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.
Providing effective treatment and making informed clinical decisions are essential goals of modern medicine and clinical care. We are interested in simulating disease dynamics for clinical decision-making, leveraging recent advances in large generative models. To this end, we introduce the Medical World Model (MeWM), the first world model in medicine that visually predicts future disease states based on clinical decisions. MeWM comprises (i) vision-language models to serve as policy models, and (ii) tumor generative models as dynamics models. The policy model generates action plans, such as clinical treatments, while the dynamics model simulates tumor progression or regression under given treatment conditions. Building on this, we propose the inverse dynamics model that applies survival analysis to the simulated post-treatment tumor, enabling the evaluation of treatment efficacy and the selection of the optimal clinical action plan. As a result, the proposed MeWM simulates disease dynamics by synthesizing post-treatment tumors, with state-of-the-art specificity in Turing tests evaluated by radiologists. Simultaneously, its inverse dynamics model outperforms medical-specialized GPTs in optimizing individualized treatment protocols across all metrics. Notably, MeWM improves clinical decision-making for interventional physicians, boosting F1-score in selecting the optimal TACE protocol by 13%, paving the way for future integration of medical world models as the second readers.
Decision trees are popular in survival analysis for their interpretability and ability to model complex relationships. Survival trees, which predict the timing of singular events using censored historical data, are typically built through heuristic approaches. Recently, there has been growing interest in globally optimized trees, where the overall tree is trained by minimizing the error function over all its parameters. We propose a new soft survival tree model (SST), with a soft splitting rule at each branch node, trained via a nonlinear optimization formulation amenable to decomposition. Since SSTs provide for every input vector a specific survival function associated to a single leaf node, they satisfy the conditional computation property and inherit the related benefits. SST and the training formulation combine flexibility with interpretability: any smooth survival function (parametric, semiparametric, or nonparametric) estimated through maximum likelihood can be used, and each leaf node of an SST yields a cluster of distinct survival functions which are associated to the data points routed to it. Numerical experiments on 15 well-known datasets show that SSTs, with parametric and spline-based semiparametric survival functions, trained using an adaptation of the node-based decomposition algorithm proposed by Consolo et al. (2024) for soft regression trees, outperform three benchmark survival trees in terms of four widely-used discrimination and calibration measures. SSTs can also be extended to consider group fairness.
We develop a framework to quantify the time-to-unsafe-sampling - the number of large language model (LLM) generations required to trigger an unsafe (e.g., toxic) response. Estimating this quantity is challenging, since unsafe responses are exceedingly rare in well-aligned LLMs, potentially occurring only once in thousands of generations. As a result, directly estimating time-to-unsafe-sampling would require collecting training data with a prohibitively large number of generations per prompt. However, with realistic sampling budgets, we often cannot generate enough responses to observe an unsafe outcome for every prompt, leaving the time-to-unsafe-sampling unobserved in many cases, making the estimation and evaluation tasks particularly challenging. To address this, we frame this estimation problem as one of survival analysis and develop a provably calibrated lower predictive bound (LPB) on the time-to-unsafe-sampling of a given prompt, leveraging recent advances in conformal prediction. Our key innovation is designing an adaptive, per-prompt sampling strategy, formulated as a convex optimization problem. The objective function guiding this optimized sampling allocation is designed to reduce the variance of the estimators used to construct the LPB, leading to improved statistical efficiency over naive methods that use a fixed sampling budget per prompt. Experiments on both synthetic and real data support our theoretical results and demonstrate the practical utility of our method for safety risk assessment in generative AI models.
Risk stratification is a key tool in clinical decision-making, yet current approaches often fail to translate sophisticated survival analysis into actionable clinical criteria. We present a novel method for unsupervised machine learning that directly optimizes for survival heterogeneity across patient clusters through a differentiable adaptation of the multivariate logrank statistic. Unlike most existing methods that rely on proxy metrics, our approach represents novel methodology for training any neural network architecture on any data modality to identify prognostically distinct patient groups. We thoroughly evaluate the method in simulation experiments and demonstrate its utility in practice by applying it to two distinct cancer types: analyzing laboratory parameters from multiple myeloma patients and computed tomography images from non-small cell lung cancer patients, identifying prognostically distinct patient subgroups with significantly different survival outcomes in both cases. Post-hoc explainability analyses uncover clinically meaningful features determining the group assignments which align well with established risk factors and thus lend strong weight to the methods utility. This pan-cancer, model-agnostic approach represents a valuable advancement in clinical risk stratification, enabling the discovery of novel prognostic signatures across diverse data types while providing interpretable results that promise to complement treatment personalization and clinical decision-making in oncology and beyond.
This study investigates the application of quantum neural networks (QNNs) for propensity score estimation to address selection bias in comparing survival outcomes between laparoscopic and open surgical techniques in a cohort of 1177 colorectal carcinoma patients treated at University Hospital Ostrava (2001-2009). Using a dataset with 77 variables, including patient demographics and tumor characteristics, we developed QNN-based propensity score models focusing on four key covariates (Age, Sex, Stage, BMI). The QNN architecture employed a linear ZFeatureMap for data encoding, a SummedPaulis operator for predictions, and the Covariance Matrix Adaptation Evolution Strategy (CMA-ES) for robust, gradient-free optimization in noisy quantum environments. Variance regularization was integrated to mitigate quantum measurement noise, with simulations conducted under exact, sampling (1024 shots), and noisy hardware (FakeManhattanV2) conditions. QNNs, particularly with simulated hardware noise, outperformed classical logistic regression and gradient boosted machines in small samples (AUC up to 0.750 for n=100), with noise modeling enhancing predictive stability. Propensity score matching and weighting, optimized via genetic matching and matching weights, achieved covariate balance with standardized mean differences of 0.0849 and 0.0869, respectively. Survival analyses using Kaplan-Meier estimation, Cox proportional hazards, and Aalen additive regression revealed no significant survival differences post-adjustment (p-values 0.287-0.851), indicating confounding bias in unadjusted outcomes. These results highlight QNNs' potential, enhanced by CMA-ES and noise-aware strategies, to improve causal inference in biomedical research, particularly for small-sample, high-dimensional datasets.
This study employs a robust analytical framework to uncover patterns in survival outcomes among breast cancer patients from diverse racial and geographical backgrounds. This research uses the SEER 2021 dataset to analyze breast cancer survival outcomes to identify and comprehend dissimilarities. Our approach integrates exploratory data analysis (EDA), through this we identify key variables that influence survival rates and employ survival analysis techniques, including the Kaplan-Meier estimator and log-rank test and the advanced modeling Cox Proportional Hazards model to determine how survival rates vary across racial groups and countries. Model validation and interpretation are undertaken to ensure the reliability of our findings, which are documented comprehensively to inform policymakers and healthcare professionals. The outcome of this paper is a detailed version of statistical analysis that not just highlights disparities in breast cancer treatment and care but also serves as a foundational tool for developing targeted interventions to address the inequalities effectively. Through this research, our aim is to contribute to the global efforts to improve breast cancer outcomes and reduce treatment disparities.
Amyotrophic lateral sclerosis (ALS) is a degenerative disorder of motor neurons that causes progressive paralysis in patients. Current treatment options aim to prolong survival and improve quality of life; however, due to the heterogeneity of the disease, it is often difficult to determine the optimal time for potential therapies or medical interventions. In this study, we propose a novel method to predict the time until a patient with ALS experiences significant functional impairment (ALSFRS-R<=2) with respect to five common functions: speaking, swallowing, handwriting, walking and breathing. We formulate this task as a multi-event survival problem and validate our approach in the PRO-ACT dataset by training five covariate-based survival models to estimate the probability of an event over a 500-day period after a baseline visit. We then predict five event-specific individual survival distributions (ISDs) for each patient, each providing an interpretable and meaningful estimate of when that event will likely take place in the future. The results show that covariate-based models are superior to the Kaplan-Meier estimator at predicting time-to-event outcomes. Additionally, our method enables practitioners to make individual counterfactual predictions, where certain features (covariates) can be changed to see their effect on the predicted outcome. In this regard, we find that Riluzole has little to no impact on predicted functional decline. However, for patients with bulbar-onset ALS, our method predicts considerably shorter counterfactual time-to-event estimates for tasks related to speech and swallowing compared to limb-onset ALS. The proposed method can be applied to current clinical examination data to assess the risk of functional decline and thus allow more personalized treatment planning.
We introduce an innovative approach that incorporates a Distributionally Robust Learning (DRL) approach into Cox regression to enhance the robustness and accuracy of survival predictions. By formulating a DRL framework with a Wasserstein distance-based ambiguity set, we develop a variant Cox model that is less sensitive to assumptions about the underlying data distribution and more resilient to model misspecification and data perturbations. By leveraging Wasserstein duality, we reformulate the original min-max DRL problem into a tractable regularized empirical risk minimization problem, which can be computed by exponential conic programming. We provide guarantees on the finite sample behavior of our DRL-Cox model. Moreover, through extensive simulations and real world case studies, we demonstrate that our regression model achieves superior performance in terms of prediction accuracy and robustness compared with traditional methods.
Survival analysis is a fundamental tool for modeling time-to-event data in healthcare, engineering, and finance, where censored observations pose significant challenges. While traditional methods like the Beran estimator offer nonparametric solutions, they often struggle with the complex data structures and heavy censoring. This paper introduces three novel survival models, iSurvM (the imprecise Survival model based on Mean likelihood functions), iSurvQ (the imprecise Survival model based on the Quantiles of likelihood functions), and iSurvJ (the imprecise Survival model based on the Joint learning), that combine imprecise probability theory with attention mechanisms to handle censored data without parametric assumptions. The first idea behind the models is to represent censored observations by interval-valued probability distributions for each instance over time intervals between events moments. The second idea is to employ the kernel-based Nadaraya-Watson regression with trainable attention weights for computing the imprecise probability distribution over time intervals for the entire dataset. The third idea is to consider three decision strategies for training, which correspond to the proposed three models. Experiments on synthetic and real datasets demonstrate that the proposed models, especially iSurvJ, consistently outperform the Beran estimator from the accuracy and computational complexity points of view. Codes implementing the proposed models are publicly available.
In Computational Pathology (CPath), the introduction of Vision-Language Models (VLMs) has opened new avenues for research, focusing primarily on aligning image-text pairs at a single magnification level. However, this approach might not be sufficient for tasks like cancer subtype classification, tissue phenotyping, and survival analysis due to the limited level of detail that a single-resolution image can provide. Addressing this, we propose a novel multi-resolution paradigm leveraging Whole Slide Images (WSIs) to extract histology patches at multiple resolutions and generate corresponding textual descriptions through advanced CPath VLM. We introduce visual-textual alignment at multiple resolutions as well as cross-resolution alignment to establish more effective text-guided visual representations. Cross-resolution alignment using a multimodal encoder enhances the model's ability to capture context from multiple resolutions in histology images. Our model aims to capture a broader range of information, supported by novel loss functions, enriches feature representation, improves discriminative ability, and enhances generalization across different resolutions. Pre-trained on a comprehensive TCGA dataset with 34 million image-language pairs at various resolutions, our fine-tuned model outperforms state-of-the-art (SOTA) counterparts across multiple datasets and tasks, demonstrating its effectiveness in CPath. The code is available on GitHub at: https://github.com/BasitAlawode/MR-PLIP
We argue that many survival analysis and time-to-event models are incorrectly evaluated. First, we survey many examples of evaluation approaches in the literature and find that most rely on concordance (C-index). However, the C-index only measures a model's discriminative ability and does not assess other important aspects, such as the accuracy of the time-to-event predictions or the calibration of the model's probabilistic estimates. Next, we present a set of key desiderata for choosing the right evaluation metric and discuss their pros and cons. These are tailored to the challenges in survival analysis, such as sensitivity to miscalibration and various censoring assumptions. We hypothesize that the current development of survival metrics conforms to a double-helix ladder, and that model validity and metric validity must stand on the same rung of the assumption ladder. Finally, we discuss the appropriate methods for evaluating a survival model in practice and summarize various viewpoints opposing our analysis.
Accurate prediction of major adverse cardiovascular events recurrence risk in acute myocardial infarction patients based on postoperative cardiac MRI and associated clinical notes is crucial for precision treatment and personalized intervention. Existing methods primarily focus on risk stratification capability while overlooking the need for intermediate robust reasoning and model interpretability in clinical practice. Moreover, end-to-end risk prediction using LLM/VLM faces significant challenges due to data limitations and modeling complexity. To bridge this gap, we propose CardioCoT, a novel two-stage hierarchical reasoning-enhanced survival analysis framework designed to enhance both model interpretability and predictive performance. In the first stage, we employ an evidence-augmented self-refinement mechanism to guide LLM/VLMs in generating robust hierarchical reasoning trajectories based on associated radiological findings. In the second stage, we integrate the reasoning trajectories with imaging data for risk model training and prediction. CardioCoT demonstrates superior performance in MACE recurrence risk prediction while providing interpretable reasoning processes, offering valuable insights for clinical decision-making.
Background: Large language models (LLMs) are attracting increasing interest in healthcare. Their ability to summarise large datasets effectively, answer questions accurately, and generate synthesised text is widely recognised. These capabilities are already finding applications in healthcare. Body: This commentary discusses LLMs usage in the clinical prediction context and highlight potential benefits and existing challenges. In these early stages, the focus should be on extending the methodology, specifically on validation, fairness and bias evaluation, survival analysis and development of regulations. Conclusion: We conclude that further work and domain-specific considerations need to be made for full integration into the clinical prediction workflows.
Federated Learning (FL) holds great promise for digital health by enabling collaborative model training without compromising patient data privacy. However, heterogeneity across institutions, lack of sustained reputation, and unreliable contributions remain major challenges. In this paper, we propose a robust, peer-driven reputation mechanism for federated healthcare that employs a hybrid communication model to integrate decentralized peer feedback with clustering-based noise handling to enhance model aggregation. Crucially, our approach decouples the federated aggregation and reputation mechanisms by applying differential privacy to client-side model updates before sharing them for peer evaluation. This ensures sensitive information remains protected during reputation computation, while unaltered updates are sent to the server for global model training. Using the Cox Proportional Hazards model for survival analysis across multiple federated nodes, our framework addresses both data heterogeneity and reputation deficit by dynamically adjusting trust scores based on local performance improvements measured via the concordance index. Experimental evaluations on both synthetic datasets and the SEER dataset demonstrate that our method consistently achieves high and stable C-index values, effectively down-weighing noisy client updates and outperforming FL methods that lack a reputation system.
Survival analysis, which estimates the probability of event occurrence over time from censored data, is fundamental in numerous real-world applications, particularly in high-stakes domains such as healthcare and risk assessment. Despite advances in numerous survival models, quantifying the uncertainty of predictions from these models remains underexplored and challenging. The lack of reliable uncertainty quantification limits the interpretability and trustworthiness of survival models, hindering their adoption in clinical decision-making and other sensitive applications. To bridge this gap, in this work, we introduce SurvUnc, a novel meta-model based framework for post-hoc uncertainty quantification for survival models. SurvUnc introduces an anchor-based learning strategy that integrates concordance knowledge into meta-model optimization, leveraging pairwise ranking performance to estimate uncertainty effectively. Notably, our framework is model-agnostic, ensuring compatibility with any survival model without requiring modifications to its architecture or access to its internal parameters. Especially, we design a comprehensive evaluation pipeline tailored to this critical yet overlooked problem. Through extensive experiments on four publicly available benchmarking datasets and five representative survival models, we demonstrate the superiority of SurvUnc across multiple evaluation scenarios, including selective prediction, misprediction detection, and out-of-domain detection. Our results highlight the effectiveness of SurvUnc in enhancing model interpretability and reliability, paving the way for more trustworthy survival predictions in real-world applications.
Estimating heterogeneous treatment effects (HTEs) is crucial for personalized decision-making. However, this task is challenging in survival analysis, which includes time-to-event data with censored outcomes (e.g., due to study dropout). In this paper, we propose a toolbox of novel orthogonal survival learners to estimate HTEs from time-to-event data under censoring. Our learners have three main advantages: (i) we show that learners from our toolbox are guaranteed to be orthogonal and thus come with favorable theoretical properties; (ii) our toolbox allows for incorporating a custom weighting function, which can lead to robustness against different types of low overlap, and (iii) our learners are model-agnostic (i.e., they can be combined with arbitrary machine learning models). We instantiate the learners from our toolbox using several weighting functions and, as a result, propose various neural orthogonal survival learners. Some of these coincide with existing survival learners (including survival versions of the DR- and R-learner), while others are novel and further robust w.r.t. low overlap regimes specific to the survival setting (i.e., survival overlap and censoring overlap). We then empirically verify the effectiveness of our learners for HTE estimation in different low-overlap regimes through numerical experiments. In sum, we provide practitioners with a large toolbox of learners that can be used for randomized and observational studies with censored time-to-event data.
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.
We introduce NeuralSurv, the first deep survival model to incorporate Bayesian uncertainty quantification. Our non-parametric, architecture-agnostic framework flexibly captures time-varying covariate-risk relationships in continuous time via a novel two-stage data-augmentation scheme, for which we establish theoretical guarantees. For efficient posterior inference, we introduce a mean-field variational algorithm with coordinate-ascent updates that scale linearly in model size. By locally linearizing the Bayesian neural network, we obtain full conjugacy and derive all coordinate updates in closed form. In experiments, NeuralSurv delivers superior calibration compared to state-of-the-art deep survival models, while matching or exceeding their discriminative performance across both synthetic benchmarks and real-world datasets. Our results demonstrate the value of Bayesian principles in data-scarce regimes by enhancing model calibration and providing robust, well-calibrated uncertainty estimates for the survival function.
Delirium represents a significant clinical concern characterized by high morbidity and mortality rates, particularly in patients with mild cognitive impairment (MCI). This study investigates the associated risk factors for delirium by analyzing the comorbidity patterns relevant to MCI and developing a longitudinal predictive model leveraging machine learning methodologies. A retrospective analysis utilizing the MIMIC-IV v2.2 database was performed to evaluate comorbid conditions, survival probabilities, and predictive modeling outcomes. The examination of comorbidity patterns identified distinct risk profiles for the MCI population. Kaplan-Meier survival analysis demonstrated that individuals with MCI exhibit markedly reduced survival probabilities when developing delirium compared to their non-MCI counterparts, underscoring the heightened vulnerability within this cohort. For predictive modeling, a Long Short-Term Memory (LSTM) ML network was implemented utilizing time-series data, demographic variables, Charlson Comorbidity Index (CCI) scores, and an array of comorbid conditions. The model demonstrated robust predictive capabilities with an AUROC of 0.93 and an AUPRC of 0.92. This study underscores the critical role of comorbidities in evaluating delirium risk and highlights the efficacy of time-series predictive modeling in pinpointing patients at elevated risk for delirium development.