Pharmacoepidemiology and Drug Safety Research Group, Department of Pharmacy, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway.
PharmaTox Strategic Research Initiative, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway.
Clin Epigenetics. 2022 Jun 28;14(1):80. doi: 10.1186/s13148-022-01299-3.
There is an increasing interest in the role of epigenetics in epidemiology, but the emerging research field faces several critical biological and technical challenges. In particular, recent studies have shown poor correlation of measured DNA methylation (DNAm) levels within and across Illumina Infinium platforms in various tissues. In this study, we have investigated concordance between 450 k and EPIC Infinium platforms in cord blood. We could not replicate our previous findings on the association of prenatal paracetamol exposure with cord blood DNAm, which prompted an investigation of cross-platform DNAm differences.
This study is based on two DNAm data sets from cord blood samples selected from the Norwegian Mother, Father and Child Cohort Study (MoBa). DNAm of one data set was measured using the 450 k platform and the other data set was measured using the EPIC platform. Initial analyses of the EPIC data could not replicate any of our previous significant findings in the 450 k data on associations between prenatal paracetamol exposure and cord blood DNAm. A subset of the samples (n = 17) was included in both data sets, which enabled analyses of technical sources potentially contributing to the negative replication. Analyses of these 17 samples with repeated measurements revealed high per-sample correlations ([Formula: see text] 0.99), but low per-CpG correlations ([Formula: see text] ≈ 0.24) between the platforms. 1.7% of the CpGs exhibited a mean DNAm difference across platforms > 0.1. Furthermore, only 26.7% of the CpGs exhibited a moderate or better cross-platform reliability (intra-class correlation coefficient ≥ 0.5).
The observations of low cross-platform probe correlation and reliability corroborate previous reports in other tissues. Our study cannot determine the origin of the differences between platforms. Nevertheless, it emulates the setting in studies using data from multiple Infinium platforms, often analysed several years apart. Therefore, the findings may have important implications for future epigenome-wide association studies (EWASs), in replication, meta-analyses and longitudinal studies. Cognisance and transparency of the challenges related to cross-platform studies may enhance the interpretation, replicability and validity of EWAS results both in cord blood and other tissues, ultimately improving the clinical relevance of epigenetic epidemiology.
表观遗传学在流行病学中的作用越来越受到关注，但新兴的研究领域面临着几个关键的生物学和技术挑战。特别是，最近的研究表明，在不同组织中，Illumina Infinium 平台上测量的 DNA 甲基化（DNAm）水平在内部和跨平台之间相关性较差。在这项研究中，我们调查了脐带血中 450k 和 EPIC Infinium 平台之间的一致性。我们无法复制我们之前关于产前扑热息痛暴露与脐带血 DNAm 之间关联的发现，这促使我们调查跨平台 DNAm 差异。
本研究基于从挪威母亲、父亲和儿童队列研究（MoBa）中选择的脐带血样本的两个 DNAm 数据集。一个数据集的 DNAm 使用 450k 平台测量，另一个数据集使用 EPIC 平台测量。对 EPIC 数据的初步分析无法复制我们之前在 450k 数据中关于产前扑热息痛暴露与脐带血 DNAm 之间关联的任何显著发现。样本的一个子集（n=17）包含在两个数据集中，这使得能够分析可能导致阴性复制的技术来源。对这 17 个具有重复测量的样本进行分析表明，每个样本的相关性非常高（[公式：见文本]＞0.99），但平台之间的每个 CpG 的相关性很低（[公式：见文本]≈0.24）。跨越平台的 1.7%的 CpG 表现出平均 DNAm 差异＞0.1。此外，只有 26.7%的 CpG 表现出中等或更好的跨平台可靠性（组内相关系数≥0.5）。
低跨平台探针相关性和可靠性的观察结果与其他组织中的先前报告一致。我们的研究无法确定平台之间差异的来源。然而，它模拟了使用来自多个 Infinium 平台的数据进行研究的情况，这些研究通常在几年后进行分析。因此，这些发现可能对未来的全基因组关联研究（EWAS）、复制、荟萃分析和纵向研究具有重要意义。在脐带血和其他组织中，对与跨平台研究相关的挑战的认识和透明度可以增强 EWAS 结果的解释、可重复性和有效性，最终提高表观遗传学流行病学的临床相关性。
