Musculoskeletal models are powerful tools that allow biomechanical investigations and predictions of muscle forces not accessible with experiments. A core challenge modelers must confront is validation. Measurements of muscle activity and joint loading are used for qualitative and indirect validation of muscle force predictions. Subject-specific models have reached high levels of complexity and can predict contact loads with surprising accuracy. However, every deterministic musculoskeletal model contains an intrinsic uncertainty due to the high number of parameters not identifiable in vivo. The objective of this work is to test the impact of intrinsic uncertainty in a scaled-generic model on estimates of muscle and joint loads. Uncertainties in marker placement, limb coronal alignment, body segment parameters, Hill-type muscle parameters, and muscle geometry were modeled with a global probabilistic approach (multiple uncertainties included in a single analysis). 5–95% confidence bounds and input/output sensitivities of predicted knee compressive loads and varus/valgus contact moments were estimated for a gait activity of three subjects with telemetric knee implants from the “Grand Challenge Competition.” Compressive load predicted for the three subjects showed confidence bounds of 333 ± 248 N, 408 ± 333 N, and 379 ± 244 N when all the sources of uncertainty were included. The measured loads lay inside the predicted 5–95% confidence bounds for 77%, 83%, and 76% of the stance phase. Muscle maximum isometric force, muscle geometry, and marker placement uncertainty most impacted the joint load results. This study demonstrated that identification of these parameters is crucial when subject-specific models are developed.

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