Score Distributions, Not Cells: Evaluating Single-Cell Perturbations Under Class Overlap

Youssef Marrakchi, Davide D'Ascenzo, Sebastiano Cultrera di Montesano

Most classification problems assume the classes are roughly separable, so that an individual sample can usually be assigned to one class. Single-cell perturbation data violates this assumption: two perturbations can produce different populations of cells while overlapping so much that an individual cell could belong to either. Per-cell accuracy then measures this overlap rather than model quality. We see this on Tahoe-100M and the Virtual Cell Challenge, where a linear classifier, an MLP, and a Transformer all plateau near macro-F1 0.2-0.3 even though almost every pair of perturbations is statistically distinguishable. The fix is to score perturbations across the whole population rather than cell by cell. We average a classifier's per-cell probability vectors over all cells of a perturbation to form a population profile, then rank candidate perturbations by this profile; we call the resulting score the Classifier Discrimination Score (CDS). Taking the top-ranked class recovers the winning perturbation. It needs no retraining, costs linear time in the number of cells, and recovers near-perfect identification from the same weak models. CDS differs from the pseudobulk-based Perturbation Discrimination Score (PDS) used in recent benchmarks only in where the average is taken, raw gene expression for PDS versus a learned discriminative space for CDS, and identifies the true perturbation more reliably on both datasets, with the gap widening as cells grow scarce. Because a metric that misranks the ground truth will misrank the models scored against it, per-cell accuracy and raw-pseudobulk scores should be used with caution when comparing perturbation models.