IUSMMT: Survival mediation analysis of gene expression with multiple DNA methylation exposures and its application to cancers of TCGA.

Effective and powerful survival mediation models are currently lacking. To partly fill such knowledge gap, we particularly focus on the mediation analysis that includes multiple DNA methylations acting as exposures, one gene expression as the mediator and one survival time as the outcome. We propose...

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Autores principales:	Zhonghe Shao, Ting Wang, Meng Zhang, Zhou Jiang, Shuiping Huang, Ping Zeng
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/3bf421620a1e4c44be8da50c319f7cc1
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spelling	oai:doaj.org-article:3bf421620a1e4c44be8da50c319f7cc12021-12-02T19:58:00ZIUSMMT: Survival mediation analysis of gene expression with multiple DNA methylation exposures and its application to cancers of TCGA.1553-734X1553-735810.1371/journal.pcbi.1009250https://doaj.org/article/3bf421620a1e4c44be8da50c319f7cc12021-08-01T00:00:00Zhttps://doi.org/10.1371/journal.pcbi.1009250https://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358Effective and powerful survival mediation models are currently lacking. To partly fill such knowledge gap, we particularly focus on the mediation analysis that includes multiple DNA methylations acting as exposures, one gene expression as the mediator and one survival time as the outcome. We proposed IUSMMT (intersection-union survival mixture-adjusted mediation test) to effectively examine the existence of mediation effect by fitting an empirical three-component mixture null distribution. With extensive simulation studies, we demonstrated the advantage of IUSMMT over existing methods. We applied IUSMMT to ten TCGA cancers and identified multiple genes that exhibited mediating effects. We further revealed that most of the identified regions, in which genes behaved as active mediators, were cancer type-specific and exhibited a full mediation from DNA methylation CpG sites to the survival risk of various types of cancers. Overall, IUSMMT represents an effective and powerful alternative for survival mediation analysis; our results also provide new insights into the functional role of DNA methylation and gene expression in cancer progression/prognosis and demonstrate potential therapeutic targets for future clinical practice.Zhonghe ShaoTing WangMeng ZhangZhou JiangShuiping HuangPing ZengPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 17, Iss 8, p e1009250 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Zhonghe Shao Ting Wang Meng Zhang Zhou Jiang Shuiping Huang Ping Zeng IUSMMT: Survival mediation analysis of gene expression with multiple DNA methylation exposures and its application to cancers of TCGA.
description	Effective and powerful survival mediation models are currently lacking. To partly fill such knowledge gap, we particularly focus on the mediation analysis that includes multiple DNA methylations acting as exposures, one gene expression as the mediator and one survival time as the outcome. We proposed IUSMMT (intersection-union survival mixture-adjusted mediation test) to effectively examine the existence of mediation effect by fitting an empirical three-component mixture null distribution. With extensive simulation studies, we demonstrated the advantage of IUSMMT over existing methods. We applied IUSMMT to ten TCGA cancers and identified multiple genes that exhibited mediating effects. We further revealed that most of the identified regions, in which genes behaved as active mediators, were cancer type-specific and exhibited a full mediation from DNA methylation CpG sites to the survival risk of various types of cancers. Overall, IUSMMT represents an effective and powerful alternative for survival mediation analysis; our results also provide new insights into the functional role of DNA methylation and gene expression in cancer progression/prognosis and demonstrate potential therapeutic targets for future clinical practice.
format	article
author	Zhonghe Shao Ting Wang Meng Zhang Zhou Jiang Shuiping Huang Ping Zeng
author_facet	Zhonghe Shao Ting Wang Meng Zhang Zhou Jiang Shuiping Huang Ping Zeng
author_sort	Zhonghe Shao
title	IUSMMT: Survival mediation analysis of gene expression with multiple DNA methylation exposures and its application to cancers of TCGA.
title_short	IUSMMT: Survival mediation analysis of gene expression with multiple DNA methylation exposures and its application to cancers of TCGA.
title_full	IUSMMT: Survival mediation analysis of gene expression with multiple DNA methylation exposures and its application to cancers of TCGA.
title_fullStr	IUSMMT: Survival mediation analysis of gene expression with multiple DNA methylation exposures and its application to cancers of TCGA.
title_full_unstemmed	IUSMMT: Survival mediation analysis of gene expression with multiple DNA methylation exposures and its application to cancers of TCGA.
title_sort	iusmmt: survival mediation analysis of gene expression with multiple dna methylation exposures and its application to cancers of tcga.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/3bf421620a1e4c44be8da50c319f7cc1
work_keys_str_mv	AT zhongheshao iusmmtsurvivalmediationanalysisofgeneexpressionwithmultiplednamethylationexposuresanditsapplicationtocancersoftcga AT tingwang iusmmtsurvivalmediationanalysisofgeneexpressionwithmultiplednamethylationexposuresanditsapplicationtocancersoftcga AT mengzhang iusmmtsurvivalmediationanalysisofgeneexpressionwithmultiplednamethylationexposuresanditsapplicationtocancersoftcga AT zhoujiang iusmmtsurvivalmediationanalysisofgeneexpressionwithmultiplednamethylationexposuresanditsapplicationtocancersoftcga AT shuipinghuang iusmmtsurvivalmediationanalysisofgeneexpressionwithmultiplednamethylationexposuresanditsapplicationtocancersoftcga AT pingzeng iusmmtsurvivalmediationanalysisofgeneexpressionwithmultiplednamethylationexposuresanditsapplicationtocancersoftcga
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IUSMMT: Survival mediation analysis of gene expression with multiple DNA methylation exposures and its application to cancers of TCGA.

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