An Effective Processing Pipeline for Harmonizing DNA Methylation Data from Illumina’s 450K and EPIC Platforms for Epidemiological Studies

Abstract Objective: Illumina BeadChip arrays are commonly used to generate DNA methylation data for large epidemiological studies. Updates in technology over time create challenges for data harmonization within and between studies, many of which obtained data from the older 450K and newer EPIC platforms. The pre-processing pipeline for DNA methylation is not trivial, and influences the downstream analyses. Incorporating different platforms adds a new level of technical variability that has not yet been taken into account by recommended pipelines. Our study evaluated the performance of various tools on different versions of platform data harmonization at each step of pre-processing pipeline, including quality control (QC), normalization, batch effect adjustment, and genomic inflation. We illustrate our novel approach using 450K and EPIC data from the Diabetes Autoimmunity Study in the Young (DAISY) prospective cohort. Results: We found normalization and probe filtering had the biggest effect on data harmonization. Employing a meta-analysis was an effective and easily executable method for accounting for platform variability. Correcting for genomic inflation also helped with harmonization. We present guidelines for studies seeking to harmonize data from the 450K and EPIC platforms, which includes the use of technical replicates for evaluating numerous pre-processing steps, and employing a meta-analysis.