Marrying Generative Model of Healthcare Events with Digital Twin of Social Determinants of Health for Disease Reasoning

Understanding how human health changes over time, and why responses to interventions vary between individuals, remains a central challenge in medicine. Here we present HealthFormer, a decoder-only transformer that models the human physiological trajectory generatively, by training on data from the Human Phenotype Project, a multi-visit cohort of over 15,000 deeply phenotyped individuals. We tokenise each participant's health trajectory across 667 measurements spanning seven domains: blood biomarkers, body composition, sleep physiology, continuous glucose monitoring, gut microbiome, wearable-derived physiology, and behaviour and medication exposure. We train HealthFormer to forecast individual physiological trajectories across these domains, and from this single generative objective a range of clinically relevant tasks can be expressed as queries on the model. We show that, without task-specific training, HealthFormer transfers to four independent cohorts and improves prediction for 27 of 30 incident-disease and mortality endpoints, exceeding established clinical risk scores in every comparison. We further show that the model can simulate interventions in silico: in a held-out personalised-nutrition trial, intervention-conditioned predictions recover individual six-month biomarker changes (e.g., Pearson r = 0.78 for diastolic blood pressure). Across 41 randomised intervention-outcome comparisons drawn from published trials, our results show that the predicted direction of effect agrees in every case, and the predicted mean falls within the reported 95% confidence interval in 30 cases. We position HealthFormer as an initial health world model, from which forecasting, risk stratification, and intervention-conditioned simulation arise as queries, providing a basis for clinical digital twins.

The digitization of healthcare has generated vast, longitudinal, and multimodal patient records over a lifetime, yet fully exploiting these data to represent and predict patient state trajectories remains a critical challenge. Current AI models often struggle to capture the complex, irregular temporal dynamics and inherent stochasticity of real-world multimodal patient data. Existing AI approaches for modeling longitudinal patient records are predominantly discriminative, limited to a few modalities, constrained by closed categorical vocabularies, treating time as a monotonic inductive bias, or they are limited in forecasting future patient states. We introduce NOAH, a time-aware, task-agnostic, generative transformer model representing and forecasting the full multimodal patient journey. NOAH features a novel bidirectional time integration and a variational latent space to capture the continuous evolution of patient states and the stochasticity of clinical trajectories. Built from over 559 million clinical events from 431,000 hospital visits of 299,000 patients across the MIMIC dataset family, NOAH natively processes medical images, time-series and numeric signals, categorical events, as well as structured and unstructured clinical records. NOAH is the first truly holistic generative model in its field, enabling autoregressive forecasting with optional time control, zero-shot classification, and counterfactual intervention simulation. It generates highly informative and predictive patient state representations that demonstrate strong performance in probing for clinical outcomes, 15 ICD chapters, and 29 comorbidities, as well as in time-to-event prediction. Seamlessly handling diverse modalities and complex temporal dynamics, NOAH provides a versatile, task-agnostic, scalable foundation for intelligent predictive systems in personalized clinical care and digital medicine.

Pediatric electronic health records capture developmentally structured clinical trajectories, yet their potential for generative healthcare foundation models remains largely unexplored. Here we present TEDDY (Temporal Event Decoder for Disease in Youth), a 1.84-million-parameter decoder transformer trained on approximately 73 million ICD-10 diagnoses from 1.6 million children at a single pediatric institution. TEDDY models longitudinal diagnosis trajectories and visit timing. Predictions were made before visit codes were revealed, limited to first occurrences, and evaluated against sex- and age-matched controls. Across 797 disease-onset prediction tasks spanning 16 ICD-10 chapters, TEDDY achieved a median AUC of 72.0%, outperforming same-data DenseNet (50.0%), CNN (57.2%), RNN (60.1%), and LSTM (62.7%) baselines on 96-99% of tasks. Performance held across sex and age and was strongest among lower-prevalence diagnoses; 202 of the 225 rarest conditions (90%) had 95% confidence intervals above chance. Predictive signal remained detectable more than two years before first recorded diagnosis, with median AUCs of 59.7% in the unrestricted analysis and 64.4% in a fixed-cohort sensitivity analysis. In asthma and attention-deficit/hyperactivity disorder benchmarks, AUCs were 79.3% and 84.7%, compared with 62.7% and 71.7% for the strongest comparators, including a general-purpose language model three orders of magnitude larger. Visit-timing predictions had a 3.0-day mean absolute restricted mean survival-time error over 365 days, although median and long-tail return intervals remained miscalibrated. Together, these results establish pediatric diagnostic histories as a substrate for compact generative models supporting broad, rare-disease, and long-horizon risk forecasting without population-scale data or billion-parameter models.