arXiv:2604.13256cs.LGcs.GR2026-04被引 1

通过反事实编辑提升T细胞受体结合预测的因果性,减少数据偏见影响。

Counterfactual Peptide Editing for Causal TCR--pMHC Binding Inference

  • 生成生物学合理的肽段反事实编辑,强制模型对非锚定位不变、锚定位敏感。
  • 在家族保留测试中达到0.831 AUROC,反事实一致性达0.724,捷径指数降低39.7%。
  • 适合需要可解释、鲁棒性高的免疫学建模研究者使用。

TCR-pMHC结合预测的神经模型易陷入捷径学习:利用训练数据中的虚假相关性(如肽段长度偏差或V基因共现),而非真实的结合界面。这导致在家族保留和距离感知评估下预测结果脆弱。本文提出反事实不变预测(CIP)训练框架,通过生成生物约束的反事实肽段编辑,强制模型在非锚定位编辑下保持预测不变,同时增强对MHC锚定位扰动的敏感性。CIP在基础分类器上引入两个辅助目标:(1) 不变性损失,惩罚非锚定位保守替换下的预测变化;(2) 对比损失,鼓励锚定位破坏时预测大幅改变。在经筛选的VDJdb-IEDB基准上,于家族保留、距离感知和随机划分下评估,CIP在家族保留协议下取得0.831 AUROC与0.724反事实一致性(CFC),相比无约束基线,捷径指数降低39.7%。消融实验表明,锚定位感知编辑生成是域外性能提升的主要驱动因素,为因果性TCR特异性建模提供实用方法。

原文摘要 · Abstract (English)

Neural models for TCR-pMHC binding prediction are susceptible to shortcut learning: they exploit spurious correlations in training data -- such as peptide length bias or V-gene co-occurrence -- rather than the physical binding interface. This renders predictions brittle under family-held-out and distance-aware evaluation, where such shortcuts do not transfer. We introduce \emph{Counterfactual Invariant Prediction} (CIP), a training framework that generates biologically constrained counterfactual peptide edits and enforces invariance to edits at non-anchor positions while amplifying sensitivity at MHC anchor residues. CIP augments the base classifier with two auxiliary objectives: (1) an invariance loss penalizing prediction changes under conservative non-anchor substitutions, and (2) a contrastive loss encouraging large prediction changes under anchor-position disruptions. Evaluated on a curated VDJdb-IEDB benchmark under family-held-out, distance-aware, and random splits, CIP achieves AUROC 0.831 and counterfactual consistency (CFC) 0.724 under the challenging family-held-out protocol -- a 39.7\% reduction in shortcut index relative to the unconstrained baseline. Ablations confirm that anchor-aware edit generation is the dominant driver of OOD gains, providing a practical recipe for causally-grounded TCR specificity modeling.

TCR预测反事实学习免疫建模

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