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Abstract When enabled by machine learning (ML), Learning Health Systems (LHS) hold promise for improving the effectiveness of healthcare delivery to patients. One major barrier to LHS research and development is the lack of access to EHR patient data. To overcome this challenge, this study demonstrated the feasibility of developing a simulated ML-enabled LHS using synthetic patient data. The ML-enabled LHS was initialized using a dataset of 30,000 synthetic Synthea patients and a risk prediction XGBoost base model for lung cancer. 4 additional datasets of 30,000 patients were generated and added to the previous updated dataset sequentially to simulate addition of new patients, resulting in datasets of 60,000, 90,000, 120,000 and 150,000 patients. New XGBoost models were built in each instance, and performance improved with data size increase, attaining 0.936 recall and 0.962 AUC (area under curve) in the 150,000 patients dataset. The effectiveness of the new ML-enabled LHS process was verified by implementing XGBoost models for stroke risk prediction on the same Synthea patient populations. By making the ML code and synthetic patient data publicly available for testing and training, this first synthetic LHS process paves the way for more researchers to start developing LHS with real patient data.