Machine Learning, Replication, and Validation

An updated biologically informed machine learning (BioMM) approach was used (eMethods in the Supplement).²⁵ BioMM is a 2-stage machine-learning approach that first builds separate machine learning models for methylation sites mapping to each of the 2846 pathways, yielding 1 machine-learning model per pathway (first-stage). This procedure compresses data from individual methylation sites into a pathway-level feature. Then, a second-stage algorithm integrates these pathway-level features into a systems-level classifier. BioMM was trained on discovery methylation and the algorithm then applied to all other data sets. In each data set, the output of BioMM was a score (PMS) that quantified the likelihood of a given participant being in the schizophrenia group. To assess predictive accuracy, we determined the area under the receiver operating characteristic curve (AUC) as well as Nagelkerke R².