Dementia of Alzheimer's Type (DAT) is a complex disorder influenced by numerous factors, but it is unclear how each factor contributes to disease progression. An in-depth examination of these factors may yield an accurate estimate of time-to-conversion to DAT for patients at various disease stages. We used 401 subjects with 63 features from MRI, genetic, and CDC (Cognitive tests, Demographic, and CSF) data modalities in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. We used a deep learning-based survival analysis model that extends the classic Cox regression model to predict time-to-conversion to DAT. Our findings showed that genetic features contributed the least to survival analysis, while CDC features contributed the most. Combining MRI and genetic features improved survival prediction over using either modality alone, but adding CDC to any combination of features only worked as well as using only CDC features. Consequently, our study demonstrated that using the current clinical procedure, which includes gathering cognitive test results, can outperform survival analysis results produced using costly genetic or CSF data.
Decisions about managing patients on the heart transplant waitlist are currently made by committees of doctors who consider multiple factors, but the process remains largely ad-hoc. With the growing volume of longitudinal patient, donor, and organ data collected by the United Network for Organ Sharing (UNOS) since 2018, there is increasing interest in analytical approaches to support clinical decision-making at the time of organ availability. In this study, we benchmark machine learning models that leverage longitudinal waitlist history data for time-dependent, time-to-event modeling of waitlist mortality. We train on 23,807 patient records with 77 variables and evaluate both survival prediction and discrimination at a 1-year horizon. Our best model achieves a C-Index of 0.94 and AUROC of 0.89, significantly outperforming previous models. Key predictors align with known risk factors while also revealing novel associations. Our findings can support urgency assessment and policy refinement in heart transplant decision making.
Survival prediction using whole slide images (WSIs) can be formulated as a multiple instance learning (MIL) problem. However, existing MIL methods often fail to explicitly capture pathological heterogeneity within WSIs, both globally -- through long-tailed morphological distributions, and locally through -- tile-level prediction uncertainty. Optimal transport (OT) provides a principled way of modeling such heterogeneity by incorporating marginal distribution constraints. Building on this insight, we propose OTSurv, a novel MIL framework from an optimal transport perspective. Specifically, OTSurv formulates survival predictions as a heterogeneity-aware OT problem with two constraints: (1) global long-tail constraint that models prior morphological distributions to avert both mode collapse and excessive uniformity by regulating transport mass allocation, and (2) local uncertainty-aware constraint that prioritizes high-confidence patches while suppressing noise by progressively raising the total transport mass. We then recast the initial OT problem, augmented by these constraints, into an unbalanced OT formulation that can be solved with an efficient, hardware-friendly matrix scaling algorithm. Empirically, OTSurv sets new state-of-the-art results across six popular benchmarks, achieving an absolute 3.6% improvement in average C-index. In addition, OTSurv achieves statistical significance in log-rank tests and offers high interpretability, making it a powerful tool for survival prediction in digital pathology. Our codes are available at https://github.com/Y-Research-SBU/OTSurv.
Accurately predicting immunotherapy response in Non-Small Cell Lung Cancer (NSCLC) remains a critical unmet need. Existing radiomics and deep learning-based predictive models rely primarily on pre-treatment imaging to predict categorical response outcomes, limiting their ability to capture the complex morphological and textural transformations induced by immunotherapy. This study introduces ImmunoDiff, an anatomy-aware diffusion model designed to synthesize post-treatment CT scans from baseline imaging while incorporating clinically relevant constraints. The proposed framework integrates anatomical priors, specifically lobar and vascular structures, to enhance fidelity in CT synthesis. Additionally, we introduce a novel cbi-Adapter, a conditioning module that ensures pairwise-consistent multimodal integration of imaging and clinical data embeddings, to refine the generative process. Additionally, a clinical variable conditioning mechanism is introduced, leveraging demographic data, blood-based biomarkers, and PD-L1 expression to refine the generative process. Evaluations on an in-house NSCLC cohort treated with immune checkpoint inhibitors demonstrate a 21.24% improvement in balanced accuracy for response prediction and a 0.03 increase in c-index for survival prediction. Code will be released soon.
Multimodal pathology-genomic analysis has become increasingly prominent in cancer survival prediction. However, existing studies mainly utilize multi-instance learning to aggregate patch-level features, neglecting the information loss of contextual and hierarchical details within pathology images. Furthermore, the disparity in data granularity and dimensionality between pathology and genomics leads to a significant modality imbalance. The high spatial resolution inherent in pathology data renders it a dominant role while overshadowing genomics in multimodal integration. In this paper, we propose a multimodal survival prediction framework that incorporates hypergraph learning to effectively capture both contextual and hierarchical details from pathology images. Moreover, it employs a modality rebalance mechanism and an interactive alignment fusion strategy to dynamically reweight the contributions of the two modalities, thereby mitigating the pathology-genomics imbalance. Quantitative and qualitative experiments are conducted on five TCGA datasets, demonstrating that our model outperforms advanced methods by over 3.4\% in C-Index performance.
Recent advances in computational pathology and artificial intelligence have significantly enhanced the utilization of gigapixel whole-slide images and and additional modalities (e.g., genomics) for pathological diagnosis. Although deep learning has demonstrated strong potential in pathology, several key challenges persist: (1) fusing heterogeneous data types requires sophisticated strategies beyond simple concatenation due to high computational costs; (2) common scenarios of missing modalities necessitate flexible strategies that allow the model to learn robustly in the absence of certain modalities; (3) the downstream tasks in CPath are diverse, ranging from unimodal to multimodal, cnecessitating a unified model capable of handling all modalities. To address these challenges, we propose ALTER, an any-to-any tri-modal pretraining framework that integrates WSIs, genomics, and pathology reports. The term "any" emphasizes ALTER's modality-adaptive design, enabling flexible pretraining with any subset of modalities, and its capacity to learn robust, cross-modal representations beyond WSI-centric approaches. We evaluate ALTER across extensive clinical tasks including survival prediction, cancer subtyping, gene mutation prediction, and report generation, achieving superior or comparable performance to state-of-the-art baselines.
The Cancer Genome Atlas (TCGA) has enabled novel discoveries and served as a large-scale reference through its harmonized genomics, clinical, and image data. Prior studies have trained bespoke cancer survival prediction models from unimodal or multimodal TCGA data. A modern paradigm in biomedical deep learning is the development of foundation models (FMs) to derive meaningful feature embeddings, agnostic to a specific modeling task. Biomedical text especially has seen growing development of FMs. While TCGA contains free-text data as pathology reports, these have been historically underutilized. Here, we investigate the feasibility of training classical, multimodal survival models over zero-shot embeddings extracted by FMs. We show the ease and additive effect of multimodal fusion, outperforming unimodal models. We demonstrate the benefit of including pathology report text and rigorously evaluate the effect of model-based text summarization and hallucination. Overall, we modernize survival modeling by leveraging FMs and information extraction from pathology reports.
Survival analysis often relies on Cox models, assuming both linearity and proportional hazards (PH). This study evaluates machine and deep learning methods that relax these constraints, comparing their performance with penalized Cox models on a benchmark of three synthetic and three real datasets. In total, eight different models were tested, including six non-linear models of which four were also non-PH. Although Cox regression often yielded satisfactory performance, we showed the conditions under which machine and deep learning models can perform better. Indeed, the performance of these methods has often been underestimated due to the improper use of Harrell's concordance index (C-index) instead of more appropriate scores such as Antolini's concordance index, which generalizes C-index in cases where the PH assumption does not hold. In addition, since occasionally high C-index models happen to be badly calibrated, combining Antolini's C-index with Brier's score is useful to assess the overall performance of a survival method. Results on our benchmark data showed that survival prediction should be approached by testing different methods to select the most appropriate one according to sample size, non-linearity and non-PH conditions. To allow an easy reproducibility of these tests on our benchmark data, code and documentation are freely available at https://github.com/compbiomed-unito/survhive.
Cancer survival prediction using multi-modal medical imaging presents a critical challenge in oncology, mainly due to the vulnerability of deep learning models to noise and protocol variations across imaging centers. Current approaches struggle to extract consistent features from heterogeneous CT and PET images, limiting their clinical applicability. We address these challenges by introducing RobSurv, a robust deep-learning framework that leverages vector quantization for resilient multi-modal feature learning. The key innovation of our approach lies in its dual-path architecture: one path maps continuous imaging features to learned discrete codebooks for noise-resistant representation, while the parallel path preserves fine-grained details through continuous feature processing. This dual representation is integrated through a novel patch-wise fusion mechanism that maintains local spatial relationships while capturing global context via Transformer-based processing. In extensive evaluations across three diverse datasets (HECKTOR, H\&N1, and NSCLC Radiogenomics), RobSurv demonstrates superior performance, achieving concordance index of 0.771, 0.742, and 0.734 respectively - significantly outperforming existing methods. Most notably, our model maintains robust performance even under severe noise conditions, with performance degradation of only 3.8-4.5\% compared to 8-12\% in baseline methods. These results, combined with strong generalization across different cancer types and imaging protocols, establish RobSurv as a promising solution for reliable clinical prognosis that can enhance treatment planning and patient care.
The integration of high-dimensional genomic data and clinical data into time-to-event prediction models has gained significant attention due to the growing availability of these datasets. Traditionally, a Cox regression model is employed, concatenating various covariate types linearly. Given that much of the data may be redundant or irrelevant, feature selection through penalization is often desirable. A notable characteristic of these datasets is their organization into blocks of distinct data types, such as methylation and clinical predictors, which requires selecting a subset of covariates from each group due to high intra-group correlations. For this reason, we propose utilizing Exclusive Lasso regularization in place of standard Lasso penalization. We apply our methodology to a real-life cancer dataset, demonstrating enhanced survival prediction performance compared to the conventional Cox regression model.
Oncologists often rely on a multitude of data, including whole-slide images (WSIs), to guide therapeutic decisions, aiming for the best patient outcome. However, predicting the prognosis of cancer patients can be a challenging task due to tumor heterogeneity and intra-patient variability, and the complexity of analyzing WSIs. These images are extremely large, containing billions of pixels, making direct processing computationally expensive and requiring specialized methods to extract relevant information. Additionally, multiple WSIs from the same patient may capture different tumor regions, some being more informative than others. This raises a fundamental question: Should we use all WSIs to characterize the patient, or should we identify the most representative slide for prognosis? Our work seeks to answer this question by performing a comparison of various strategies for predicting survival at the WSI and patient level. The former treats each WSI as an independent sample, mimicking the strategy adopted in other works, while the latter comprises methods to either aggregate the predictions of the several WSIs or automatically identify the most relevant slide using multiple-instance learning (MIL). Additionally, we evaluate different Graph Neural Networks architectures under these strategies. We conduct our experiments using the MMIST-ccRCC dataset, which comprises patients with clear cell renal cell carcinoma (ccRCC). Our results show that MIL-based selection improves accuracy, suggesting that choosing the most representative slide benefits survival prediction.
The integration of pathologic images and genomic data for survival analysis has gained increasing attention with advances in multimodal learning. However, current methods often ignore biological characteristics, such as heterogeneity and sparsity, both within and across modalities, ultimately limiting their adaptability to clinical practice. To address these challenges, we propose AdaMHF: Adaptive Multimodal Hierarchical Fusion, a framework designed for efficient, comprehensive, and tailored feature extraction and fusion. AdaMHF is specifically adapted to the uniqueness of medical data, enabling accurate predictions with minimal resource consumption, even under challenging scenarios with missing modalities. Initially, AdaMHF employs an experts expansion and residual structure to activate specialized experts for extracting heterogeneous and sparse features. Extracted tokens undergo refinement via selection and aggregation, reducing the weight of non-dominant features while preserving comprehensive information. Subsequently, the encoded features are hierarchically fused, allowing multi-grained interactions across modalities to be captured. Furthermore, we introduce a survival prediction benchmark designed to resolve scenarios with missing modalities, mirroring real-world clinical conditions. Extensive experiments on TCGA datasets demonstrate that AdaMHF surpasses current state-of-the-art (SOTA) methods, showcasing exceptional performance in both complete and incomplete modality settings.
Multimodal learning combining pathology images and genomic sequences enhances cancer survival analysis but faces clinical implementation barriers due to limited access to genomic sequencing in under-resourced regions. To enable survival prediction using only whole-slide images (WSI), we propose the Visual-Genomic Answering-Guided Transformer (VGAT), a framework integrating Visual Question Answering (VQA) techniques for genomic modality reconstruction. By adapting VQA's text feature extraction approach, we derive stable genomic representations that circumvent dimensionality challenges in raw genomic data. Simultaneously, a cluster-based visual prompt module selectively enhances discriminative WSI patches, addressing noise from unfiltered image regions. Evaluated across five TCGA datasets, VGAT outperforms existing WSI-only methods, demonstrating the viability of genomic-informed inference without sequencing. This approach bridges multimodal research and clinical feasibility in resource-constrained settings. The code link is https://github.com/CZZZZZZZZZZZZZZZZZ/VGAT.
Breast cancer survival prediction in computational pathology presents a remarkable challenge due to tumor heterogeneity. For instance, different regions of the same tumor in the pathology image can show distinct morphological and molecular characteristics. This makes it difficult to extract representative features from whole slide images (WSIs) that truly reflect the tumor's aggressive potential and likely survival outcomes. In this paper, we present PathoHR, a novel pipeline for accurate breast cancer survival prediction that enhances any size of pathological images to enable more effective feature learning. Our approach entails (1) the incorporation of a plug-and-play high-resolution Vision Transformer (ViT) to enhance patch-wise WSI representation, enabling more detailed and comprehensive feature extraction, (2) the systematic evaluation of multiple advanced similarity metrics for comparing WSI-extracted features, optimizing the representation learning process to better capture tumor characteristics, (3) the demonstration that smaller image patches enhanced follow the proposed pipeline can achieve equivalent or superior prediction accuracy compared to raw larger patches, while significantly reducing computational overhead. Experimental findings valid that PathoHR provides the potential way of integrating enhanced image resolution with optimized feature learning to advance computational pathology, offering a promising direction for more accurate and efficient breast cancer survival prediction. Code will be available at https://github.com/AIGeeksGroup/PathoHR.
To improve the prediction of cancer survival using whole-slide images and transcriptomics data, it is crucial to capture both modality-shared and modality-specific information. However, multimodal frameworks often entangle these representations, limiting interpretability and potentially suppressing discriminative features. To address this, we propose Disentangled and Interpretable Multimodal Attention Fusion (DIMAF), a multimodal framework that separates the intra- and inter-modal interactions within an attention-based fusion mechanism to learn distinct modality-specific and modality-shared representations. We introduce a loss based on Distance Correlation to promote disentanglement between these representations and integrate Shapley additive explanations to assess their relative contributions to survival prediction. We evaluate DIMAF on four public cancer survival datasets, achieving a relative average improvement of 1.85% in performance and 23.7% in disentanglement compared to current state-of-the-art multimodal models. Beyond improved performance, our interpretable framework enables a deeper exploration of the underlying interactions between and within modalities in cancer biology.
Multimodal learning that integrates histopathology images and genomic data holds great promise for cancer survival prediction. However, existing methods face key limitations: 1) They rely on multimodal mapping and metrics in Euclidean space, which cannot fully capture the hierarchical structures in histopathology (among patches from different resolutions) and genomics data (from genes to pathways). 2) They discretize survival time into independent risk intervals, which ignores its continuous and ordinal nature and fails to achieve effective optimization. 3) They treat censorship as a binary indicator, excluding censored samples from model optimization and not making full use of them. To address these challenges, we propose HySurvPred, a novel framework for survival prediction that integrates three key modules: Multimodal Hyperbolic Mapping (MHM), Angle-aware Ranking-based Contrastive Loss (ARCL) and Censor-Conditioned Uncertainty Constraint (CUC). Instead of relying on Euclidean space, we design the MHM module to explore the inherent hierarchical structures within each modality in hyperbolic space. To better integrate multimodal features in hyperbolic space, we introduce the ARCL module, which uses ranking-based contrastive learning to preserve the ordinal nature of survival time, along with the CUC module to fully explore the censored data. Extensive experiments demonstrate that our method outperforms state-of-the-art methods on five benchmark datasets. The source code is to be released.
An important goal in cancer research is the survival prognosis of a patient based on a minimal panel of genomic and molecular markers such as genes or proteins. Purely data-driven models without any biological knowledge can produce non-interpretable results. We propose a penalized semiparametric Bayesian Cox model with graph-structured selection priors for sparse identification of multi-omics features by making use of a biologically meaningful graph via a Markov random field (MRF) prior to capturing known relationships between multi-omics features. Since the fixed graph in the MRF prior is for the prior probability distribution, it is not a hard constraint to determine variable selection, so the proposed model can verify known information and has the potential to identify new and novel biomarkers for drawing new biological knowledge. Our simulation results show that the proposed Bayesian Cox model with graph-based prior knowledge results in more trustable and stable variable selection and non-inferior survival prediction, compared to methods modeling the covariates independently without any prior knowledge. The results also indicate that the performance of the proposed model is robust to a partially correct graph in the MRF prior, meaning that in a real setting where not all the true network information between covariates is known, the graph can still be useful. The proposed model is applied to the primary invasive breast cancer patients data in The Cancer Genome Atlas project.
The histopathological classification of whole-slide images (WSIs) is a fundamental task in digital pathology; yet it requires extensive time and expertise from specialists. While deep learning methods show promising results, they typically process WSIs by dividing them into artificial patches, which inherently prevents a network from learning from the entire image context, disregards natural tissue structures and compromises interpretability. Our method overcomes this limitation through a novel graph-based framework that constructs WSI graph representations. The WSI-graph efficiently captures essential histopathological information in a compact form. We build tissue representations (nodes) that follow biological boundaries rather than arbitrary patches all while providing interpretable features for explainability. Through adaptive graph coarsening guided by learned embeddings, we progressively merge regions while maintaining discriminative local features and enabling efficient global information exchange. In our method's final step, we solve the diagnostic task through a graph attention network. We empirically demonstrate strong performance on multiple challenging tasks such as cancer stage classification and survival prediction, while also identifying predictive factors using Integrated Gradients. Our implementation is publicly available at https://github.com/HistoGraph31/pix2pathology
Histo-genomic multimodal survival prediction has garnered growing attention for its remarkable model performance and potential contributions to precision medicine. However, a significant challenge in clinical practice arises when only unimodal data is available, limiting the usability of these advanced multimodal methods. To address this issue, this study proposes a prototype-guided cross-modal knowledge enhancement (ProSurv) framework, which eliminates the dependency on paired data and enables robust learning and adaptive survival prediction. Specifically, we first introduce an intra-modal updating mechanism to construct modality-specific prototype banks that encapsulate the statistics of the whole training set and preserve the modality-specific risk-relevant features/prototypes across intervals. Subsequently, the proposed cross-modal translation module utilizes the learned prototypes to enhance knowledge representation for multimodal inputs and generate features for missing modalities, ensuring robust and adaptive survival prediction across diverse scenarios. Extensive experiments on four public datasets demonstrate the superiority of ProSurv over state-of-the-art methods using either unimodal or multimodal input, and the ablation study underscores its feasibility for broad applicability. Overall, this study addresses a critical practical challenge in computational pathology, offering substantial significance and potential impact in the field.
Accurate survival prediction in oncology requires integrating diverse imaging modalities to capture the complex interplay of tumor biology. Traditional single-modality approaches often fail to leverage the complementary insights provided by radiological and pathological assessments. In this work, we introduce M4Survive (Multi-Modal Mamba Modeling for Survival Prediction), a novel framework that learns joint foundation model representations using efficient adapter networks. Our approach dynamically fuses heterogeneous embeddings from a foundation model repository (e.g., MedImageInsight, BiomedCLIP, Prov-GigaPath, UNI2-h), creating a correlated latent space optimized for survival risk estimation. By leveraging Mamba-based adapters, M4Survive enables efficient multi-modal learning while preserving computational efficiency. Experimental evaluations on benchmark datasets demonstrate that our approach outperforms both unimodal and traditional static multi-modal baselines in survival prediction accuracy. This work underscores the potential of foundation model-driven multi-modal fusion in advancing precision oncology and predictive analytics.