Deep-learning-based gene perturbation effect prediction does not yet outperform simple linear baselines

Recent research in deep-learning-based foundation models promises to learn representations of single-cell data that enable prediction of the effects of genetic perturbations. Here we compared five foundation models and two other deep learning models against deliberately simple baselines for predicting transcriptome changes after single or double perturbations. None outperformed the baselines, which highlights the importance of critical benchmarking in directing and evaluating method development. The analysis presented in this Brief Communication shows that, despite their complexity, current deep learning models do not outperform linear baselines in predicting gene perturbation effects, thus emphasizing the importance of further method development and thorough evaluation.