TY - JOUR

T1 - Prediction of drug combination effects with a minimal set of experiments

AU - Ianevski, Aleksandr

AU - Giri, Anil K.

AU - Gautam, Prson

AU - Kononov, Alexander

AU - Potdar, Swapnil

AU - Saarela, Jani

AU - Wennerberg, Krister

AU - Aittokallio, Tero

PY - 2019

Y1 - 2019

N2 - High-throughput drug combination screening provides a systematic strategy to discover unexpected combinatorial synergies in pre-clinical cell models. However, phenotypic combinatorial screening with multi-dose matrix assays is experimentally expensive, especially when the aim is to identify selective combination synergies across a large panel of cell lines or patient samples. Here, we implement DECREASE, an efficient machine learning model that requires only a limited set of pairwise dose–response measurements for accurate prediction of drug combination synergy in a given sample. Using a compendium of 23,595 drug combination matrices tested in various cancer cell lines and malaria and Ebola infection models, we demonstrate how cost-effective experimental designs with DECREASE capture almost the same degree of information for synergy and antagonism detection as the fully measured dose–response matrices. Measuring only the matrix diagonal provides an accurate and practical option for combinatorial screening. The minimal-input web implementation enables applications of DECREASE to both pre-clinical and translational studies.

AB - High-throughput drug combination screening provides a systematic strategy to discover unexpected combinatorial synergies in pre-clinical cell models. However, phenotypic combinatorial screening with multi-dose matrix assays is experimentally expensive, especially when the aim is to identify selective combination synergies across a large panel of cell lines or patient samples. Here, we implement DECREASE, an efficient machine learning model that requires only a limited set of pairwise dose–response measurements for accurate prediction of drug combination synergy in a given sample. Using a compendium of 23,595 drug combination matrices tested in various cancer cell lines and malaria and Ebola infection models, we demonstrate how cost-effective experimental designs with DECREASE capture almost the same degree of information for synergy and antagonism detection as the fully measured dose–response matrices. Measuring only the matrix diagonal provides an accurate and practical option for combinatorial screening. The minimal-input web implementation enables applications of DECREASE to both pre-clinical and translational studies.

U2 - 10.1038/s42256-019-0122-4

DO - 10.1038/s42256-019-0122-4

M3 - Journal article

C2 - 32368721

VL - 1

SP - 568

EP - 577

JO - Nature Machine Intelligence

JF - Nature Machine Intelligence

SN - 2522-5839

IS - 12

ER -