用对抗网络去除癌种来源信号,更准识别影响生存的通用基因特征。
Domain-Adversarial Neural Network and Explainable AI for Reducing Tissue-of-Origin Signal in Pan-cancer Mortality Classification
- 设计对抗神经网络,让模型忽略组织来源特征,聚焦生存相关信号。
- 层感知SHAP揭示了跨癌种的生存关联基因,优于传统方法。
- 适合做泛癌生存预测与可解释性分析的研究者参考。
癌种来源信号主导泛癌基因表达,常掩盖与患者生存相关的分子特征,导致模型过度拟合组织特异性模式而非生存相关信号,阻碍通用生物标志物发现。为此,我们基于TCGA RNA-seq数据训练域对抗神经网络(DANN),学习更少受组织偏倚、更关注生存的表征。识别组织无关的遗传特征是揭示核心癌症程序的关键。评估采用两种方式:(1) 标准SHAP,基于原始输入空间和DANN的死亡率分类器;(2) 层感知策略,应用于隐藏激活,包括原始激活的无监督流形与基于死亡率特异性SHAP值的有监督流形。标准SHAP仍受组织信号干扰,因其计算固有偏差。原始激活流形由高幅值激活主导,掩盖了细微的组织与死亡率相关信号。相比之下,层感知SHAP流形提供更优的低维表示,独立于激活强度,支持亚群分层及泛癌生存相关基因识别。
原文摘要 · Abstract (English)
Tissue-of-origin signals dominate pan-cancer gene expression, often obscuring molecular features linked to patient survival. This hampers the discovery of generalizable biomarkers, as models tend to overfit tissue-specific patterns rather than capture survival-relevant signals. To address this, we propose a Domain-Adversarial Neural Network (DANN) trained on TCGA RNA-seq data to learn representations less biased by tissue and more focused on survival. Identifying tissue-independent genetic profiles is key to revealing core cancer programs. We assess the DANN using: (1) Standard SHAP, based on the original input space and DANN's mortality classifier; (2) A layer-aware strategy applied to hidden activations, including an unsupervised manifold from raw activations and a supervised manifold from mortality-specific SHAP values. Standard SHAP remains confounded by tissue signals due to biases inherent in its computation. The raw activation manifold was dominated by high-magnitude activations, which masked subtle tissue and mortality-related signals. In contrast, the layer-aware SHAP manifold offers improved low-dimensional representations of both tissue and mortality signals, independent of activation strength, enabling subpopulation stratification and pan-cancer identification of survival-associated genes.
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