Subjects

All of the subjects underwent a complete ophthalmologic examination, including measurement of best-corrected visual acuity, refractive error, axial length, central corneal thickness, and intraocular pressure by Goldmann applanation tonometry. Gonioscopy and dilated fundus examination also were performed. Red-free retinal nerve fiber layer photography (RNFLP; Vx-10; Kowa Optimed, Inc, Tokyo, Japan), SDP, and SDOCT (Cirrus-HD; Carl Zeiss Meditec, Inc, Dublin, California, USA) images were obtained for all of the subjects, and SAP with the Swedish interactive thresholding algorithm and 30-2 standard program (Humphrey Field Analyzer II; Carl Zeiss Meditec, Inc) was performed.

Eyes were included if they showed a best-corrected visual acuity of 20/40 or better (regardless of refractive error or axial length) and an open anterior chamber angle on gonioscopic and slit-lamp examination. Eyes were excluded if there was a history of any of the following: intraocular disease or optic neuropathy other than glaucoma, disease that could affect a visual field test, or intraocular surgery other than simple cataract surgery. In cases where both eyes were eligible, 1 eye was randomly selected.

Spectral-domain Optical Coherence Tomography Imaging

The optic disc and RNFL were imaged using Cirrus-HD OCT (software version 6.0), which procedure has been described previously. All of the SDOCT images were acquired by a single, well-trained technician and showed signal strengths of 8 or more, no motion artifacts, no overt misalignment, and no overt decentration of the measurement circle around the optic disc. For the present study, RNFL and ONH algorithms based on the data obtained from a 200 × 200 cube optic disc scan were employed. The ONH and RNFL analysis printout was used as an SDOCT image containing an RNFL thickness map, an RNFL deviation map, a temporal-superior-nasal-inferior-temporal RNFL thickness plot, quadrant and clock-hour maps with RNFL thickness measurements and diagnostic classification, and ONH-parameter analyses.

Classification of Diagnoses

A total of 109 healthy individuals and 151 patients who had been diagnosed with and followed up on for glaucoma at least 6 months before the enrollment period were included in the present study. Two experienced glaucoma specialists (K.H.P. and K.E.K.) reviewed each subject’s examination and clinical information in an independent manner, classifying eyes as either “glaucoma” or “healthy individual.” In cases of disagreement, the final decision was made by a third observer (D.M.K.).

The glaucoma diagnosis was based on a combination of structural (SDP and red-free RNFLP) and functional (SAP) measurements. The present study included eyes with perimetric glaucoma having a glaucomatous optic disc appearance and corresponding glaucomatous visual field defect. Glaucomatous optic neuropathy was defined as characteristic optic disc changes (eg, rim notching, thinning, increased cup-to-disc ratio, and/or RNFL abnormalities). Glaucomatous visual field defect was defined as (1) the presence of a cluster of 3 or more non-edge points within P < .05 of being normal, 1 with P < .01 on pattern deviation plot; (2) a pattern standard deviation with P < .05; or (3) a glaucoma hemifield test result outside the normal limits, when proved by 2 consecutive tests within a month. Only reliable fields with false-positive and false-negative error rates of 15% and fixation loss of 15% or less were included. Glaucomatous eyes were further divided into groups of different severity based on the SAP mean deviation (MD): early (MD >−6 dB), moderate (−12 < MD ≤ −6 dB), and advanced (MD ≤−12 dB) stages.

Healthy eyes were those of individuals from the general population who had visited the clinic for regular health check-ups, correction of refractive error, or dry-eye treatment. Those with no history of IOP >21 mm Hg, no history of IOP-lowering medication use, no family history of glaucoma, no evidence of ocular disease, no abnormal appearance of optic disc (eg, absence of glaucomatous optic neuropathy, pallor, swelling) or RNFL, and a normal visual field were included.

Preparation and Evaluation of Diagnostic Combination Sets of Structural Examinations

To examine the additive diagnostic role of SDOCT in structural diagnosis, sets containing different combinations of structural examinations were prepared and sent to glaucoma specialists for evaluation. Four combination sets of structural examinations were prepared for each subject using SDP, RNFLP, and SDOCT: (1) set S: SDP, (2) set SO: SDP and SDOCT, (3) set SR: SDP and RNFLP, and (4) set SRO: SDP, RNFLP, and SDOCT. Because optic disc examination is considered to be an initial step in glaucoma diagnosis, combination sets were created by adding RNFLP, SDOCT, or both to the S set. Each set was composed of the single most recent reliable image from each device. Images that were taken on the same day were used as much as possible, but in cases where this was not feasible, a 4 month interval between examinations was allowed. Additionally, the same image from each device was included in each set: the same SDP image was used for the S, SO, SR, and SRO sets; the same SDOCT image for the SO and SRO sets; and the same RNFLP image for the SR and SRO sets. Each subject’s images were saved as JPEG files, and only the relevant images were put into the specific folder for the corresponding combination set: folders in set S contained only the SDP images, those in set SO contained only the SDP and SDOCT images, and so on. In each combination set, the folders containing the subjects’ examinations were randomly sorted and numbered independently of diagnosis or of glaucoma severity. Additionally, when each combination set was created, the folders were newly assigned in random order.

These combination sets were sent to 5 fellowship-trained glaucoma specialists (S.H.K., J.W.J., M.H.S., J.H.S., M.K.) from different professional medical institutes, who had been invited and signed informed consents to take part in this study. They were routine users of the provided examinations, including Cirrus-HD OCT. All of the glaucoma specialists received the combination sets in the order of sets S, SO, SR, and SRO. They were allowed to evaluate each set within a week, and a 1-month interval between set evaluations was provided. For each set, they were instructed to evaluate eyes as normal or glaucoma in an independent manner, being masked to all of the relevant information and to any of the previous readings. They were allowed to diagnose without specified guidelines, based on their knowledge and clinical experience alone.

Statistical Analysis

For the comparison of group characteristics, 1-way analysis of variance with post hoc Tukey test was used for continuous variables and χ ² test or Fisher exact test for categorical variables. Kappa (κ) statistics were used to evaluate the interobserver agreement among the glaucoma specialists’ glaucoma diagnoses. The strength of agreement was categorized according to the method of Landis and Koch : 0 = poor, 0 to 0.20 = slight, 0.21 to 0.40 = fair, 0.41 to 0.60 = moderate, 0.61 to 0.80 = substantial, and 0.81 to 1.00 = almost perfect. The McNemar test was used to compare individual diagnostic sensitivity and specificity. To compare the collective diagnostic performance of the glaucoma specialists according to the different diagnostic combination sets and the differing glaucoma severity, the generalized estimating equation (GEE), a method for estimating generalized linear model parameters with a possible unknown correlation between outcomes, was used. The GEE was also used for quantitative evaluation of how each combination set increased the sensitivity and specificity of the specialists’ assessments, presenting as an odds ratio (OR) with 95% confidence interval (CI). To adjust for multiple comparisons, Bonferroni correction was applied.