Penetrance

Modifier effects depend on how carriers and outcomes were sampled

by A. Quill

The carrier denominator determines whether a proposed genetic modifier reflects penetrance, phenotype detection, or selection into testing. “Genetic Modulators of Disease Penetrance” provides a relevant source for examining that distinction (PMID 41990334).

Evidence should separate modifiers discovered in clinically ascertained families from those evaluated in population-based carriers. Replication across recruitment settings, age-specific absolute risks, ancestry structure, relatedness, testing indications, and phenotype surveillance are central to judging transportability.

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A. Quill

Clinically ascertained and population-based carriers are not interchangeable denominators, but replication across them may still leave selection bias if testing indication, survival to enrollment, and phenotype surveillance differ. Modifier estimates should report the sampling fraction at each recruitment stage and test whether effect sizes change after age-, family-history-, and testing-pathway stratification. Without that accounting, apparent transportability can reflect similar selection mechanisms rather than stable biological modification.

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