title: BRAID: A Unifying Paradigm for the Analysis of Combined Drug Action.
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.
authors.affiliation: Departments of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Nathaniel R
authors.initials: NR
authors.lastname: Twarog
authors.affiliation: Developmental Neurobiology St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Stewart
authors.affiliation: Departments of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Courtney Vowell
authors.initials: CV
authors.lastname: Hammill
authors.affiliation: Departments of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Anang A
authors.initials: AA
authors.lastname: Shelat
mesh_terms: D000465:Algorithms; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D003198:Computer Simulation; D066264:Datasets as Topic; D004336:Drug Antagonism; D004357:Drug Synergism; D004359:Drug Therapy, Combination / Q000009:adverse effects / Q000379:methods; D006801:Humans; D015233:Models, Statistical; D012512:Sarcoma, Ewing / Q000188:drug therapy; D016896:Treatment Outcome