External Validation of a CT-Based Radiogenomics Model for the Detection of EGFR Mutation in NSCLC and the Impact of Prevalence in Model Building by Using Synthetic Minority Over Sampling (SMOTE): Lessons Learned.

Rationale and objectives: Radiogenomics holds promise in identifying molecular alterations in nonsmall cell lung cancer (NSCLC) using imaging features. Previously, we developed a radiogenomics model to predict epidermal growth factor receptor (EGFR) mutations based on contrast-enhanced computed tomography (CECT) in NSCLC patients. The current study aimed to externally validate this model using a publicly available National Institutes of Health (NIH)-based NSCLC dataset and assess the effect of EGFR mutation prevalence on model performance through synthetic minority oversampling technique (SMOTE).

Materials and methods: The original radiogenomics model was validated on an independent NIH cohort (n=140). For assessing the influence of disease prevalence, six SMOTE-augmented datasets were created, simulating EGFR mutation prevalence from 25% to 50%. Seven models were developed (one from original data, six SMOTE-augmented), each undergoing rigorous cross-validation, feature selection, and logistic regression modeling. Models were tested against the NIH cohort. Performance was compared using area under the receiver operating characteristic curve (Area Under the Curve [AUC]), and differences between radiomic-only, clinical-only, and combined models were statistically assessed.

Results: External validation revealed poor diagnostic performance for both our model and a previously published EGFR radiomics model (AUC ∼0.5). The clinical model alone achieved higher diagnostic accuracy (AUC 0.74). SMOTE-augmented models showed increased sensitivity but did not improve overall AUC compared to the clinical-only model. Changing EGFR mutation prevalence had minimal impact on AUC, challenging previous assumptions about the influence of sample imbalance on model performance.

Conclusion: External validation failed to reproduce prior radiogenomics model performance, while clinical variables alone retained strong predictive value. SMOTE-based oversampling did not improve diagnostic accuracy, suggesting that, in EGFR prediction, radiomics may offer limited value beyond clinical data. Emphasis on robust external validation and data-sharing is essential for future clinical implementation of radiogenomic models.