Causality-Guided Machine Learning for Retinoblastoma Survival Prediction: Development and Comparative Evaluation Using SEER.
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Background: Retinoblastoma (RB) is a rare pediatric malignancy characterized by small sample sizes and low event rates, where conventional association-driven feature selection may lead to unstable models, overadjustment, and limited generalizability. However, existing survival prediction studies lack a careful treatment of feature selection that accounts for underlying causal structure. Objectives: To develop and validate a causality-guided machine learning model for RB survival prediction by jointly incorporating survival time and survival status as outcome variables. Methods: We analyzed 1015 RB patients from the SEER database (1975-2020). A causality-informed feature selection framework was developed to address the challenges of rare-disease data. Specifically, candidate variables were evaluated through a three-step evidence-integration process: (1) univariate Cox proportional hazards (CPH) analysis for initial statistical screening; (2) causal structure learning using the PC algorithm on the variables retained from Step 1 to construct a directed acyclic graph (DAG) and exclude structurally inappropriate variables (colliders or descendants of the outcome); and (3) LASSO-based feature screening performed independently on the full set of candidate variables. The final features were obtained by taking the intersection of the variables retained from Step 2 and Step 3. Survival models were then trained using the selected features, with model comparison performed as a secondary step. Results: The proposed framework consistently identified four structurally and prognostically robust predictors-laterality, "SEER historic stage A", "RX Summ", and sequence number-through this evidence-integration process. Compared with conventional approaches, the causality-informed framework reduced the feature set while improving model stability and interpretability. Notably, compared with LASSO-only selection, which retained a larger set of variables, the causality-informed approach yielded a more parsimonious feature set with improved predictive performance, suggesting reduced overfitting in a low-event setting. Survival models trained on this refined feature set demonstrated reliable predictive performance, with the random survival forest achieving the highest discrimination (C-index = 0.739). Importantly, the selected predictors aligned with clinically plausible pathways in the learned DAG, supporting their causal relevance. Conclusions: This study demonstrates that incorporating causal structure into feature selection provides a more reliable and interpretable foundation for survival modeling in retinoblastoma. Rather than focusing on algorithmic comparison alone, our findings highlight that careful, causality-informed feature selection is critical for improving robustness in rare-disease prediction tasks. This framework may serve as a generalizable methodological template for other rare clinical settings prone to spurious associations.