Lin 2015.

Study characteristics
Patient Sampling	In total, we collected 1416 serum samples from five groups of participants: healthy controls, inactive HBsAg carriers, patients with chronic hepatitis B, patients with HBV‐induced liver cirrhosis, and patients with diagnosed hepatocellular carcinoma. Age range: 39‐57. Males 83%
Patient characteristics and setting	The recruited participants were defined as healthy individuals, inactive HBsAg carriers, patients with chronic hepatitis B, patients with HBV‐induced liver cirrhosis, or patients with hepatocellular carcinoma by medical doctors, according to eligibility criteria listed in the Appendix.
Index tests	The miRNA classifier established in the training stage was initially validated in two cohorts of patients with hepatocellular carcinoma and controls. These two validation cohorts were independent of the discovery cohort and training cohort and were also independent of each other. They were recruited at different times or different hospitals. We compared the ability of the classifier to diagnose hepatocellular carcinoma with the performance of α‐fetoprotein at two commonly used cut‐offs of 20 ng/mL (AFP20) and 400 ng/mL (AFP400).
Target condition and reference standard(s)	Patients with hepatocellular carcinoma were diagnosed based on at least two imaging technologies (i.e. hepatic ultrasound together with CT, or MRI, or both), and most cases were further confirmed histopathologically according to the AASLD guidelines.
Flow and timing	No information on interval between index test and reference standard
Comparative
Notes	No conflicts of interest declared
Methodological quality
Item	Authors' judgement	Risk of bias	Applicability concerns
DOMAIN 1: Patient Selection
Was a consecutive or random sample of patients enrolled?	Unclear
Was a case‐control design avoided?	No
Did the study avoid inappropriate exclusions?	Yes
Could the selection of patients have introduced bias?		High 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?	Yes
Could the conduct or interpretation of the index test have introduced bias?		Low 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?	Yes
Could the reference standard, its conduct, or its interpretation have introduced bias?		Low 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?	Yes
Were all patients included in the analysis?	Yes
Could the patient flow have introduced bias?		Unclear risk