AbstractBackgroundAutism spectrum disorder (ASD) is characterized by a spectrum of social and communication impairments and rigid and stereotyped behaviors that have a neurodevelopmental origin. Although many imaging studies have reported structural and functional alterations in multiple brain regions, clinically useful diagnostic imaging biomarkers for ASD remain unavailable.MethodsIn this study, we applied machine learning (ML) models to regional volumetric and cortical thickness data from the largest structural magnetic resonance imaging (sMRI) dataset available from the Enhancing Neuro Imaging Genetics Through Meta‐Analysis (ENIGMA) consortium (1833 subjects with ASD and 1838 without ASD; age range: 1.5–64; average age: 15.6; male/female ratio: 4.2:1).ResultsThe highest classification accuracy on a hold‐out test set was achieved using a stacked Extra Tree Classifier. The area under the receiver operating characteristic (ROC) curve (AUC) was 0.62 (95% confidence interval [CI]: 0.57, 0.68) and the area under the precision‐recall curve was 0.58. Learning curve analysis showed the good fit of the model and suggests that more training examples will not likely benefit model performance.ConclusionsOur results suggest that sMRI volumetric and cortical thickness data alone may not provide clinically sufficient useful diagnostic biomarkers for ASD. Developing clinically useful imaging classifiers for ASD will benefit from combining other data modalities or feature types, such as functional MRI data and raw images that can leverage other machine learning (ML) techniques such as convolutional neural networks.