Worldwide, hepatocellular carcinoma (HCC) is the most common cancer-related cause of death, in part due to the lack of effective early detection methods. According to current guidelines, screening for cirrhosis patients and demographic categories with chronic hepatitis B infection includes semi-annual abdominal ultrasounds with or without serum alpha-fetoprotein. 

The screening approach, however, had a number of flaws, including subpar early-stage sensitivity, false positives with negative consequences, operator-to-operator ultrasonography performance variability, and low adherence. Several of the obstacles to better early-stage detection could be solved by a blood-based biomarker with the performance qualities for early-stage illness. However, multistep validation was needed to establish test performance characteristics before using a biomarker for screening in clinical practice. Validation in prospective cohorts of patients at risk was one of these processes, followed by validation using case-control studies. 

The Hepatocellular Carcinoma Early Detection Study and the Texas Hepatocellular Carcinoma Consortium were two growing validation cohorts that would allow for the thorough validation of proposed biomarkers. However, until recently, they lacked suitable longitudinal validation cohorts for early HCC detection. Although there were a number of interesting biomarkers awaiting confirmation, for a prospective biomarker to replace abdominal ultrasonography, it must perform well in tests and clear, practical obstacles. 

Given the limits of ultrasound-based screening, the potential of blood-based biomarkers was great; yet, they needed appropriate validation and must overcome various logistical challenges before being used in clinical settings.