Abstract
To solve major limitations in algorithms for the metabolite-based prediction of psychiatric phenotypes, a novel prediction model for depressive symptoms based on nonlinear feature selection machine learning, the Hilbert-Schmidt independence criterion least absolute shrinkage and selection operator (HSIC Lasso) algorithm, was developed and applied to a metabolomic dataset with the largest sample size to date. In total, 897 population-based subjects were recruited from the communities affected by the Great East Japan Earthquake; 306 metabolite features (37 metabolites identified by nuclear magnetic resonance measurements and 269 characterized metabolites based on the intensities from mass spectrometry) were utilized to build prediction models for depressive symptoms as evaluated by the Center for Epidemiologic Studies-Depression Scale (CES-D). The nested fivefold cross-validation was used for developing and evaluating the prediction models. The HSIC Lasso-based prediction model showed better predictive power than the other prediction models, including Lasso, support vector machine, partial least squares, random forest, and neural network. L-leucine, 3-hydroxyisobutyrate, and gamma-linolenyl carnitine frequently contributed to the prediction. We have demonstrated that the HSIC Lasso-based prediction model integrating nonlinear feature selection showed improved predictive power for depressive symptoms based on metabolome data as well as on risk metabolites based on nonlinear statistics in the Japanese population. Further studies should use HSIC Lasso-based prediction models with different ethnicities to investigate the generality of each risk metabolite for predicting depressive symptoms.