ObjectivesTo predict treatment response for overactive bladder (OAB) for a specific patient remains elusive. We sought to develop accurate models using machine learning for prediction of objective and patient-reported treatment response to intravesical botulinum toxin (OBTX-A) injection. We sought to validate the models in a challenging setting using an external dataset of a markedly different patient cohort and dosing regimen. We hypothesized the model would outperform human experts and top available algorithms. MethodsAlgorithms using “operator splitting” designed for accuracy and efficiency even in small training data sets with variable completeness, were trained to predict objective response and patient-reported symptomatic improvement using the ROSETTA trial cohort and validated using the ABC trial cohort of patients who underwent OBTX-A. Areas under the curve (AUC) of algorithms were compared to the top publicly-available machine learning classifier XGBoost, logistic regression with cross validation, and human expert predictions in the external validation set. ResultsIn the validation set, the operator splitting neural network had AUC 0.66 and outperformed XGBoost with DART (top available machine learning classifier, AUC 0.58), logistic regression (AUC 0.55), and human experts (AUC 0.47 – 0.53) for prediction of clinical responder status. It was similarly accurate in prediction of patient subjective improvement in symptoms following OBTX-A (AUC: 0.64), again outperforming other algorithms and human experts (AUC 0.41 – 0.62). ConclusionsThe neural network outperformed human experts and other machine learning approaches in prediction of objective and patient-reported OBTX-A outcomes for overactive bladder in a challenging independent validation cohort. Clinical implementation could improve counseling and treatment selection.