Singal 2012.

Study characteristics
Patient Sampling	Between January 2004 and September 2006, consecutive patients with cirrhosis were prospectively identified and entered into a surveillance program using ultrasound and AFP. Patients were enrolled from the University of Michigan (Ann Arbor, MI) General Hepatology or Liver Transplant outpatient clinics if they had Child‐Pugh class A or B cirrhosis and absence of known HCC at the time of initial evaluation. Exclusion criteria included clinical evidence of significant hepatic decompensation (refractory ascites, grade III–IV encephalopathy, active variceal bleeding, or hepatorenal syndrome), co‐morbid medical conditions with a life expectancy of less than 1 year, prior solid organ transplant, and a known extrahepatic primary tumour. HCC cases diagnosed within the first 6 months of enrolment (prevalent cases) were excluded. Age age: 24‐82. Males 59%
Patient characteristics and setting
Index tests	AFP and US: patients with an AFP level greater than 20 ng/mL or mass lesion on ultrasound underwent further evaluation.
Target condition and reference standard(s)	HCC: HCC was diagnosed using AASLD guidelines, and the Barcelona Clinic Liver Cancer (BCLC) system was used for tumour staging. For tumours greater than 2 cm in size, the diagnosis was made by the presence of a typical vascular pattern on dynamic imaging (arterial enhancement and washout on delayed images) or an AFP level greater than 200 ng/mL. For tumours with a maximum diameter of 1 cm to 2 cm, the diagnosis was made by the presence of a typical vascular pattern on 2 dynamic imaging studies or histology. Absence of HCC was determined by imaging lacking any suspicious appearing masses within 6 months of enrolment. Patients with an AFP level greater than 20 ng/mL at enrolment were only included if computed tomography (CT) or MRI confirmed the absence of any suspicious masses within 3 months of enrolment.
Flow and timing	No information on interval between index test and reference standard
Comparative
Notes	No potential conflicts of interests were disclosed.
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?	Yes
Could the selection of patients have introduced bias?		Low 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)
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)
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 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?	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