BRAID: A Unifying Paradigm for the Analysis of Combined Drug Action

Sci Rep. 2016 May 10:6:25523. doi: 10.1038/srep25523.

Abstract

With combination therapies becoming increasingly vital to understanding and combatting disease, a reliable method for analyzing combined dose response is essential. The importance of combination studies both in basic and translational research necessitates a method that can be applied to a wide range of experimental and analytical conditions. However, despite increasing demand, no such unified method has materialized. Here we introduce the Bivariate Response to Additive Interacting Doses (BRAID) model, a response surface model that combines the simplicity and intuitiveness needed for basic interaction classifications with the versatility and depth needed to analyze a combined response in the context of pharmacological and toxicological constraints. We evaluate the model in a series of simulated combination experiments, a public combination dataset, and several experiments on Ewing's Sarcoma. The resulting interaction classifications are more consistent than those produced by traditional index methods, and show a strong relationship between compound mechanisms and nature of interaction. Furthermore, analysis of fitted response surfaces in the context of pharmacological constraints yields a more concrete prediction of combination efficacy that better agrees with in vivo evaluations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms*
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Computer Simulation
  • Datasets as Topic
  • Drug Antagonism
  • Drug Synergism
  • Drug Therapy, Combination* / adverse effects
  • Drug Therapy, Combination* / methods
  • Humans
  • Models, Statistical*
  • Sarcoma, Ewing / drug therapy
  • Treatment Outcome