Published online Dec 14, 2026. doi: 10.3748/wjg.121840
Revised: May 23, 2026
Accepted: June 4, 2026
Published online: December 14, 2026
Processing time: 200 Days and 20.7 Hours
The age-male-albumin-bilirubin-platelets score-based stepwise enrichment approach sequentially applies common biomarkers, alpha-fetoprotein (AFP), and circulating cell-free DNA (cfDNA), offering a cost- and performance-balanced framework for hepatocellular carcinoma (HCC) risk stratification.
To evaluate whether incorporating this approach into HCC screening is cost-effective for Chinese patients with compensated cirrhosis and identify the optimal combined strategy.
A Markov model was developed to evaluate 600 screening strategies combining whether to apply stratification with different screening frequencies and methods from the healthcare system perspective. Strategies were compared using incre
All three non-dominated strategies under the 3 × GDP threshold are risk-stratified. Screening with ultrasonography (US) + AFP quarterly for high-risk and annually for low-risk groups, and screening with quarterly alternating US + AFP/gadoxetic-enhanced magnetic resonance imaging (Gd-MRI) for high-risk and six-monthly US + AFP for low-risk groups, are the most cost-effective under the 1 × and 3 × GDP thresholds, respectively (ICER = United States dollar 11137/QALY and United States dollar 31507/QALY). Both strategies have the highest probabilities of being cost-effective at their corresponding thresholds (0.58 and 0.24) in probabilistic sensitivity analysis. Even if re-stratification is required every two years, an approximately 40% reduction in cfDNA testing costs allows both strategies to remain probabilistically optimal, particularly the former strategy.
Risk-stratified HCC screening using the stepwise enrichment approach is more cost-effective than unstratified screening for Chinese compensated cirrhosis patients, with US + AFP at varying frequencies for high- and low-risk groups being the optimal combination. Stratified screening involving alternating US + AFP/Gd-MRI may be optimal only under higher willingness-to-pay thresholds.
Core Tip: This study developed a Markov model to evaluate the cost-effectiveness of risk-stratified hepatocellular carcinoma screening using age-male-albumin-bilirubin-platelets score-based stepwise enrichment approach in compensated cirrhosis. A total of 600 screening strategies were evaluated, combining whether to apply stratification with different screening fre
- Citation: Zhang YB, Li YX, Zhang WD, Hou XB, Li R, Xia RY, Shen MW, Zou ZR, Zhuang GH. Cost-effectiveness of risk-stratified hepatocellular carcinoma screening using the age-male-albumin-bilirubin-platelets score-based stepwise enrichment approach in patients with cirrhosis. World J Gastroenterol 2026; 32(46): 121840
- URL: https://www.wjgnet.com/1007-9327/full/v32/i46/121840.htm
- DOI: https://dx.doi.org/10.3748/wjg.121840
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide. Although the overall prognosis of HCC remains poor, with a 5-year survival rate below 20%[1,2], patients detected at an early stage, such as Barcelona Clinic Liver Cancer (BCLC) stage 0 and A can achieve markedly higher 5-year survival rates of 69%-86% following curative treatment[3]. HCC can develop through various pathogenic pathways, but 80%-90% of cases arise in the setting of cirrhosis. Early HCC patients with compensated cirrhosis (CC) are eligible for curative treatment, making HCC screening in CC patients potentially the last opportunity for early detection and timely intervention throughout the development of HCC. Studies have demonstrated that HCC screening in patients with cirrhosis enhances early detection and improves survival outcomes[1], with favorable cost-effectiveness[4].
Current international and Chinese guidelines recommend semi-annual ultrasonography (US) combined with alpha-fetoprotein (AFP) test as the routine HCC screening strategy for patients with cirrhosis[5-8]. Guidelines from Japan and China also recommend enhanced imaging modalities including multiphasic contrast-enhanced computed tomography (CE-CT), multiphasic contrast-enhanced magnetic resonance imaging (CE-MRI), and gadoxetic-enhanced magnetic re
Recent years have witnessed rapid advancement in multiparametric biomarker-based prediction models, such as the platelet-age-gender-hepatitis B score, Toronto HCC risk index, and the age-male-albumin-bilirubin-platelets (aMAP) score, all of which have shown remarkable performance in stratifying HCC risk[15-18]. Notably, two novel aMAP scores, namely aMAP-2 and aMAP-2 plus were reported in 2023, exhibiting superior predictive performance over the original aMAP score and other existing models, particularly for HCC risk assessment in Chinese patients with cirrhosis[16]. aMAP-2 improves predictive accuracy by adding AFP into aMAP, while aMAP-2 plus achieves a substantial enhance
China bears the heaviest burden of cirrhosis, with 6.83 million cases accounting for 14.9% of the global total[19]. Limited healthcare resources further highlight the need for implementing HCC risk-stratified screening in the country. Accordingly, this study focuses on patients with CC and evaluates the cost-effectiveness of risk-stratified HCC screening based on the stepwise enrichment approach of aMAP scores, using routine unstratified screening as the comparator. Various screening frequencies and methods including the alternating use of two methods were also combined into screening strategies, considering their difference in cost, performance, and potential availability. The aim is to determine whether this risk-stratified HCC screening is cost-effective in Chinese CC patients and to identify the optimal (i.e., most cost-effective) combined strategy. The findings may provide important evidence to support the advancement of precision HCC screening in China and other comparable settings.
We conducted a model-based cost-effectiveness analysis from the healthcare system perspective. The model was developed using TreeAge Pro (version 2024, Williamstown, MA, United States) and the reporting adhered to the Consolidated Health Economic Evaluation Reporting Standards 2022 statement[20].
Screening strategies were designed by combining three factors. The first was whether risk stratification was applied, based on the stepwise enrichment approach that divides the target population into low- and high-risk groups. The subsequent factors were screening frequency (every 3 months, 6 months, or 12 months) and screening method (US + AFP, CE-CT, CE-MRI, or Gd-MRI alone, or alternating between two of these methods), determined according to Chinese and international guidelines and clinical feasibility (Supplementary Table 1)[5-11]. This resulted in a total of 600 combinations, comprising 576 stratified and 24 unstratified screening strategies. Given that the aMAP score includes the blood indices albumin, bilirubin, and platelet, with aMAP-2 adding AFP and aMAP-2 plus further incorporating cfDNA which may vary over time periodic testing of these indices for re-stratification was considered. An interval of once every three years was assumed, based on the median follow-up duration of participants in the study reporting the stepwise enrichment approach[16].
We developed a Markov model with a three-month cycle length to simulate disease progression in a hypothetical cohort of 100000 diagnosed CC patients aged 50 years, over a lifetime horizon (up to age 79, the average life expectancy in China). The cohort’s initial age was set consistent with the median age of participants in the study reporting the stepwise enrichment approach[16]. The model comprised eight health states, including a background death state that accounts for deaths from other causes in all states except for the state representing death from HCC or decompensated cirrhosis (DC) (Supplementary Figure 1). Following the BCLC staging system, stages 0 and A were defined as early HCC, and stages B to D as advanced HCC. Individuals in the CC state may progress to the early-HCC state without specific symptoms. Periodic screening may detect early HCC, but it would fail to identify rapidly progressing cases. Detected early-HCC cases are assumed to receive curative treatment immediately and subsequently enter the post-treatment (PT) early-HCC state. Individuals in the PT early-HCC state may experience HCC recurrence, and those with early recurrent HCC are assumed to receive curative treatment again if clinically detected in a timely manner, after which they enter the post-retreatment early-HCC state. To simplify the model, curative treatment was limited to liver resection (LR) and radiofrequency ablation (RFA), the predominant curative modalities in China, whereas liver transplantation was excluded due to the limited availability of donor organs in the face of the substantial burden of HCC and DC[21]. The diagnostic processes following different screening methods were defined for individuals in the CC and undetected early-HCC states based on current international and Chinese clinical guidelines[5,8], for estimating the associated costs (Supplementary Figure 2). For individuals in the CC state, false positives from screening (i.e., 1-specificity) were considered, but it was assumed that they could be completely excluded through subsequent diagnostic examinations. For individuals in the undetected early-HCC state, false negatives from screening (i.e., 1-sensitivity) were considered, leading to missed diagnoses, whereas positive results were assumed to be fully confirmed through subsequent diagnostic examinations.
Parameters for the stepwise enrichment approach were derived from the original published literature[16], as summarized in Table 1, including the proportions of individuals entering each stratification step, the final high- and low-risk distributions, and the group-specific quarterly transition probabilities from cirrhosis to HCC. The originally reported annual HCC incidence rates in participants with cirrhosis (0.8% and 12.5% for the low- and high-risk groups, respectively) were converted into the quarterly transition probabilities. Due to the absence of reported confidence intervals for these parameters, a ± 20% variation around the base-case value was assumed as the uncertainty interval (UI) for each proportion parameter. To conservatively estimate the performance of the stepwise enrichment approach, however, the base-case quarterly transition probability was only increased by 20% for the low-risk group and only decreased by 20% for the high-risk group to define the UIs.
| Parameter | Base-case value | Uncertainty interval | Distribution |
| Proportion of individuals entering each stratification step | |||
| First: AMAP assessment | 1 | ||
| Second: AMAP-2 assessment | 0.8953 | 0.7162-1 | Triangular (0.7162, 0.8953, 1) |
| Third: AMAP-2 plus assessment | 0.5094 | 0.4075-0.6113 | Triangular (0.4075, 0.5093, 0.6113) |
| Identified as high-risk | 0.2201 | 0.1761-0.2641 | Triangular (0.1761, 0.2201, 0.2641) |
| Remainder as low-risk | 0.7799 | 0.7359-0.8239 | Triangular (0.7359, 0.7799, 0.8239) |
| Quarterly transition probability from cirrhosis to HCC | |||
| Low-risk | 0.0020 | 0.0020-0.0024 | Triangular (0.0020, 0.0020, 0.0024) |
| High-risk | 0.0328 | 0.0263-0.0328 | Triangular (0.0263, 0.0328, 0.0328) |
Other transition probabilities between health states and their associated proportions were estimated through literature review (Supplementary Table 2). HCC recurrence probabilities following curative treatment were stratified by treatment modality (i.e., LR or RFA). The performance characteristics of screening methods including their sensitivities and specificities were obtained from two major meta-analyses specifically targeting patients with cirrhosis (Supplementary Table 3)[22,23]. The classification proportions in the diagnostic processes were derived from published literature (Supplementary Table 4). Age-specific background death rates were obtained from the China Population and Employ
Costs for testing the blood indices associated with the stepwise enrichment approach (excluding cfDNA), as well as for US, were estimated from the latest medical service price lists issued by various provincial and municipal governments. The cost of platelet testing was based on a complete blood count, while the costs of albumin and bilirubin testing were based on a routine liver function test. Median values were adopted as base-case estimates, with the lowest and highest values defining the UIs. The cost of cfDNA testing was determined according to prevailing market prices in China. Costs for other imaging modalities (CE-CT, CE-MRI, and Gd-MRI), liver biopsy, and curative treatments (LR and RFA) were derived from a published economic study on HCC diagnosis and treatment in China[24]. Additionally, annual routine management costs for individuals in different health states were estimated based on published literature from China and prorated to quarterly costs (see Supplementary Table 5 for details of all cost estimates). Costs were converted from Chinese yuan to United States dollars using the 2024 exchange rate (1 United States dollar = 7.1217 Chinese yuan).
Utility estimates for the model’s health states were determined based on published health-related quality of life surveys and economic evaluations involving Chinese populations (Supplementary Table 6). In the model, the distribution of each parameter was determined based on its inherent property and the supporting data available. Both internal and external validations were conducted, and the results demonstrated that the model is reliable (Supplementary material).
Expected quality-adjusted life-years (QALYs) and costs were calculated by the model for each strategy. Results were compared across strategies, and the resulting incremental cost-effectiveness ratios (ICERs) defined as additional costs per QALY gained were used to determine whether one strategy is more cost-effective than another. One-time and three-times China’s per-capita gross domestic product (GDP) were adopted as willingness-to-pay (WTP) thresholds per QALY gained[25], due to the absence of an established threshold in China. China’s per-capita GDP was United States dollar 13445 in 2024. Both costs and QALYs were discounted to 2024 at an annual rate of 3% (UI: 0%-8%)[26].
Univariate sensitivity analysis was performed on all parameters within their UIs to identify key drivers of the model outcomes. Probabilistic sensitivity analysis was conducted using 5000 simulations to assess the robustness of the base-case results. Additionally, given the potential uncertainty in the temporal variation of blood indices associated with the stepwise enrichment approach and the expected reduction in cfDNA test costs with technological advances and broader utilization, we evaluated the cost-effectiveness of screening strategies under varying intervals of periodic testing for re-stratification and under a cfDNA test cost-reduction scenario.
As shown in Figure 1, among all 600 screening strategies evaluated, seven lie on the cost-effectiveness frontier and are identified as non-dominated strategies (for details, see Supplementary Table 7). Among these, stratified screening with US + AFP quarterly for high-risk and annually for low-risk groups is the most cost-effective strategy under the WTP threshold of one-time per-capita GDP, with an ICER of United States dollar 11137/QALY compared with the next most effective non-dominated strategy. Under the WTP threshold of three-times per-capita GDP, stratified screening with quarterly alternating US + AFP/Gd-MRI for high-risk and six-monthly US + AFP for low-risk groups is the most cost-effective strategy, with an ICER of United States dollar 31507/QALY compared with stratified screening with US + AFP quarterly for high-risk and six-monthly for low-risk groups. Although there are three strategies with increasing health benefits, including unstratified quarterly US + AFP screening, their ICERs are substantially higher than the three-times per-capita GDP threshold due to the additional costs required.
Figure 2 illustrates the probabilistic decision uncertainty across the full WTP spectrum. When the WTP threshold is below United States dollar 12014/QALY, unstratified annual US + AFP screening has the highest probability of being cost-effective among all strategies. As the threshold increases beyond this value, stratified screening with US + AFP quarterly for high-risk and annually for low-risk groups becomes the optimal strategy, achieving a probability of being cost-effective of 0.58 at the one-time per-capita GDP threshold and maintaining the highest probability up to a threshold of United States dollar 31800. With further increases in the threshold, stratified screening with US + AFP quarterly for high-risk and six-monthly for low-risk groups may have the highest probability of being cost-effective, but only within a very narrow range of threshold values. Beyond this range, stratified screening with quarterly alternating US + AFP/Gd-MRI for high-risk and six-monthly US + AFP for low-risk groups would become the optimal strategy and maintain the highest probability of being cost-effective through the three-times per-capita GDP threshold. However, the probability at this threshold remains low (0.24), indicating substantial uncertainty regarding this optimal selection.
Only a limited number of parameters are identified as potentially influencing the selection of the optimal strategy when they vary independently within their respective UIs (Supplementary Table 8), including the transition probability from cirrhosis to HCC in the low-risk group, the transition probability from early HCC to advanced HCC, and the cost of Gd-MRI. However, under the WTP threshold of one-time per-capita GDP, only uncertainty in the transition probability from early HCC to advanced HCC is found to affect the optimal strategy identified in the base-case analysis.
As shown in Figure 3, if periodic re-stratification testing is required to be conducted at a two-year interval, stratified screening with US + AFP quarterly for high-risk and annually for low-risk groups still has the highest probability of being cost-effective (0.45) at the WTP threshold of one-time per-capita GDP, but this probability is only slightly higher than that of unstratified annual US + AFP screening. However, under the three-times per-capita GDP threshold, un
As shown in Figure 4, even if periodic re-stratification testing is required at a two-year interval, as long as cfDNA testing costs decrease to a certain extent for example, by 40% from the base-case value stratified screening with quarterly alternating US + AFP/Gd-MRI for high-risk and six-monthly US + AFP for low-risk groups may emerge as the optimal strategy. Moreover, as the reduction increases, the optimal strategies under both thresholds identified in the base-case analysis would be more robust.
This study finds that risk-stratified HCC screening using the aMAP score-based stepwise enrichment approach is more cost-effective than the current routine unstratified screening among patients with CC in China. Under the WTP threshold of three-times per-capita GDP, all three non-dominated strategies are risk-stratified screening strategies. Although unstratified quarterly US + AFP screening which increases screening frequency compared with the typically recom
How often the blood indices associated with the stepwise enrichment approach need to retested for re-stratification is a key factor that sensitively influences the choice of the optimal strategy. A three-year interval was assumed as the base-case value based on the study reporting the stepwise enrichment approach, and under this assumption, the results described above were obtained. The scenario analysis indicates that if periodic re-stratification testing is required every two years, unstratified quarterly US + AFP screening becomes the most cost-effective strategy under the three-times per-capita GDP threshold; however, stratified screening with US + AFP quarterly for high-risk and annually for low-risk groups remains as the most cost-effective strategy under the one-time per-capita GDP threshold, although with only a marginal probability advantage. Conversely, if re-stratification is required at intervals of three-year or longer, the optimal strategies identified in the base-case analysis are robust under both thresholds, particularly the optimal strategy under the one-time per-capita GDP threshold, which retains a substantial probability advantage. Therefore, the applicability of the aMAP score-based stepwise enrichment approach for risk-stratified screening largely depends on how long its stratification results remain reliably predictive.
Testing of cfDNA biomarkers has garnered increasing attention for early cancer screening. By incorporating cfDNA testing, the aMAP-2 plus score significantly enhances the predictive performance for HCC risk[16]. However, the current high cost of cfDNA testing limits its widespread adoption. The stepwise enrichment approach was specifically proposed to take advantage of cfDNA testing while keeping the overall cost of stratification under control. Our study predicted the potential impact of a reduction in cfDNA testing costs on the most cost-effective strategy. If cfDNA testing costs decrease by approximately 40% from the current level, even with periodic re-stratification testing every two years, stratified screening with quarterly alternating US + AFP/Gd-MRI for high-risk and six-monthly US + AFP for low-risk groups could become the optimal strategy under the three-times per-capita GDP threshold. Meanwhile, under the one-time per-capita GDP threshold, stratified screening with US + AFP quarterly for high-risk and annually for low-risk groups would maintain a substantial probability advantage as the optimal strategy. The results provide additional confidence in applying the aMAP score-based stepwise enrichment approach for risk-stratified screening.
Two previous studies have explored the cost-effectiveness of risk-stratified HCC screening using different biomarker-based scores in patients with CC[27,28]. One, from the United States[27], used either a 186-gene liver signature-based score, which included bilirubin and platelet, or an epidermal growth factor single-nucleotide polymorphism-based score, which included alkaline phosphatase and platelet. Another, from Australia[28], used the “Liver Outcome Score HCC”, which included alkaline phosphatase and α-2-macroglobulin. Both studies concluded that risk-stratified HCC screening is cost-effective compared with the current routine unstratified screening. However, neither study accounted for the potential need for periodic testing of associated blood indices for re-stratification, which could result in an overestimation of the cost-effectiveness of risk-stratified screening.
Our study has several limitations. First, as noted in the study reporting the stepwise enrichment approach[16], the aMAP score series were developed in Chinese patients with chronic liver diseases, the majority of whom had hepatitis B virus infection, and their performance needs to be further investigated in patients of other ethnicities and with different etiologies (e.g., metabolic dysfunction-associated fatty liver disease). Therefore, our results cannot be directly generalized to cirrhosis patients with other specific etiologies or from other ethnicities. Second, although the original study demon
In conclusion, risk-stratified HCC screening using the aMAP score-based stepwise enrichment approach is more cost-effective than the current routine unstratified screening in Chinese patients with CC, with US + AFP quarterly for high-risk and annually for low-risk groups being the most cost-effective strategy under the WTP threshold of one-time per-capita GDP. Stratified screening with quarterly alternating US + AFP/Gd-MRI for high-risk and six-monthly US + AFP for low-risk groups may be the most cost-effective strategy only under a higher WTP threshold. Substantially reducing cfDNA testing costs would ensure the robustness of the optimal strategies, even when periodic re-stratification testing is required every two years.
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