Critical evaluation of the reliability of DNA methylation probes on the Illumina MethylationEPIC BeadChip microarrays for dementia research
Year: 2023
Type: preprint
Abstract: Background DNA methylation (DNAm) has been implicated in many diseases including dementia. Array-based technologies offer a cost-effective and comprehensive approach for measuring DNAm on a genome-wide scale. However, the accuracy of DNAm measurements obtained using Illumina arrays can vary across different probes. Previous research has focused primarily on assessing the reliability of DNAm in younger subjects, and have compared duplicate samples between the 450k-450k or 450k-EPIC platforms, with limited investigations on EPIC-EPIC comparisons. Methods We conducted a comprehensive assessment of probe reliability on the Illumina EPIC arrays using 138 duplicated blood DNAm samples from subjects older than 65 years in the Alzheimer's Disease Neuroimaging Initiative (ADNI) study. To assess the reliability of each probe, we computed intraclass correlations (ICCs) for each probe. Both the magnitude and patterns of reliability in the EPIC-EPIC comparison were assessed. Furthermore, we also investigated the impact of probe reliability on the analyses of epigenome-wide association studies (EWAS). Results Our findings revealed the reliability of probes on the EPIC arrays is higher than those of previous studies involving duplicate measurements on 450k-EPIC or 450k-450k arrays. Consistent with earlier research, we observed increased reliability in probes with substantial between-subject variances or average methylation beta values ranging from 0.2 to 0.8. Lower reliability was observed in type I probes or probes located within the promoter and CpG island regions. In addition, we found some probes can yield high ICC values despite significant disagreement in duplicate measurements, primarily due to their relatively high between-subject variance. To account for such discrepancies explicitly, we introduced a novel statistical measure called the modified ICC, which penalizes the ICC based on the half-width of the 95% confidence limits of agreement. Importantly, we found probe reliability has significant implications in various downstream analyses of EWAS, such as meta-analysis, differentially methylated regions analysis, and integrative analyses within the cross-tissue or multi-omics contexts. Conclusion We developed a valuable resource for dementia research, providing crucial reliability information for probes on the EPIC array. This resource can be utilized to identify and prioritize high-quality probes, thereby minimizing the potential for false discoveries and maximizing the potential of EWAS.
Source: Research Square
Institutions: University of Miami, Dr. John T. Macdonald Foundation
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: U.S. Department of Defense, Alzheimer's Association, Bristol-Myers Squibb, Eli Lilly and Company, Pfizer, Biogen, University of Southern California, F. Hoffmann-La Roche, Meso Scale Diagnostics, Alzheimer's Disease Neuroimaging Initiative, BioClinica, Novartis Pharmaceuticals Corporation, Northern California Institute for Research and Education, Eisai, Servier, H. Lundbeck A/S, IXICO, National Institutes of Health, Genentech, University of California, San Diego, National Institute on Aging, National Institute of Neurological Disorders and Stroke, National Institute of Biomedical Imaging and Bioengineering
Awards: G1012222616, G104586243, G1298807586, Building blood based DNA methylation signatures for AD that are reflective of CNS changes, G1554142629, G1593117279, G1650819308, G1880935189, G2100670906, G2105457377, G2152643862, G2189010064, G2340207221, G2423387114, G2471646051, G2522063444, G2835601961, G29951154, G3130427885, G3131374986, G3146424788, G3216574877, G3553156159, G3710456697, G3752451908, G3870774570, G3966393351, New computational tools for understanding and predicting AD via age-associated DNA methylation changes, G4119534169, G43180419, G4475667458, G4501223628, G4800177743, G4860885537, G5207404921, G5209990037, G5365730499, EFFECTS OF TRAUMATIC BRAIN INJURY (TBI) AND POST TRAUMATIC STRESS DISORDER (PTSD) ON ALZHEIMER'S DISEASE (AD) IN VETERANS USING IMAGING AND BIOMARKERS IN THE AD NEUROIMAGING INITIATIVE (ADNI)", G5389965057, G5654639750, Alzheimer's Disease Neuroimaging Initiative, G5740349702, G5850682332, G613619302, G6173816828, G6210868510, G6371410416, G6412110892, G6447063303, G6719828067, G6792506723, G6899163935, G6948409098, G72415811, G7298697282, G764699806, G7799614282, G781725486, G8228018387, G8281378126, G839208290, Integrative Genomic Approaches for Understanding Sex Differences in Alzheimer's Disease, G8852128998, G8895907669, G8897063270, G8957659042, G9000039018, G9000074849, G9000122335, New DNA methylation biomarkers for predicting AD and cognitive decline, G920654007
OpenAlex ID: W4382049407