Background: Data linkage in pharmacoepidemiological research is commonly employed to ascertain exposures and outcomes or to obtain additional information on confounding variables. However, to protect patient confidentiality, unique patient identifiers are not provided, which makes data linkage across multiple sources challenging. The Saudi Real-World Evidence Network (SRWEN) aggregates electronic health records from various hospitals, which may require robust linkage techniques. Objective: We aimed to evaluate and compare the performance of deterministic, probabilistic, and machine learning (ML) approaches for linking deidentified data of patients with multiple sclerosis (MS) from the SRWEN and Ministry of National Guard Health Affairs electronic health record systems. Methods: A simulation-based validation framework was applied before linking real-world data sources. Deterministic linkage was based on predefined rules, whereas probabilistic linkage was based on a similarity score–based matching. For ML, both similarity score–based and classification approaches were applied using neural networks, logistic regression, and random forest models. The performance of each approach was assessed using confusion matrices, focusing on sensitivity, positive predictive value, F ₁ score, and computational efficiency. Results: The study included linked data of 2247 patients with MS from 2016 to 2023. The deterministic approach resulted in an average F ₁ score of 97.2% in the simulation and demonstrated varying match rates in real-world linkage: 1046/2247 (46.6%) to 1946/2247 (86.6%). This linkage was computationally efficient, with run times of <1 second per rule. The probabilistic approach provided an average F ₁ score of 93.9% in the simulation, with real-world match rates ranging from 1472/2247 (65.5%) to 2144/2247 (95.4%) and processing times ranging from approximately 0.1 to 5 seconds per rule. ML approaches achieved high performance ( F ₁ score reached 99.8%) but were computationally expensive. Processing times ranged from approximately 13 to 16,936 seconds for the classification-based approaches and from approximately 13 to 7467 seconds for the similarity score–based approaches. Real-world match rates from ML models were highly variable depending on the method used; the similarity score–based approach identified 789/2247 (35.1%) matched pairs, whereas the classification-based approach identified 2014/2247 (89.6%). Conclusions: Probabilistic linkage offers high linkage capacity by recovering matches missed by deterministic methods and proved to be both flexible and efficient, particularly in real-world scenarios where unique identifiers are lacking. This method achieved a great balance between recall and precision, enabling better integration of various data sources that could be useful in MS research.

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