scCBGM: Interpretable Single-Cell Counterfactual Editing

Understanding cellular phenotypes and how they respond to perturbations is critical for disease biology and therapeutic design. Single-cell RNA sequencing enables characterization at cellular resolution, yet the combinatorial space of conditions makes exhaustive experimental mapping infeasible. We introduce single-cell Concept Bottleneck Generative Models (scCBGM), a framework for interpretable and precise counterfactual editing of individual cells. scCBGM adapts concept bottleneck architectures for single-cell data through decoder skip connections and a cross-covariance penalty that promotes disentanglement without dimensional constraints. We extend the framework to flow matching models, enabling concept-guided editing in both encoding-decoding and generation regimes. To enable rigorous evaluation, we develop a synthetic benchmark with ground-truth counterfactuals. Across multiple real datasets, scCBGM demonstrates superior performance in combinatorial generalization and counterfactual prediction, supported by cell-level validation on synthetic data and population-level benchmarks on real datasets.

Anomaly Classification with the Anti-Profile Support Vector Machine

We introduce the anti-profile Support Vector Machine (apSVM) as a novel algorithm to address the anomaly classification problem, an extension of anomaly detection where the goal is to distinguish data samples from a number of anomalous and heterogeneous classes based on their pattern of deviation from a normal stable class. We show that under heterogeneity assumptions defined here that the apSVM can be solved as the dual of a standard SVM with an indirect kernel that measures similarity of anomalous samples through similarity to the stable normal class. We characterize this indirect kernel as the inner product in a Reproducing Kernel Hilbert Space between representers that are projected to the subspace spanned by the representers of the normal samples. We show by simulation and application to cancer genomics datasets that the anti-profile SVM produces classifiers that are more accurate and stable than the standard SVM in the anomaly classification setting.