PurposeTo develop and interpret optimal predictive models to identify epidermal growth factor receptor (EGFR) mutation status and subtypes in patients with lung adenocarcinoma based on multicentric18F-FDG PET/CT data, and further construct a prognostic model to predict their clinical outcome.MethodsThe18F-FDG PET/CT imaging and clinical characters of 767 patients with lung adenocarcinoma from 4 cohorts were collected. Seventy-six radiomics candidates using cross-combination method to identity EGFR mutation status and subtypes were built. Further, Shapley additive explanations and local interpretable model-agnostic explanations were used for optimal models’ interpretation. Moreover, in order to predict the overall survival, a multivariate Cox proportional hazard model based on handcrafted radiomics features and clinical characteristics was constructed. The predictive performance and clinical net benefit of the models were evaluatedviaarea under receiver operating characteristic (AUC), C-index and decision curve analysis.ResultsAmong the 76 radiomics candidates, light gradient boosting machine classifier (LGBM) combined with recursive feature elimination wrapped LGBM feature selection method achieved best performance in predicting EGFR mutation status (AUC reached 0.80, 0.61, 0.71 in the internal test cohort and two external test cohorts, respectively). And extreme gradient boosting classifier combined with support vector machine feature selection method achieved best performance in predicting EGFR subtypes (AUC reached 0.76, 0.63, 0.61 in the internal test cohort and two external test cohorts, respectively). The C-index of the Cox proportional hazard model achieved 0.863.ConclusionsThe integration of cross-combination method and the external validation from multi-center data achieved a good prediction and generalization performance in predicting EGFR mutation status and its subtypes. The combination of handcrafted radiomics features and clinical factors achieved good performance in predicting prognosis. With the urgent needs of multicentric18F-FDG PET/CT trails, robust and explainable radiomics models have great potential in decision making and prognosis prediction of lung adenocarcinoma.