Benchmarking Transcriptomics Foundation Models for Perturbation Analysis : one PCA still rules them all

Understanding the relationships among genes, compounds, and their interactions in living organisms remains limited due to technological constraints and the complexity of biological data. Deep learning has shown promise in exploring these relationships using various data types. However, transcriptomics, which provides detailed insights into cellular states, is still underused due to its high noise levels and limited data availability. Recent advancements in transcriptomics sequencing provide new opportunities to uncover valuable insights, especially with the rise of many new foundation models for transcriptomics, yet no benchmark has been made to robustly evaluate the effectiveness of these rising models for perturbation analysis. This article presents a novel biologically motivated evaluation framework and a hierarchy of perturbation analysis tasks for comparing the performance of pretrained foundation models to each other and to more classical techniques of learning from transcriptomics data. We compile diverse public datasets from different sequencing techniques and cell lines to assess models performance. Our approach identifies scVI and PCA to be far better suited models for understanding biological perturbations in comparison to existing foundation models, especially in their application in real-world scenarios.

Automated Discovery of Pairwise Interactions from Unstructured Data

Pairwise interactions between perturbations to a system can provide evidence for the causal dependencies of the underlying underlying mechanisms of a system. When observations are low dimensional, hand crafted measurements, detecting interactions amounts to simple statistical tests, but it is not obvious how to detect interactions between perturbations affecting latent variables. We derive two interaction tests that are based on pairwise interventions, and show how these tests can be integrated into an active learning pipeline to efficiently discover pairwise interactions between perturbations. We illustrate the value of these tests in the context of biology, where pairwise perturbation experiments are frequently used to reveal interactions that are not observable from any single perturbation. Our tests can be run on unstructured data, such as the pixels in an image, which enables a more general notion of interaction than typical cell viability experiments, and can be run on cheaper experimental assays. We validate on several synthetic and real biological experiments that our tests are able to identify interacting pairs effectively. We evaluate our approach on a real biological experiment where we knocked out 50 pairs of genes and measured the effect with microscopy images. We show that we are able to recover significantly more known biological interactions than random search and standard active learning baselines.