A Proof-of-Concept Simulation-Driven Digital Twin Framework for Decision-Aware Diabetes Modeling

Alzheimer's disease (AD) progression is highly heterogeneous and is typically observed through sparse and irregular longitudinal data, posing challenges for prediction and personalised monitoring. Existing machine learning approaches have improved AD prediction using multimodal data, yet often focus on static classification or cohort-level risk estimation, providing limited support for subject-specific modelling and uncertainty-aware reasoning. To address these limitations, we present a personalised digital twin framework for AD prediction and scenario-based analysis using multimodal longitudinal data. The proposed approach integrates complementary modelling strategies to capture clinical transitions and temporal dependencies across visits. Using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), including cognitive assessments, clinical variables, and MRI-derived phenotypes, the framework predicts cognitive status and diagnostic categories while quantifying predictive uncertainty and enabling patient-specific what-if trajectory analysis. Evaluation on leak-free subject-level splits demonstrates strong performance in score forecasting and diagnosis classification. In this sparse and irregular ADNI setting, transition-based modelling of adjacent visits achieved higher predictive accuracy than the sequence-based branch, suggesting that local transition modelling may be more data-efficient. While sequence models remain valuable for uncertainty-aware trajectory forecasting, local transition modelling offers a more data-efficient and robust predictive strategy. These findings highlight the importance of aligning temporal modelling strategies with clinical data structure and suggest that transition-based digital twin formulations may provide a practical and interpretable approach for personalised disease forecasting in neurodegenerative disorders.

Despite the central role of sensor-derived measurements such as imaging traits and plasma biomarkers in biomedical research and clinical practice, existing generative models for disease prediction largely depend on event-level representations from hospital and registry data. Given the multi-factorial nature of human disease, the absence of explicit modeling of social determinants of health (SDoH), even in the limited form of ICD-coded proxies (chapters Z and V--Y in ICD-10), limits the capacity for personalized disease modeling and clinical decision support. To address this limitation, we propose a generative model with ICD-coded proxies of SDoH for \textit{in silico} modeling of disease reasoning, a conditioned latent diffusion framework that establishes the connection between multi-organ sensor data with tokenized healthcare events. Specifically, we introduce a novel geometric diffusion model to characterize the temporal evolution of complex data representation such as brain networks (region-to-region connectivity encoded in a graph), in parallel with diffusion models for tabular data from other organ systems. Together, we integrate the generative model with digitalized SDoH proxies (coined \modelname{}) for simulated intervention and reasoning of future disease trajectories. We conduct extensive experiments on the UK Biobank (UKB) dataset, which contains organ-specific imaging traits, including brain (44,834), heart (23,987), liver (28,722), and kidney (32,155), along with nearly 500k medical history sequences (age range: 25$\sim$89 years). Our \modelname{} achieves significant improvements over state-of-the-art human disease autoregressive models and imaging trait generative baselines.

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.