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Published on: September 30, 2021
Validation of longitudinal biomarker screening algorithms for HCC detection in patients with cirrhosis
Amit G Singal1, Qingchun Jin2, Jorge Marrero3
1Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA.
Insights
Longitudinal GALAD algorithms improve false-positive rates for hepatocellular carcinoma (HCC) detection but significantly decrease sensitivity. Fixed-threshold GALAD shows higher sensitivity but also a higher false-positive rate in HCC surveillance.
Area of Science:
- Hepatology
- Biomarker Discovery
- Cancer Surveillance
Background:
- Blood-based biomarker panels, including GALAD, are explored as alternatives to ultrasound for hepatocellular carcinoma (HCC) surveillance.
- Longitudinal evaluation of biomarkers may enhance test performance, but large-scale validation is lacking.
Purpose of the Study:
- To compare the performance of fixed-threshold GALAD and four longitudinal algorithms (longitudinal GALAD, PALAD, mFB-ALAD, mPEB-ALAD) for HCC surveillance.
- To validate these algorithms in an external cohort and examine subgroup performance.
Main Methods:
- Utilized the HCC Early Detection Strategy (HEDS) and Texas HCC Consortium (THCCC) studies.
- Compared fixed-threshold GALAD (cutoff -1.36) against longitudinal GALAD, PALAD, mFB-ALAD, and mPEB-ALAD algorithms.
- Assessed sensitivity and false-positive rate (FPR) overall and by age, sex, and cirrhosis etiology.
Main Results:
- In the THCCC cohort, fixed-threshold GALAD demonstrated higher sensitivity (71.4%) for HCC detection within 6 months of diagnosis compared to longitudinal algorithms (42.9%-55.1%).
- Fixed-threshold GALAD exhibited a higher FPR (25.4%) than longitudinal GALAD (15.0%) and PALAD (13.0%), but comparable to mPEB-ALAD (22.9%).
- Longitudinal algorithms showed lower FPRs in subgroups but with reduced HCC sensitivity.
Conclusions:
- While longitudinal GALAD algorithms improve FPRs compared to fixed-threshold GALAD, this benefit is counteracted by a significant reduction in HCC detection sensitivity.
- Fixed-threshold GALAD offers higher sensitivity but at the cost of increased false positives, particularly in males and older individuals.
Background:
Blood-based biomarker panels, including GALAD, have been proposed as an alternative to abdominal ultrasound for hepatocellular carcinoma (HCC) surveillance. Studies suggest longitudinal evaluation of biomarkers can improve test performance; however, no large studies have validated these findings.
Methods:
We leveraged the HCC Early Detection Strategy (HEDS) study (n=1019 patients with cirrhosis; 99 incident HCC) and Texas HCC Consortium (THCCC) (n=2345 patients with cirrhosis; 126 incident HCC) to compare the performance of fixed-threshold GALAD (cutoff of -1.36), and 4 longitudinal algorithms: longitudinal GALAD, PALAD, mFB-ALAD, and mPEB-ALAD. The HEDS cohort was used to derive longitudinal algorithms, and external validation was performed in THCCC. Patient-level sensitivity and test-level false-positive rate (FPR) were examined overall and across subgroups by age, sex, and cirrhosis etiology.
Results:
In THCCC, fixed-threshold GALAD had higher sensitivity in the 6 months before HCC diagnosis (71.4%, 95% CI: 62.9%-81.7%) than longitudinal GALAD (55.1%, 95% CI: 49.3-66.4), PALAD (55.1%, 95% CI: 50.0%-70.5%), mPEB-ALAD (53.1%, 95% CI: 43.6%-62.0%), and mFB-ALAD (42.9%, 95% CI: 32.3-48.5). However, fixed-threshold GALAD had a higher FPR (25.4%, 95% CI: 23.7%-26.9%) compared with longitudinal GALAD (15.0%, 95% CI: 12.8%-15.8%), PALAD (13.0%, 95% CI: 10.2%-14.6%), and mFB-ALAD (11.2%, 95% CI: 9.6%-12.1%) but comparable to mPEB-ALAD (22.9%, 95% CI: 21.2%-23.8%). In subgroup analyses, fixed-threshold GALAD had the highest FPR in males (35.6%) and those aged ≥65 (43.5%); longitudinal algorithms had significantly lower FPRs in subgroups but with lower sensitivity for HCC.
Conclusions:
Improvements in FPRs with longitudinal GALAD algorithms, as compared with fixed-threshold GALAD, are offset by significantly decreased sensitivity for HCC detection.
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