Journal Article

Comparison of different cell type correction methods for genome-scale epigenetics studies

Kaushal, Akhilesh, Ray, Meredith, Zhang, Hongmei, Smith, Alicia K., Karmaus, Wilfried J. J., Torres, Mylin A., Wang, Shu-Li

2017

Overview

Background Whole blood is frequently utilized in genome-wide association studies of DNA methylation patterns in relation to environmental exposures or clinical outcomes. These associations can be confounded by cellular heterogeneity. Algorithms have been developed to measure or adjust for this heterogeneity, and some have been compared in the literature. However, with new methods available, it is unknown whether the findings will be consistent, if not which method(s) perform better. Results Methods : We compared eight cell-type correction methods including the method in the minfi R package, the method by Houseman et al., the Removing unwanted variation (RUV) approach, the methods in FaST-LMM-EWASher, ReFACTor, RefFreeEWAS, and RefFreeCellMix R programs, along with one approach utilizing surrogate variables (SVAs). We first evaluated the association of DNA methylation at each CpG across the whole genome with prenatal arsenic exposure levels and with cancer status, adjusted for estimated cell-type information obtained from different methods. We then compared CpGs showing statistical significance from different approaches. For the methods implemented in minfi and proposed by Houseman et al., we utilized homogeneous data with composition of some blood cells available and compared them with the estimated cell compositions. Finally, for methods not explicitly estimating cell compositions, we evaluated their performance using simulated DNA methylation data with a set of latent variables representing “cell types”. Results : Results from the SVA-based method overall showed the highest agreement with all other methods except for FaST-LMM-EWASher. Using homogeneous data, minfi provided better estimations on cell types compared to the originally proposed method by Houseman et al. Further simulation studies on methods free of reference data revealed that SVA provided good sensitivities and specificities, RefFreeCellMix in general produced high sensitivities but specificities tended to be low when confounding is present, and FaST-LMM-EWASher gave the lowest sensitivity but highest specificity. Conclusions Results from real data and simulations indicated that SVA is recommended when the focus is on the identification of informative CpGs. When appropriate reference data are available, the method implemented in the minfi package is recommended. However, if no such reference data are available or if the focus is not on estimating cell proportions, the SVA method is suggested.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Algorithms / Arsenic / Arsenic - toxicity / Bioinformatics / Biomedical and Life Sciences / Blood / Blood cells / Blood Cells - chemistry / Cancer / Cell-type composition / Computational Biology/Bioinformatics / Computer Appl. in Life Sciences / Computer simulation / CpG Islands / CpG sites / Datasets / Deoxyribonucleic acid / DNA / DNA methylation / DNA Methylation - drug effects / Epigenesis, Genetic / Epigenetic inheritance / Epigenetics / Epigenomics - methods / Estimation / Exposure / Female / Fetal Blood - chemistry / Gene expression / Genome-scale DNA methylation / Genome-Wide Association Study / Genomes / Heterogeneity / Humans / Life Sciences / Maternal Exposure / Mathematical models / Methods / Methylation / Microarrays / Neoplasms - genetics / Ontology / Prenatal experience / Research Article / Results and data / Sensitivity / Software / Studies / Surrogate variables / Variables