Background DNA methylation (DNAm) is an epigenetic regulator of gene expression programs that can be altered by environmental exposures, aging, and in pathogenesis. Traditional analyses that associate DNAm alterations with phenotypes suffer from multiple hypothesis testing and multi-collinearity due to the high-dimensional, continuous, interacting and non-linear nature of the data. Deep learning analyses have shown much promise to study disease heterogeneity. DNAm deep learning approaches have not yet been formalized into user-friendly frameworks for execution, training, and interpreting models. Here, we describe MethylNet, a DNAm deep learning method that can construct embeddings, make predictions, generate new data, and uncover unknown heterogeneity with minimal user supervision.Results The results of our experiments indicate that MethylNet can study cellular differences, grasp higher order information of cancer sub-types, estimate age and capture factors associated with smoking in concordance with known differences.Conclusion The ability of MethylNet to capture nonlinear interactions presents an opportunity for further study of unknown disease, cellular heterogeneity and aging processes.*   450K    :   HumanMethylation450    850K    :   HumanMethylationEPIC    ANN    :   Artificial Neural Networks    CpG    :   Cytosine-Guanine Dinucleotides    CWL    :   Common Workflow Language    DNAm    :   DNA Methylation    EWAS    :   Epigenome-Wide Association Studies    GPUs    :   Graphics Processing Units    L-DMR    :   Leukocyte Differentially Methylated Regions    RPMM    :   Recursively Partitioned Mixture Models    SHAP    :   Shapley Additive Feature Explanations    SVM    :   Support Vector Machine    TCGA    :   The Cancer Genome Atlas    UMAP    :   Uniform Manifold Approximation and Projection    VAE    :   Variational Auto-encoders

MethylNet: An Automated and Modular Deep Learning Approach for DNA Methylation Analysis