Fig. 2

Estimation of bias in our simulation study. Bias was estimated for each of the four constant parameters (in columns) of the piecewise constant β(t) referring to the additional effect of the SORL1 variant of interest through 4 scenarios of simulation (in rows). The results are provided for probands included and excluded from the analysis during the maximization step of the EM algorithm. For the baseline scenario, we generated 27 families mimicking what we observed in our dataset in terms of SORL1-LoF variant effect, ascertainment, and available genotypes. Then, the model was challenged through three additional scenarios: (i) Unbalanced phenotype information: if one of the parents was affected, we removed all the phenotypic information of the parental branch with the unaffected parent. (ii) Relatives’ genotypes 100% missing: we removed all information about relatives’ genotypes. (iii) Heterogeneous variant effect: instead of generating age at onset based on a constant variant effect, we generated age at onset based on a normal distribution of the variant effect with a variance equaling to 1. A bias greater than 0 indicates an overestimation and a bias lower than 0 indicates an underestimation of the risk associated with SORL1-LoF variants