Application of IATA - A case study in evaluating the global and local performance of a Bayesian network model for skin sensitization.

The information characterizing key events in an Adverse Outcome Pathway (AOP) can be generated from in silico, in chemico, in vitro and in vivo approaches. Integration of this information and interpretation for decision making are known as integrated approaches to testing and assessment (IATA). One such IATA was published by Jaworska et al., which describes a Bayesian network model known as ITS-2. The current work evaluated the performance of ITS-2 using a stratified cross-validation approach. We also characterized the impact of replacing the most significant component of the network, output from the expert system TIMES-SS, with structural alert information from the OECD Toolbox and Toxtree. Lack of structural alerts or TIMES-SS predictions yielded a sensitization potential prediction of 79%. If the TIMES-SS prediction was replaced by a structural alert indicator, the network predictivity increased up to 87%. The original network's predictivity was 89%. The local applicability domain of the original ITS-2 network was also evaluated using reaction mechanistic domains to understand what types of chemicals ITS-2 was able to make the best predictions for. We found that the original network was successful at predicting which chemicals would be sensitizers, but not at predicting their potency.