Specify the penetrance estimand before comparing cohorts

A penetrance estimate is interpretable only after its target population, time scale, outcome definition, and competing-event treatment are fixed. Population carriers, clinically referred families, and affected case series generally identify different quantities, even when they contain the same variant class.

The studies indexed as PMID 41130550 and PMID 41763641 provide contrasting settings in which to report a common audit table: carrier denominator, recruitment route, testing indication, age origin, surveillance method, censoring, competing mortality, and handling of relatedness. The modifier perspective indexed as PMID 41990334 adds a second requirement. Modifier effects should be recalculated under each defensible sampling model rather than transported directly from an enriched cohort. Without that comparison, differences attributed to biological penetrance may remain compatible with ascertainment and detection.