title: Correcting for cell-type effects in DNA methylation studies: reference-based method outperforms latent variable approaches in empirical studies.
abstract: Based on an extensive simulation study, McGregor and colleagues recently recommended the use of surrogate variable analysis (SVA) to control for the confounding effects of cell-type heterogeneity in DNA methylation association studies in scenarios where no cell-type proportions are available. As their recommendation was mainly based on simulated data, we sought to replicate findings in two large-scale empirical studies. In our empirical data, SVA did not fully correct for cell-type effects, its performance was somewhat unstable, and it carried a risk of missing true signals caused by removing variation that might be linked to actual disease processes. By contrast, a reference-based correction method performed well and did not show these limitations. A disadvantage of this approach is that if reference methylomes are not (publicly) available, they will need to be generated once for a small set of samples. However, given the notable risk we observed for cell-type confounding, we argue that, to avoid introducing false-positive findings into the literature, it could be well worth making this investment.Please see related Correspondence article: https://genomebiology.biomedcentral.com/articles/10/1186/s13059-017-1149-7 and related Research article: https://genomebiology.biomedcentral.com/articles/10.1186/s13059-016-0935-y.
authors.affiliation: Center for Biomarker Research and Precision Medicine, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Mohammad W
authors.initials: MW
authors.lastname: Hattab
authors.affiliation: Center for Biomarker Research and Precision Medicine, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Andrey A
authors.initials: AA
authors.lastname: Shabalin
authors.affiliation: Center for Biomarker Research and Precision Medicine, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Shaunna L
authors.initials: SL
authors.lastname: Clark
authors.affiliation: Center for Biomarker Research and Precision Medicine, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Center for Biomarker Research and Precision Medicine, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Gaurav
authors.initials: G
authors.lastname: Kumar
authors.affiliation: Center for Biomarker Research and Precision Medicine, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Robin F
authors.initials: RF
authors.lastname: Chan
authors.affiliation: Center for Biomarker Research and Precision Medicine, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Lin Ying
authors.initials: LY
authors.lastname: Xie
authors.affiliation: Department of Psychiatry, VU University Medical Center/GGZ inGeest, Amsterdam, The Netherlands.
authors.forename: Rick
authors.initials: R
authors.lastname: Jansen
authors.affiliation: Department of Psychiatry, VU University Medical Center/GGZ inGeest, Amsterdam, The Netherlands.
authors.forename: Laura K M
authors.initials: LK
authors.lastname: Han
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, SE-171 77, Stockholm, Sweden.
authors.forename: Patrik K E
authors.initials: PK
authors.lastname: Magnusson
authors.affiliation: Department of Psychiatry, VU University Medical Center/GGZ inGeest, Amsterdam, The Netherlands.
authors.forename: Gerard
authors.initials: G
authors.lastname: van Grootheest
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, SE-171 77, Stockholm, Sweden.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Hultman
authors.affiliation: Department of Psychiatry, VU University Medical Center/GGZ inGeest, Amsterdam, The Netherlands.
authors.forename: Brenda W J H
authors.initials: BW
authors.lastname: Penninx
authors.affiliation: Center for Biomarker Research and Precision Medicine, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Karolina A
authors.initials: KA
authors.lastname: Aberg
authors.affiliation: Center for Biomarker Research and Precision Medicine, Virginia Commonwealth University, Richmond, VA, USA. ejvandenoord@vcu.edu.
authors.forename: Edwin J C G
authors.initials: EJ
authors.lastname: van den Oord
mesh_terms: D019175:DNA Methylation