When label-free morphology is sufficient for targeted cellular measurements
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.
Show 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.
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