A bootstrap model comparison test for identifying genes with context-specific patterns of genetic regulation.

IF 1.3 4区 数学 Q2 STATISTICS & PROBABILITY Annals of Applied Statistics Pub Date : 2024-09-01 Epub Date: 2024-08-05 DOI:10.1214/23-aoas1859
Mykhaylo M Malakhov, Ben Dai, Xiaotong T Shen, Wei Pan
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Abstract

Understanding how genetic variation affects gene expression is essential for a complete picture of the functional pathways that give rise to complex traits. Although numerous studies have established that many genes are differentially expressed in distinct human tissues and cell types, no tools exist for identifying the genes whose expression is differentially regulated. Here we introduce DRAB (differential regulation analysis by bootstrapping), a gene-based method for testing whether patterns of genetic regulation are significantly different between tissues or other biological contexts. DRAB first leverages the elastic net to learn context-specific models of local genetic regulation and then applies a novel bootstrap-based model comparison test to check their equivalency. Unlike previous model comparison tests, our proposed approach can determine whether population-level models have equal predictive performance by accounting for the variability of feature selection and model training. We validated DRAB on mRNA expression data from a variety of human tissues in the Genotype-Tissue Expression (GTEx) Project. DRAB yielded biologically reasonable results and had sufficient power to detect genes with tissue-specific regulatory profiles while effectively controlling false positives. By providing a framework that facilitates the prioritization of differentially regulated genes, our study enables future discoveries on the genetic architecture of molecular phenotypes.

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用于识别具有特定遗传调控模式的基因的自举模型比较检验。
要全面了解导致复杂性状的功能途径,就必须了解遗传变异是如何影响基因表达的。尽管大量研究已经证实,许多基因在不同的人体组织和细胞类型中表达不同,但目前还没有工具可以识别表达受到不同调控的基因。在这里,我们介绍一种基于基因的方法--DRAB(自举法差异调控分析),用于测试不同组织或其他生物环境中的基因调控模式是否存在显著差异。DRAB 首先利用弹性网来学习局部基因调控的特定背景模型,然后应用一种新颖的基于引导的模型比较测试来检验它们的等效性。与以往的模型比较测试不同,我们提出的方法可以通过考虑特征选择和模型训练的可变性来确定群体级模型是否具有相同的预测性能。我们在基因型-组织表达(GTEx)项目中对来自各种人体组织的 mRNA 表达数据进行了 DRAB 验证。DRAB 得出了生物学上合理的结果,并有足够的能力检测出具有组织特异性调控特征的基因,同时有效控制了假阳性。我们的研究提供了一个框架,有助于确定差异调控基因的优先次序,从而有助于未来发现分子表型的遗传结构。
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来源期刊
Annals of Applied Statistics
Annals of Applied Statistics 社会科学-统计学与概率论
CiteScore
3.10
自引率
5.60%
发文量
131
审稿时长
6-12 weeks
期刊介绍: Statistical research spans an enormous range from direct subject-matter collaborations to pure mathematical theory. The Annals of Applied Statistics, the newest journal from the IMS, is aimed at papers in the applied half of this range. Published quarterly in both print and electronic form, our goal is to provide a timely and unified forum for all areas of applied statistics.
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