论文标题
癌症治疗树的概率学习
Probabilistic Learning of Treatment Trees in Cancer
论文作者
论文摘要
在许多疾病领域(尤其是癌症)中,准确鉴定协同治疗组合及其潜在的生物学机制至关重要。在翻译肿瘤研究中,临床前系统(例如患者衍生的异种移植物(PDX))已成为一项独特的研究设计,评估了对植入遗传相同小鼠的相同人类肿瘤的多种治疗方法。在本文中,我们提出了一种新型的贝叶斯基于概率的概率树框架,用于PDX数据,以通过推断处理簇树(RX-Tree)来研究治疗簇树之间治疗之间的分层关系。该框架激发了两种或多个处理之间的机械相似性的新指标,这些治疗方法涉及树木估计中固有的不确定性;具有高估计相似性的治疗具有潜在的机械协同作用。在Dirichlet扩散树的基础上,我们得出了编码树结构的封闭形式的边际似然,这有助于通过新的两级算法来促进计算有效的后验推断。模拟研究表明,提出的方法在恢复树木结构和治疗相似性方面的表现卓越。我们对最近整理的PDX数据集的分析产生了治疗相似性估计值,该估计表明,五种不同癌症中跨处理的已知生物学机制具有很高的一致性。更重要的是,我们发现了新的且潜在的有效组合疗法,这些疗法允许对特定下游生物学途径进行协同调节,以进行未来的临床研究。我们随附的代码,数据和可视化结果可视化的应用程序可在以下网址提供:https://github.com/bayesrx/rxtree。
Accurate identification of synergistic treatment combinations and their underlying biological mechanisms is critical across many disease domains, especially cancer. In translational oncology research, preclinical systems such as patient-derived xenografts (PDX) have emerged as a unique study design evaluating multiple treatments administered to samples from the same human tumor implanted into genetically identical mice. In this paper, we propose a novel Bayesian probabilistic tree-based framework for PDX data to investigate the hierarchical relationships between treatments by inferring treatment cluster trees, referred to as treatment trees (Rx-tree). The framework motivates a new metric of mechanistic similarity between two or more treatments accounting for inherent uncertainty in tree estimation; treatments with a high estimated similarity have potentially high mechanistic synergy. Building upon Dirichlet Diffusion Trees, we derive a closed-form marginal likelihood encoding the tree structure, which facilitates computationally efficient posterior inference via a new two-stage algorithm. Simulation studies demonstrate superior performance of the proposed method in recovering the tree structure and treatment similarities. Our analyses of a recently collated PDX dataset produce treatment similarity estimates that show a high degree of concordance with known biological mechanisms across treatments in five different cancers. More importantly, we uncover new and potentially effective combination therapies that confer synergistic regulation of specific downstream biological pathways for future clinical investigations. Our accompanying code, data, and shiny application for visualization of results are available at: https://github.com/bayesrx/RxTree.