Marrero 2003.

Study characteristics
Patient Sampling	All the patients were enrolled from the liver and liver transplantation clinics at the University of Michigan Medical Center between September 2001 and May 2002. Four groups of consecutive participants were enrolled. Group 1 (G1): normal healthy individuals with no history of liver disease, alcohol consumption less than 40 g/week, and no risk factors for viral hepatitis. All participants were documented to have normal liver biochemistry Group 2 (G2): patients with histologically‐confirmed noncirrhotic chronic hepatitis Group 3 (G3): patients with histologically‐proven cirrhosis and compensated liver disease (i.e. Child‐Turcotte‐Pugh [CTP] score 7) Group 4 (G4): patients with histologically‐proven HCC Age range: 43‐69. Males 54%.
Patient characteristics and setting
Index tests	AFP: AFP was tested using commercially available immunometric assays utilising enhanced chemiluminescence at the University of Michigan Hospital Clinical Diagnostic Laboratory. To determine the optimal cut‐ off value for DCP and AFP in the diagnosis of HCC, receiver operating characteristic (ROC) curves were constructed using all possible cut‐offs for each assay.
Target condition and reference standard(s)	HCC: histology Computed tomography and magnetic resonance imaging studies of patients with HCC were reviewed by a radiologist who was not aware of the serum marker results.
Flow and timing	No information on interval between index test and reference standard
Comparative
Notes	No information on 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?	No
Did the study avoid inappropriate exclusions?	Unclear
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?			High
DOMAIN 2: Index Test (AFP)
Were the index test results interpreted without knowledge of the results of the reference standard?	No
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?	No
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?		High risk
Are there concerns that the target condition as defined by the reference standard does not match the question?			High
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