Learning Normal Representations for Blood Biomarkers

Routine laboratory panels drawn during cancer treatment constitute longitudinal physiological recordings of organ function, yet their temporal structure is discarded by single-timepoint prognostic tools. A transformer trained on 2,777,595 laboratory measurements from 3,905 patients with multiple myeloma or ovarian cancer predicted the two-year onset of 162 treatment-associated complications, including therapy-related myelodysplastic syndromes, spanning eight clinical categories, achieving 1.5- to 6.1-fold enrichment above prevalence at the group level. It matched or outperformed non-sequential baselines across grouped endpoints (AUROC gains up to +0.11), demonstrating that longitudinal laboratory trajectories capture evolving complication-specific physiology inaccessible from isolated measurements. Predictions generalised across both cancers, divergence concentrating in disease-specific complications, and biomarker masking recovered signatures consistent with established pathophysiology. External validation on MIMIC-IV and MMRF CoMMpass confirmed transferability across independent healthcare systems (AUROC up to 0.85). Routine oncological laboratory data encode organ deterioration weeks to months before clinical onset, enabling complication-specific surveillance without additional testing infrastructure.

Structured tabular data dominates clinical medicine, yet existing benchmarks fail to reflect real-world properties like complex survey sampling, demographic oversampling, and subgroup fairness. We introduce the NHANES Accelerometry Cardiometabolic Benchmark, derived from NHANES 2003-2006, comprising 1,381 adults with hip-worn accelerometry, fasting laboratory biomarkers, dietary intake, and anthropometrics. We evaluate three tabular learning methods -- ridge regression, XGBoost, and the foundation model TabPFN v2 -- to predict glycated haemoglobin (HbA1c), fasting triglycerides, and C-reactive protein (CRP) from activity phenotypes and lifestyle covariates. TabPFN v2 achieves the best overall performance (HbA1c R^2=0.156, CRP R^2=0.383), while triglycerides remain largely unpredictable (R^2 < 0.05), consistent with known genetic dominance. We apply split conformal prediction to generate distribution-free 90% prediction intervals and evaluate demographic coverage equity across sex and race/ethnicity subgroups. Marginal coverage aligns with the 90% target for CRP and HbA1c but falls below for triglycerides. At the subgroup level, we observe localized undercoverage (e.g., HbA1c for Mexican American participants), illustrating the gap between marginal guarantees and the conditional coverage required for clinical fairness. Code and data are at https://github.com/felizzi/nhanes-accel-cardiometabolic-benchmark.

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.