Clerx 2013a.

Study characteristics
Patient sampling	Primary objectives: to compare the diagnostic accuracy of 4 different measures of the medial temporal lobe volume Study population: participants with mild cognitive impairment (MCI) selected from the "Development of Screening Guidelines and Clinical Criteria for Predementia AD (DESCRIPA) study (Visser 2008), and the Alzheimer Center of the VU University Medical centre (VUmc) in Amsterdam Selection criteria: inclusion criteria for both cohorts were age ≥ 54 years, diagnosis of MCI, availability of results for each MRI measure and outcome at follow‐up. Patients were included if data of the 4 MRI tests were available; no differences between included and excluded participants were found with respect to age, sex, education, cognitive results. Exclusion criteria: diagnosis of dementia at baseline or any somatic, psychiatric, or neurological disorder (e.g. epilepsy) that might have caused cognitive impairment. Patients excluded from the study: for 54 participants follow‐up data were missing, for 21 digital format scan was not available, and for 53 cases not all 4 MRI measurements were available. Data for all 4 medial temporal lobe measurements were available for 328. Study design: prospective cohort study
Patient characteristics and setting	Clinical presentation: MCI defined according to the criteria of Petersen 1999; Petersen 2004 (37% non‐amnestic and 63% amnestic MCI) Age years mean (SD): 70.6 ± 7.6 years Gender (% men): 48.5 % (40.4 DESCRIPA; 55.8 University Medical Center Amsterdam (VUmc) Education years mean (SD): 10.0 ± 3.8 (8.5 ± 3.9 DESCRIPA; 11.2 ± 3.3 VUmc) ApoE4 carriers (%): 51% (45% DESCRIPA; 56% VUmc) Neuropsychological tests: MMSE mean (SD): 27.0 ± 2.5 (27.2 ± 2.3 DESCRIPA; 26.6 ± 2.6 VUmc) Clinical stroke excluded: not specified Co‐morbidities: not reported Number enrolled: 328 Number available for analysis: 328, 156 from the DESCRIPA cohort and 172 from the VUmc cohort Setting: tertiary university hospitals; 9 of the 20 participating centres in the DESCRIPA study and Alzheimer Center of the VU University Medical centre (VUmc) in Amsterdam Country: Europe Period of study: not reported Language: English
Index tests	Index test: MRI visual, manual and automated methods for estimation of hippocampal volume, MRI automated method for estimation of lateral ventricles measure Manufacturer: several (Philips and Siemens) Tesla strength: 1.0 or 1.5 T Assessment methods: regarding the manual method, the hippocampal ROI was constructed by manual delineation of hippocampal borders using the software package developed in house, Show_Images 3.7.0 and using criteria according to Van de Pol 2007. Automated hippocampal volumetry was performed using a multi‐atlas segmentation method named "learning embedding for atlas propagation" (LEAP). Measurements of the lateral ventricle was executed with an extension of SIENAX that is a package for single‐time‐point ('cross‐sectional') analysis of brain change. After the tissue segmentation, a registered mask was used to exclude the CSF on the outer side of the brain. The visual rating of MTA was performed using a qualitative scale (Scheltens 1992). Rating was performed on coronal T1‐weighted images Description of positive case definition by index test as reported: specified only for the visual method: score ranging from 0 (no atrophy)‐4 (severe atrophy). Diagnostic accuracy based on Youden index (Youden 1950), was used to construct 2 x 2 table; results based on a cut point for a sensitivity of 85% were also available Examiners: 3 trained technicians, blinded to the diagnosis, performed the manual segmentation of the hippocampus. Scans from the VU University Medical centre were rated using the visual method by a group of 3 trained raters supervised by a neuroradiologist. Scans from the DESCRIPA study were rated by a single rater from the VU University Medical centre. The blindness of raters was specified only for the manual method Interobserver variability: the inter‐rater coefficient of variation was < 8% and the intra‐rater was < 5% for the manual method. In the VU University Medical centre cohort, the inter‐ and intra‐rater Cohen kappa values were > 0.80, and in the DESCRIPA cohort the intra‐rater weighted Cohen kappa value was 0.68 for the visual method
Target condition and reference standard(s)	Target condition: AD Prevalence of AD in the sample: 91/328 (28% of cases included in the analysis); 19.2% in the DESCRIPA and 35.5% in the VU University Medical centre Stable MCI or converted to other dementia: 237/328 (72.0%; 80.8% in the DESCRIPA and 64.5% in the VU University Medical centre) Stable MCI 225, converted to other dementia 12 (4 participants converted to FTD, 6 converted to LBD, 1 to VD, 1 to another form of dementia). Reference standard: DSM IV and NINCDS‐ADRDA criteria (McKhann 1984). According to the DESCRIPA protocol, clinician was blinded to index test results Mean clinical follow‐up: 2 years
Flow and timing	Withdrawals and losses to follow‐up: none reported Uninterpretable results were not reported
Comparative
Key conclusions by the authors	Volumetric hippocampal measurements are the best predictors of conversion to AD‐type dementia in subjects with MCI after 2‐year follow‐up and are able to predict annual cognitive decline. Because of the limited rater time, learning embedding for atlas propagation (LEAP) automated hippocampal measurement might be preferred
Conflict of interests	Study authors declared conflicts of interest
Notes	Source of funding: grant 02N‐01, FP7/2007‐2013 2 x 2 table: data extracted from the 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?	No
		High	Low
DOMAIN 2: Index Test All tests
Were the index test results interpreted without knowledge of the results of the reference standard?	Unclear
Did the study provide a clear pre‐specified definition of what was considered to be a "positive" result of the index test?	No
Was the index test performed by a single operator or interpreted by consensus in a joint session?	No
		High	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