Locked Evaluation Surfaces: Transfer Failure and Sampling-Depth Entanglement in CRISPRi Perturbation-Effect Prediction

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arXiv:2608.00152v2 Announce Type: replace Abstract: Predicting how held-out target genes respond to CRISPRi perturbation, and whether such predictions transfer across biological screens, is hard to evaluate: a representation can be informative within one screen yet fail across screens, while endpoint definitions and design factors such as sampling depth differ between datasets. We evaluate a frozen Geneformer representation under a locked, pre-registered protocol, with heads and model selection frozen before test evaluation, external outcome labels withheld until final unblinding, and analysis-governing decisions fixed before the evaluations they govern. In-distribution on the Virtual Cell Challenge (VCC), the frozen representation carries measurable predictive information beyond a dimension-matched random-feature control (Delta R^2 = +0.1645, 95% CI [+0.1375, +0.1920]), satisfying the pre-registered informativeness gate required before interpreting transfer. It then fails zero-shot transfer on both external screens (Spearman rho = -0.139 and -0.267), lying below that control on each. Adding a predefined magnitude block improves the representation externally (Delta rho = +0.032 and +0.143) but does not rescue transfer: both remain negative. A pre-registered, count-adjusted max-response secondary is positively associated with the outcome on both screens; we report it as correlational and secondary, not as a recovered magnitude signal. Finally, the VCC endpoint is strongly sample-size associated: a count-only linear model reaches R^2 = +0.4325, versus +0.2589 for the four …

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