When label-free morphology is sufficient for targeted cellular measurements

Authors

Li, M., Zhu, J., Li, B., Zhang, C., Tang, Z., Wang, J., Xing, W., Zhang, B., Xu, J., Meng, L., Zhang, B., Chen, J., Zhang, R., Zhang, L., Xu, J.

Abstract

Label-free morphology captures cellular responses, but its ability to substitute for targeted cellular measurements depends on the intended use. We assess measurement sufficiency using nearly 10 million paired phase-reporter observations across 1,000 gene knockouts, 52 fluorescent reporters and 73 A549 screens. Ten predictors differed in recovery across held-out fields, genes and screens. Same-cell pairing controls identified reporter-state information beyond perturbation averages and measured covariates. Perturbation ranking often persisted despite reduced variation in predicted response magnitudes. Predictions of held-out knockout responses retained a median 79% of the strongest hits, whereas functional-term retention varied. Atlas-derived criteria identified 30 quantitative and 7 ranking proxies for a fixed ensemble, with reference reproducibility constraining interpretation. In independent primary-hepatocyte data, brightfield predictions prioritized 10 of the 11 compounds with the largest measured metabolic-activity losses among 217 held-out compounds. Measurement sufficiency therefore depends on target, predictor, context and scientific task, beyond predictive correlation alone.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 29 Sep 2026.

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