Willem B. Bruin, Paul Zhutovsky, Guido van Wingen, Janna Marie Bas-Hoogendam, Nynke A. Groenewold, Kevin Hilbert, Anderson M. Winkler, André Zugman, Federica Agosta, Fredrik Åhs, Carmen Andreescu, Chase Antonacci, Takeshi Asami, Michal Assaf, Jacques Barber, Jochen Bauer, Shreya Bavdekar, Katja Beesdo-Baum, Francesco Benedetti, Rachel Bernstein, Johannes Björkstrand, Robert Blair, Karina S. Blair, Laura Blanco-Hinojo, Joscha Böhnlein, Paolo Brambilla, Rodrigo Bressan, Fabian Breuer, Marta Cano, Elisa Canu, Elise M Cardinale, Narcís Cardoner, Camilla Cividini, Henk Cremers, Udo Dannlowski, Gretchen J. Diefenbach, Katharina Domschke, Alexander Doruyter, Thomas Dresler, Angelika Erhardt, Massimo Filippi, Gregory Fonzo, Gabrielle Felice Freitag, Tomas Furmark, Tian Ge, Andrew J. Gerber, Savannah Gosnell, Hans J. Grabe, Dominik Grotegerd, Ruben C. Gur, Raquel E. Gur, Alfons O. Hamm, Laura K. M. Han, Jennifer Harper, Anita Harrewijn, Alexandre Heeren, David Hoffman, Andrea P. Jackowski, Neda Jahanshad, Laura Jett, Antonia N. Kaczkurkin, Parmis Khosravi, Ellen Kingsley, Tilo Kircher, Milutin Kostić, Bart Larsen, Sang-Hyuk Lee, Elisabeth Leehr, Ellen Leibenluft, Christine Lochner, Su Lui, Eleonora Maggioni, Gisele Gus Manfro, Kristoffer Månsson, Claire Marino, Frances Meeten, Barbara Milrod, Ana Munjiza, Benson Irungu, Michael Myers, Susanne Neufang, Jared Nielsen, Patricia Ohrmann, Cristina Ottaviani, Martin P Paulus, Michael T. Perino, K Luan Phan, Sara Poletti, Daniel Porta-Casteràs, Jesus Pujol, Andrea Reinecke, Grace Ringlein, Pavel Rjabtsenkov, Karin Roelofs, Ramiro Salas, Giovanni Salum, Theodore D. Satterthwaite, Elisabeth Schrammen, Lisa Sindermann, Jordan Smoller, Jair Soares, Rudolf Stark, Frederike Stein, thomas straube, Benjamin Straube, Jeffrey Strawn, Benjamin Suarez-Jimenez, Chad M. Sylvester, Ardesheer Talati, Sophia I Thomopoulos, Raşit Tükel, Helena van Nieuwenhuizen, Katy E. Werwath, Katharina Wittfeld, Barry Wright, Mon-Ju Wu, Yunbo Yang, Anna Zilverstand, Peter Zwanzger, Jennifer Blackford, Suzanne Avery, Jacqueline Clauss, Ulrike Lueken, Paul Thompson, Daniel Pine, Dan J. Stein, Nic van der Wee, Dick Veltman, and Moji Aghajani
Neuroimaging studies point to neurostructural abnormalities in youth with anxiety disorders. Yet, findings are based on small-scale studies, often with small effect sizes, and have limited generalizability and clinical relevance. These issues have prompted a paradigm shift in the field towards highly powered (i.e., big data) individual-level inferences, which are data-driven, transdiagnostic, and neurobiologically informed. Here, we built and validated neurostructural machine learning (ML) models for individual-level inferences based on the largest-ever multi-site neuroimaging sample of youth with anxiety disorders (age: 10-25 years, N=3,343 individuals from 32 global sites), as compiled by three ENIGMA Anxiety Working Groups: Panic Disorder (PD), Generalized Anxiety Disorder (GAD), and Social Anxiety Disorder (SAD). ML classifiers were trained on MRI-derived regional measures of cortical thickness, surface area, and subcortical volumes to classify patients and healthy controls (HC) for each anxiety disorder separately and across disorders (transdiagnostic classification). Modest, yet robust, classification performance was achieved for PD vs. HC (AUC=0.62), but other disorder-specific and transdiagnostic classifications were not significantly different from chance. However, above chance-level transdiagnostic classifications were obtained in exploratory subgroup analyses of male patients vs. male HC, unmedicated patients vs. HC, and patients with low anxiety severity vs. HC (AUC 0.59-0.63). The above chance-level classifications were based on plausible and specific neuroanatomical features in fronto-striato-limbic and temporo-parietal regions. This study provides a realistic estimate of classification performance in a large, ecologically valid, multi-site sample of youth with anxiety disorders, and may as such serve as a benchmark.