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arXiv · 2602.10152

Validating Interpretability in siRNA Efficacy Prediction: A Perturbation-Based, Dataset-Aware Protocol

Zahra Khodagholi·Niloofar Yousefi
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Abstract

Saliency maps are increasingly used as design guidance in siRNA efficacy prediction, yet attribution methods are rarely validated before motivating sequence edits. We introduce a pre-synthesis gate: a protocol for counterfactual sensitivity faithfulness that tests whether mutating high-saliency positions changes model output more than composition-matched controls. Cross-dataset transfer reveals two failure modes that would otherwise go undetected: faithful-but-wrong (saliency valid, predictions fail) and inverted saliency (top-saliency edits less impactful than random). Strikingly, models trained on mRNA-level assays collapse on a luciferase reporter dataset, demonstrating that protocol shifts can silently invalidate deployment. Across four benchmarks, 19/20 fold instances pass; the single failure shows inverted saliency. A biology-informed regularizer (BioPrior) strengthens saliency faithfulness with modest, dataset-dependent predictive trade-offs. Our results establish saliency validation as essential pre-deployment practice for explanation-guided therapeutic design. Code is available at https://github.com/shadi97kh/BioPrior.

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Zahra Khodagholi, Niloofar Yousefi. 2026-03-06. Validating Interpretability in siRNA Efficacy Prediction: A Perturbation-Based, Dataset-Aware Protocol. https://arxiv.org/abs/2602.10152

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