提出SVC-Probe框架,检验细胞空间模型对药物扰动的泛化能力。
SVC-Probe: A Framework for Evaluating Perturbation Generalization in Spatial Foundation-Model Embeddings
- 用三重指标评估嵌入稳定性、邻域重构与中心点预测。
- 98.6%分类准确率下跨药预测性能骤降,余弦相似度从0.944降至0.30。
- 可诊断模型是否真正理解药物机制,适合生物医学表征研究者。
本文研究基于荧光显微图像的空间基础模型嵌入在药物扰动下的泛化能力。尽管这些模型能精准区分药物条件,但其学习到的表示是否反映预期扰动轴并跨药物迁移仍不明确。我们提出SVC-Probe框架,结合亚细胞嵌入图谱稳定性、Mondrian邻域图和基础模型扰动探测器,评估嵌入稳定性、邻域重连与中心点预测在药物处理下的表现。该框架应用于包含462个抗体标记和1536维嵌入的CM4AI MDA-MB-468化学扰动图谱,结果显示:98.6%的三类条件分类准确率与跨药预测可靠性无关联,余弦相似度在留一药测试中从域内0.944降至0.30,仅构成双药压力测试而非通用基准。空模型校准表明,原始残差流转耦合主要受通用嵌入结构影响;而伏立诺特(vorinostat)下出现药物特异性信号,与染色质重组一致;紫杉醇(paclitaxel)轴则未稳健重建,可能因微管相关蛋白覆盖稀疏。结果表明,该框架可复用诊断空间虚拟细胞表示的抗压能力,提示扰动泛化或为比基线分类更严格、更有信息量的评估标准。
原文摘要 · Abstract (English)
This work examines perturbation generalization in spatial foundation-model embeddings derived from fluorescence microscopy images. Although these models can discriminate drug conditions accurately, it remains unclear whether the learned representations reflect patterns consistent with expected perturbation axes that transfer across drugs. We introduce SVC-Probe, a perturbation-aware framework that combines Subcellular Embedding Atlas Stability, Mondrian Neighborhood Graphs, and a Foundation Model Perturbation Probe to assess embedding stability, neighborhood rewiring, and centroid prediction under drug treatment. Applied to the CM4AI MDA-MB-468 chemical-perturbation atlas comprising 462 antibody labels and SubCell 1536-dimensional embeddings, SVC-Probe demonstrates that 98.6% three-way condition accuracy does not correlate with reliable cross-drug prediction, with cosine similarity diminishing from 0.944 in-domain to 0.30 under leave-one-drug-out evaluation, constituting a two-drug stress test rather than a general benchmark. Null calibration indicates that raw residual-turnover coupling is largely influenced by generic embedding structure, whereas a drug-specific signal emerges under vorinostat and is consistent with chromatin-related reorganization. In contrast, the paclitaxel axis is not robustly reconstructed, likely due to sparse coverage of microtubule-associated proteins. Together, these results introduce and demonstrate a reusable diagnostic framework for stress-testing spatial virtual-cell representations and indicate that perturbation generalization may serve as a stricter and more informative benchmark than baseline condition discrimination.
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