Modelling the impact of Multi Cancer Early Detection tests:a review of natural history of disease models

Introduction: The potential for multi-cancer early detection (MCED) tests to detect cancer at earlier stages is currently being evaluated in screening clinical trials. Once trial evidence becomes available, modelling will be necessary to predict impacts on final outcomes (benefits and harms), account for heterogeneity in determining clinical and cost-effectiveness, and explore alternative screening programme specifications. The natural history of disease (NHD) component of a MCED model will use statistical, mathematical or calibration methods. Methods: Modelling approaches for MCED screening that include an NHD component were identified from the literature, reviewed and critically appraised. Purposively selected (non-MCED) cancer screening models were also reviewed. The appraisal focussed on the scope, data sources, evaluation approaches and the structure and parameterisation of the models. Results: Five different MCED NHD models were identified and reviewed, alongside four additional (non-MCED) models. The critical appraisal highlighted several features of this literature. In the absence of trial evidence, MCED effects are based on predictions derived from test accuracy. These predictions rely on simplifying assumptions with unknown impacts, such as the stage-shift assumption used to estimate mortality impacts from predicted stage-shifts. None of the MCED models fully characterised uncertainty in the NHD or examined uncertainty in the stage-shift assumption. Conclusion: MCED technologies are developing rapidly, and large and costly clinical studies are being designed and implemented across the globe. Currently there is no modelling approach that can integrate clinical study evidence and therefore, in support of policy, it is important that similar efforts are made in the development of MCED models that make best use of the available data on benefits and harms.