Multimodality Stacking with Blockwise missing values and application to the PIONeeR biomarkers study for prediction of resistance to immunotherapy
Authors: Mohamed Boussena, Florence Monville, Jacques Fieschi-Meric, Frederic Vely, Pierre Milpied, Julien Mazieres, Maurice Perol, Eric Vivier, +3 more
Organizations: Inria – Inserm team COMPO, COMPutational pharmacology and clinical Oncology, Centre Inria Sophia Antipolis - M´editerran´ee, Centre de Recherches en Canc´erologie de Marseille, Inserm U1068, CNRS UMR7258, Institut Paoli-Calmettes, Pharmacy faculty, Aix-Marseille University · Veracyte SAS, Marseille, France · Assistance Publique-Hˆopitaux de Marseille (APHM), Marseille, France · Toulouse University Hospital, Toulouse, France · Centre Leon Berard, Lyon, France · Innate Pharma, Marseille, France · Universit´e Paris Saclay, Gustave Roussy, Inserm, Pr´edicteurs Mol´eculaires et nouvelles cibles en oncologie (U981), F-94805, Villejuif, France
Abstract
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.
Recent multimodal survival prediction models have demonstrated strong predictive performance by leveraging complementary information across modalities. However, such models generally assume data completeness and exhibit limited robustness toward missing modalities, which are frequently encountered in real-world clinical settings. We propose the Evidential Missing Modality Survival Fusion (EMMS) model for multimodal survival prediction under missing modalities. EMMS offers a straightforward, computationally effective approach to survival analysis without requiring a generative phase for missing data. By employing Dempster-Shafer theory and Gaussian Random Fuzzy Numbers for multimodal decision fusion, it considers both aleatoric and epistemic uncertainty alongside modality reliability for fusion. Moreover, the model treats missing modalities as vacuous evidence, preventing interference with available inputs and naturally reflecting increased uncertainty and calibrated predictions. Extensive experiments on four cancer datasets demonstrate state-of-the-art performance while providing calibrated and interpretable uncertainty estimates under incomplete multimodal observations, without introducing additional computational overhead.
We propose a novel multimodal deep learning framework for patient-level survival prediction, which integrates whole-slide histology features, RNA-seq expression profiles, and clinical variables. Our architecture combines an ABMIL module~\cite{ilse2018attention} for slide-level representation with feedforward encoders for RNA and clinical data. These embeddings are then integrated through low-rank bilinear cross-modal fusion~\cite{liu2018efficient} to model conditional interactions across modalities while controlling parameter growth. The model outputs continuous risk scores that are subsequently mapped to survival times using a nonparametric calibration procedure based on the Kaplan--Meier estimator~\cite{kaplan1958nonparametric}. By decomposing multimodal reasoning into independent pairwise interactions, the proposed fusion design promotes structural interpretability and parameter efficiency compared with full tensor and hierarchical fusion strategies. Experiments on the CHIMERA challenge dataset demonstrate improved predictive performance over concatenation-based baselines and competitive generalization on hidden evaluation cohorts. These results indicate that the proposed framework is a promising approach for multimodal survival prediction in HR-NMIBC. The implementation is publicly available at https://github.com/hassancpu/ChimeraChallenge2025_Task_3.
Hassan Keshvarikhojasteh, Josien P. W. Pluim, Mitko Veta
Multimodal survival prediction, a crucial yet challenging task, demands the integration of multimodal medical data (\eg Whole Slide Images (WSIs) and Genomic Profiles) to achieve accurate prognostic modeling. Given the inherent heterogeneity across modalities, the feature decoupling-fusion paradigm has emerged as a dominant approach. However, these methods have the following shortcomings: (1) fail to reduce the redundant information of modality features before decoupling, which negatively affects the feature decoupling and fusion effect;(2) lack the ability to model the fine-grained relationships of the features and capture the local information interactions between intra- and inter-modality features. To address these issues, we propose a \underline{H}ierarchical \underline{D}ecoupling-Fusion \underline{M}ixture-\underline{o}f-\underline{E}xperts (HDMoE) framework with two levels of MoE and \underline{R}andom \underline{F}eature \underline{R}eorganization (RFR) modules.In the first-level MoE, shared experts and routed experts are employed to remove redundant information and extract fine-grained specific features within each modality, while the second-level MoE facilitates fine-grained inter-modality feature decoupling. Besides, we design two RFR modules following each level of MoE to finely fuse intra- and inter-modality features, which can help the model capture more fine-grained relationships between modalities. Extensive experimental results on our private Liver Cancer (LC) and three TCGA public datasets confirm the effectiveness of our proposed method. Codes are available at https://github.com/ZJUMAI/HDMoE.