An interventional study of GAAD score in Hepatecellular Carcinoma, Cirrhosis and HBV Infection, sponsored by Mahidol University. Enrolling by invitation at 1 site in Thailand. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2026-01-06.
Sponsored by Mahidol University · Not applicable, Interventional, and Screening
Hepatocellular carcinoma (HCC) surveillance is frequently underutilized, and currently available biomarkers, such as alpha-fetoprotein (AFP), demonstrate suboptimal diagnostic performance. This prospective study aims to evaluate a simplified multivariate index, the GAAD score-comprising gender, age, alpha-fetoprotein (AFP), and protein induced by vitamin K absence or antagonist-II (PIVKA-II)-for its ability to improve the detection of hepatocellular carcinoma in patients with chronic liver disease.
The study hypothesizes that incorporation of the GAAD score into standard HCC surveillance strategies will improve diagnostic performance compared with existing surveillance modalities alone and may provide evidence to support its inclusion in future clinical practice guidelines.
Surveillance and early detection of hepatocellular carcinoma (HCC) increase the likelihood of potentially curative treatment. However, HCC surveillance remains substantially underutilized, even in countries with adequate healthcare resources. Early-stage HCC can be treated with curative intent using local ablation, surgical resection, or liver transplantation.
The role of serum alpha-fetoprotein (AFP) in HCC surveillance varies across international guidelines. AFP is recommended for surveillance by the Asian Pacific Association for the Study of the Liver (APASL), considered optional by the American Association for the Study of Liver Diseases (AASLD), and not recommended by the European Association for the Study of the Liver (EASL). Similar considerations have informed recommendations for combined use of AFP with ultrasound (US) in HCC surveillance by the World Health Organization (WHO) Guidelines for the Prevention, Care and Treatment of Viral Hepatitis (references 1-4).
AFP has demonstrated suboptimal performance as a serologic surveillance marker for HCC. Serum AFP levels may fluctuate in patients with cirrhosis due to hepatitis B virus (HBV) or hepatitis C virus (HCV) activity, exacerbations of underlying liver disease, or the development of HCC, thereby limiting its diagnostic accuracy.
Recently, the GALAD score-a multivariable model incorporating gender, age, AFP-L3, AFP, and protein induced by vitamin K absence or antagonist-II (PIVKA-II)-has been proposed as an alternative approach to improve HCC detection and has demonstrated strong diagnostic performance in patients with cirrhotic HCC. A simplified version of this model, the GAAD score (Roche Diagnostics International Ltd., Rotkreuz, Switzerland), which includes gender, age, AFP, and PIVKA-II, has been shown to achieve comparable diagnostic performance in preliminary analyses (Piratvisuth et al., 2023, submitted).
However, the existing evidence supporting the use of the GALAD and GAAD scores is primarily derived from retrospective and/or case-control studies. Prospective validation in real-world surveillance settings remains limited. This study is therefore designed to prospectively evaluate the diagnostic performance of the GAAD score, alone and in combination with standard surveillance modalities, in patients with chronic liver disease undergoing routine HCC surveillance.
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Exclusion Criteria:
All enrolled participants will undergo standard hepatocellular carcinoma (HCC) surveillance consisting of blood sampling and abdominal ultrasound performed every 6 months for a total follow-up period of 24 months. Blood samples will be analyzed for serum alpha-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist-II (PIVKA-II) to calculate the GAAD score, a multivariable index incorporating gender, age, AFP, and PIVKA-II. A GAAD score ≥ 2.57 will trigger a recall procedure, defined as diagnostic evaluation with multiphasic contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) of the liver. This recall procedure is conducted in addition to standard surveillance recall criteria, which include detection of a suspicious hepatic lesion measuring ≥ 1 cm on ultrasound or elevated or rising serum AFP levels (≥ 20 ng/mL).
Diagnostic Test: GAAD score
All enrolled participants will undergo standard hepatocellular carcinoma (HCC) surveillance, consisting of blood sampling and abdominal ultrasound performed every 6 months for a total follow-up period of 24 months. Blood samples will be analyzed for serum alpha-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist-II (PIVKA-II) to calculate the GAAD score, a multivariable index incorporating gender, age, AFP, and PIVKA-II. A GAAD score of ≥ 2.57 will trigger a recall procedure, defined as further diagnostic evaluation using multiphasic contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) of the liver. This recall procedure is performed in addition to standard surveillance recall criteria, which include detection of a suspicious hepatic lesion measuring ≥ 1 cm on ultrasound or elevated or rising serum AFP levels (≥ 20 ng/mL).
True Positive Rate (Sensitivity) of Ultrasound, AFP, and GAAD Score as Standalone Surveillance Modalities
To evaluate the true positive rate (sensitivity) of Ultrasound, serum alpha-fetoprotein (AFP), and the GAAD score when used individually for hepatocellular carcinoma (HCC) surveillance. Sensitivity will be calculated for each modality separately by comparing surveillance results with the reference standard diagnosis of HCC. Unit of Measure: Proportion (percentage)
Time frame: Over 24 months of patient follow-up
False Positive Rate of Ultrasound, AFP, and GAAD Score as Standalone Surveillance Modalities
To evaluate the false positive rate of Ultrasound, serum AFP, and the GAAD score when used individually for HCC surveillance. The false positive rate will be calculated for each modality separately based on surveillance results compared with the reference standard diagnosis. Unit of Measure: Proportion (percentage)
Time frame: Over 24 months of patient follow-up
True Positive Rate (Sensitivity) of Combined Ultrasound + GAAD Score for HCC Surveillance
To evaluate the true positive rate (sensitivity) of the combined Ultrasound and GAAD score strategy for HCC surveillance. A positive surveillance result will be defined according to the prespecified combination criteria (e.g., either test positive or both tests positive, as defined in the protocol). Unit of Measure: Proportion (percentage)
Time frame: Over 24 months of patient follow-up
False Positive Rate of Combined Ultrasound + GAAD Score for HCC Surveillance
To evaluate the false positive rate of the combined Ultrasound and GAAD score strategy for HCC surveillance, using the reference standard diagnosis of HCC. Unit of Measure: Proportion (percentage)
Time frame: Over 24 months of patient follow-up
True Positive Rate (Sensitivity) of Combined Ultrasound + AFP for HCC Surveillance
To evaluate the true positive rate (sensitivity) of the combined Ultrasound and serum AFP strategy for HCC surveillance, based on predefined combination criteria. Unit of Measure: Proportion (percentage)
Time frame: Over 24 months of patient follow-up
False Positive Rate of Combined Ultrasound + AFP for HCC Surveillance
To evaluate the false positive rate of the combined Ultrasound and serum AFP strategy for HCC surveillance, compared with the reference standard diagnosis of HCC. Unit of Measure: Proportion (percentage)
Time frame: Over 24 months of patient follow-up
Area Under the Receiver Operating Characteristic Curve (AUC) of GAAD Compared With Ultrasound, AFP, and PIVKA-II
o compare the overall discriminative ability of the GAAD algorithm with Ultrasound, serum AFP, and serum PIVKA-II for the detection of hepatocellular carcinoma (HCC). Performance will be assessed using the area under the receiver operating characteristic curve (AUC), stratified by HCC stage and underlying liver disease etiology. Unit of Measure: AUC (unitless)
Time frame: Over 24 months of patient follow-up
Sensitivity and Specificity of GAAD Compared With Ultrasound, AFP, and PIVKA-II
To compare the sensitivity and specificity of the GAAD algorithm with Ultrasound, serum AFP, and serum PIVKA-II for HCC surveillance. Sensitivity and specificity will be calculated separately for each modality and stratified by HCC stage and etiology. Unit of Measure: Proportion (percentage)
Time frame: Over 24 months of patient follow-up
Positive Predictive Value (PPV) and Negative Predictive Value (NPV) of GAAD Compared With Ultrasound, AFP, and PIVKA-II
To compare the positive predictive value (PPV) and negative predictive value (NPV) of the GAAD algorithm with Ultrasound, serum AFP, and serum PIVKA-II for HCC surveillance, stratified by HCC stage and etiology. Unit of Measure: Proportion (percentage)
Time frame: Over 24 months of patient follow-up
Area Under the Receiver Operating Characteristic Curve (AUC) of Combined Ultrasound + AFP
To evaluate the discriminative performance of the combined Ultrasound and serum AFP strategy for HCC surveillance using the area under the receiver operating characteristic curve (AUC), stratified by HCC stage and etiology. Unit of Measure: AUC (unitless)
Time frame: Over 24 months of patient follow-up
Sensitivity and Specificity of Combined Ultrasound + AFP
To evaluate the sensitivity and specificity of the combined Ultrasound and serum AFP strategy for HCC surveillance, stratified by HCC stage and etiology. Unit of Measure: Proportion (percentage)
Time frame: Over 24 months of patient follow-up
Positive Predictive Value (PPV) and Negative Predictive Value (NPV) of Combined Ultrasound + AFP
To evaluate the positive predictive value (PPV) and negative predictive value (NPV) of the combined Ultrasound and serum AFP strategy for HCC surveillance, stratified by HCC stage and etiology. Unit of Measure: Proportion (percentage)
Time frame: Over 24 months of patient follow-up
Longitudinal Changes in AFP Levels Prior to HCC Diagnosis
To assess longitudinal changes in serum Elecsys AFP concentrations preceding an HCC diagnosis among confirmed HCC cases. Unit of Measure: Nanograms per milliliter (ng/mL)
Time frame: Over 24 months of patient follow-up
Longitudinal Changes in PIVKA-II Levels Prior to HCC Diagnosis
To assess longitudinal changes in serum Elecsys PIVKA-II concentrations preceding an HCC diagnosis among confirmed HCC cases. Unit of Measure: milli-arbitrary units per milliliter (mAU/mL)
Time frame: Over 24 months of patient follow-up
Longitudinal Changes in GAAD Score Prior to HCC Diagnosis
To assess longitudinal changes in the GAAD score preceding an HCC diagnosis among confirmed HCC cases. Unit of Measure: Unitless score
Time frame: Over 24 months of patient follow-up
Number of Additional Early-Stage HCCs Detected Using GAAD
To quantify the number of additional early-stage hepatocellular carcinoma cases identified using the GAAD score compared with standard surveillance modalities. Unit of Measure: Number of participants
Time frame: Over 24 months of patient follow-up
Number of Additional CT or MRI Imaging Procedures Triggered by Surveillance Tests
To count the number of additional CT or MRI imaging procedures triggered by positive results from GAAD, AFP, or Ultrasound surveillance tests. Unit of Measure: Number of imaging procedures
Time frame: Over 24 months of patient follow-up
Relative False Positive Rate of Additional CT or MRI Imaging Procedures
To calculate the relative false positive rate of additional CT or MRI imaging procedures triggered by positive GAAD, AFP, or Ultrasound surveillance results. Unit of Measure: Proportion (percentage)
Time frame: Over 24 months of patient follow-up
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