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.
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.
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.
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.
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.
The integrative analysis of histopathological images and genomic data has received increasing attention for survival prediction of human cancers. However, the existing studies always hold the assumption that full modalities are available. As a matter of fact, the cost for collecting genomic data is high, which sometimes makes genomic data unavailable in testing samples. A common way of tackling such incompleteness is to generate the genomic representations from the pathology images. Nevertheless, such strategy still faces the following two challenges: (1) The gigapixel whole slide images (WSIs) are huge and thus hard for representation. (2) It is difficult to generate the genomic embeddings with diverse function categories in a unified generative framework. To address the above challenges, we propose a Conditional Latent Differentiation Variational AutoEncoder (LD-CVAE) for robust multimodal survival prediction, even with missing genomic data. Specifically, a Variational Information Bottleneck Transformer (VIB-Trans) module is proposed to learn compressed pathological representations from the gigapixel WSIs. To generate different functional genomic features, we develop a novel Latent Differentiation Variational AutoEncoder (LD-VAE) to learn the common and specific posteriors for the genomic embeddings with diverse functions. Finally, we use the product-of-experts technique to integrate the genomic common posterior and image posterior for the joint latent distribution estimation in LD-CVAE. We test the effectiveness of our method on five different cancer datasets, and the experimental results demonstrate its superiority in both complete and missing modality scenarios.
Leveraging multimodal data, particularly the integration of whole-slide histology images (WSIs) and transcriptomic profiles, holds great promise for improving cancer survival prediction. However, excessive redundancy in multimodal data can degrade model performance. In this paper, we propose Adaptive Prototype Learning (APL), a novel and effective approach for multimodal cancer survival analysis. APL adaptively learns representative prototypes in a data-driven manner, reducing redundancy while preserving critical information. Our method employs two sets of learnable query vectors that serve as a bridge between high-dimensional representations and survival prediction, capturing task-relevant features. Additionally, we introduce a multimodal mixed self-attention mechanism to enable cross-modal interactions, further enhancing information fusion. Extensive experiments on five benchmark cancer datasets demonstrate the superiority of our approach over existing methods. The code is available at https://github.com/HongLiuuuuu/APL.
Cancer survival prediction from whole slide images (WSIs) is a challenging task in computational pathology due to the large size, irregular shape, and high granularity of the WSIs. These characteristics make it difficult to capture the full spectrum of patterns, from subtle cellular abnormalities to complex tissue interactions, which are crucial for accurate prognosis. To address this, we propose CrossFusion, a novel multi-scale feature integration framework that extracts and fuses information from patches across different magnification levels. By effectively modeling both scale-specific patterns and their interactions, CrossFusion generates a rich feature set that enhances survival prediction accuracy. We validate our approach across six cancer types from public datasets, demonstrating significant improvements over existing state-of-the-art methods. Moreover, when coupled with domain-specific feature extraction backbones, our method shows further gains in prognostic performance compared to general-purpose backbones. The source code is available at: https://github.com/RustinS/CrossFusion
Foundation models are reshaping computational pathology by enabling transfer learning, where models pre-trained on vast datasets can be adapted for downstream diagnostic, prognostic, and therapeutic response tasks. Despite these advances, foundation models are still limited in their ability to encode the entire gigapixel whole-slide images without additional training and often lack complementary multimodal data. Here, we introduce Threads, a slide-level foundation model capable of generating universal representations of whole-slide images of any size. Threads was pre-trained using a multimodal learning approach on a diverse cohort of 47,171 hematoxylin and eosin (H&E)-stained tissue sections, paired with corresponding genomic and transcriptomic profiles - the largest such paired dataset to be used for foundation model development to date. This unique training paradigm enables Threads to capture the tissue's underlying molecular composition, yielding powerful representations applicable to a wide array of downstream tasks. In extensive benchmarking across 54 oncology tasks, including clinical subtyping, grading, mutation prediction, immunohistochemistry status determination, treatment response prediction, and survival prediction, Threads outperformed all baselines while demonstrating remarkable generalizability and label efficiency. It is particularly well suited for predicting rare events, further emphasizing its clinical utility. We intend to make the model publicly available for the broader community.
Survival prediction is a crucial task in the medical field and is essential for optimizing treatment options and resource allocation. However, current methods often rely on limited data modalities, resulting in suboptimal performance. In this paper, we propose an Integrated Cross-modal Fusion Network (ICFNet) that integrates histopathology whole slide images, genomic expression profiles, patient demographics, and treatment protocols. Specifically, three types of encoders, a residual orthogonal decomposition module and a unification fusion module are employed to merge multi-modal features to enhance prediction accuracy. Additionally, a balanced negative log-likelihood loss function is designed to ensure fair training across different patients. Extensive experiments demonstrate that our ICFNet outperforms state-of-the-art algorithms on five public TCGA datasets, including BLCA, BRCA, GBMLGG, LUAD, and UCEC, and shows its potential to support clinical decision-making and advance precision medicine. The codes are available at: https://github.com/binging512/ICFNet.
Purpose: Immunotherapies have revolutionized the landscape of cancer treatments. However, our understanding of response patterns in advanced cancers treated with immunotherapy remains limited. By leveraging routinely collected noninvasive longitudinal and multimodal data with artificial intelligence, we could unlock the potential to transform immunotherapy for cancer patients, paving the way for personalized treatment approaches. Methods: In this study, we developed a novel artificial neural network architecture, multimodal transformer-based simple temporal attention (MMTSimTA) network, building upon a combination of recent successful developments. We integrated pre- and on-treatment blood measurements, prescribed medications and CT-based volumes of organs from a large pan-cancer cohort of 694 patients treated with immunotherapy to predict mortality at three, six, nine and twelve months. Different variants of our extended MMTSimTA network were implemented and compared to baseline methods incorporating intermediate and late fusion based integration methods. Results: The strongest prognostic performance was demonstrated using a variant of the MMTSimTA model with area under the curves (AUCs) of $0.84 \pm $0.04, $0.83 \pm $0.02, $0.82 \pm $0.02, $0.81 \pm $0.03 for 3-, 6-, 9-, and 12-month survival prediction, respectively. Discussion: Our findings show that integrating noninvasive longitudinal data using our novel architecture yields an improved multimodal prognostic performance, especially in short-term survival prediction. Conclusion: Our study demonstrates that multimodal longitudinal integration of noninvasive data using deep learning may offer a promising approach for personalized prognostication in immunotherapy-treated cancer patients.
Understanding how deep learning models predict oncology patient risk can provide critical insights into disease progression, support clinical decision-making, and pave the way for trustworthy and data-driven precision medicine. Building on recent advances in the spatial modeling of the tumor microenvironment using graph neural networks, we present an explainable cell graph (xCG) approach for survival prediction. We validate our model on a public cohort of imaging mass cytometry (IMC) data for 416 cases of lung adenocarcinoma. We explain survival predictions in terms of known phenotypes on the cell level by computing risk attributions over cell graphs, for which we propose an efficient grid-based layer-wise relevance propagation (LRP) method. Our ablation studies highlight the importance of incorporating the cancer stage and model ensembling to improve the quality of risk estimates. Our xCG method, together with the IMC data, is made publicly available to support further research.
Survival prediction often involves estimating the time-to-event distribution from censored datasets. Previous approaches have focused on enhancing discrimination and marginal calibration. In this paper, we highlight the significance of conditional calibration for real-world applications -- especially its role in individual decision-making. We propose a method based on conformal prediction that uses the model's predicted individual survival probability at that instance's observed time. This method effectively improves the model's marginal and conditional calibration, without compromising discrimination. We provide asymptotic theoretical guarantees for both marginal and conditional calibration and test it extensively across 15 diverse real-world datasets, demonstrating the method's practical effectiveness and versatility in various settings.
In survival analysis, subjects often face competing risks; for example, individuals with cancer may also suffer from heart disease or other illnesses, which can jointly influence the prognosis of risks and censoring. Traditional survival analysis methods often treat competing risks as independent and fail to accommodate the dependencies between different conditions. In this paper, we introduce HACSurv, a survival analysis method that learns Hierarchical Archimedean Copulas structures and cause-specific survival functions from data with competing risks. HACSurv employs a flexible dependency structure using hierarchical Archimedean copulas to represent the relationships between competing risks and censoring. By capturing the dependencies between risks and censoring, HACSurv improves the accuracy of survival predictions and offers insights into risk interactions. Experiments on synthetic dataset demonstrate that our method can accurately identify the complex dependency structure and precisely predict survival distributions, whereas the compared methods exhibit significant deviations between their predictions and the true distributions. Experiments on multiple real-world datasets also demonstrate that our method achieves better survival prediction compared to previous state-of-the-art methods.