Khan 2015.

Study characteristics
Patient sampling	Primary objectives: investigate patterns of hippocampal subfield volume loss in MCI and AD determine the pattern of subfield volume loss due to age, gender, education, APOE e4 genotype, and neuropsychological test scores compare combined subfield volumes to hippocampal volume alone at discriminating between AD and healthy controls, and predicting future MCI conversion to AD at 12 months Study population: MCI participants from ADNI (ADNI 2010) and AddNeuroMed cohorts (Lovestone 2009). Data from the ADNI study were downloaded from the ADNI at the LONI website. For the AddNeuroMed cohort, patients attended local memory clinics and received a diagnosis of MCI. Selection criteria: Participants had MMSE scores between 24 and 30 Subjective memory complaint with preserved ADL CDR score of 0.5 GDS score ≤ 5 absence of dementia in accordance with NINCDS‐ADRDA criteria. Exclusion criteria according to the corresponding study protocols: for ADNI as in Gaser 2013; for AddNeuromed, other neurological or psychiatric disease, significant unstable systemic illness or organ failure, and alcohol or substance misuse Study design: prospective longitudinal study (data from ADNI study and AddNeuromed study)
Patient characteristics and setting	Clinical presentations: MCI with subjective memory complaint Age mean (SD): MCI who progressed to AD: 74 ± 7; stable MCI: 75 ± 7 Gender (% men): MCI who progressed to AD: 60%; stable MCI: 61% Education years mean (SD): MCI who progressed to AD: 14.0 ± 4.1; stable MCI: 14.3 ± 4.4 ApoE4 carriers (%): MCI who progressed to AD: 63%; stable MCI: 48% 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: 447 Number available for analysis: 447 Setting: ADNI cohort and AddNeuroMed cohort Country: USA and Canada (ADNI); Finland, Italy, Greece, UK, Poland, France (AddNeuroMed) Period: not specified Language: English
Index tests	Index test: MRI automated method for estimation of hippocampal volume and subvolumes Manufacturer: several. 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 MRIs according to the AddNeuroMed quality control framework Tesla strength: 1.5 Assessment methods: image analyses were carried out using the Freesurfer image analysis pipeline (version 5.1.0). Automated segmentation of the hippocampus was performed to define anatomical subfields. Hippocampal subfields were analysed using a supervised multivariate data analysis method included in the software package SIMCA Description of positive cases definition by index test as reported: the MRI images of MCI participants were classified as "more similar to healthy" (negative cases) and "more similar to AD" (positive cases) Examiners: no details about radiologist; imaging interpretation was reserved to an automatic classifier Interobserver variability: not evaluable
Target condition and reference standard(s)	Target condition: AD Prevalence of AD in the sample: 90/447 (20% enrolled participants) Stable MCI or converted to other dementia: 357 (80%) stable MCI Reference standards: not reported in the published article. Referring to the study protocols, NINCDS‐ADRDA criteria were applied for both cohorts (McKhann 1984). 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	Multiple subfield volumes were atrophied in AD and MCI and were related to age, gender, education, APOE e4 genotype, and neuropsychological test scores. For predicting MCI conversion to AD combined subfield volumes and presubiculum volume were more accurate than total hippocampal volume
Conflict of interests	Information not available
Notes	Source of funding: ADNI (Grant U01 AG024904) and Department of Defense ADNI (award number W81XWH‐12‐2‐0012); InnoMed (an integrated project funded by the European Union of the sixth framework program priority FP6‐2004‐LIFESCIHEALTH‐5, Life Sciences, Genomics and Biotechnology for Health 2 x 2 table: data from the published article; we only used data regarding the total hippocampal volume for the review
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?	Unclear
		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?	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