Wang 2016a.

Study characteristics
Patient Sampling	This was a nested case–control study from the University of Michigan (UM). Patients with cirrhosis were enrolled from UM Liver Clinics between September 2001 and August 2004. Age range: 45‐71. Males 63%
Patient characteristics and setting
Index tests	AFP was tested using commercially available immunoassays utilising enhanced chemiluminescence at the UM Hospital Clinical Diagnostic Laboratory with no predefined cut‐off value.
Target condition and reference standard(s)	HCC: the diagnosis of HCC was made by histopathology, including all T1 lesions, or by two imaging modalities MRI or CT, showing a vascular enhancing mass > 2 cm with delayed washout. Control: cirrhosis controls were followed for a median of 12 months (range, 7–18 months) after enrolment to confirm absence of HCC.
Flow and timing	No information on interval between index test and reference standard
Comparative
Notes	"Conflicts of interest: T. Block reported receiving commercial research grant from Arbutus BioPharma, has ownership interest (including patents) in Glycotest, and was consultant/advisory board member for Glycotest. No potential conflicts of interest were disclosed by the other authors."
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
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?			High
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?	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?	No
Were all patients included in the analysis?	Yes
Could the patient flow have introduced bias?		High risk