Cardiovascular Digital Twins from Physics Based to Data Driven Approaches

Cardiovascular digital twins aim to create patient-specific computational models that evolve with clinical data to support diagnosis, prognosis, and therapy optimisation. Mechanistic models provide physiological interpretability but remain computationally demanding, whereas data-driven approaches improve scalability yet risk limited robustness. Emerging physics-informed, graph-based, and hybrid methods integrate physical constraints with relational learning across vascular networks. We review modelling paradigms, data assimilation frameworks, validation challenges, and translational pathways toward clinically deployable cardiovascular digital twins.

tFUSOperator: Operator Learning for Transcranial Focused Ultrasound Digital Twins

Transcranial focused ultrasound (tFUS) requires accurate estimation of the intracranial acoustic field, which is distorted by skull-induced aberrations. Numerical solvers are accurate but computationally expensive for digital twins, where the field must be re-estimated repeatedly as treatment conditions change. Existing deep-learning surrogates are fast but typically use voxel-to-voxel regression on a fixed grid, with no mechanism reflecting how acoustic energy propagates through the skull. We instead cast tFUS simulation as an operator learning problem and propose tFUSOperator, a coordinate-aware neural operator that maps the free-field pressure, skull anatomy, and treatment parameters to the intracranial field within a shared physical coordinate frame. To our knowledge, this is the first operator-based formulation of tFUS field prediction. On both seen and unseen skulls, the model localizes the acoustic focus accurately-reaching about 90% and 72% Dice, respectively-and it performs nearly as well from magnetic resonance (MR) as from computed tomography (CT) input while running $5.6 \times 10^4$ times faster than numerical simulation. These results suggest a fast, radiation-free route to safe and practical digital twins for patient-specific tFUS treatment. The code is available at: https://github.com/CMME-Lab/tFUSOperator.git.

Medical world models in healthcare: foundations, applications, and challenges for trustworthy clinical translation

Medical world models offer a framework for extending medical artificial intelligence beyond static prediction by representing evolving patient states and modelling how they change over time and in response to clinical interventions. This Review defines the conceptual boundaries, technical foundations, application domains, and evidence requirements of the field through a structured narrative synthesis with reproducible evidence mapping.We screened 1,455 unique records and assembled a corpus of 98 sources, including 14 studies that met a strict empirical definition of a medical world model. The field is organised around four capabilities: patient state representation, temporal dynamics modelling, intervention-conditioned simulation, and clinician-supervised planning. Evidence spans medical imaging, longitudinal electronic health records, treatment response modelling, physiological and multimodal state modelling, ultrasound and surgical interaction, and population and health-system simulation; clinical digital twins are treated as a cross-cutting integration framework.Current studies provide early evidence of technical feasibility for trajectory forecasting and comparison of candidate interventions, but most remain retrospective, task-specific, or preclinical. The evidence base is further limited by incomplete longitudinal intervention data, inconsistent action semantics, limited causal identifiability, long-horizon error accumulation, inadequate uncertainty estimation, and limited external validation. Clinical translation will therefore depend on precise intervention representations, robust causal and mechanistic grounding, calibrated trajectory-level uncertainty, safety-constrained planning, and prospective multicentre validation against clinically meaningful endpoints.

Trustworthy Privacy-Preserving Multimodal Federated Learning for Personalised Breast Cancer Prediction

Federated learning has emerged as a potential solution to privacy concerns associated with using sensitive health data for training predictive models, particularly in personalised cancer care. This research investigates whether federated learning can support the development of robust models for predicting tumour progression in breast cancer patients while addressing four critical deployment pillars: transparency, scalability, security, and fairness. This study evaluates a federated learning framework using multimodal data, including clinical information, tumour characteristics, biomarker data, and patient demographics, alongside medical imaging data such as MRI scans, to model changes in tumour characteristics over time. The performance of the federated approach was compared with that of a centralised model trained on aggregated data. The report then further examines strategies to enhance secure model updates, maintain performance across patient subgroups, and support scalability across institutions. The findings assess whether federated learning can achieve predictive performance comparable to centralised learning while preserving data locality. These results contribute to understanding the feasibility of privacy-preserving, multimodal predictive modelling and support future applications such as digital twins to assist clinicians and patients in personalised treatment planning.

From Operations to Elderly Care Outcomes: A Thematic Review of Industrial Engineering and Decision-Support Approaches

The rapid growth of the global aging population presents severe challenges to healthcare systems, necessitating efficient, equitable, and patient-centered care models. While Industrial Engineering and Operations Research (OR) provide robust optimization and decision-support tools to address these multidimensional complexities, current applications often remain fragmented. This paper presents a thematic review of 30 seminal studies at the intersection of OR and elderly care, categorizing the literature into home healthcare operations, polypharmacy management, and clinical chronotherapy. Our analysis highlights a significant methodological evolution from static, deterministic models toward dynamic and stochastic frameworks integrated with artificial intelligence (AI). Despite these advancements, a critical translational gap persists: the current OR literature is heavily dominated by process-level optimizations, such as staff routing, and struggles to translate these operational efficiencies into measurable clinical outcomes. Furthermore, holistic models bridging the transition between hospital and community care remain critically underexplored. To develop resilient and smart healthcare systems, this study proposes a conceptual framework that shifts the research focus from isolated operational tasks to integrated, multi-level decision-making. We emphasize the critical need for robust systems analysis, human-inclusive design, and the smartification of care through emerging digital technologies - including digital twins and large language models - to successfully bridge the gap between theoretical operational metrics and tangible patient-level health outcomes.

Timesynth: A Temporal Fidelity Framework for Health Signal Digital Twins

Forecasting models for health-signal digital twins must preserve the oscillatory, frequency, phase, and state-transition dynamics of physiological signals, yet the pointwise metrics used to benchmark them cannot detect when these fundamental properties are lost. We show that this blind spot misranks models: across 11 architectures, models with comparable pointwise error diverge by up to 53° in phase accuracy, equivalent to roughly 123 ms for a 1.2 Hz cardiac rhythm and invisible to standard metrics. To enable development of models that escape such failures, we introduce TimeSynth, a controlled benchmarking framework with two reusable components: a physiologically grounded generator producing signals with analytically known ground-truth dynamics from parametric models fitted to real electroencephalography, electrocardiography and photoplethysmogram signals, along with diagnostics quantifying amplitude, frequency, phase, and state-transition fidelity. Linear and full-sequence attention models systematically lose frequency and phase information despite acceptable amplitude error, whereas architectures with localized temporal structure better preserve dynamical fidelity and adapt to observable state transitions; none, however, reliably preserves stochastic switching. Because the dominant determinant of fidelity is architectural, model choice becomes a principled, use-case-driven decision rather than a search for a single winner. TimeSynth thus supplies the controlled preclinical stress test missing before models are coupled to patient data, with a reusable generator and diagnostics for fidelity-aware development.

Autonomous mechanistic discovery of colorectal cancer vulnerabilities via multi-scale AI swarms

The acceleration of automated scientific discovery has been fundamentally bottlenecked by the epistemic gap between the semantic reasoning of large language models (LLMs) and the deterministic physics of mammalian biology. While recent multi-agent frameworks have achieved autonomous hypothesis generation and in vitro experimental analysis, they lack the mathematically grounded, causal constraints required for multi-scale clinical translation. Furthermore, while algorithmic clinical digital twins successfully forecast biological states, they rely on black-box latent spaces, sacrificing mechanistic interpretability for predictive accuracy. Here, we introduce the Multi-Scale Autonomous Discovery Engine (Octopus), a neuro-symbolic architecture that unites zero-leakage, local LLM swarms with strict algorithmic physics engines. Rather than stopping at isolated cellular assays, the system autonomously generated therapeutic hypotheses against in vitro CRISPR dependency data (CCLE), traced dynamic causal cascades using mechanistic interpretability (XGBoost SHAP vectors), and orthogonally translated the emergent vulnerabilities in silico to predict in vivo mammalian tumor trajectory (PDX) and human overall survival (Marisa). In a fully unsupervised sweep of colorectal cancer transcriptomes, the pipeline autonomously identified Insulin-like Growth Factor 2 (IGF2) as a strictly bounded vulnerability to 5-Fluorouracil resistance. The discovery maintained significance after rigorous Benjamini-Hochberg false discovery rate correction (q=0.0292, Log-Rank p=0.0007 ) and successfully predicted significant in vivo tumor volume shrinkage in an independent mouse cohort (Mann-Whitney p=0.0373). By bridging the chasm between multi-agent reasoning and mathematically bounded clinical survival, this framework establishes a verifiable, zero-leakage paradigm for automated, end-to-end biomedical discovery.

Federated Temporal Attention Intelligence for Cyber-Resilient IoMT: Lightweight Digital Twins and PPO-Driven Honeypot Deception

The rapid proliferation of Internet of Medical Things (IoMT) devices introduces critical cybersecurity vulnerabilities in healthcare environments where resource-constrained medical devices operate under strict latency requirements and stringent data-privacy regulations. To address these challenges, this paper presents the Lightweight Digital Twin and Federated Reinforcement Learning (LDT-FRL) framework, a privacy-preserving defense architecture integrating four complementary mechanisms: a Temporal Attention Encoder (TAE) built on a GRU backbone with learned temporal self-attention for flow-level threat classification; lightweight LSTM-based Digital Twins trained on normal-class traffic to generate per-device anomaly scores that gate the TAE classifier through a learned sigmoid coupling; a Federated Proximal Policy Optimization (PPO) agent selecting among ALLOW, ISOLATE, and HONEYPOT_REDIRECT actions based on a seven-dimensional state; and an intelligent honeypot layer that converts redirected suspicious traffic into actionable threat intelligence. A federated aggregation strategy employing EMA-smoothed per-client validation losses as inverse-weighted FedAvg coefficients stabilizes global model updates under non-IID client distributions. Evaluated on CICDDoS 2019 and TON-IoT benchmarks, LDT-FRL achieves 99.66% and 99.95% test accuracy respectively, with macro-F1 scores of 0.9913 and 0.9995, converging 81% faster than the DTFL-CD baseline while attaining perfect F1=1.000 on the severely imbalanced MITM class. Explainability analysis via SHAP, LIME, Grad-CAM, and counterfactual methods confirms that the TAE focuses on semantically meaningful flow features, providing interpretable evidence for each defense decision.

Learning Cardiac Electrophysiology Digital Twins Through Agentic Discovery of Hybrid Structure

Building personalized cardiac electrophysiology (EP) digital twins requires identifying the appropriate model structure for each patient, not merely fitting parameters. Traditional methods rely on experts to manually prescribe hybrid physics-neural architectures, which requires deep domain expertise and does not transfer across patients. Recent works have applied large language models (LLMs) to generate or act as hybrid models. However, despite their promising generalization capacity, these LLM-based methods lack the structural priors needed for stable cardiac simulations. Hence, we propose LEADS, a framework that formulates cardiac EP domain knowledge as a structured action space and utilizes an LLM agent to discover hybrid models. The agent follows an iterative reasoning-and-action loop to select, combine, and refine hybrid models, whilst gradient descent handles parameter fitting. The proposed LEADS designs every candidate model towards physically grounded, interpretable, and numerically stable, while allowing open-ended architectural discovery. We validate LEADS on synthetic data with three ground-truth reaction models and on real cardiac EP data, demonstrating that it outperforms both human-designed hybrid models and other LLM-based hybrid modeling.

OmniBioTwin: A System-of-Twinned-Systems Framework for Health Digital Twins

Health digital twins (HDTs) promise patient-specific modeling and decision support but current approaches remain structurally fragmented: monolithic models that address a single organ or task lack cross-scale fidelity, while system-level twins lack generalizable architectural frameworks. We propose OmniBioTwin, a System-of-Twinned-Systems (SoTS) framework that organizes HDTs as modular computational entities coupled through explicit interaction operators within a multi-layer network architecture. The framework comprises seven coordinated layers - spanning data integration, autonomous twin modeling, cross-scale coupling, temporal synchronization, and human-in-the-loop decision support. We demonstrate OmniBioTwin by instantiating a multiscale twin for glucagon-like peptide-1 (GLP-1) signaling pathways in Alzheimer's disease, illustrating how molecular, cellular, and organ-level twins can be composed and coupled within a unified system.

Personalized 3D Myocardial Infarct Geometry Reconstruction from Cine MRI for Cardiac Digital Twins

Accurate 3D geometric characterization of myocardial infarction (MI) is essential for building cardiac digital twins (CDTs) to precisely simulate infarct-related electrophysiology. Late gadolinium enhancement magnetic resonance imaging (LGE MRI) is the clinical reference for locating MI, yet its reliance on contrast agents restricts use in renally impaired patients and limits longitudinal follow-ups. As an alternative, contrast-free cine MRI visualizes abnormal ventricular wall motion, which is highly indicative of the infarcted area. In this study, we propose a novel explicit geometry-motion embedded model to fully automatically reconstruct personalized, simulation-ready 3D MI geometries directly from multi-view cine MRIs. Specifically, we construct a 4D (3D + t) biventricular mesh to explicitly extract and decouple geometry-aware and motion-aware features. We further design a dual-branch module for adaptive geometry-motion fusion to capture spatiotemporal dependencies for mapping infarcted region. Furthermore, we introduce multi-scale supervision utilizing an AHA-17 segment-guided cross-attention mechanism to steer the prediction, ensuring biophysically consistent reconstruction. Experimental results on 225 cine MRIs demonstrated that the proposed 3D MI reconstruction achieved high performance with an average Dice score of 0.678 $\pm$ 0.011. In the downstream in-silico electrophysiological simulation evaluations, the results were highly consistent with the LGE-derived ground truth, highlighting the great potential of the proposed model for contrast-free scar characterization and seamless integration into CDT modeling. The code will be released publicly upon acceptance of the manuscript for publication.