The essence of linkage-based imprinting detection: comparing power, type 1 error, and the effects of confounders in...

Imprinting is critical to understanding disease expression. It can be detected using linkage information, but the effects of potential confounders (heterogeneity, sex-specific penetrance, and sex-biased ascertainment) have not been explored. We examine power and confounders in two imprinting detection approaches, and we explore imprinting-linkage interaction. One method (PP) models imprinting by maximising lod scores w.r.t. parent-specific penetrances. The second (DRF) approximates imprinting by maximising lods over differential male-female recombination fractions. We compared power, type 1 error, and confounder effects in these two methods, using computer-simulated data. We varied heterogeneity, penetrance, family and dataset size, and confounders that might mimic imprinting. Without heterogeneity, PP had more imprinting-detecting power than DRF. PP's power increased when parental affectedness status was ignored, but decreased with heterogeneity. With heterogeneity, type 1 error increased dramatically for both methods. However, DRF's power also increased under heterogeneity, more than was attributable to inflated type 1 error. Sex-specific penetrance could increase false positives for PP but not for DRF. False positives did not increase on ascertainment through an affected "mother". For PP, non-penetrant individuals increased information, arguing against using affected-only methods. The high type 1 error levels under some circumstances means these methods must be used cautiously.