A Contrastive Variational AutoEncoder for NSCLC Survival Prediction with Missing Modalities

Accurate survival prediction from multimodal medical data is essential for precision oncology, yet clinical deployment faces a persistent challenge: modalities are frequently incomplete due to cost constraints, technical limitations, or retrospective data availability. While recent methods attempt to address missing modalities through feature alignment or joint distribution learning, they fundamentally lack explicit modeling of the unique contributions of each modality as opposed to the information derivable from other modalities. We propose MUST (Modality-Specific representation-aware Transformer), a novel framework that explicitly decomposes each modality's representation into modality-specific and cross-modal contextualized components through algebraic constraints in a learned low-rank shared subspace. This decomposition enables precise identification of what information is lost when a modality is absent. For the truly modality-specific information that cannot be inferred from available modalities, we employ conditional latent diffusion models to generate high-quality representations conditioned on recovered shared information and learned structural priors. Extensive experiments on five TCGA cancer datasets demonstrate that MUST achieves state-of-the-art performance with complete data while maintaining robust predictions in both missing pathology and missing genomics conditions, with clinically acceptable inference latency.

Lung cancer results in roughly 1.8 million fatalities annually worldwide, with non-small cell lung cancer (NSCLC) comprising the majority of cases. Despite advancements in treatment, survival stratification remains challenging due to intratumoral heterogeneity inadequately captured by conventional descriptors. Standard radiomic and deep learning techniques regard imaging features as independent quantities, overlooking structured interactions between tumor characteristics. We evaluate whether structured proxy features can enhance multimodal NSCLC survival prediction by augmenting pretreatment computed tomography (CT) representations, radiomics, and clinical variables with six simulation-derived features designed to capture interactions between heterogeneity and morphology. A radiomic-parameterized cellular automaton generates growth-rate and necrosis-ratio proxy features from baseline CT by using entropy and sphericity to compute low-dimensional proxy parameters. The imaging backbone is a Transformer-based Masked Autoencoder (TMAE), which was chosen after a systematic evaluation with alternative encoders within the same pipeline and provides attention-based visualizations that highlight tumor regions receiving higher model attention. On the public Lung1 cohort (n = 390), the primary four-modality fusion attained a C-index of 0.641 (iAUC 0.731, log-rank p < 0.001). The primary result compares favorably with prior multimodal results on Lung1 (C-index 0.631; iAUC 0.592 [15]) under a comparable evaluation protocol, while a separate exploratory coefficient-optimization analysis achieved a best observed C-index of 0.662 (iAUC 0.748). These results indicate that, in addition to conventional radiomic, deep, and clinical representations within the Lung1 benchmark, simulation-derived proxy features may provide complementary predictive information within this fixed Lung1 benchmark.

Integrating multimodal datasets in clinical oncology is frequently hindered by high dimensionality and blockwise missingness, where entire data sources are unavailable for specific patient subsets. Standard survival models often struggle with these gaps, leading to biased results or patient exclusion. We introduce Multimodality Stacking with Blockwise missing values (MSB), a late-fusion framework for survival analysis that independently models modality-specific features before aggregating predictions via a cross-validated stacking meta-learner. MSB was validated on the PIONeeR study (n=443 patients, 378 biomarkers across eight heterogeneous sources) to predict progression-free survival in advanced non-small cell lung cancer patients receiving immunotherapy. MSB yielded higher predictive performance (C-index) than baseline algorithms. Improvements varied by baseline strength: linear models showed a 15.9% increase (p<0.001 for the Wilcoxon signed-rank test), random survival forests gained 5.4% (p=0.002), and gradient boosting methods improved by 2.1% (p=0.030). Beyond discrimination, MSB reduced the generalization gap (train-test difference in 5 folds cross-validation repeated 3 times: 0.055 vs 0.380 for linear models). Permutation importance analysis identified routine laboratory markers, clinical features, and PD-L1 expression as primary predictive drivers. Missing block indicators showed negligible importance, suggesting the model learned from biomarker values rather than data availability patterns. MSB provides a statistically validated framework for multimodal survival prediction with blockwise missingness. By enabling systematic biomarker evaluation without requiring complete data, MSB offers a practical tool for predictive modeling in biomedical research, pending external validation. Implementation is available at https://github.com/MohamedBoussena/MSB under Inria license.