Earlier detection of pancreatic cancer is key to enabling wider access to curative treatment and reducing cancer deaths; however, screening is presently not viable. Latent digital indicators of pathology are evident in an individual's disease and blood test trajectories and may predict the development of pancreatic cancer. Longitudinal sequences of coded diagnoses and blood test values accrued by patients throughout their clinical interactions were used to train a custom Transformer-based neural network with a multi-head attention mechanism to predict risk of pancreatic cancer with a multi-year lead time and risk-stratify populations for targeted screening. Mayo Clinic Platform with trained model from Mayo Clinic Rochester validated at Mayo Clinic Arizona, Mayo Clinic Florida, and Mayo Clinic Health Systems. The cohort comprised 6,017 adults with pancreatic cancer and 177,081 controls (median age 75, 45% female) with median 12 years (interquartile range 6.9-16.2) of medical history prior to pancreatic cancer diagnosis. External validation via leave-one-site-out, out-of-sample testing predicting pancreatic cancer 1-, 2-, and 3-years prior to diagnosis demonstrated mean area under the receiver operating characteristic of 0.837 (95% confidence interval 0.827-0.848), 0.797 (95% confidence interval 0.782-0.813), and 0.760 (95% confidence interval 0.745-0.776), respectively. Estimated pancreatic cancer risks were well-calibrated (calibration plot slope 1.08, intercept of -0.077; Brier score 0.025), and a Bayesian population pancreatic cancer prevalence update allows estimated cancer risk outputs to be transportable across settings. At testing, a screening threshold of >3.3% risk of pancreatic cancer in 1-year offered a diagnostic odds ratio of 18.2. Our work therefore lays the foundation for a digital population-level risk enrichment tool that could widen access to curative-intent management.

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