Deriving reproducible biomarkers from multi-site resting-state data: An Autism-based example

Resting-state functional Magnetic Resonance Imaging (RfMRI) holds the promise to reveal functional biomarkers of neuropsychiatric disorders. However, extracting such biomarkers is challenging for complex multifaceted neuropathologies, such as autism spectrum disorders. Large multi-site datasets increase sample sizes to compensate for this complexity, at the cost of uncontrolled heterogeneity. This heterogeneity raises new challenges, akin to those face in realistic diagnostic applications. Here, we demonstrate the feasibility of inter-site classification of neuropsychiatric status, with an application to the Autism Brain Imaging Data Exchange (ABIDE) database, a large (N 871) multi-site autism dataset. For this purpose, we investigate pipelines that extract the most predictive biomarkers from the data. These RfMRI pipelines build participant-specific connectomes from functionally-defined brain areas. Connectomes are then compared across participants to learn patterns of connectivity that differentiate typical controls from individuals with autism. We predict this neuropsychiatric status for participants from the same acquisition sites or different, unseen, ones. Good choices of methods for the various steps of the pipeline lead to 67% prediction accuracy on the full ABIDE data, which is significantly better than previously reported results. We perform extensive validation on multiple subsets of the data defined by different inclusion criteria. These enables detailed analysis of the factors contributing to successful connectome-based prediction. First, prediction accuracy improves as we include more subjects, up to the maximum amount of subjects available. Second, the definition of functional brain areas is of paramount importance for biomarker discovery: brain areas extracted from large RfMRI datasets outperform reference atlases in the classification tasks. Keywords: 1. Introduction data heterogeneity, resting-state fMRI, data pipelines, biomarkers, connectome, autism spectrum disorders In psychiatry, as in other fields of medicine, both the standardized observation of signs, as well as the symptom profile are critical for diagnosis. However, compared to other fields of medicine, psychiatry lacks accompanying objective markers that could lead to more refined diagnoses and targeted treatment [1]. Advances in noninvasive brain imaging techniques and analyses (e. g. [2, 3]) are showing great promise for uncovering patterns of brain structure and function that can be used as objective measures of mental illness.