Reassessing pharmacogenomic cell sensitivity with multilevel statistical models.
Reassessing pharmacogenomic cell sensitivity with multilevel statistical models.
复制标题
使用多级统计模型重新评估药物基因组细胞敏感性。
DOI：
10.1093/biostatistics/kxac010
复制
发表时间：
2023
期刊：
影响因子：
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通讯作者：
Irizarry,Rafael
中科院分区：
文献类型：
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作者：
Ploenzke,Matt;Irizarry,Rafael
药物基因组学实验允许在不同的剂量浓度下对药物进行系统测试，以研究基因组标记如何与细胞对治疗的敏感性相关。分析的第一步是量化细胞系对不同剂量浓度的被测药物的反应。由于生物和实验的可变性，这些测量中的信噪比可能很低。然而，越来越多的药物基因组研究提供了复制的数据集，可以用来获得力量。为此，我们建立了一个分层混合模型来估计药物特定的混合物分布，以估计细胞敏感性，并评估药物效应类型作为广泛或靶向效应。我们使用这个公式来提出一个统一的方法，它可以产生细胞对药物敏感的后验概率，条件是细胞是靶向效应或相对效应大小，条件是细胞是广泛的。我们通过案例研究证明了我们方法的有效性。首先，我们评估了两个数据集交集内的细胞系/药物的配对协议，并确认了许多公开可用的药物基因组数据集之间的适度配对协议。然后，我们提出了一项分析，确定了含有EML4-ALK或NPM1-ALK基因融合的细胞对药物Crizotinib的敏感性，以及与Crizotinib敏感性相关的显著下调的细胞基质途径。
Pharmacogenomic experiments allow for the systematic testing of drugs, at varying dosage concentrations, to study how genomic markers correlate with cell sensitivity to treatment. The first step in the analysis is to quantify the response of cell lines to variable dosage concentrations of the drugs being tested. The signal to noise in these measurements can be low due to biological and experimental variability. However, the increasing availability of pharmacogenomic studies provides replicated data sets that can be leveraged to gain power. To do this, we formulate a hierarchical mixture model to estimate the drug-specific mixture distributions for estimating cell sensitivity and for assessing drug effect type as either broad or targeted effect. We use this formulation to propose a unified approach that can yield posterior probability of a cell being susceptible to a drug conditional on being a targeted effect or relative effect sizes conditioned on the cell being broad. We demonstrate the usefulness of our approach via case studies. First, we assess pairwise agreements for cell lines/drugs within the intersection of two data sets and confirm the moderate pairwise agreement between many publicly available pharmacogenomic data sets. We then present an analysis that identifies sensitivity to the drug crizotinib for cells harboring EML4-ALK or NPM1-ALK gene fusions, as well as significantly down-regulated cell-matrix pathways associated with crizotinib sensitivity.