The Delta Gap: Cellular World Models for Perturbation Response Prediction Are Far Harder Than Global Correlation Implies

원문 초록

Cellular world models aim to predict how cells respond to genetic perturbations, analogous to world models in reinforcement learning. Perturbation response models are evaluated almost exclusively by global Pearson correlation between predicted and observed transcriptomes. We show this metric is dominated by thousands of non-responsive genes and severely inflates apparent performance. On the Replogle K562 screen (509 unseen perturbations, 5000 genes), GEARS achieves global Pearson 0.977, but its delta Pearson is only 0.076. A trivial baseline predicting mean training delta achieves 0.267, which is 3.5x better than GEARS. Our primary contribution is methodological: we identify and quantify this delta gap as a systematic evaluation artifact, and propose delta-space evaluation as the primary benchmark. We provide two post-hoc corrections (RWR on co-expression graphs and kNN matching) and show that 2.8x of the remaining gap lies in perturbation representation geometry, not decoder capacity. We further show the gap is partially addressable end-to-end: delta-aligned training (lambda = 3.0) raises delta Pearson to 0.179 on Replogle (2.35x over GEARS) and surpasses the trivial baseline on direction accuracy (0.680 vs 0.567) and gene recovery (1.52 vs 1.19); combined with kNN it reaches 0.217. An amplitude-calibration variant (eta = 0.3) further raises gene recovery to 2.16 while reaching 0.218. Critically, these representations transfer zero-shot across cell lines: from Replogle K562 to unseen Norman A549, the delta-aligned model reaches 0.328 on 741 shared genes, 4.7x a trivial baseline and 2.1x standard GEARS. This is the first systematic quantification of the delta gap, and the first diagnostic framework localizing the residual gap to perturbation representation geometry via an oracle upper bound.