A framework evaluating the utility of multi-gene, multi-disease population-based panel testing that accounts for uncertainty in penetrance estimates

Abstract

AbstractPanel germline testing allows for efficient detection of deleterious variants for multiple conditions, but the benefits and harms of identifying these variants are not always well-understood. We present a multi-gene, multi-disease aggregate utility formula that allows the user to consider adding or removing each gene in a panel based on variant frequency; estimated penetrances; and subjective disutilities for testing positive but not developing the disease and testing negative but developing the disease. We provide credible intervals for utility that reflect uncertainty in penetrance estimates. Rare, highly-penetrant deleterious variants tend to contribute positive net utilities for a wide variety of user-specified utility costs, even when accounting for parameter estimation uncertainty. However, the clinical utility of deleterious variants with moderate, uncertain penetrance depends more on assumed disutilities. The decision to include a gene on a panel depends on variant frequency, penetrance, and subjective utilities, and should account for uncertainties around these factors.