Frolich 2017.

Study characteristics
Patient sampling	Primary objectives: investigate which combination of biomarkers best predict a short‐term conversion from MCI to AD dementia Study population: participants from the Dementia Competence Network (DCN), a German multicenter cohort study Selection criteria: patients who sought evaluation at the participating memory clinics, aged ≥ 50 years and in whom organic cognitive impairment was suspected underwent a screening assessment. The diagnoses of MCI were made on the basis of clinical and neuropsychological data. A specific MMSE threshold was not applied for diagnosis. A broader definition of MCI was used, the core features being complaints of cognitive deficit in ADL and objectified decline of cognitive abilities (> 1 SD) in at least 1 of main cognitive domains as evidenced by standardised neuropsychological tests; B‐ADL score < 4; no major depressive episode. The following exclusion criteria were applied: substance abuse or dependence, insufficient German language skills, multimorbidity, comorbid condition with excess mortality, circumstances that make regular attendance at follow‐up visits questionable and lack of an informant. In most centres, a consecutive series of patients was included in the study, nevertheless 115/1071 MCI patients (12%) were included on the basis of biomarkers availability, follow‐up length (for at least 12 months) and outcome (MCI stable or progressed to AD only) Study design: prospective multisite longitudinal observational study on memory clinic patients with MCI or early dementia
Patient characteristics and setting	Clinical presentation: MCI was broadly defined including amnestic and nonamnestic syndromes according to Winblad 2004 Age mean (SD): MCI who progressed to AD: 65.4 ± 9.37 years; MCI non‐converters to AD: 66.5 ± 8.95 years Gender (% men): MCI who progressed to AD: 54%; MCI non‐converters to AD: 60% Education years mean (SD): MCI who progressed to AD: 8.75 ± 1.58 years; MCI non‐converters to AD: 9.75 ± 1.95 years ApoE4 carriers (%): MCI who progressed to AD: 36%; MCI non‐converters to AD: 41% Neuropsychological tests: employed; MMSE mean (SD): MCI who progressed to AD: 28 ± 2.34; MCI non‐converters to AD: 27.5 ± 1.87 Clinical stroke excluded: not specified Co‐morbidities: not reported Number enrolled: 115 Number available for analysis: 115 Setting: Dementia Competence Network Country: Germany Period of study: participants were recruited between May 2003 and November 2007 Language: English
Index tests	Index test: automated method for estimation of hippocampal volume Manufacturer: Siemens, Philips Tesla strength: 1.5 T Assessment methods: hippocampal volume was calculated as the mean value of the left and right hemisphere and was determined from high‐resolution structural MRI using Oxford Centre for Functional MRI of the Brain Integrated Registration and Segmentation Tool from the Functional MRI of the Brain Software Library package of tools (Patenaude 2011). Description of positive cases definition by index test as reported: not specified. Sensitivity, specificity and Youden's index of various predictors were calculated (Youden 1950). Examiners: no details about radiologist Interobserver variability: not reported. Special measures were taken for standardisation of MRI acquisition across centres. Acquisition parameters were provided to all centres as guideline. The phantom test of the American College of radiology MRI Accreditation Program was conducted repeatedly at 11 sites of the Dementia Competence Network. Furthermore a single volunteer was investigated at each of these centres.
Target condition and reference standard(s)	Target condition: AD Prevalence of AD in the sample: 28/115 (24% of cases included in the analysis) Stable MCI or converted to other dementia: 87/115 (76%) stable MCI Reference standard: Dementia Competence Network study used NINCDS‐ADRDA (McKhann 1984) for the AD diagnosis Mean clinical follow‐up: 2.2 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	A combination of two biomarkers of neurodegeneration (e.g., HCV and t‐Tau) is not superior over the single parameters in identifying patients with MCI who are most likely to progress to AD dementia, although there is a gradual increase in the statistical measures across increasing biomarker combinations
Conflict of interests	LF has received payment for consultancy, expert testimony, honorarium, or travelling support from AstraZeneca, Eisai, Eli Lilly, GE Healthcare, Janssen‐Cilag, Lundbeck, Merz Pharma, Novartis, Pfizer, and Schering‐Plough, and Apotex Inc., and has received a research grant from Novartis, Pfizer paid to his institution. OP is on scientific advisory boards for Roche, Kyowa Kirin, Novartis, Lilly, and Piramal. He has received funding for travel or speaker honoraria from GSK, Nutricia, and Merck Serono. He has acted as a consultant for Affiris and Roche. He has received research support from Affiris, Piramal, BMS, Eli Lilly, Pfizer, Servier, TRX Pharmaceuticals, Lundbeck, and Genentech. FJ has received consultation board honoraria and speaker's fees from AC Immune, Lilly, GE Healthcare, Janssen, USB, Schwabe, Esai, Pfizer, Novartis, and Roche. He has received a research grant paid to his institution from Schwabe. JP has received honoraria from Merz, Janssen‐Cilag, and Novartis. MH has received a research grant from Schwabe GmbH, has received speaker's honoraria from Pfizer Inc., Merz Pharmaceuticals, and GlaxoSmithKline, and served on an advisory board for Hoffmann‐La Roche. ER is a Merz GmbH collaborator, is on the speakers' bureau of/has received a travel grant from BMS, Lundbeck, Servier, and Otsouka, and has received a research grant from Lilly, BMS, AstraZeneca, and Lundbeck. FH was a consultant to AstraZeneca in the area of depression between June 2011 and November 2012. WM has received payment for educational lectures from Merz. JW is on the advisory board for Eli Lilly and has received consulting fee or honorarium and support for travelling to Board meetings. He received payment for lectures from Novartis. JK has received financial support for conducting clinical trials from various pharmaceutical companies manufacturing anti‐dementia drugs. He is mentioned as coinventor on the following patents: Substituted piperidines or pyrrolidine compounds for treating sigma‐receptor modulated disorders (WO001996031208A3); Method of differentially diagnosing dementias (WO002008058764A1); Soluble amyloid precursor proteins in CSF as biomarkers of AD (EP000002068151A1); Immunoglobulinbound Aβ and immunoglobulins‐binding Aβ peptides in diagnosis and therapy of AD (WO002007082750A1); and Method of diagnosing acute cerebral ischemia (WO002008058764A1). The remaining study authors declare that they have no competing interests.
Notes	Source of funding: this study was supported by a grant from the German Federal Ministry of Education and Research (BMBF): Kompetenznetz Demenzen (01GI0420) 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?	Yes
Was a case‐control design avoided?	Yes
Did the study avoid inappropriate exclusions?	Unclear
		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