A split-control criterion for few-shot adaptation in single-cell perturbation prediction

Liang, W.-L.; Yang, Y.-B.; Zhang, Q.-Y.; Feng, J.-C.; Wang, Q.-F.; Zou, D.; Tang, J.-L.; Liu, Y.; Wang, S.-Y.; Duan, J.; Bai, Y.; Li, Y.-F.; Sun, W.-Y.; Cao, Y.-F.; He, R.-R.

doi:10.64898/2026.10.05.756906

bioRxiv · 10.64898/2026.10.05.756906

A split-control criterion for few-shot adaptation in single-cell perturbation prediction

Liang, W.-L.·Yang, Y.-B.·Zhang, Q.-Y.·Feng, J.-C.·Wang, Q.-F.·Zou, D.·Tang, J.-L.·Liu, Y.·Wang, S.-Y.·Duan, J.·Bai, Y.·Li, Y.-F.·Sun, W.-Y.·Cao, Y.-F.·He, R.-R.

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Abstract

Few-shot adaptation can help or harm single-cell perturbation prediction, but conventional evaluation shares a control estimate between calibration responses and held-out targets. We show how methods carry control error into their predictions and derive its contribution to score inflation. Nested control-depth experiments support inverse-depth scaling of inner-product inflation; correlation inflation also depends on the control noise-to-signal ratio. Independent-control scoring changed the rank of 40 of 52 configuration-dataset entries. We introduce SafeDelta, a split-control criterion that uses calibration data to decide whether to adapt. Across six datasets, mean gated gain was non-negative under the original two-control evaluation. On a deep plate, fixed predictions and decisions retained positive mean gains under three additional independent control references. The same reproducibility principle identified a fibrosis programme that localises to scar in human liver. These results inform adaptation decisions and control-depth planning.

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Liang, W.-L., Yang, Y.-B., Zhang, Q.-Y., Feng, J.-C., Wang, Q.-F., Zou, D., Tang, J.-L., Liu, Y., Wang, S.-Y., Duan, J., Bai, Y., Li, Y.-F., Sun, W.-Y., Cao, Y.-F., He, R.-R.. 2026-10-13. A split-control criterion for few-shot adaptation in single-cell perturbation prediction. https://doi.org/10.64898/2026.10.05.756906

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