用空间转录组验证病理大模型注意力,发现其关注的是多基因程序而非单个基因。
Do Foundation Models See Biology? Evaluating Attention Coherence with Spatial Transcriptomics in Glioblastoma

- 基于空间转录组设计无假设评估框架,定量检验注意力与生物学的关联性。
- 注意力在通路层面有五倍富集梯度,但对单个基因几乎不敏感(d=0.055)。
- 不同模型关注不同生物区域,提示需避免仅凭视觉平滑判断生物学可信度。
病理领域大模型的注意力机制是否反映真实生物学仍未知,而这直接影响临床信任与监管审批。本文提出一种基于空间转录组的正交、无假设评估框架,应用于五个病理大模型(CONCH v1.5、UNI v2、Virchow2、GigaPath、H-Optimus-1)和一个ResNet50基线。采用基于注意力的多实例学习,在CPTAC队列上训练单任务与多任务模型预测胶质母细胞瘤五种分子改变,并在独立TCGA队列上验证。通过18个样本的共注册Visium空间转录组数据,评估注意力图与87个转录谱的生物学一致性。内部表现中无单一编码器在所有任务上领先,外部验证则逆转了内部排名。注意力图在通路层面(Cohen's d=0.329)至基因层面(d=0.055)呈现五倍富集梯度,表明模型捕捉的是多基因转录程序而非个体分子事件。空间平滑的注意力并不等同于生物学相关性,不同编码器关注不同的生物区室。该框架提供客观量化评估,推动领域超越定性注意力图审查。
原文摘要 · Abstract (English)
Whether attention maps from pathology foundation models capture genuine biology remains unknown, yet this question is critical for clinical trust and regulatory approval. We propose a spatial transcriptomics-based framework for orthogonal, hypothesis-free evaluation of attention and apply it to five pathology foundation models (CONCH v1.5, UNI v2, Virchow2, GigaPath, H-Optimus-1) and a ResNet50 baseline. Using attention-based multiple instance learning, we train single-task and multi-task models to predict five molecular alterations in glioblastoma on the CPTAC cohort, validate on an independent TCGA cohort, and evaluate biological coherence of attention maps against 87 transcriptional signatures using co-registered Visium spatial transcriptomics data from 18 samples. Internally, no single encoder dominates across all tasks, and external validation inverts internal performance rankings. Attention maps show a five-fold enrichment gradient from pathways (Cohen's d=0.329) to individual genes (d=0.055), indicating that attention captures emergent multi-gene transcriptional programs rather than individual molecular events. Spatially smooth attention maps do not imply biological coherence, and different encoders attend to distinct biological compartments. Our framework provides objective, quantitative assessment of what foundation models learn from histopathology, moving the field beyond qualitative saliency map review.
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