AbstractMotivationThere exists a range of different quantification frameworks to estimate the synergistic effect of drug combinations. The diversity and disagreement in estimates make it challenging to determine which combinations from a large drug screening should be proceeded with. Furthermore, the lack of accurate uncertainty quantification for those estimates precludes the choice of optimal drug combinations based on the most favourable synergistic effect.ResultsIn this work, we propose SynBa, a flexible Bayesian approach to estimate the uncertainty of the synergistic efficacy and potency of drug combinations, so that actionable decisions can be derived from the model outputs. The actionability is enabled by incorporating the Hill equation into SynBa, so that the parameters representing the potency and the efficacy can be preserved. Existing knowledge may be conveniently inserted due to the flexibility of the prior, as shown by the empirical Beta prior defined for the normalized maximal inhibition. Through experiments on large combination screenings and comparison against benchmark methods, we show that SynBa provides improved accuracy of dose–response predictions and better-calibrated uncertainty estimation for the parameters and the predictions.Availability and implementationThe code for SynBa is available athttps://github.com/HaotingZhang1/SynBa. The datasets are publicly available (DOI of DREAM:10.7303/syn4231880; DOI of the NCI-ALMANAC subset: 10.5281/zenodo.4135059).