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解释图卷积神经网络决策:乳腺癌转移预测中与患者特异性相关的分子子网络。

Explaining decisions of graph convolutional neural networks: patient-specific molecular subnetworks responsible for metastasis prediction in breast cancer.

机构信息

Medical Bioinformatics, University Medical Center Göttingen, Göttingen, Germany.

Dept. of Medicine A (Hematology, Oncology, Hemostaseology and Pulmonology), University Hospital Münster, Münster, Germany.

出版信息

Genome Med. 2021 Mar 11;13(1):42. doi: 10.1186/s13073-021-00845-7.


DOI:10.1186/s13073-021-00845-7
PMID:33706810
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7953710/
Abstract

BACKGROUND: Contemporary deep learning approaches show cutting-edge performance in a variety of complex prediction tasks. Nonetheless, the application of deep learning in healthcare remains limited since deep learning methods are often considered as non-interpretable black-box models. However, the machine learning community made recent elaborations on interpretability methods explaining data point-specific decisions of deep learning techniques. We believe that such explanations can assist the need in personalized precision medicine decisions via explaining patient-specific predictions. METHODS: Layer-wise Relevance Propagation (LRP) is a technique to explain decisions of deep learning methods. It is widely used to interpret Convolutional Neural Networks (CNNs) applied on image data. Recently, CNNs started to extend towards non-Euclidean domains like graphs. Molecular networks are commonly represented as graphs detailing interactions between molecules. Gene expression data can be assigned to the vertices of these graphs. In other words, gene expression data can be structured by utilizing molecular network information as prior knowledge. Graph-CNNs can be applied to structured gene expression data, for example, to predict metastatic events in breast cancer. Therefore, there is a need for explanations showing which part of a molecular network is relevant for predicting an event, e.g., distant metastasis in cancer, for each individual patient. RESULTS: We extended the procedure of LRP to make it available for Graph-CNN and tested its applicability on a large breast cancer dataset. We present Graph Layer-wise Relevance Propagation (GLRP) as a new method to explain the decisions made by Graph-CNNs. We demonstrate a sanity check of the developed GLRP on a hand-written digits dataset and then apply the method on gene expression data. We show that GLRP provides patient-specific molecular subnetworks that largely agree with clinical knowledge and identify common as well as novel, and potentially druggable, drivers of tumor progression. CONCLUSIONS: The developed method could be potentially highly useful on interpreting classification results in the context of different omics data and prior knowledge molecular networks on the individual patient level, as for example in precision medicine approaches or a molecular tumor board.

摘要

背景: 当代深度学习方法在各种复杂的预测任务中表现出了领先水平。尽管如此,深度学习在医疗保健领域的应用仍然受到限制,因为深度学习方法通常被视为不可解释的黑盒模型。然而,机器学习社区最近对可解释性方法进行了详细阐述,解释了深度学习技术对数据点特定决策的影响。我们认为,通过解释患者特定的预测结果,可以为个性化精准医学决策提供帮助。

方法: 逐层关联传播(LRP)是一种用于解释深度学习方法决策的技术。它被广泛用于解释应用于图像数据的卷积神经网络(CNN)。最近,CNN 开始扩展到非欧几里得领域,如图。分子网络通常被表示为详细描述分子间相互作用的图。基因表达数据可以被分配到这些图的顶点上。换句话说,可以利用分子网络信息作为先验知识来对基因表达数据进行结构化处理。图卷积神经网络(Graph-CNN)可用于结构化基因表达数据,例如,预测乳腺癌中的转移事件。因此,需要有一种方法可以解释对于每个个体患者,哪些分子网络的部分与预测事件(例如癌症的远处转移)相关。

结果: 我们扩展了 LRP 的过程使其适用于 Graph-CNN,并在一个大型乳腺癌数据集上测试了它的适用性。我们提出了图逐层关联传播(GLRP)作为一种新的方法,用于解释 Graph-CNN 做出的决策。我们在手写数字数据集上对开发的 GLRP 进行了合理性检查,然后将该方法应用于基因表达数据。结果表明,GLRP 提供了患者特定的分子子网络,这些子网络与临床知识基本一致,并识别出常见的、新颖的、潜在可靶向的肿瘤进展驱动因素。

结论: 该方法在解释不同组学数据和个体患者分子网络先验知识背景下的分类结果方面具有潜在的重要作用,例如在精准医学方法或分子肿瘤委员会中。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a4d/7953710/5ba2decd0322/13073_2021_845_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a4d/7953710/a93518f1910e/13073_2021_845_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a4d/7953710/e6b90f47abf5/13073_2021_845_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a4d/7953710/7728302f232b/13073_2021_845_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a4d/7953710/5ba2decd0322/13073_2021_845_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a4d/7953710/a93518f1910e/13073_2021_845_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a4d/7953710/e6b90f47abf5/13073_2021_845_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a4d/7953710/7728302f232b/13073_2021_845_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a4d/7953710/5ba2decd0322/13073_2021_845_Fig4_HTML.jpg

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引用本文的文献

[1]
Gene expression inference based on graph neural networks using L1000 data.

Brief Bioinform. 2025-5-1

[2]
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Am J Med Genet B Neuropsychiatr Genet. 2025-9

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Strategies to include prior knowledge in omics analysis with deep neural networks.

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[4]
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Multimodal data integration in early-stage breast cancer.

Breast. 2025-4

[7]
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Cancer Innov. 2024-7-3

[8]
Designing interpretable deep learning applications for functional genomics: a quantitative analysis.

Brief Bioinform. 2024-7-25

[9]
Deep Learning of radiology-genomics integration for computational oncology: A mini review.

Comput Struct Biotechnol J. 2024-6-20

[10]
Smart Biosensor for Breast Cancer Survival Prediction Based on Multi-View Multi-Way Graph Learning.

Sensors (Basel). 2024-5-21

本文引用的文献

[1]
GNNExplainer: Generating Explanations for Graph Neural Networks.

Adv Neural Inf Process Syst. 2019-12

[2]
Utilizing Molecular Network Information via Graph Convolutional Neural Networks to Predict Metastatic Event in Breast Cancer.

Stud Health Technol Inform. 2019-9-3

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Cancer Discov. 2019-7-8

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Oncol Lett. 2019-1

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