Developing a novel Comorbidities Index for predicting 10-year mortality in Prostate Cancer patients: A computational data-driven approach
Authors: Davide Farinati, Francesco Barletta, Paolo Zaurito, Simone Scuderi, Nicholas Raison, Alejandro Granados, Prokar Dasgupta, Giorgio Gandaglia, +1 more
Abstract
The Charlson Comorbidities Index (CCI) is a weighted additive index widely used to estimate ten-year mortality risk, but its original weights may not reflect contemporary prognoses. This limitation is critical in Prostate Cancer (PCa), where radical treatment is recommended only for patients with a life expectancy of at least ten years. For candidates eligible for Radical Prostatectomy (RP), accurate estimation of ten-year other-cause mortality is essential to balance oncological benefit against competing risks and avoid overtreatment. We propose a data-driven framework to derive a comorbidity index tailored to PCa patients considered for RP. Using a retrospective single-institution cohort, we apply Population-Based Bio-Inspired Algorithms (PBBIAs) to recalibrate comorbidity weights and evolve alternative symbolic formulations optimized for ten-year survival discrimination. We compared six optimization strategies, including symbolic regression approaches based on Genetic Programming (GP), population-based metaheuristics, clinically validated baselines, and survival prediction models. Results show that GA, FST-PSO, and SLIM outperform both the original CCI and the PCCI, particularly when PCa-specific variables are included, improving the Concordance Index by up to 0.1. GPLearn yields compact and interpretable models with competitive performance. Overall, the proposed approach provides an updated and interpretable tool to improve patient selection for RP.
Biochemical recurrence (BCR) after radical prostatectomy is a critical endpoint in prostate cancer, yet risk stratification relies almost entirely on variables dominated by Gleason grade. Whether H&E whole slide images (WSIs) carry prognostic signal beyond grade, and whether multiple instance learning (MIL) can recover it, remains unsettled. A key obstacle is that many pipelines select model checkpoints on the evaluation fold, artificially inflating concordance. We construct a rigorous benchmark on TCGA-PRAD (487 patients, 101 BCR events) using strict out-of-fold scoring over five-fold cross-validation repeated across five seeds. The choice of MIL aggregator (ABMIL, CLAM, TransMIL, PatchGCN) has little effect (C-index 0.61-0.64 with UNI2-h), while the feature extractor is the dominant factor (ResNet50 0.566 versus pathology foundation models up to 0.639). A clinical Cox model on grade, stage, and age reaches 0.687; no imaging-only model significantly outperforms it (p > 0.10). We introduce Grade-Disentangled MIL (GD-MIL), a gated-attention MIL encoder trained with a gradient-reversal grade adversary that encourages the slide representation to be invariant to Gleason grade before late fusion with clinical variables. GD-MIL achieves C-index 0.704, significantly outperforming both the clinical baseline (delta-c = +0.029, p = 0.0005) and the best imaging-only model (delta-c = +0.062, p = 0.039), suggesting H&E morphology contains prognostic information complementary to grade. A median risk split yields log-rank p < 0.0001 separation in BCR-free survival (~20% vs ~70% at five years).
Non-invasive prediction of Gleason Grade Group (GGG) in prostate cancer using multiparametric MRI (mpMRI) is clinically vital for reducing unnecessary biopsies. Existing GGG prediction methods face two major limitations. First, they often overlook non-image information critical for GGG prediction, including age, prostate-specific antigen (PSA), and expert priors embedded in radiology reports. Second, they tend to oversimplify GGG as flat categorical labels, failing to account for its intrinsic hierarchy of primary and secondary Gleason patterns. To this end, we propose a novel Knowledge-Driven Ordinal-Aware Learning (KOAL) framework with three synergistic modules. Specifically, the Clinical-Context Modulation (CCM) module uses clinical variables (e.g., age and PSA) to dynamically modulate discriminative image representations. The Knowledge-Guided Prototype Alignment (KGPA) module leverages an LLM to extract group-specific expert knowledge from training radiology reports and clinical guidelines, producing offline semantic anchors describing grade-specific radiological findings without requiring patient-specific reports at inference. Through prototype contrastive alignment, patient-specific mpMRI representations are matched with these anchors to promote pathology-aligned representation learning. The Hierarchical Ordinal-aware Constraints (HOC) module decouples primary and secondary Gleason pattern prediction and maps their probabilistic outputs to GGG via a Differentiable Bio-logic Mapping Layer (DBML), ensuring pathological grading consistency. Experiments on public PI-CAI and in-house datasets demonstrate that KOAL outperforms state-of-the-art methods. Code is available at: https://github.com/Gother-GZ/KOAL.
Traditional comorbidity scores (e.g., Charlson and Elixhauser) are widely used for risk adjustment and patient stratification, but they have two key limitations: (i) they are largely mortality-centric and do not align well with other clinical outcomes, and (ii) their linear, rule-based structure cannot capture nonlinear, outcome-specific risk relationships. We propose a Machine-Learned Comorbidity Index (MLCI) that maps diagnosis codes to a single scalar by maximizing the normalized Hilbert-Schmidt Independence Criterion (nHSIC) between the learned score and multiple clinical outcomes. MLCI captures nonlinear risk-outcome dependence and is supported by a theory that characterizes when a unified, informative admission-level ordering can be achieved across outcomes. Empirical results on multiple benchmark electronic health record (EHR) datasets show that MLCI outperforms strong baselines across multiple evaluation metrics.