Prestia 2013 (ADNI).

Study characteristics
Patient sampling	Primary objectives: capitalise on data from different clinical series to compare sensitivity and specificity of individual biomarkers for predicting MCI progression to AD Study population: MCI patients come from two independent data sets: ADNI and Translational Outpatient Memory Clinic (TOMC) Selection criteria: patients included in the study were all MCI with prodromal AD taken from ADNI and TOMC databases, with available baseline MRI, FDG‐PET and CSF sampling. MCI who converted to non‐AD dementia were excluded from the study. Stable MCI coming from the same databases were included. Exclusion criteria according to ADNI protocol for the ADNI cohort, as in Gaser 2013. For the TOMC cohort all patients were self‐referred or referred by general practitioners or specialists, complaining of memory or other cognitive disturbances unaccountable by focal cerebral, physical, psychiatric, or metabolic diseases. Patients who converted to non‐AD dementia were excluded from the study. Study design: prospective longitudinal study
Patient characteristics and setting	Clinical presentations: MCI according to Petersen 1999 Age mean (SD): MCI who progressed to AD in ADNI: 75 ± 8; stable MCI in ADNI: 75 ± 8; MCI who progressed to AD in TOMC: 71 ± 8; stable MCI in TOMC: 72 ± 8 Gender (% men): MCI who progressed to AD in ADNI: 58%; stable MCI in ADNI: 61%; MCI who progressed to AD in TOMC: 33%; stable MCI in TOMC: 50% Education years mean (SD): not reported ApoE4 carriers (%): not reported Neuropsychological tests: employed; MMSE mean (SD): MCI who progressed to AD in ADNI: 28 ± 2; stable MCI in ADNI: 27 ± 2; MCI who progressed to AD in TOMC: 26 ± 2;stable MCI in TOMC: 26 ± 2 Clinical stroke excluded: yes in the TOMC cohort, not specified in ADNI cohort Co‐morbidities: not reported Number enrolled: 57 MCI from ADNI, 36 MCI from TOMC Number available for analysis: 57 MCI from ADNI, 36 MCI from TOMC (manual method), 32 MCI from TOMC (automated method) Setting: ADNI and TOMC databases Country: USA and CAnada for ADNI; Italy for TOMC Period: nor reported Language: English
Index tests	Index test: MRI manual, automated, semiautomated methods for estimation of hippocampal volume Manufacturer: several for the ADNI cohort; Philips for TOMC (Caroli 2007) Tesla strength: high‐resolution MRI (Tesla strength not specified in the published article, anyway 1.5‐3 T for the ADNI cohort according to the study protocol, 1.0 T for the TOMC cohort as reported in (Caroli 2007) Assessment methods: Freesurfer software version 4.5.0 was used in ADNI and TOMC cohort for automated volume estimation, DISPLAY was used in the TOMC cohort for manual volume estimation, Medtronic Surgical Navigation Technologies tool was used in the ADNI cohort for semiautomated volume estimation. Manual tracing was performed according the protocol of Pruessner 2000. The semiautomated method was applied basing on fluid imaging transformation according to Christensen 1997 Description of positive cases definition by index test as reported: hippocampal volume cutoffs were computed specifically based on hippocampal volume performance in correctly identifying a group of 287 cognitively healthy elders taken from a reference normative database (manual segmentation) or a group of 66 ADNI cognitively healthy elders (both semi‐automated and automated procedures). Examiners: a single rater performed the manual method. Regarding the semiautomated method, boundaries were checked by qualified reviewers and in case of failure, edited manually Interobserver variability: not reported
Target condition and reference standard(s)	Target condition: AD Prevalence of AD in the sample: 24/57 (42%) of enrolled participants in the ADNI cohort; 18/36 (50%) of enrolled participants in the TOMC cohort Stable MCI or converted to other dementia: 33 (58%) stable MCI in the ADNI cohort 18 (50%) stable MCI in the TOMC cohort. Reference standards: NINCDS‐ADRDA criteria (McKhann 1984). Baseline biomarker results were at the clinician's disposal; anyway progression to AD was ascertained basing on clinical criteria. Mean clinical follow‐up: 3 ± 1 years for the ADNI cohort, 2.2 ± 1 years for the TOMC cohort
Flow and timing	Withdrawals explained and losses to follow‐up: Missing data for 3 stable MCI and 1 converted MCI patient because of failed the automated processing. Uninterpretable MRI results have not been reported
Comparative
Key conclusions by the authors	Current findings suggest that β‐amyloid concentrations in CSF and hippocampal volumes may be used in combination to best identify podromal AD.
Conflict of interests	information not available
Notes	Source of funding: ADNI National Institutes of Health Grant U01 AG024904, Progetto Finalizzato Strategico 2006 and 2007, Ricerca Corrente Italian Ministry of Health, grant from the Associazione Fatebenefratelli per la Ricerca Information from authors: for the selection of patients the same criteria were used for MCI converters and non converters 2 x 2 table: data from the published article; in order to avoid duplicate, only the results of the TOMC cohort were used for the review purpose
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?	Yes
Was the index test performed by a single operator or interpreted by consensus in a joint session?	Yes
		Unclear	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?	Unclear
		Unclear	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?	No
		High