This study was collaborative, with subjects recruited from the Hamilton Glaucoma Center Diagnostic Innovations in Glaucoma Study (DIGS) at the University of California, San Diego, and the Department of Ophthalmology and Visual Sciences of The Chinese University of Hong Kong (CUHK). The data in the present study were obtained from the databases in CUHK and DIGS. These databases were established for a prospective longitudinal study designed to evaluate optic nerve structure and visual function in glaucoma. Data meeting the inclusion criteria in this study were exported from the databases for analyses. One eye was selected randomly from 101 normal individuals and 156 patients with glaucoma. The study was conducted in accordance with the ethical standards stated in the 1964 Declaration of Helsinki and approved by the respective Institutional Review Boards.
All subjects underwent a full ophthalmic examination, including visual acuity, refraction, intraocular pressure measurement with Goldmann tonometry, gonioscopy, dilated fundus examination with stereoscopic biomicroscopy of the optic nerve head under slit lamp and indirect ophthalmoscopy. The inclusion criteria were best corrected visual acuity of not worse than 20/40, spherical refractive error within the range of −6.00 to + 3.00 D, and <5.00 D of cylinder. Individuals were excluded if they had a history of any retinal disease, surgery or laser procedures, diabetes mellitus, or neurologic diseases. Normal subjects were individuals with no ocular or intraocular diseases. In particular, they had no abnormal visual fields based on reliable visual field perimetry results (SITA standard, Humphrey Field Analyzer II; Carl Zeiss Meditec, Inc., Dublin, CA) and no history of intraocular pressure higher than 21 mm Hg. A reliable visual field perimetry result is defined as fixation losses less than 30% and false-positive and -negative errors each less than 33%. Eyes were classified as glaucomatous if they had at least two consecutive abnormal visual field test results, defined as a pattern SD (PSD) outside the 95% normal confidence limits and/or a Glaucoma Hemifield Test (Carl Zeiss Meditec, Inc.) result outside normal limits, regardless of the appearance of the optic disc. Twenty-one eyes from the DIGS were also classified as glaucomatous because of a history of documented evidence of progressive glaucomatous change in the appearance of the optic disc as assessed by simultaneous stereoscopic optic disc photographs, regardless of visual field test results. The evidence of progressive glaucomatous damage had to be present before the imaging test date. The use of this composite reference standard for glaucoma diagnosis allowed us to evaluate the accuracy of diagnostic tests in a broad spectrum of patients with the disease, in that both those with visual field loss and those with normal visual fields, but confirmed progressive glaucomatous optic nerve damage, were included.
For evaluation of progressive optic disc damage, stereoscopic sets of slides were obtained using a simultaneous stereo camera (TRC-SS; Topcon Instrument Corp. of America, Paramus, NJ) and examined with a stereoscopic viewer (Pentax; Asahi Optical Co., Tokyo, Japan). The photographs were evaluated by two experienced graders, each of whom was masked to the subject’s identity and to the other test results. For inclusion, photographs had to be of adequate quality or better. To identify a subgroup of patients with progressive glaucomatous optic disc change for this study, the research database in the DIGS was reviewed for all patients who had been imaged with the three instruments and who had been observed for at least 1 year before the imaging test date. For each patient, the most recent stereophotograph was compared to the oldest available one, to maximize the chance of detecting progressive optic disc change. Each observer was masked to the temporal sequence of the photographs. The definition of change was based on focal or diffuse thinning of the neuroretinal rim, increased excavation, or enlargement of RNFL defects. Changes in rim color, presence of disc hemorrhage, or progressive parapapillary atrophy were not sufficient for characterization of progression. Discrepancies between the two graders were either resolved by consensus or by adjudication of a third experienced grader. Initial agreement between graders was obtained in 83% of the cases.