721.2]) than with the Gaussian-LMM (192595 [697.4], with a difference of 157.2 [22.6]). There was a significant difference between the eCDF and the GaussianLMM distribution (P < 0.0001), but not with the exGaussian-LMM distribution (P = 0.108). The estimated mean (95% credible intervals, CIs) “true” RoP (−0.377, 95% CI = −0.396 to −0.359 dB/year) was more negative than the observed mean RoP (−0.283, 95% CI = −0.299 to −0.268 dB/year), indicating a bias likely due to learning in standard LMMs. Conclusions: The distribution of “true” RoPs can be estimated with an exGaussian-LMM, improving model accuracy. Translational Relevance: We used these results to develop a fast and accurate analytical approximation for sample-size calculations in clinical trials using standard LMMs, which was integrated in a freely available web application
Relationship Between Intraocular Pressure and the True Rate of Functional and Structural Progression in the United Kingdom Glaucoma Treatment Study
Full text linkExperimental assessment of human corneal hysteresis
No full texthttp://hdl.handle.net/20.500.11768/96991Purpose: Hysteresis is a viscoelastic property characterized by the difference in behavior under loading and unloading. The aim of the study was to determine corneal hysteresis using experimental means. Methods: Twenty-nine human corneas with 50-95 year age were subjected to cycles of pressure loading and unloading. Two pressure application rates were adopted to approximate static and dynamic loading conditions. Results: The behavior under both loading and unloading was found to stiffen with increased age. The unloading behavior appeared to be largely independent of the pressure level at which unloading started. The difference between the behavior patterns under loading and unloading was quantified and used as a measure of corneal hysteresis. The hysteresis area was significantly larger with faster loading and with decreased age. Conclusions: The trend for hysteresis to decrease with age is in agreement with previous clinical observations. Hysteresis was also found to increase with faster pressure application
Relationship between Intraocular Pressure Fluctuation and Visual Field Progression Rates in the United Kingdom Glaucoma Treatment Study
No full textPurpose: 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. Design: Randomized, double-masked, placebo-controlled multicenter trial. Participants: Participants with ≥5 VFs (213 placebo, 217 treatment). Methods: 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. Main Outcome Measures: Associations between IOP fluctuation metrics and rates of MD and the five fastest test locations. Results: 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. Conclusions: 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. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article
Peripheral blood mononuclear cell respiratory function is associated with progressive glaucomatous vision loss
No full textIntraocular pressure (IOP) is currently the only modifiable risk factor for glaucoma and all licensed treatments lower IOP. However, many patients continue to lose vision despite IOP-lowering treatment. Identifying biomarkers for progressive vision loss would have considerable clinical utility. We demonstrate that lower peripheral blood mononuclear cell (PBMC) oxygen consumption rate (OCR) is strongly associated with faster visual field (VF) progression in patients treated by lowering IOP (P < 0.001, 229 eyes of 139 participants), explaining 13% of variance in the rate of progression. In a separate reference cohort of untreated patients with glaucoma (213 eyes of 213 participants), IOP explained 16% of VF progression variance. OCR is lower in patients with glaucoma (n = 168) than in controls (n = 50; P < 0.001) and is lower in patients with low baseline IOP (n = 99) than those with high baseline IOP (n = 69; P < 0.01). PBMC nicotinamide adenine dinucleotide (NAD) levels are lower in patients with glaucoma (n = 29) compared to controls (n = 25; P < 0.001) and strongly associated with OCR (P < 0.001). Our results support PBMC OCR and NAD levels as new biomarkers for progressive glaucoma
Validating Trend-Based End Points for Neuroprotection Trials in Glaucoma
No full textPurpose: The purpose of this study was to evaluate the power of trend-based visual field (VF) progression end points against long-term development of event-based end points accepted by the US Food and Drug Administration (FDA). Methods: One eye from 3352 patients with ≥10 24-2 VFs (median = 11 years) follow-up were analyzed. Two FDA-compatible criteria were applied to these series to label “true-progressed” eyes: ≥5 locations changing from baseline by more than 7 dB (FDA-7) or by more than the expected test-retest variability (GPA-like) in 2 consecutive tests. Observed rates of progression (RoP) were used to simulate trial-like series (2 years) randomly assigned (1000 times) to a “placebo” or a “treatment” arm. We simulated neuroprotec-tive “treatment” effects by changing the proportion of “true progressed” eyes in the two arms. Two trend-based methods for mean deviation (MD) were assessed: (1) linear mixed model (LMM), testing average difference in RoP between the two arms, and (2) time-to-progression (TTP), calculated by linear regression as time needed for MD to decline by predefined cutoffs from baseline. Power curves with 95% confidence intervals were calculated for trend and event-based methods on the simulated series. Results: The FDA-7 and GPA-like progression was achieved by 45% and 55% of the eyes in the clinical database. LMM and TTP had similar power, significantly superior to the event-based methods, none of which reached 80% power. All methods had a 5% false-positive rate. Conclusions: The trend-based methods can efficiently detect treatment effects defined by long-term FDA-compatible progression. Translational Relevance: The assessment of the power of trend-based methods to detect clinically relevant progression end points
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