Modelling multi-cancer screening data to infer on natural history of disease: when can valid, identifiable and precise inference be obtained?

MO Soares; J Lange; K Gogebakan; S Dias; NJ Welton; R Etzioni; AE Ades; S Palmer

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arXiv · 2606.02076

Modelling multi-cancer screening data to infer on natural history of disease: when can valid, identifiable and precise inference be obtained?

MO Soares·J Lange·K Gogebakan·S Dias·NJ Welton·R Etzioni·AE Ades·S Palmer

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Abstract

Background: Multistate models (MSMs) applied to screening data can characterise the natural history of cancer and predict "stage-shifts" from screening. However, inferring parameters like mean sojourn time (MST) is challenging as disease onset is inherently unobserved in these data. This is even more challenging when characterising heterogeneity between cancer types in multicancer early detection (MCED) trial data. Methods: We utilised simulated longitudinal MCED screening datasets to evaluate the inferential bounds of MSMs under increasing clinical disaggregation: a 3-state (overall MST), 5-state (early/late stage), and 9-state (stages I-IV) model. Bayesian estimation was performed via Markov chain Monte Carlo. Robustness was assessed through chain convergence, parameter identifiability (via profile likelihood), and precision of estimates. We also explored hierarchical models and the use of informative priors to improve identifiability. Results: Based only on MCED trial data, many cancer types exhibited inferential challenges. Generally, the 5-state model was as robust as the 3-state model, showing slight improvements to convergence and identifiability while maintaining precision for overall MST. In contrast, the 9-state model showed worsened convergence and identifiability, and a significant reduction in the precision of overall MST estimates. Hierarchical models successfully improved performance, as have informative prior models but the latter introduced bias towards the prior values. Conclusions: While disaggregating natural history models by individual cancer stages is desirable for policy, these higher-dimensional models show a greater reliance on external data/assumptions. We recommend explicit identifiability assessments and assessments of the influence of external data/assumptions to support inference for MCED screening evaluations.

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MO Soares, J Lange, K Gogebakan, S Dias, NJ Welton, R Etzioni, AE Ades, S Palmer. 2026-06-01. Modelling multi-cancer screening data to infer on natural history of disease: when can valid, identifiable and precise inference be obtained?. https://arxiv.org/abs/2606.02076

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