Pereira 2014.

Study characteristics
Patient sampling	Primary objectives: assess the influence of age, disease onset and ApoE4 on visual MTA cut‐offs Study population: participants with MCI from 2 large independent cohorts: ADNI and AddNeuroMed. Participants were recruited through local hospital and memory clinics. Selection criteria: participants with MCI and clinical follow‐up at 1 year were included. Inclusion criteria for both cohorts: MMSE score 24‐30, memory complaint reported by the patient, family member or physician, normal ADL, CDR memory score of 0.5 or 1 (total CDR = 0.5), memory loss measured by the WMS Logical Memory II for the ADNI cohort only, GDS score of ≤ 5, age ≥ 65 years, stable medication and good general health. Exclusion criteria: meeting the DSM‐IV and NINCDS‐ADRDA criteria for AD, significant neurological or psychiatric illness other than AD and significant unstable systemic illness or organ failure Study design: prospective longitudinal study. Participants from ADNI (ADNI 2010) and AddNeuroMed studies (Lovestone 2009)
Patient characteristics and setting	Clinical presentations: amnestic MCI Age mean (SD): MCI who progressed to AD: 74 ± 6.5; stable MCI: 75 ± 7 Gender (% men): MCI who progressed to AD: 59%; stable MCI: 61% Education years mean (SD): MCI who progressed to AD: 13.7 ± 4.2; stable MCI: 14.0 ± 4.6 ApoE4 carriers (%): MCI who progressed to AD: 62.1%; stable MCI: 46% Neuropsychological tests: employed; MMSE mean (SD): MCI who progressed to AD: 26.5 ± 1.8; stable MCI 27.1 ± 1.7 Clinical stroke excluded: not specified Co‐morbidities: not reported Number enrolled: 480 Number available for analysis: 480 Setting: ADNI cohort and AddNeuroMed cohort Country: USA and Canada (ADNI); Finland, Italy, Greece, UK, Poland, France (AddNeuroMed) Period: not reported Language: English
Index tests	Index test: MRI visual method for estimation of MTA Manufacturer: standardised MRI data acquisition techniques were in place for AddNeuroMed and ADNI to ensure homogeneity across data acquisition sites. A comprehensive quality control procedure was carried out on all MRI images according to the AddNeuroMed quality control framework Tesla strength: not specified (information from study protocols: 1.5‐3 T for ADNI, 1.5 T for AddNeuroMed) Assessment methods: for each participant, MTA was rated on a single MRI slice posterior to the amygdala and the mammillary bodies, positioned in such a way that the hippocampus, cerebral peduncles and pons were all visible. MTA score attributed according to Scheltens 1992. The right and left sides of the medial temporal lobe are rated separately Description of positive cases definition by index test as reported: 2 different and independent cut‐off values: the age‐dependent cut‐off (an MTA score of ≥ 2 was considered abnormal for participants < 75 years, whereas a score of ≥ 3 was considered abnormal for participants > 75 years) and the averaged left and right cut‐off (the average of the MTA scores of both hemispheres with a resulting score ≥ 1.5 was considered abnormal). We used the averaged cut‐off for this review. Examiners: single MTA rater (LC) was blind to gender, age and diagnosis. High intrarater reliability (weighted kappa 0.93 and 0.94) Interobserver variability: a highly significant correlation was found between the MTA score and manual delineation by hippocampal volume by another experienced radiologist
Target condition and reference standard(s)	Target condition: AD Prevalence of AD in the sample: 95/480 (20% of enrolled participants) Stable MCI or converted to other dementia: 385 (80%) stable MCI Reference standards: not specified in the published article. NINCDS‐ADRDA criteria (McKhann 1984) were used according to the study protocols (as reported in Gaser 2013 and Liu 2010) Mean clinical follow‐up: 1 year
Flow and timing	Withdrawals explained and losses to follow‐up: none reported Uninterpretable MRI results have not been reported
Comparative
Key conclusions by the authors	Clinical, demographic and genetic variables can influence the classification of MTA cut‐off scores, leading to misdiagnosis in some cases. These variables, in addition to the differential sensitivity and specificity of each cut‐off, should be carefully considered when performing visual MTA assessment.
Conflict of interests	Study authors report no conflict of interest
Notes	Source of funding: study was supported by InnoMed (Innovative Medicines in Europe), an Integrated Project funded by the European Union of the Sixth Framework programme priority FP6‐2004‐LIFESCIHEALTH‐5. Data collection and sharing for this project was funded by the ADNI NIH Grant U01 AG024904. This research was also supported by NIH Grants P30 AG010129 and K01 AG030514 2 x 2 table: data from the published article
Methodological quality
Item	Authors' judgement	Risk of bias	Applicability concerns
DOMAIN 1: Patient Selection
Was a consecutive or random sample of patients enrolled?	No
Was a case‐control design avoided?	Yes
Did the study avoid inappropriate exclusions?	Yes
		High	Low
DOMAIN 2: Index Test All tests
Were the index test results interpreted without knowledge of the results of the reference standard?	Yes
Did the study provide a clear pre‐specified definition of what was considered to be a "positive" result of the index test?	Yes
Was the index test performed by a single operator or interpreted by consensus in a joint session?	Yes
		Low	Low
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
		Low	Low
DOMAIN 4: Flow and Timing
Was there an appropriate interval between index test and reference standard?	Yes
Did all patients receive the same reference standard?	Yes
Were all patients included in the analysis?	Yes
		Low