Abstract: We included 106 studies in this review, which analysed 16,260 eyes (8353 cases, 7907 controls) in total. Forty studies (5574 participants) assessed GDx, 18 studies (3550 participants) HRT, and 63 (9390 participants) OCT, with 12 of these studies comparing two or three tests. Regarding study quality, a case-control design in 103 studies raised concerns as it can overestimate accuracy and reduce the applicability of the results to daily practice. Twenty-four studies were sponsored by the manufacturer, and in 15 the potential conflict of interest was unclear. Comparisons made within each test were more reliable than those between tests, as they were mostly based on direct comparisons within each study.The Nerve Fibre Indicator yielded the highest accuracy (estimate, 95% confidence interval (CI)) among GDx parameters (sensitivity: 0.67, 0.55 to 0.77; specificity: 0.94, 0.92 to 0.95). For HRT measures, the Vertical Cup/Disc (C/D) ratio (sensitivity: 0.72, 0.60 to 0.68; specificity: 0.94, 0.92 to 0.95) was no different from other parameters. With OCT, the accuracy of average RNFL retinal thickness was similar to the inferior sector (0.72, 0.65 to 0.77; specificity: 0.93, 0.92 to 0.95) and, in different studies, to the vertical C/D ratio. Comparing the parameters with the highest diagnostic odds ratio (DOR) for each device in a single HSROC model, the performance of GDx, HRT and OCT was remarkably similar. At a sensitivity of 0.70 and a high specificity close to 0.95 as in most of these studies, in 1000 people referred by primary eye care, of whom 200 have manifest glaucoma, such as in those who have already undergone some functional or anatomic testing by optometrists, the best measures of GDx, HRT and OCT would miss about 60 cases out of the 200 patients with glaucoma, and would incorrectly refer 50 out of 800 patients without glaucoma. If prevalence were 5%, e.g. such as in people referred only because of family history of glaucoma, the corresponding figures would be 15 patients missed out of 50 with manifest glaucoma, avoiding referral of about 890 out of 950 non-glaucomatous people. Heterogeneity investigations found that sensitivity estimate was higher for studies with more severe glaucoma, expressed as worse average mean deviation (MD): 0.79 (0.74 to 0.83) for MD < -6 db versus 0.64 (0.60 to 0.69) for MD ≥ -6 db, at a similar summary specificity (0.93, 95% CI 0.92 to 0.94 and, respectively, 0.94; 95% CI 0.93 to 0.95; P < 0.0001 for the difference in relative DOR). The accuracy of imaging tests for detecting manifest glaucoma was variable across studies, but overall similar for different devices. Accuracy may have been overestimated due to the case-control design, which is a serious limitation of the current evidence base. We recommend that further diagnostic accuracy studies are carried out on patients selected consecutively at a defined step of the clinical pathway, providing a description of risk factors leading to referral and bearing in mind the consequences of false positives and false negatives in the setting in which the diagnostic question is made. Future research should report accuracy for each threshold of these continuous measures, or publish raw data.

Plain-language summary: We found 106 studies, mostly assessing a single device, which analysed 16,260 eyes (8353 cases, 7907 controls). Forty studies (5574 participants) assessed GDx, 18 studies (3550 participants) HRT, and 63 (9390 patients) OCT. Twenty-four studies were sponsored by the manufacturer, and in 15 the study funding was unclear. The final diagnosis of glaucoma had to be confirmed by clinical examination, including visual field testing or clinical optic nerve examination or both. However, we could not find studies comparing two tests, the most robust way to test these instruments, and including a series of consecutive patients at risk as seen in routine care, as we had hoped. Rather, we found studies assessing the performance of a single test in people without glaucoma as opposed to its performance in people with a previous diagnosis of glaucoma. The study search is current to 19 February 2015. The performance of all devices was very variable across studies, but overall similar. In 1000 people referred by primary eye care, of whom 200 (20%) have manifest glaucoma, such as in those who have already undergone some functional or anatomic testing by optometrists, the best measures of GDx, HRT and OCT would miss about 60 cases out of the 200 patients with glaucoma (sensitivity 70%), and would incorrectly refer 50 out of 800 patients without glaucoma (at specificity 95%). If prevalence were 5%, for example, in people referred only because of family history of glaucoma, the corresponding figures would be 15 patients missed out of 50 with manifest glaucoma, avoiding referral of about 890 out of 950 non-glaucomatous people. The tests were better at detecting more severe glaucoma compared to early glaucoma. The selection of two well-defined groups of healthy and glaucoma eyes in nearly all studies, rather than the use of these imaging tests in a series of patients at risk of glaucoma as in the real world, may overestimate the accuracy of these devices compared to what could be achieved in daily practice.