ABSTRACT

DNA methylation at CpG dinucleotides is one of the most extensively studied epigenetic marks. With technological advancements, geneticists can profile DNA methylation with multiple reliable approaches. However, profiling platforms can differ substantially in the CpGs they assess, consequently hindering integrated analysis across platforms. Here, we present CpG impUtation Ensemble (CUE), which leverages multiple classical statistical and modern machine learning methods, to impute from the Illumina HumanMethylation450 (HM450) BeadChip to the Illumina HumanMethylationEPIC (HM850) BeadChip. Data were analysed from two population cohorts with methylation measured both by HM450 and HM850: the Extremely Low Gestational Age Newborns (ELGAN) study (n = 127, placenta) and the VA Boston Posttraumatic Stress Disorder (PTSD) genetics repository (n = 144, whole blood). Cross-validation results show that CUE achieves the lowest predicted root-mean-square error (RMSE) (0.026 in PTSD) and the highest accuracy (99.97% in PTSD) compared with five individual methods tested, including k-nearest-neighbours, logistic regression, penalized functional regression, random forest, and XGBoost. Finally, among all 339,033 HM850-only CpG sites shared between ELGAN and PTSD, CUE successfully imputed 289,604 (85.4%) sites, where success was defined as RMSE < 0.05 and accuracy >95% in PTSD. In summary, CUE is a valuable tool for imputing CpG methylation from the HM450 to HM850 platform.

 抽象的

CpG 二核苷酸的 DNA 甲基化是研究最广泛的表观遗传标记之一。随着技术的进步，遗传学家可以通过多种可靠的方法来分析 DNA 甲基化。然而，分析平台在评估的 CpG 方面可能存在很大差异，从而阻碍了跨平台的集成分析。在这里，我们提出了 CpG impUtation Ensemble (CUE)，它利用多种经典统计和现代机器学习方法，从 Illumina HumanMmethylation450 (HM450) BeadChip 插补到 Illumina HumanMmethylationEPIC (HM850) BeadChip。数据分析来自两个通过 HM450 和 HM850 测量甲基化的人群队列：极低胎龄新生儿 (ELGAN) 研究（ n = 127，胎盘）和 VA 波士顿创伤后应激障碍 (PTSD) 遗传学存储库（ n = 144，全血）。交叉验证结果表明，与测试的五种单独方法（包括 k 最近邻法、逻辑回归法）相比，CUE 实现了最低的预测均方根误差 (RMSE)（PTSD 中为 0.026）和最高准确度（PTSD 中为 99.97%）回归、惩罚函数回归、随机森林和 XGBoost。最后，在 ELGAN 和 PTSD 之间共享的所有 339,033 个仅 HM850 的 CpG 位点中，CUE 成功估算了 289,604 个（85.4%）位点，其中成功定义为 PTSD 中的 RMSE < 0.05 且准确度 >95%。总之，CUE 是将 CpG 甲基化从 HM450 转移到 HM850 平台的宝贵工具。