Gene-Level Representation Learning via Interventional Style Transfer in Optical Pooled Screening

Optical pooled screening (OPS) combines automated microscopy and genetic perturbations to systematically study gene function in a scalable and cost-effective way. Leveraging the resulting data requires extracting biologically informative representations of cellular perturbation phenotypes from images. We employ a style-transfer approach to learn gene-level feature representations from images of genetically perturbed cells obtained via OPS. Our method outperforms widely used engineered features in clustering gene representations according to gene function, demonstrating its utility for uncovering latent biological relationships. This approach offers a promising alternative to investigate the role of genes in health and disease.

Weakly Supervised Set-Consistency Learning Improves Morphological Profiling of Single-Cell Images

Optical Pooled Screening (OPS) is a powerful tool combining high-content microscopy with genetic engineering to investigate gene function in disease. The characterization of high-content images remains an active area of research and is currently undergoing rapid innovation through the application of self-supervised learning and vision transformers. In this study, we propose a set-level consistency learning algorithm, Set-DINO, that combines self-supervised learning with weak supervision to improve learned representations of perturbation effects in single-cell images. Our method leverages the replicate structure of OPS experiments (i.e., cells undergoing the same genetic perturbation, both within and across batches) as a form of weak supervision. We conduct extensive experiments on a large-scale OPS dataset with more than 5000 genetic perturbations, and demonstrate that Set-DINO helps mitigate the impact of confounders and encodes more biologically meaningful information. In particular, Set-DINO recalls known biological relationships with higher accuracy compared to commonly used methods for morphological profiling, suggesting that it can generate more reliable insights from drug target discovery campaigns leveraging OPS.