A biomarker discovery framework for childhood anxiety

Introduction: Anxiety is the most common manifestation of psychopathology in youth, negatively affecting academic, social, and adaptive functioning and increasing risk for mental health problems into adulthood. Anxiety disorders are diagnosed only after clinical symptoms emerge, potentially missing opportunities to intervene during critical early prodromal periods. In this study, we used a new empirical approach to extracting nonlinear features of the electroencephalogram (EEG), with the goal of discovering differences in brain electrodynamics that distinguish children with anxiety disorders from healthy children. Additionally, we examined whether this approach could distinguish children with externalizing disorders from healthy children and children with anxiety. Methods: We used a novel supervised tensor factorization method to extract latent factors from repeated multifrequency nonlinear EEG measures in a longitudinal sample of children assessed in infancy and at ages 3, 5, and 7 years of age. We first examined the validity of this method by showing that calendar age is highly correlated with latent EEG complexity factors (r = 0.77). We then computed latent factors separately for distinguishing children with anxiety disorders from healthy controls using a 5-fold cross validation scheme and similarly for distinguishing children with externalizing disorders from healthy controls. Results: We found that latent factors derived from EEG recordings at age 7 years were required to distinguish children with an anxiety disorder from healthy controls; recordings from infancy, 3 years, or 5 years alone were insufficient. However, recordings from two (5, 7 years) or three (3, 5, 7 years) recordings gave much better results than 7 year recordings alone. Externalizing disorders could be detected using 3- and 5 years EEG data, also giving better results with two or three recordings than any single snapshot. Further, sex assigned at birth was an important covariate that improved accuracy for both disorder groups, and birthweight as a covariate modestly improved accuracy for externalizing disorders. Recordings from infant EEG did not contribute to the classification accuracy for either anxiety or externalizing disorders. Conclusion: This study suggests that latent factors extracted from EEG recordings in childhood are promising candidate biomarkers for anxiety and for externalizing disorders if chosen at appropriate ages.