Background: Ventilator-associated pneumonia (VAP) in traumatic brain injury (TBI) patients poses a significant mortality risk and imposes a considerable financial burden on patients and healthcare systems. Timely detection and prognostication of VAP in TBI patients are crucial to improve patient outcomes and alleviate the strain on healthcare resources. Methods: We implemented six machine learning models using the MIMIC-III database. Our methodology included preprocessing steps, such as feature selection with CatBoost and expert opinion, addressing class imbalance with the Synthetic Minority Oversampling Technique (SMOTE), and rigorous model tuning through 5-fold cross-validation to optimize hyperparameters. Key models evaluated included SVM, Logistic Regression, Random Forest, XGBoost, ANN, and AdaBoost. Additionally, we conducted SHAP analysis to determine feature importance and performed an ablation study to assess feature impacts on model performance. Results: XGBoost outperformed the baseline models and the best existing literature. We used metrics, including AUC, Accuracy, Specificity, Sensitivity, F1 Score, PPV, and NPV. XGBoost demonstrated the highest performance with an AUC of 0.940 and an Accuracy of 0.875, which are 23.4% and 23.5% higher than the best results in the existing literature, with an AUC of 0.706 and an Accuracy of 0.640, respectively. This enhanced performance underscores the models' effectiveness in clinical settings. Conclusions: This study enhances the predictive modeling of VAP in TBI patients, improving early detection and intervention potential. Refined feature selection and advanced ensemble techniques significantly boosted model accuracy and reliability, offering promising directions for future clinical applications and medical diagnostics research.

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