Cause-excluded Effect Evaluation: a framework for the faithful assessment of genetic perturbation target identification

Abstract

Identifying which gene drives a desired cell-state transition is a foundational inverse problem in target discovery and cell-state engineering, yet far less developed than forward prediction. We show that prevailing benchmarks inflate performance through two artefacts: training leakage, where test-perturbation cells are seen during fitting, and evaluation leakage, where the perturbed gene's own expression change exposes the answer. Here, we introduce Cause-excluded Effect Evaluation (CEE), a framework that separates train and test perturbation targets, removes target-gene self-effects from expression profiles and scores candidates in downstream response space. With CEE, we find that simple structure-based methods consistently outperform complex deep learning models across 16 single-cell perturbation datasets, revealing that the recoverable signal is governed by low-rank and additive structure in perturbation responses rather than by model complexity. Our work disentangles evaluation artefacts from genuine predictive capacity and offers a design principle for developing perturbation target identification methods.