SHERLOCK models perturbation effects as structured interventions on a latent state, recovering pathway relationships and predicting combinatorial effects across CRISPR, chemical, and spatial perturbation data
The authors present SHERLOCK, an interpretable deep generative framework that represents genetic and pharmacological perturbations as structured interventions on a latent baseline cellular state, learns correlated and sparse perturbation representations, enables counterfactual estimation of downstream transcriptional effects under explicit identifiability assumptions, quantifies condition-dependent responses, and compositionally models combinatorial perturbations; across genome-scale CRISPR, chemical, and spatial perturbation datasets, it recovers perturbation relationships concordant with known biological pathways and pharmacological properties, identifies condition-dependent responses, and predicts combinatorial perturbation effects.