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Imputation of missing covariate values in epigenome-wide analysis of DNA methylation data.

TitleImputation of missing covariate values in epigenome-wide analysis of DNA methylation data.
Publication TypeJournal Article
Year of Publication2016
AuthorsWu C, Demerath EW, Pankow JS, Bressler J, Fornage M, Grove ML, Chen W
Secondary AuthorsGuan W
Date Published2016
KeywordsComputational Biology, Computer Simulation, CpG Islands, DNA Methylation, Epigenesis, Genetic, Female, Humans, Leukocyte Count, Male, Middle Aged, Models, Statistical, Smoking

DNA methylation is a widely studied epigenetic mechanism and alterations in methylation patterns may be involved in the development of common diseases. Unlike inherited changes in genetic sequence, variation in site-specific methylation varies by tissue, developmental stage, and disease status, and may be impacted by aging and exposure to environmental factors, such as diet or smoking. These non-genetic factors are typically included in epigenome-wide association studies (EWAS) because they may be confounding factors to the association between methylation and disease. However, missing values in these variables can lead to reduced sample size and decrease the statistical power of EWAS. We propose a site selection and multiple imputation (MI) method to impute missing covariate values and to perform association tests in EWAS. Then, we compare this method to an alternative projection-based method. Through simulations, we show that the MI-based method is slightly conservative, but provides consistent estimates for effect size. We also illustrate these methods with data from the Atherosclerosis Risk in Communities (ARIC) study to carry out an EWAS between methylation levels and smoking status, in which missing cell type compositions and white blood cell counts are imputed.

Alternate JournalEpigenetics
PubMed ID26890800
PubMed Central IDPMC4846117
Grant List5RC2HL102419 / HL / NHLBI NIH HHS / United States
HHSN268201100005C / / PHS HHS / United States
HHSN268201100009C / / PHS HHS / United States
HHSN268201100010C / / PHS HHS / United States
HHSN268201100008C / / PHS HHS / United States
HHSN268201100007C / / PHS HHS / United States
HHSN268201100011C / / PHS HHS / United States
HHSN268201100006C / / PHS HHS / United States