Common use of Imputation Clause in Contracts

Imputation. To expand the number of interrogated SNVs, imputation can be used for technologies that do not cover the entire genome (Table 2.2). Imputation is predominantly used in GWAS analysis and to expand the PGx panel in genome wide arrays [8]. With imputation, the presence of a genomic variant is inferred based on the absence or presence of a linked SNV. These predictions all come with a probability for the occurrence of the SNV of interest. Often only imputations with a high probability are included (e.g., >90%) to avoid inaccurate assignments. ▇▇▇▇▇▇▇▇ et al. have shown that imputation accuracies as high as 99% can be reached for PGx variants [8]. Nevertheless, a probability of 90% also means that there is a 10% change that the imputed variant is not correct. While this is certainly acceptable for population studies, it is not sufficient for tailoring drug treatment in an individual patient. Furthermore, to reach high imputation accuracy, an imputation dataset specific to each patient’s ethnical background is needed as the level of linkage disequilibrium (LD) between two SNVs can differ between different populations [8,75]. One clear example of the differences in LD between populations is the HLA tagging SNVs; to identify the HLA-A*3101 allele, associated with carbamazepine toxicity, a linked SNV is used. In Caucasians, the rs1061235 (NC_000006.12:g.29945521A>T) variant is in full LD with the *3101 haplotype, therefore the presence of the HLA-A*3101 allele can be inferred based on the presence of the rs1061235 variant [76]. However, in the Asian population, this variant is not in LD with the *3101 allele. For individuals of Asian descent, the rs1633021 (NC_000006.12:g.29779092T>C) variant can be used as a linked SNV as this variant is in LD with HLA-A*3101 in this population [77]. Using the Caucasian-linked SNV in the wrong population can lead to errors in the inferred haplotype, phenotype and ultimately lead to treatment errors. Therefore, the application of imputation should be limited to research purposes until the reliability for an individual patient has been proven.