Objectives: There has been increased appreciation of the differences between marginal and conditional estimates and different types of effect measures regarding their applicability to different target populations. This issue of transportability is of concern in model-based cost-effectiveness analysis (CEA) when treatment effects from (international) trials are applied to (country-specific) baseline risk estimates. The objective of this paper is to create awareness regarding the issues that arise when using different types of treatment effect and baseline risk estimates in a model-based CEA to inform health technology assessment (HTA). Methods: We clarify collapsibility, marginal versus conditional estimation, and transportability; derive the ideal modeling approach implied by a marginal cost-effectiveness estimand; and characterize the issues of common modeling approaches, illustrated with a fictitious state-transition model. Results: An individual-level simulation that predicts outcomes from conditional inputs and averages them over the target population targets the marginal cost-effectiveness estimand. Cohort-model approaches that marginalize inputs early, use conditional inputs at mean covariate values, or combine a conditional effect with a marginal baseline (or vice versa) can misstate cost-effectiveness results even with correct-population inputs; inputs from the wrong population add further error. Conclusions: The most rigorous approach is an individual-level simulation that carries conditional inputs (baseline risk, treatment effect, prognostic effects and effect modifiers) and marginalizes late. Cohort approaches instead marginalize early, relying on aggregated inputs, and do not necessarily target the marginal cost-effectiveness estimand of interest for HTA. Model developers should document, for each input, whether it is marginal or conditional and its population.

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