R methylCIPHER: A Methylation Clock Investigational Package for Hypothesis-Driven Evaluation & Research

Background Epigenetic clocks are promising tools for the study of aging in humans. The clocks quantify biological aging above and beyond chronological age, demonstrate systematic associations with risk factors that accelerate aging, and predict age-related morbidity and mortality. There is interest in using them as surrogate endpoints in intervention studies. However, the large number of clocks, decentralized publication and explosive popularity in the last decade has made for poor accessibility and standardization. This has hampered the abilities of new researchers to conduct truly hypothesis driven research—whether by not knowing about the best available clocks for a given question, or by systematically testing many or all as they become available. Results We report a centralized R package which can be installed and run locally on the user’s machine, and provides a standardized syntax for epigenetic clock calculation. The package includes a set of helper functions to assist with navigating clock literature and selecting clocks for analysis, as well as affording the user with the details of clock calculation. We describe each clock’s resilience to missing CpG information, combined with functionality to assess the need for imputation in the user’s own data. Furthermore, we demonstrate that while CpGs may not be shared among clocks with similar outputs, many clocks have highly correlated outputs. Conclusions Due to the previous decentralization of epigenetic clocks, gathering code and performing systematic analysis, particularly in protected datasets, has required significant information gathering effort. Here, we offer an R package with standardized implementation and potential for future growth and clock incorporation to assist with hypothesis driven investigation of aging as measured by epigenetic clocks. We show the potential of this package to drive the user to think globally about signals captured by epigenetic clocks, as well as to properly identify the potential and limitations of each clock in their current research. ### Competing Interest Statement The authors have declared no competing interest.