Caviglia 2016.

Study characteristics
Patient Sampling	This single‐centre cross‐sectional study included 98 prospectively enrolled outpatients (68 men, 30 women; mean age, 62.2 ± 14.1years) with chronic liver disease (CLD) or cirrhosis that underwent US screening for hepatic nodular lesions. All the patients were screened for HCC every 6 or 12 months with abdominal US according to presence or absence of cirrhosis, respectively. Age range not reported. Males 69%
Patient characteristics and setting
Index tests	Sera were stored at –80°C and subsequently analysed for the concentration of AFP, AFP‐L3, and des‐γ‐carboxy prothrombin (DCP) using an automated immunoassay system assay on the μTASWako i30 immuno‐analyser (Wako Chemicals, Neuss, Germany).
Target condition and reference standard(s)	Final diagnosis of HCC was established by four‐phase multidetector CT or dynamic contrast‐enhanced MRI showing arterial hypervascularity and washout in the venous/late phase.3 The degree of liver disease was classified according to clinical, serological and histological criteria where appropriate. Liver cirrhosis was diagnosed by liver biopsy or by laboratory data and imaging findings (abdominal US and transient elastography).
Flow and timing	No information on interval between index test and reference standard
Comparative
Notes	No information on funding or conflicts of interest
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?	Unclear
Did the study avoid inappropriate exclusions?	Unclear
Could the selection of patients have introduced bias?		Unclear risk
Are there concerns that the included patients and setting do not match the review question?			Low concern
DOMAIN 2: Index Test (AFP)
Were the index test results interpreted without knowledge of the results of the reference standard?	Yes
If a threshold was used, was it pre‐specified?	No
Could the conduct or interpretation of the index test have introduced bias?		High risk
Are there concerns that the index test, its conduct, or interpretation differ from the review question?			Low concern
DOMAIN 2: Index Test (US+AFP)
DOMAIN 2: Index Test (US)
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?	No
Could the reference standard, its conduct, or its interpretation have introduced bias?		High risk
Are there concerns that the target condition as defined by the reference standard does not match the question?			Low concern
DOMAIN 4: Flow and Timing
Was there an appropriate interval between index test and reference standard?	Unclear
Did all patients receive the same reference standard?	No
Were all patients included in the analysis?	Yes
Could the patient flow have introduced bias?		High risk