Comparing Explanations of Molecular Machine Learning Models Generated with Different Methods for the Calculation of Shapley Values

Feature attribution methods from explainable artificial intelligence (XAI) provide explanations of machine learning models by quantifying feature importance for predictions of test instances. While features determining individual predictions have frequently been identified in machine learning applications, the consistency of feature importance-based explanations of machine learning models using different attribution methods has not been thoroughly investigated. We have systematically compared model explanations in molecular machine learning. Therefore, a test system of highly accurate compound activity predictions for different targets using different machine learning methods was generated. For these predictions, explanations were computed using methodological variants of the Shapley value formalism, a popular feature attribution approach in machine learning adapted from game theory. Predictions of each model were assessed using a model-agnostic and model-specific Shapley value-based method. The resulting feature importance distributions were characterized and compared by a global statistical analysis using diverse measures. Unexpectedly, methodological variants for Shapley value calculations yielded distinct feature importance distributions for highly accurate predictions. There was only little agreement between alternative model explanations. Our findings suggest that feature importance-based explanations of machine learning predictions should include an assessment of consistency using alternative methods.