Fifteen-year population attributable fractions and causal pies of risk factors for newly developed hepatocellular carcinomas in 11,801 men in Taiwan

Abstract

Development of hepatocellular carcinoma (HCC) is a multi-factorial process. Chronic infections with hepatitis B virus (HBV) and hepatitis C virus (HCV) are important risk factors of HCC. Host factors, such as alcohol drinking, may also play a role. This study aims to provide a synthesis view on the development of HCC by examining multiple risk factors jointly and collectively. Causal-pie modeling technique was applied to analyze a cohort of 11,801 male residents (followed up for 15 years) in Taiwan, during which a total of 298 incident HCC cases were ascertained. The rate ratios adjusted by age were further modeled by an additive Poisson regression. Population attributable fractions (PAFs) and causal-pie weights (CPWs) were calculated. A PAF indicates the magnitude of case-load reduction under a particular intervention scenario, whereas a CPW for a particular class of causal pies represents the proportion of HCC cases attributable to that class. Using PAF we observed a chance to reduce around 60% HCC risk moving from no HBV-related intervention to the total elimination of the virus. An additional ∼15% (or ∼5%) reduction can be expected, if the HBV-related intervention is coupled with an HCV-related intervention (or an anti-drinking campaign). Eight classes of causal pies were found to be significant, including four dose-response classes of HBV (total CPW=52.7%), one independent-effect class of HCV (CPW=14.4%), one HBV-alcohol interaction class (CPW=4.2%), one HBV-HCV interaction class (CPW=1.7%), and one all-unknown class (CPW=27.0%). Causal-pie modeling for HCC helps clarify the relative importance of each viral and host factor, as well as their interactions.

Figure 1. Causal pies and causal-pie weights for a hypothetical example.

Four possible classes of causal pies for two hypothetical binary risk factors, A and B, in disease causation. The numbers shown below the pies are the causal-pie weights.

Figure 2. Population attributable fractions under various intervention strategies.

Figure 3. Causal-pie weights and the bootstrapped 95% confidence intervals for newly-developed hepatocellular carcinoma.

A total of eight classes of causal pies (U: unmeasured factors) are presented. The eight pies are grouped into three intersecting sets (the dotted circles).