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Abstract Deep neural networks (DNNs) capture complex relationships among variables, however, because they require copious samples, their potential has yet to be fully tapped for understanding relationships between gene expression and human phenotypes. Here we introduce an analysis framework, namely MD-AD (Multi-task Deep learning for Alzheimer’s Disease neuropathology), which leverages an unexpected synergy between DNNs and multi-cohort settings. In these settings, true joint analysis can be stymied using conventional statistical methods, which require “harmonized” phenotypes and tend to capture cohort-level variations, obscuring subtler true disease signals. Instead, MD-AD incorporates related phenotypes sparsely measured across cohorts, and learns interactions between genes and phenotypes not discovered using linear models, identifying subtler signals than cohort-level variations which can be uniquely recapitulated in animal models and across tissues. We show that MD-AD exploits sex-specific relationships between microglial immune response and neuropathology, providing a nuanced context for the association between inflammatory genes and Alzheimer’s Disease. 

Tree-based machine learning models such as random forests, decision trees and gradient boosted trees are popular nonlinear predictive models, yet comparatively little attention has been paid to explaining their predictions. Here we improve the interpretability of tree-based models through three main contributions. (1) A polynomial time algorithm to compute optimal explanations based on game theory. (2) A new type of explanation that directly measures local feature interaction effects. (3) A new set of tools for understanding global model structure based on combining many local explanations of each prediction. We apply these tools to three medical machine learning problems and show how combining many high-quality local explanations allows us to represent global structure while retaining local faithfulness to the original model. These tools enable us to (1) identify high-magnitude but low-frequency nonlinear mortality risk factors in the US population, (2) highlight distinct population subgroups with shared risk characteristics, (3) identify nonlinear interaction effects among risk factors for chronic kidney disease and (4) monitor a machine learning model deployed in a hospital by identifying which features are degrading the model’s performance over time. Given the popularity of tree-based machine learning models, these improvements to their interpretability have implications across a broad set of domains.