arXiv:2610.40664v1 Announce Type: cross

Abstract: Chronic diseases evolve through long, heterogeneous trajectories shaped by interacting mediators, confounders, and treatment histories. Estimating long-term patient trajectories under alternative interventions is essential for in silico clinical trial design. However, most existing models overlook irregular visit intervals and cross-mediator dependencies, both of which are crucial for reliable long-term longitudinal prediction. Moreover, these models typically focus on outcome prediction rather than generating complete patient-state trajectories. To address these challenges, we propose CHDT, an intervention-conditioned Human Digital Twin generator under standard identification assumptions for multimodal longitudinal trajectory estimation. Its main empirical advantage arises from explicit modeling of irregular visit intervals, while cross-mediator refinement provides additional gains in selected intervention-conditioned settings. Across real-world ADNI and simulator-generated ALPACA cohorts, CHDT shows improved long-horizon patient-state fidelity relative to competing baselines. Ablation results indicate that irregular-time conditioning provides the primary empirical gain, and cross-mediator refinement provides additional improvements.