Diverse environmental and biological systems interact to influence individual differences in response to environmental stress. Understanding the nature of these complex relationships can enhance the development of methods to (1) identify risk, (2) classify individuals as healthy or ill, (3) understand mechanisms of change, and (4) develop effective treatments. The Research Domain Criteria initiative provides a theoretical framework to understand health and illness as the product of multiple interrelated systems but does not provide a framework to characterize or statistically evaluate such complex relationships. Characterizing and statistically evaluating models that integrate multiple levels (e.g. synapses, genes, and environmental factors) as they relate to outcomes that are free from prior diagnostic benchmarks represent a challenge requiring new computational tools that are capable to capture complex relationships and identify clinically relevant populations. In the current review, we will summarize machine learning methods that can achieve these goals.