Bolondi 2001.

Study characteristics
Patient Sampling	Between March 1989 and November 1991, a cohort of patients with liver cirrhosis and without HCC. Exclusion criteria were: (1) Child‐Pugh C class 16 in patients older than 60 years; (2) a previous diagnosis of focal liver lesion at US; and (3) a serum AFP level > 200 ng/dL. Patients were withdrawn from further surveillance when they were > 60 years old and belonged to Child‐Pugh C class, developed other neoplasms, or underwent orthotopic liver transplantation. Age range not reported. Males 62%
Patient characteristics and setting
Index tests	Cut‐off value 20 ng/mL
Target condition and reference standard(s)	Serum AFP determinations and abdominal US, together with physical examination and routine biochemical tests, were repeated every six months. The diagnostic protocol for detection of a nodular liver lesion at US was based on contrast enhanced computed tomography (CT) and echo guided biopsy (when feasible, according to location of the nodule and bleeding risk). When a negative result was obtained after CT and echo guided biopsy, a strict follow up procedure was followed (three month intervals) and the nodule was rebiopsied when an increase in size was detected at US.
Flow and timing	No information on interval between index test and reference standard
Comparative
Notes	This research was supported by grants of MURST (Italian Ministry for Technological and Scientifi Research). 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?	Yes
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?			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?	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