Multivariate Normative Comparison, a Novel Method for Improved Use of Retinal Nerve Fiber Layer Thickness to Detect Early Glaucoma

Purpose: Detection of early glaucoma remains limited with the conventional analysis of the retinal nerve fiber layer (RNFL). This study assessed whether compensating the RNFL thickness for multiple demographic and anatomic factors improves the detection of glaucoma. Design: Cross-sectional study. Participants: Three hundred eighty-seven patients with glaucoma and 2699 healthy participants. Methods: Two thousand six hundred ninety-nine healthy participants were enrolled to construct and test a multivariate compensation model, which then was applied in 387 healthy participants and 387 patients with glaucoma (early glaucoma, n = 219; moderate glaucoma, n = 97; and advanced glaucoma, n = 71). Participants underwent Cirrus spectral-domain OCT (Carl Zeiss Meditec) imaging of the optic disc and macular cubes. Compensated RNFL thickness was generated based on ethnicity, age, refractive error, optic disc (ratio, orientation, and area), fovea (distance and angle), and retinal vessel density. The RNFL thickness measurements and their corresponding areas under the receiver operating characteristic curve (AUCs) were obtained. Main Outcome and Measures: Measured and compensated RNFL thickness measurements. Results: After applying the Asian-specific compensation model, the standard deviation of RNFL thickness reduced, where the effect was greatest for Chinese participants (16.9%), followed by Malay participants (13.9%), and Indian participants (12.1%). Multivariate normative comparison outperformed measured RNFL for discrimination of early glaucoma (AUC, 0.90 vs. 0.85; P < 0.001), moderate glaucoma (AUC, 0.94 vs. 0.91; P < 0.001), and advanced glaucoma (AUC, 0.98 vs. 0.96; P < 0.001). Conclusions: The multivariate normative database of RNFL showed better glaucoma discrimination capability than conventional age-matched comparisons, suggesting that accounting for demographic and anatomic variance in RNFL thickness may have usefulness in improving glaucoma detection. Agency for Science, Technology and Research (A*STAR) National Medical Research Council (NMRC) National Research Foundation (NRF) Published version Supported by the National Medical Research Council, Singapore, Republic of Singapore (grant nos.: CG/C010A/2017, OFIRG/0048/2017, OFLCG/004c/2018, TA/MOH-000249-00/2018, and MOH-OFIRG20nov-0014); the National Research Foundation, Singapore, Republic of Singapore (grant nos.: NRF-CRP24-2020-0001 and NRF2019-THE002-0006); A*STAR (grant no.: A20H4b0141); the Singapore Eye Research Institute & Nanyang Technological University (SERI-NTU Advanced Ocular Engineering [STANCE] Program); the Duke-NUS Medical School (grant no. Duke-NUS-KP(Coll)/2018/0009A); and the SERI-Lee Foundation, Singapore, Republic of Singapore (grant no.: LF1019-1).