Methods

The allele frequency table was made by searching the PubMed® database (no start date to May 2018). Studies were considered for inclusion in the CYP2B6 Frequency Table if (1) the ethnicity of the population was clearly indicated; (2) either allele frequencies or genotype frequencies were reported; and (3) the method by which genes were genotyped was indicated. Allele frequencies reported in the gnomAD browser (http://gnomad.broadinstitute.org/ - exomes and genomes) and 1000 Genomes Project phase 3 data on Ensemble browser (https://uswest.ensembl.org/index.html) were also included.

Diplotype and Phenotype Calculations. Diplotype and phenotype frequencies were estimated using the equation describing Hardy Weinberg equilibrium based on reported allele frequencies.

Caveats to estimated allele, diplotype and phenotype frequencies:

Sampling. Allele frequencies collected by CPIC for the supplemental tables are based on published literature reports which typically study small groups of people based on a geographic location (e.g. Malaysia, Berlin, Cairo). Almost no studies use genetic markers to estimate ancestry. Manuscripts are often focused on a specific phenotype (e.g. disease) or study only individuals taking a particular drug. Such samples would not be considered a random sample of the general population. Another consideration is that sample size is important, and PGx studies are typically not large. Studies were included in the frequency calculation regardless of number. The frequencies collected from these studies are then used to estimate general estimates of entire ethnic population allele frequencies. Therefore, frequencies from larger groups of subjects and frequencies averaged from many sample populations probably result in better estimates.

Estimation of *1 frequency. In general, there are no population studies that test for all known variant alleles. Because *1 is not genotyped directly in many studies, all alleles that are negative for a sequence variation are defaulted to a *1 assignment. The inferred frequency for *1 is estimated as: 1 - (sum of averaged variant allele frequencies). For genes where many alleles are not tested for in any population, and frequency of 'common' alleles is not well documented in many understudied populations (Oceania, Middle eastern, South Asian, Latino), the *1 frequency will deviate even more from true values.

Diplotype/Phenotype frequency estimates. Diplotype and phenotype frequencies were estimated using the equation describing Hardy Weinberg equilibrium based on reported allele frequencies. When calculating diplotype frequencies from these allele frequencies, the margin of error is compounded based on the margin of error on each allele in the diplotype. So, the margin of error will necessarily increase for diplotype frequency estimates compared to allele frequency estimates. For allele frequencies with already large margins of error due to small and non-random sampling, the diplotype margin of error could potentially be quite large. On the other hand, for well-studied alleles, the margin of error is likely low.

Biogeographical groups. Biogeographical groups are derived from PMID 30506572. Further details, including the definitions of each group, can be found at https://www.pharmgkb.org/page/biogeographicalGroups. We strongly recommend that users use either the publication or the PharmGKB link provided to familiarize themselves with the grouping system before using these allele frequencies. These tables group individuals from particular geographic locations into larger biogeographical groups. It is difficult to group populations with certainty, because some populations are often admixed, or at the least, a combination of different ethnicities. Therefore, the margin of error is increased when different subpopulations are grouped together.