Participants

In this observational cohort study, participants were included from a prospective longitudinal study designed to evaluate optic nerve structure and visual function in glaucoma (Diagnostic Innovations in Glaucoma Study [DIGS] and African Descent and Glaucoma Evaluation Study [ADAGES]). Participants in these cohorts were longitudinally evaluated according to a pre-established protocol that included regular follow-up visits in which patients underwent a clinical examination and several imaging and functional tests. All participants from the DIGS and ADAGES study who met the inclusion criteria described below were enrolled in the current study. Written informed consent was obtained from all participants. The University of California, San Diego Human Subjects Committee approved all protocols, and the methods described adhered to the tenets of the Declaration of Helsinki. ADAGES and DIGS were designed with similar testing protocols, and details of the procedures in DIGS and ADAGES have been previously published.

Subjects underwent annual comprehensive ophthalmologic examinations, including a review of medical history, best-corrected visual acuity, slitlamp biomicroscopy, IOP measurement, dilated funduscopic examination, stereoscopic optic disc photography, and standard automated perimetry using Swedish Interactive Threshold Standard Algorithm (Humphrey Field Analyzer; Carl Zeiss Meditec). Semiannual examinations included standard automated perimetry (10-2 VF and 24-2 VF) and IOP measurement. Only subjects with open angles on gonioscopy at baseline were included. Subjects were excluded if they had a baseline best-corrected visual acuity <20/40, axial length of more than 26.5 mm, baseline 24-2 mean deviation (MD) of worse than −20 dB, or any ocular or systemic disease that could affect the optic nerve or VF.

The study included eyes diagnosed as glaucoma or glaucoma suspect with baseline CH measurements and a minimum follow-up time of 2.5 years with a minimum of five 10-2 and 24-2 VF tests. Eyes were classified as glaucomatous if they had repeatable (≥2 consecutive) abnormal VF test results or evidence of glaucomatous optic neuropathy defined as excavation, the presence of focal thinning, notching of the neuroretinal rim, or localized or diffuse atrophy of the retinal nerve fiber layer based on masked grading of optic disc photographs by 2 graders or clinical examination by a glaucoma specialist. An abnormal VF test was defined as a pattern standard deviation (PSD) outside of the 95% normal confidence limits or a Glaucoma Hemifield Test result outside normal limits. Glaucoma suspects were defined as those having elevated IOP (≥22 mm Hg) or suspicious-appearing optic discs without the presence of repeatable glaucomatous VF damage.

standard automated perimetry

The 10-2 and 24-2 VF tests were considered unreliable and excluded if there was >33% fixation losses, >33% false-positive errors, or >33% false-negative errors. Experienced graders at the University of California, San Diego Visual Field Assessment Center reviewed the results, excluding tests with eyelid or rim artifacts, fatigue or learning effects, inappropriate fixation, or evidence that the VF results were caused by a disease other than glaucoma (eg, homonymous hemianopia) or inattention. Patients with glaucoma were stratified into 2 groups based on the severity of their VF damage. Patients with baseline 24-2 MD > −6.0 dB were classified as mild glaucoma, and patients with baseline 24-2 MD ≤ −6.0 were classified as moderate-to-severe glaucoma.

10-2 regions proposed by Hood and associates were divided into 5 zones: the superior nasal (zone 1), superior temporal (zone 2), superior temporal band (zone 3), inferior temporal (zone 4), and inferior nasal (zone 5). For the calculation of the mean sensitivity in each zone, threshold sensitivity values in decibels (dB) were used. The zonal mean sensitivity measurements were calculated as the average threshold sensitivity values of all points tested in that region.

Central visual field progression

Different trend-based and event-based analyses that were used to characterize progression in the 10-2 VF tests are described below.

Corneal hysteresis measurements

CH measurements were acquired at the baseline visit using the Ocular Response Analyzer (Reichert Ophthalmic Instruments Inc). A trained technician obtained 3 measurements from each eye, and the average of 3 measurements was calculated for analysis. The Ocular Response Analyzer determines corneal biomechanical properties using an applied force-displacement relationship. Details of its operation have been previously described. In brief, within a 20-ms time frame, a metered air pulse is delivered to the eye, causing the cornea to move inward in a concave fashion (past a first applanation point), and then the cornea returns (past a second applanation point) to its initial position. An electro-optical collimation detector system monitors the corneal curvature in the central 3.0-mm diameter during the measurement period and defines 2 peaks produced by the applanation events. CH is the difference between these 2 applanation pressures measured in millimeters of mercury. CH thus relates to the viscous dampening ability of the cornea. The device provides a waveform score to reflect the quality of measurements. Three measurements were obtained for each eye in each visit, and the average of the qualified measurements with a waveform score greater than 4 was considered for analysis. Baseline VF tests were chosen as those closest to the baseline CH measurement date.

Statistical analysis

Continuous and categorical data were presented as mean (95% confidence interval) and count (%). Statistically significant differences in characteristics between glaucoma suspect and glaucoma patients were determined by 2-sample t tests for continuous variables and the Fisher exact test for categorical variables. Eye characteristics were compared using linear mixed-effects models with random intercepts to account for within-subject variability. In the trend-based analysis, VF trajectories were estimated using linear mixed-effects models with random eye-within-patient intercepts and independent random slopes-within-eye. The details on the use of these models for evaluation of rates of change in glaucoma and to model longitudinal processes have been published. ^{, ,} In linear mixed models, the average evolution of the outcome variable (VF measurements) is described using a linear function of time, and random intercepts and random slopes introduce subject- and eye-specific deviations from this average evolution. The model can account for the fact that different eyes can have different rates of VF loss over time, while also accommodating correlations between both eyes of the same individual. ^, Interaction terms between time and putative predictors (eg, CH) can be included in the model to test whether there is a significant effect of the putative predictor on changes of the outcome variable over time. Multivariable models were fit after including all variables with a P value of ≤.10 in univariable analysis. In addition to age, demographic characteristics, and follow-up duration, all models were adjusted for both mean IOP during follow-up ^, and positive history of disc hemorrhage ^{, ,} because of their reported associations with glaucomatous VF progression. In the event-based analysis, univariable and multivariable mixed-effects logistic regression models were used to identify characteristics associated with an increased likelihood of 10-2 VF progression defined by the clustered pointwise linear regression (PLR) criterion. Linear mixed-effect models with random intercepts and random slopes were used to compare the rates of 10-2 MD loss and age-adjusted zonal rates of mean sensitivity loss between 2 groups of eyes divided based on baseline CH (CH ≥ 10 mm Hg and CH < 10 mm Hg). All statistical analyses were performed with commercially available software (STATA, version 17.0; Stata Corp LP). The alpha level (type I error) was set at 0.05.