Ledig 2018.

Study characteristics
Patient sampling	Primary objectives: assess biomarkers by determining their power to predict diagnostic classification and by comparing atrophy rates to published meta‐studies Study population: participants from the ADNI study including MCI with 2‐year follow‐up Selection criteria: the stable MCI group was represented by “late MCI” at baseline that remained stable for at least 2 years and until the most recent diagnosis that was available; the progressive MCI group was represented by MCI at baseline that converted within 2 years to probable AD. Exclusion criteria: participants who reverted at any time point from a more severe to a less severe disease stage (N = 68), participants with baseline diagnosis of early MCI (N = 277), participants who were diagnosed as MCI at baseline but converted to probable AD > 2 years later (N = 54). Study design: prospective longitudinal study (participants from ADNI study)
Patient characteristics and setting	Clinical presentation: MCI according to ADNI protocol Age median (min; max): MCI who progressed to AD: 74.3 (48.1; 88.3) years; MCI non‐converters to AD: 74.4 (55.9; 91.4) years Gender (% men): MCI who progressed to AD: 59%; MCI non‐converters to AD: 59% Education years mean (SD): not reported ApoEers (%): MCI who progressed to AD: 68%; MCI non‐converters to AD: 44% Neuropsychological tests: employed; MMSE median (min; max) MCI who progressed to AD: 26 (23;30); MCI non‐converters to AD: 28 (24; 30) Clinical stroke excluded: not specified Co‐morbidities: not reported Number enrolled: 343 (399 excluded a priori) Number available for analysis: 343 Setting: ADNI database (multicentre study) Country: USA and Canada Period of study: not reported Language: English
Index tests	Index test: MRI automated method for estimation of brain volumes of hippocampal, entorhinal cortex,amygdala, middle temporal gyrus, ventricles, cortical grey matter, white matter, deep grey matter, brain tissue Manufacturer: those used in ADNI study (GE Healthcare, Philips Medical System, Siemens Medical Solution (Jack 2008b)) Tesla strength: 1.5‐3 T Assessment methods: brain extraction (pincram) and MRI automatic segmentation method for robust segmentation of whole brain MRIs into 138 distinct anatomical structures using Multi‐Atlas Label Propagation with Expectation–Maximisation based refinement (MALPEM) (Ledig 2015) Description of positive cases definition by index test as reported: not specified (a threshold was not reported) Examiners: not specified Interobserver variability: not specified in the paper; test‐retest reliability for the method was estimated in Ledig 2015: using MALPEM the average ICC was 0.97 for non‐cortical and 0.94 for cortical regions
Target condition and reference standard(s)	Target condition: AD Prevalence of AD in the sample: 177/343 (52% of cases included in the analysis) Stable MCI or converted to other dementia: 166/343 (48%) stable MCI Reference standard: AD diagnosis according to NINCDS‐ADRDA (McKhann 1984) Mean clinical follow‐up: 2 years
Flow and timing	Withdrawals and losses to follow‐up: none reported Uninterpretable MRI results have not been reported
Comparative
Key conclusions by the authors	The identified biomarkers hold great potential for deeper analysis, and the validated methodology can readily be applied to other imaging cohorts.
Conflict of interests	CL, AS and RG conducted this research while being employees of Imperial College London, UK (CL, AS, RG) and IXICO plc, UK (CL, RG). DR is a co‐founder and scientific advisor of IXICO plc, UK, a provider of medical image analysis services. CL is currently employed by Imagen Technologies, Inc, NY, USA. This does not alter their adherence to Scientifc Reports policies on sharing data and materials.
Notes	Source of funding: European Union's Seventh Framework Programme under grant agreement no. 611005. RG was funded by an Innovative UK (101685) grant. Data collection and sharing for this project was funded by the ADNI and Department of Defense ADNI. 2 x 2 table: data from the published article; we considered volume estimation data for these regions: hippocampal, entorhinal cortex, amygdala, middle temporal gyrus, lateral ventricles, cortical grey matter, whole brain
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?	Unclear
		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