Plate design confounds donor variation and model evaluation in single-cell perturbation screens

In a 90-cytokine single-cell immune-cell perturbation screen, well effects explain most replicate-control variation in abundant cell types, and identical control wells differ by hundreds of differentially expressed genes.

• Why it matters: Donor-to-donor differences and shared plate layouts can make technical artifacts appear biological, undermining how response models are benchmarked and interpreted.
• What they did: The study analyzed a 90-cytokine screen plus two compound screens across four cohorts and simulations, comparing replicate controls and evaluating models with design-aware estimators and perturbation-specific scoring.
• The result: Design-aware evaluation changes interpretation of four recent analyses, and a deep-learning model outperforms a baseline on perturbation-specific differences in two of three cell types, while predicting the component shared with inert wells less well.

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