Identifying and correcting epigenetics measurements for systematic sources of variation
Posted on 2018-03-21 - 05:00
Abstract Background Methylation measures quantified by microarray techniques can be affected by systematic variation due to the technical processing of samples, which may compromise the accuracy of the measurement process and contribute to bias the estimate of the association under investigation. The quantification of the contribution of the systematic source of variation is challenging in datasets characterized by hundreds of thousands of features. In this study, we introduce a method previously developed for the analysis of metabolomics data to evaluate the performance of existing normalizing techniques to correct for unwanted variation. Illumina Infinium HumanMethylation450K was used to acquire methylation levels in over 421,000 CpG sites for 902 study participants of a case-control study on breast cancer nested within the EPIC cohort. The principal component partial R-square (PC-PR2) analysis was used to identify and quantify the variability attributable to potential systematic sources of variation. Three correcting techniques, namely ComBat, surrogate variables analysis (SVA) and a linear regression model to compute residuals were applied. The impact of each correcting method on the association between smoking status and DNA methylation levels was evaluated, and results were compared with findings from a large meta-analysis. Results A sizeable proportion of systematic variability due to variables expressing ‘batch’ and ‘sample position’ within ‘chip’ was identified, with values of the partial R2 statistics equal to 9.5 and 11.4% of total variation, respectively. After application of ComBat or the residuals’ methods, the contribution was 1.3 and 0.2%, respectively. The SVA technique resulted in a reduced variability due to ‘batch’ (1.3%) and ‘sample position’ (0.6%), and in a diminished variability attributable to ‘chip’ within a batch (0.9%). After ComBat or the residuals’ corrections, a larger number of significant sites (k = 600 and k = 427, respectively) were associated to smoking status than the SVA correction (k = 96). Conclusions The three correction methods removed systematic variation in DNA methylation data, as assessed by the PC-PR2, which lent itself as a useful tool to explore variability in large dimension data. SVA produced more conservative findings than ComBat in the association between smoking and DNA methylation.
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Perrier, Flavie; Novoloaca, Alexei; Ambatipudi, Srikant; Baglietto, Laura; Ghantous, Akram; Perduca, Vittorio; et al. (2018). Identifying and correcting epigenetics measurements for systematic sources of variation. figshare. Collection. https://doi.org/10.6084/m9.figshare.c.4038686.v1
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AUTHORS (21)
FP
Flavie Perrier
AN
Alexei Novoloaca
SA
Srikant Ambatipudi
LB
Laura Baglietto
AG
Akram Ghantous
VP
Vittorio Perduca
MB
Myrto Barrdahl
SH
Sophia Harlid
KO
Ken Ong
AC
Alexia Cardona
SP
Silvia Polidoro
TN
Therese Nøst
KO
Kim Overvad
HO
Hanane Omichessan
MD
Martijn Dollé
CB
Christina Bamia
JH
José Huerta
PV
Paolo Vineis
ZH
Zdenko Herceg
IR
Isabelle Romieu