Epigenetic age prediction drifts resulting from next-generation methylation arrays

Abstract Background Epigenetic clocks based on DNA methylation data are routinely used to obtain surrogate measures of biological age and estimate epigenetic age acceleration rates. These tools are mathematical models that rely on the methylation state of specific sets of CpG islands quantified using microarrays. The set of CpG islands probed in the microarrays differed between the models. Thus, as new methylation microarrays are developed and older models are discontinued, existing epigenetic clocks might become obsolete. Here, we explored the effects of the changes introduced in the new DNA methylation array from Illumina (EPICv2) on existing epigenetic clocks. Methods We compiled a whole-blood DNA methylation dataset of 10835 samples to test the performance of four epigenetic clocks on the probe set of the EPICv2 array. We then used the same data to train a new epigenetic age prediction model compatible across the 450k, EPICv1 and EPICv2 microarrays. We compiled a validation dataset of 2095 samples to compare our model with a state-of-the-art epigenetic clock. We used a dataset of cancer survivors who had undergone different types of therapy and a dataset of breast cancer patients and controls to test the ability of our model to detect alterations in epigenetic age acceleration. Results We found that the results of the four epigenetic clocks tested are significantly distorted by the absence of specific probes in the EPICv2 microarray, causing an average drift of up to 25 years. We developed an epigenetic age prediction model compatible with the 450k, EPICv1 and EPICv2 microarrays. Our model produced highly accurate chronological age predictions that were comparable to those of a state-of-the-art epiclock. This finding reproduced previous results showing increased epigenetic age acceleration in cancer patients and in survivors who had been treated with radiation therapy. Conclusion Our work demonstrated that existing epigenetic clocks need to be updated to be applicable to data generated with the new EPICv2 microarray, which has phased out the 450k and EPICv1 models. To overcome this technical hurdle, we developed a new model that translates the capabilities of state-of-the-art epigenetic clocks to the new EPICv2 platform and is cross-compatible with the 450k and EPICv1 microarrays.