When label-free morphology is sufficient for targeted cellular measurements

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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BibTeX RIS

BibTeX

@misc{li2026when,
  title = {{When label-free morphology is sufficient for targeted cellular measurements}},
  author = {M. Li and J. Zhu and B. Li and C. Zhang and Z. Tang and J. Wang and W. Xing and B. Zhang and J. Xu and L. Meng and B. Zhang and J. Chen and R. Zhang and L. Zhang and J. Xu},
  howpublished = {bioRxiv},
  year = {2026},
  month = sep,
  doi = {10.64898/2026.09.22.753654},
  url = {https://www.biorxiv.org/content/10.64898/2026.09.22.753654v1},
  note = {CC BY},
}

RIS

TY  - UNPB
TI  - When label-free morphology is sufficient for targeted cellular measurements
AU  - M. Li
AU  - J. Zhu
AU  - B. Li
AU  - C. Zhang
AU  - Z. Tang
AU  - J. Wang
AU  - W. Xing
AU  - B. Zhang
AU  - J. Xu
AU  - L. Meng
AU  - B. Zhang
AU  - J. Chen
AU  - R. Zhang
AU  - L. Zhang
AU  - J. Xu
PY  - 2026
DA  - 2026/09/22
PB  - bioRxiv
DO  - 10.64898/2026.09.22.753654
UR  - https://www.biorxiv.org/content/10.64898/2026.09.22.753654v1
AB  - 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.
ER  -

Abstract

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