Nguyen 2002.

Study characteristics
Patient Sampling	"We conducted a case‐control study of patients with HCC and chronic HCV infection and patients with hepatitis C‐related cirrhosis whose clinical records were available for retrospective reviews at Stanford University Medical Center (SUMC), Veterans Administration Medical Center in San Francisco (VASF), San Francisco General Hospital (SFGH), and University of California Medical Center in San Francisco (UCSF) between 1995 and 2001. All patients in this study had positive anti‐HCV and/or HCV‐RNA and at least 1 serum AFP measurement. Patients with positive hepatitis B surface antigen (HBsAg), anti‐HIV, active nonhepatic malignancies, and hereditary or autoimmune liver diseases were excluded. All patients were sampled consecutively from liver transplant and liver clinic records." Age range: 35‐84. Males 80.5%
Patient characteristics and setting
Index tests	AFP: laboratory tests including serum AFP, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (TB), platelet count, prothrombin time and international normalised ratio (INR), creatinine, HBsAg, anti‐HCV, and HCV RNA were determined using standard, commercially available assays. Sensitivity and specificity of various AFP cut‐off values were determined for: AFP greater than 10 ng/mL (normal upper limit for most commercial laboratories), AFP greater than 20 ng/mL (recommended threshold for further investigation), and AFP greater than 100 ng/mL and 200 ng/mL (suggested confirmatory values for HCC in patients with hepatic masses.
Target condition and reference standard(s)	HCC: "In total, 163 cases of HCV‐related HCC meeting inclusion criteria were identified and confirmed by cytology and/or histology (87 patients, 53.4%) or by the presence of characteristic (i.e. enlarging tumours and/or tumours with typical arterial hypervascularisation) hepatic masses on liver computed tomography (CT), and/or magnetic resonance imaging tests (MRI), and/or hepatic angiography tests (76 patients, 46.6%). Control group: In total, 149 control patients with chronic HCV infection and cirrhosis were identified and confirmed by liver biopsies (89 patients, 59.7%) and/or clinical or radiographic evidence of portal hypertension (60 patients, 40.3%). HCC was excluded by imaging studies [US, CT, MRI, and/or hepatic angiography], one of which must have been performed at least 6 months following the measurement of AFP."
Flow and timing	The median time between diagnostic imaging studies and AF tests was 14 days (range 0‐300 days).
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?	No
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?	Yes
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?	No
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