Prognosis of the long-term functional outcome of traumatic brain injury is essential for personalized management of that injury. Nonetheless, accurate prediction remains unavailable. Although machine learning has shown promise in many fields, including medical diagnosis and prognosis, such models are rarely deployed in real-world settings due to a lack of transparency and trustworthiness. To address these drawbacks, we propose a machine learning-based framework that is explainable and aligns with clinical domain knowledge. To build such a framework, additional layers of statistical inference and human expert validation are added to the model, which ensures the predicted risk score’s trustworthiness. Using 831 patients with moderate or severe traumatic brain injury to build a model using the proposed framework, an area under the receiver operating characteristic curve (AUC) and accuracy of 0.8085 and 0.7488 were achieved, respectively, in determining which patients will experience poor functional outcomes. The performance of the machine learning classifier is not adversely affected by the imposition of statistical and domain knowledge “checks and balances”. Finally, through a case study, we demonstrate how the decision made by a model might be biased if it is not audited carefully.

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