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Musculoskeletal (MSK) models offer great potential for predicting the muscle forces required to inform more detailed simulations of vertebral endplate loading in adolescent idiopathic scoliosis (AIS). In this work, simulations based on static optimization were compared with in vivo measurements in two AIS patients to determine whether computational approaches alone are sufficient for accurate prediction of paraspinal muscle activity during functional activities. We used biplanar radiographs and marker-based motion capture, ground reaction force, and electromyography (EMG) data from two patients with mild and moderate thoracolumbar AIS (Cobb angles: 21° and 45°, respectively) during standing while holding two weights in front (reference position), walking, running, and object lifting. Using a fully automated approach, 3D spinal shape was extracted from the radiographs. Geometrically personalized OpenSim-based MSK models were created by deforming the spine of pre-scaled full-body models of children/adolescents. Simulations were performed using an experimentally controlled backward approach. Differences between model predictions and EMG measurements of paraspinal muscle activity (both expressed as a percentage of the reference position values) at three different locations around the scoliotic main curve were quantified by root mean square error (RMSE) and cross-correlation (XCorr). Predicted and measured muscle activity correlated best for mild AIS during object lifting (XCorr's ≥ 0.97), with relatively low RMSE values. For moderate AIS as well as the walking and running activities, agreement was lower, with XCorr reaching values of 0.51 and comparably high RMSE values. This study demonstrates that static optimization alone seems not appropriate for predicting muscle activity in AIS patients, particularly in those with more than mild deformations as well as when performing upright activities such as walking and running., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)