Lisboa 2013.

Study characteristics
Patient Sampling	A cohort of participants suspected of having glaucoma was selected from the Diagnostic Innovations in Glaucoma Study database, and followed for at least 5 years. A documented evidence of progressive glaucomatous change in the appearance of the optic disc was used as reference standard. Participants with progressive optic disc damage and no visual field loss were included in the preperimetric glaucoma group. Patients followed untreated for about 14 years without any evidence of progressive change in the appearance of the optic disc or visual field loss were used as the control group. Both eyes were selected for some patients.
Patient characteristics and setting	Sample size: 142 eyes (48 glaucoma, 94 controls) of 91 participants. Age: glaucoma eyes mean ± SD 65.9 ± 9.1 years; controls 64.2 ± 11.2 years. Sex: glaucoma: male 53%; controls: male 31% Ethnicity: 12 African‐American (8 glaucoma, 4 controls). Country: USA. Setting: Hamilton Glaucoma Center, University of California, San Diego. Ocular comorbidities: patients with co‐existing retinal disease, uveitis, or non‐glaucomatous optic neuropathy were excluded. All eyes had to have BCVA ≥ 20/40, spherical refraction within ±5.0 D, cylinder correction within ±3.0 D, and open angles on gonioscopy. Spectrum of glaucoma severity: the mean (first, third quartile) MD and PSD on the VF test were ‐0.81 (‐1.82, 0.12) dB and 1.75 (1.46, 1.84) dB respectively, for glaucoma. Control participants: participants followed untreated for a long period (13.6 ± 3.6 years) without any evidence of progressive change in the appearance of the optic disc or VF loss in both eyes.
Index tests	Optical coherence tomography: RTVue (software version 6.1.0.4; Optovue, Inc., Fremont, CA, USA). The ONH protocol and ganglion cell complex scanning protocols were used. Only good‐quality images, as defined by a signal strength index ≥ 28 for RNFL and ONH measurements, and ≥ 32 for macular measurements were included in the analysis. Some authors had potential conflict of interest
Target condition and reference standard(s)	Manifest preperimetric glaucoma: documented evidence of progressive glaucomatous change in the appearance of the optic disc (based on focal or diffuse thinning of the neuroretinal rim, increased excavation, or enlargement of the RNFL defects) and normal VF result (defined as a MD and PSD within 95% confidence limits and a GHT result within normal limits). Visual field testing: 24‐2 SITA standard programme (Carl Zeiss Meditec, Dublin, CA, USA). Optic disc and RNFL evaluation: stereoscopic optic disc photographs (TRC‐SS, Topcon Instrument Corp. of America, Paramus, NJ). Stereoscopic sets of slides were examined using a stereoscopic viewer (Asahi, Pentax, Tokyo, Japan). 2 experienced graders, masked to the participant’s identity, to other test results, and to the chronological sequence of the photographs, evaluated the stereophotographs.
Flow and timing	Reference standard was performed before index test but time interval between index test and reference standard was not reported. Index test different scanning protocols were performed within 6 months. No patients were reported by the authors as excluded from the analysis.
Comparative
Notes	Supported in part by National Institutes of Health/National Eye Institute Grants EY021818 (FAM), EY11008 (LMZ), and EY14267 (LMZ); Coordena¸ca˜o de Aperfei¸coamento de Pessoal de N´ıvel Superior (CAPES) grant Bolsas no Exterior (BEX) 1066/11‐0; an unrestricted grant from Research to Prevent Blindness (New York, New York); and grants for participants’ glaucoma medications from Alcon, Allergan, Pfizer, Merck, and Santen.
Methodological quality
Item	Authors' judgement	Risk of bias	Applicability concerns
DOMAIN 1: Patient Selection
Was a consecutive or random sample of patients enrolled?	Unclear
Was a case‐control design avoided?	Yes
Did the study avoid inappropriate exclusions?	Yes
Could the selection of patients have introduced bias?		Low risk
Are there concerns that the included patients and setting do not match the review question?			Low concern
DOMAIN 2: Index Test (All tests)
If a threshold was used, was it pre‐specified?	Yes
Were imaging test's quality assessed?	Yes
Were any conflict of interest avoided	No
Could the conduct or interpretation of the index test have introduced bias?		High risk
Are there concerns that the index test, its conduct, or interpretation differ from the review question?			Low concern
DOMAIN 3: Reference Standard
Is the reference standards likely to correctly classify the target condition?	Yes
Were the reference standard results interpreted without knowledge of the results of the index tests?	Yes
Could the reference standard, its conduct, or its interpretation have introduced bias?		Low risk
Are there concerns that the target condition as defined by the reference standard does not match the question?			Low concern
DOMAIN 4: Flow and Timing
Was there an appropriate interval between index test and reference standard?	No
Did all patients receive the same reference standard?	Yes
Were all patients included in the analysis?	Yes
Did all patients receive a reference standard	Yes
Could the patient flow have introduced bias?		High risk