CODEX: COunterfactual Deep learning for thein-silicoEXploration of cancer cell line perturbations

Abstract

MotivationHigh-throughput screens (HTS) provide a powerful tool to decipher the causal effects of chemical and genetic perturbations on cancer cell lines. Their ability to evaluate a wide spectrum of interventions, from single drugs to intricate drug combinations and CRISPR-interference, has established them as an invaluable resource for the development of novel therapeutic approaches. Nevertheless, the combinatorial complexity of potential interventions makes a comprehensive exploration intractable. Hence, prioritizing interventions for further experimental investigation becomes of utmost importance.ResultsWe propose CODEX as a general framework for the causal modeling of HTS data, linking perturbations to their downstream consequences. CODEX relies on a stringent causal modeling strategy based on counterfactual reasoning. As such, CODEX predicts drug-specific cellular responses, comprising cell survival and molecular alterations, and facilitates thein-silicoexploration of drug combinations. This is achieved for both bulk and single-cell HTS. We further show that CODEX provides a rationale to explore complex genetic modifications from CRISPR-interferencein silicoin single cells.Availability and ImplementationOur implementation of CODEX is publicly available athttps://github.com/sschrod/CODEX. All data used in this article are publicly available.