Predicting single-cell cellular responses to perturbations using cycle consistency learning

Phenotype-based drug screening emerges as a powerful approach for identifying compounds that actively interact with cells. Transcriptional and proteomic profiling of cell lines and individual cells provide insights into the cellular state alterations that occur at the molecular level in response to external perturbations, such as drugs or genetic manipulations. In this paper, we propose cycleCDR, a novel deep learning framework to predict cellular response to external perturbations. We leverage the autoencoder to map the unperturbed cellular states to a latent space, in which we postulate the effects of drug perturbations on cellular states follow a linear additive model. Next, we introduce the cycle consistency constraints to ensure that unperturbed cellular state subjected to drug perturbation in the latent space would produces the perturbed cellular state through the decoder. Conversely, removal of perturbations from the perturbed cellular states can restore the unperturbed cellular state. The cycle consistency constraints and linear modeling in the latent space enable to learn transferable representations of external perturbations, so that our model can generalize well to unseen drugs during training stage. We validate our model on four different types of datasets, including bulk transcriptional responses, bulk proteomic responses, and single-cell transcriptional responses to drug/gene perturbations. The experimental results demonstrate that our model consistently outperforms existing state-of-the-art methods, indicating our method is highly versatile and applicable to a wide range of scenarios. Availability and implementation: The source code is available at: https://github.com/hliulab/cycleCDR.