A Bayesian approach to study synergistic interaction effects in in-vitro drug combination experiments

Abstract

In cancer translational research, increasing effort is devoted to the study of the combined effect of two drugs when they are administered simultaneously. In this paper, we introduce a new approach to estimate the part of the effect of the two drugs due to the interaction of the compounds, i.e. which is due to synergistic or antagonistic effects of the two drugs, compared to a reference value representing the condition when the combined compounds do not interact, called zero-interaction. We describe an in-vitro cell viability experiment as a random experiment, by interpreting cell viability as the probability of a cell in the experiment to be viable after treatment, and including information related to different exposure conditions. We propose a flexible Bayesian spline regression framework for modelling the viability surface of two drugs combined as a function of the concentrations. Since the proposed approach is based on a statistical model, it allows to include replicates of the experiments, to evaluate the uncertainty of the estimates, and to perform prediction. We test the model fit and prediction performance on a simulation study, and on an ovarian cancer cell dataset. Posterior estimates of the zero-interaction level and of the synergy term, obtained via adaptive MCMC algorithms, are used to compute interpretable measures of efficacy of the combined experiment, including relative volume under the surface (rVUS) measures to summarise the zero-interaction and synergy terms and a bi-variate alternative to the well-known EC50 measure.