Julia A. Beiser

Central corneal thickness in the ocular hypertension treatment study (OHTS)

OBJECTIVE Central corneal thickness influences intraocular pressure (IOP) measurement. We examined the central corneal thickness of subjects in the Ocular Hypertension Treatment Study (OHTS) and determined if central corneal thickness is related to race. DESIGN Cross-sectional study. PARTICIPANTS One thousand three hundred one OHTS subjects with central corneal thickness measurements. INTERVENTION Central corneal thickness was determined with ultrasonic pachymeters of the same make and model at all clinical sites of the OHTS. MAIN OUTCOME MEASURES Correlation of mean central corneal thickness with race, baseline IOP, refraction, age, gender, systemic hypertension, and diabetes. RESULTS Mean central corneal thickness was 573.0 +/- 39.0 microm. Twenty-four percent of the OHTS subjects had central corneal thickness > 600 microm. Mean central corneal thickness for African American subjects (555.7 +/- 40.0 microm; n = 318) was 23 microm thinner than for white subjects (579.0 +/- 37.0 microm; P < 0.0001). Other factors associated with greater mean central corneal thickness were younger age, female gender, and diabetes. CONCLUSIONS OHTS subjects have thicker corneas than the general population. African American subjects have thinner corneas than white subjects in the study. The effect of central corneal thickness may influence the accuracy of applanation tonometry in the diagnosis, screening, and management of patients with glaucoma and ocular hypertension.

Contralateral effect of topical β-adrenergic antagonists in initial one-eyed trials in the Ocular Hypertension Treatment Study

PURPOSE To evaluate the magnitude of the contralateral effect of topically administered beta-blockers on intraocular pressure. METHODS The Ocular Hypertension Treatment Study enrolled 1,636 subjects. Of these, 817 subjects were randomized to receive topical ocular hypotensive medication and 819 subjects were randomized to close observation (i.e., no topical medication). We compared the intraocular pressure of the contralateral eye of subjects at the baseline visit and after an initial one-eyed therapeutic trial of topical beta-blockers. We examined differences between baseline and follow-up intraocular pressure in untreated eyes of subjects randomized to close observation. RESULTS The mean reduction in intraocular pressure in the beta-blocker-treated eyes was -5.9 +/- 3. 4 mm Hg (-22% +/- 12%; Student t test, P <.0001). In the contralateral eyes, mean intraocular pressure reduction was -1.5 +/- 3.0 mm Hg (-5.8% +/- 12%; P <.0001). Of the contralateral eyes, 35% showed a reduction of 3 mm Hg or more, and 10% showed a reduction of 6 mm Hg or more. The contralateral effect of the relatively selective beta-blocker betaxolol did not differ from that of any of the nonselective beta-blockers. Factors associated with the magnitude of the contralateral effect were the degree of intraocular pressure reduction in the treated eye and baseline intraocular pressure of the contralateral eye. In the close observation group, no significant reduction in intraocular pressure was noted between the baseline and follow-up visit. CONCLUSIONS The contralateral effect is important in clinical practice and in clinical trials when the hypotensive effect of a topical beta-blocker is evaluated by means of a one-eyed therapeutic trial.

Changes in central corneal thickness over time: the ocular hypertension treatment study.

OBJECTIVE To describe how much change, if any, occurs between central corneal thickness (CCT) measurements performed an average of 3.8 years apart in participants in the Ocular Hypertension Treatment Study (OHTS) and to identify clinical and demographic factors that are associated with changes in CCT, including baseline intraocular pressure, duration and class of ocular hypotensive medication, medical history, and systemic medication. DESIGN Secondary analysis of data from a randomized clinical trial. PARTICIPANTS Ocular Hypertension Treatment Study participants. Participants who had undergone incisional intraocular or keratorefractive surgery between CCT measurements were excluded. TESTING The first CCT measurements were performed starting in 1999, and the second measurements were performed starting in 2002. Measurements were performed by OHTS certified technicians using an ultrasonic pachymeter under a standardized protocol. MAIN OUTCOME MEASURE Central corneal thickness measurement (micrometers). RESULTS First and second CCT measurements were available from 73% (1191) of the 1636 OHTS participants randomized. Central corneal thickness decreased a mean rate of -0.74+/-3.5 microm/year between the first and second CCT measurements. The mean medication exposure between first and second CCT measurements in participants originally randomized to observation (n = 595) was 1.1+/-1.6 years, versus 5.0+/-2.7 years in participants originally randomized to medication (n = 596). Central corneal thickness decreased by a mean of 1.0+/-3.4 microm/year among participants originally randomized to observation, compared with 0.5+/-3.5 microm/year among participants originally randomized to medication (P<0.0001). Subgroup analyses suggest that participants treated only with topical prostaglandin analogues (PGAs) between the two CCT measurements had a greater rate of decrease per year than participants treated only with topical beta-blockers. CONCLUSIONS The rate of CCT decrease over 3.8 years is comparable to the cross-sectional age differences reported in the OHTS at the first measurement (0.6 microm/year) and comparable to other cross-sectional studies. Use of topical PGAs may be associated with a slightly higher rate of thinning. The modest age- and drug-related rates of thinning observed are unlikely to influence tonometry or clinical decision-making substantially in most clinical situations.

Adjusting Intraocular Pressure for Central Corneal Thickness Does Not Improve Prediction Models for Primary Open-Angle Glaucoma

PURPOSE To determine if the accuracy of the baseline prediction model for the development of primary open-angle glaucoma (POAG) in patients with ocular hypertension can be improved by correcting intraocular pressure (IOP) for central corneal thickness (CCT). DESIGN Reanalysis of the baseline prediction model for the development of POAG from the Ocular Hypertension Treatment Study (OHTS) substituting IOP adjusted for CCT using 5 different correction formulae for unadjusted IOP. PARTICIPANTS A total of 1433 of 1636 participants randomized to OHTS who had complete baseline data for factors in the prediction model: age, IOP, CCT, vertical cup-to-disc ratio (VCDR), and pattern standard deviation (PSD). METHODS Reanalysis of the prediction model for the risk of developing POAG using the same baseline variables (age, IOP, CCT, VCDR, and PSD) except that IOP was adjusted for CCT using correction formulae. A separate Cox proportional hazards model was run using IOP adjusted for CCT by each of the 5 formulae published to date. Models were run including and excluding CCT. MAIN OUTCOME MEASURES Predictive accuracy of each Cox proportional hazards model was assessed using the c-statistic and calibration chi-square. RESULTS C-statistics for prediction models that used IOP adjusted for CCT by various formulas ranged from 0.75 to 0.77, no better than the original prediction model (0.77) that did not adjust IOP for CCT. Calibration chi-square was acceptable for all models. Baseline IOP, whether adjusted for CCT or not, was statistically significant in all models including those with CCT in the same model. The CCT was statistically significant in all models including those with IOP adjusted for CCT in the same model. CONCLUSIONS The calculation of individual risk for developing POAG in ocular hypertensive individuals is simpler and equally accurate using IOP and CCT as measured, rather than applying an adjustment formula to correct IOP for CCT.

Application of a hemolysis assay for analysis of complement activation by perfluorocarbon nanoparticles

UNLABELLED Nanoparticles offer new options for medical diagnosis and therapeutics with their capacity to specifically target cells and tissues with imaging agents and/or drug payloads. The unique physical aspects of nanoparticles present new challenges for this promising technology. Studies indicate that nanoparticles often elicit moderate to severe complement activation. Using human in vitro assays that corroborated the mouse in vivo results we previously presented mechanistic studies that define the pathway and key components involved in modulating complement interactions with several gadolinium-functionalized perfluorocarbon nanoparticles (PFOB). Here we employ a modified in vitro hemolysis-based assay developed in conjunction with the mouse in vivo model to broaden our analysis to include PFOBs of varying size, charge and surface chemistry and examine the variations in nanoparticle-mediated complement activity between individuals. This approach may provide the tools for an in-depth structure-activity relationship study that will guide the eventual development of biocompatible nanoparticles. FROM THE CLINICAL EDITOR Unique physical aspects of nanoparticles may lead to moderate to severe complement activation in vivo, which represents a challenge to clinical applicability. In order to guide the eventual development of biocompatible nanoparticles, this team of authors report a modified in vitro hemolysis-based assay developed in conjunction with their previously presented mouse model to enable in-depth structure-activity relationship studies.

The effect of changes in intraocular pressure on the risk of primary open-angle glaucoma in patients with ocular hypertension: an application of latent class analysis

BackgroundPrimary open-angle glaucoma (POAG) is one of the leading causes of blindness in the United States and worldwide. While lowering intraocular pressure (IOP) has been proven to be effective in delaying or preventing the onset of POAG in many large-scale prospective studies, one of the recent hot topics in glaucoma research is the effect of IOP fluctuation (IOP lability) on the risk of developing POAG in treated and untreated subjects.MethodIn this paper, we analyzed data from the Ocular Hypertension Treatment Study (OHTS) and the European Glaucoma Prevention Study (EGPS) for subjects who had at least 2 IOP measurements after randomization prior to POAG diagnosis. We assessed the interrelationships among the baseline covariates, the changes of post-randomization IOP over time, and the risk of developing POAG, using a latent class analysis (LCA) which allows us to identify distinct patterns (latent classes) of IOP trajectories.ResultThe IOP change in OHTS was best described by 6 latent classes differentiated primarily by the mean IOP levels during follow-up. Subjects with high post-randomization mean IOP level and/or large variability were more likely to develop POAG. Five baseline factors were found to be significantly predictive of the IOP classification in OHTS: treatment assignment, baseline IOP, gender, race, and history of hypertension. In separate analyses of EGPS, LCA identified different patterns of IOP change from those in OHTS, but confirmed that subjects with high mean level and large variability were at high risk to develop POAG.ConclusionLCA provides a useful tool to assess the impact of post-randomization IOP level and fluctuation on the risk of developing POAG in patients with ocular hypertension. The incorporation of post-randomization IOP can improve the overall predictive ability of the original model that included only baseline risk factors.

Ocular hypertension treatment study: Baseline factors that predict the onset of primary open-angle glaucoma

BACKGROUND The Ocular Hypertension Treatment Study (OHTS) has shown that topical ocular hypotensive medication is effective in delaying or preventing the onset of primary open-angle glaucoma (POAG) in individuals with elevated intraocular pressure (ocular hypertension) and no evidence of glaucomatous damage. OBJECTIVE To describe baseline demographic and clinical factors that predict which participants in the OHTS developed POAG. METHODS Baseline demographic and clinical data were collected prior to randomization except for corneal thickness measurements, which were performed during follow-up. Proportional hazards models were used to identify factors that predicted which participants in the OHTS developed POAG. RESULTS In univariate analyses, baseline factors that predicted the development of POAG included older age, race (African American), sex (male), larger vertical cup-disc ratio, larger horizontal cup-disc ratio, higher intraocular pressure, greater Humphrey visual field pattern standard deviation, heart disease, and thinner central corneal measurement. In multivariate analyses, baseline factors that predicted the development of POAG included older age, larger vertical or horizontal cup-disc ratio, higher intraocular pressure, greater pattern standard deviation, and thinner central corneal measurement. CONCLUSIONS Baseline age, vertical and horizontal cup-disc ratio, pattern standard deviation, and intraocular pressure were good predictors for the onset of POAG in the OHTS. Central corneal thickness was found to be a powerful predictor for the development of POAG.

Predicting Clinical Binary Outcome Using Multivariate Longitudinal Data: Application to Patients with Newly Diagnosed Primary Open- Angle Glaucoma

Primary open angle glaucoma (POAG) is a chronic, progressive, irreversible, and potentially blinding optic neuropathy. The risk of blindness due to progressive visual field (VF) loss varies substantially from patient to patient. Early identification of those patients destined to rapid progressive visual loss is crucial to prevent further damage. In this article, a latent class growth model (LCGM) was developed to predict the binary outcome of VF progression using longitudinal mean deviation (MD) and pattern standard deviation (PSD). Specifically, the trajectories of MD and PSD were summarized by a functional principal component (FPC) analysis, and the estimated FPC scores were used to identify subgroups (latent classes) of individuals with distinct patterns of MD and PSD trajectories. Probability of VF progression for an individual was then estimated as weighted average across latent classes, weighted by posterior probability of class membership given baseline covariates and longitudinal MD/PSD series. The model was applied to the participants with newly diagnosed POAG from the Ocular Hypertension Treatment Study (OHTS), and the OHTS data was best fit by a model with 4 latent classes. Using the resultant optimal LCGM, the OHTS participants with and without VF progression could be accurately differentiated by incorporating longitudinal MD and PSD.

Estimating correlation between multivariate longitudinal data in the presence of heterogeneity

BackgroundEstimating correlation coefficients among outcomes is one of the most important analytical tasks in epidemiological and clinical research. Availability of multivariate longitudinal data presents a unique opportunity to assess joint evolution of outcomes over time. Bivariate linear mixed model (BLMM) provides a versatile tool with regard to assessing correlation. However, BLMMs often assume that all individuals are drawn from a single homogenous population where the individual trajectories are distributed smoothly around population average.MethodsUsing longitudinal mean deviation (MD) and visual acuity (VA) from the Ocular Hypertension Treatment Study (OHTS), we demonstrated strategies to better understand the correlation between multivariate longitudinal data in the presence of potential heterogeneity. Conditional correlation (i.e., marginal correlation given random effects) was calculated to describe how the association between longitudinal outcomes evolved over time within specific subpopulation. The impact of heterogeneity on correlation was also assessed by simulated data.ResultsThere was a significant positive correlation in both random intercepts (ρ = 0.278, 95% CI: 0.121–0.420) and random slopes (ρ = 0.579, 95% CI: 0.349–0.810) between longitudinal MD and VA, and the strength of correlation constantly increased over time. However, conditional correlation and simulation studies revealed that the correlation was induced primarily by participants with rapid deteriorating MD who only accounted for a small fraction of total samples.ConclusionConditional correlation given random effects provides a robust estimate to describe the correlation between multivariate longitudinal data in the presence of unobserved heterogeneity (NCT00000125).