论文标题

Graphix:基于图XAI的图形(可解释的人工智能),用于从生物制药网络中重新定位药物

GraphIX: Graph-based In silico XAI(explainable artificial intelligence) for drug repositioning from biopharmaceutical network

论文作者

Takagi, Atsuko, Kamada, Mayumi, Hamatani, Eri, Kojima, Ryosuke, Okuno, Yasushi

论文摘要

药物重新定位具有巨大的希望,因为它可以减少新药开发的时间和成本。尽管药物重新定位可以忽略各种研发过程,但确认对生物分子的药理作用对于应用新疾病至关重要。药物重新定位模型中的生物医学解释性可以支持随后的深入研究中的适当见解。但是,XAI方法论的有效性仍在争论中,XAI在药物重新定位预测应用中的有效性尚不清楚。在这项研究中,我们提出了Graphix,这是一种使用生物网络的可解释的药物重新定位框架,并定量评估其解释性。 Graphix首先使用已知药物指示和知识图的图神经网络学习网络权重和节点特征,该图是由三种类型的节点组成(但没有给出的节点类型信息):疾病,药物和蛋白质。对学习后特征的分析表明,模型未知的节点类型是基于图形结构的学习过程来区分的。从学习的权重和特征中,Graphix随后预测了疾病 - 药物的关联,并计算位于预测疾病和药物附近的节点的贡献值。我们假设该模型给予很高贡献的相邻蛋白质节点对于理解实际的药理作用很重要。使用现实世界数据库对蛋白节点贡献的有效性的定量评估表明,Graphix所示的高贡献蛋白是合理的,作为药物作用的机制。 Graphix是一个基于证据的药物发现的框架,可以向用户展示新的疾病 - 药物关联,并确定该蛋白质对从大而复杂的知识库中理解其药理作用的重要性。

Drug repositioning holds great promise because it can reduce the time and cost of new drug development. While drug repositioning can omit various R&D processes, confirming pharmacological effects on biomolecules is essential for application to new diseases. Biomedical explainability in a drug repositioning model can support appropriate insights in subsequent in-depth studies. However, the validity of the XAI methodology is still under debate, and the effectiveness of XAI in drug repositioning prediction applications remains unclear. In this study, we propose GraphIX, an explainable drug repositioning framework using biological networks, and quantitatively evaluate its explainability. GraphIX first learns the network weights and node features using a graph neural network from known drug indication and knowledge graph that consists of three types of nodes (but not given node type information): disease, drug, and protein. Analysis of the post-learning features showed that node types that were not known to the model beforehand are distinguished through the learning process based on the graph structure. From the learned weights and features, GraphIX then predicts the disease-drug association and calculates the contribution values of the nodes located in the neighborhood of the predicted disease and drug. We hypothesized that the neighboring protein node to which the model gave a high contribution is important in understanding the actual pharmacological effects. Quantitative evaluation of the validity of protein nodes' contribution using a real-world database showed that the high contribution proteins shown by GraphIX are reasonable as a mechanism of drug action. GraphIX is a framework for evidence-based drug discovery that can present to users new disease-drug associations and identify the protein important for understanding its pharmacological effects from a large and complex knowledge base.

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