PharmGKB FAQs: How do I read a clinical annotation?

Clinical annotations are written to summarize associations between variants and drug response and are based on annotations of published literature. As an example, please refer to this clinical annotation for rs4149056 in the gene SLCO1B1 and the drug simvastatin.

Clinical annotations consist of 3 main parts:

1. Genotype/diplotype-based summaries describe the pharmacogenetic associations with specific genotypes or diplotypes (or in some cases, haplotypes) and the association for any given genotype or diplotype is reported relative to the other genotypes and diplotypes. Clinical annotations can include evidence from individual or multiple papers. 

In the example clinical annotation the summaries are for the following genotypes at rs4149056: CC, CT, and TT. Notice that the summaries are written relative to one another.

2. Evidence is based on variant annotations, which report the pharmacogenetic association between a variant (eg. SNPs, indels, repeats, haplotypes, etc.) and a pharmacogenetic phenotype from a single publication. The variant annotations support the assertions in the clinical annotation summaries and are listed underneath. 

In our example, there are eight variant annotations under the summaries that support the assertions of the genotype summaries.

3. Level of Evidence (LoE) is assigned for each clinical annotation and is based on the strength of evidence when assessing all of the variant annotations. LoE ranges from 1- 4, with level 1 meeting the highest criteria, meaning the strongest evidence, and level 4 meeting minimal criteria, meaning the weakest level of evidence. LoE 1 and 2 have two additional categories denoted by letters, A and B so that LoE 1A is higher than 1B. LoE is based on multiple criteria including replication, statistical significance and study size.

The example clinical annotation is a level 1A, the highest evidence. The criteria used for scoring LoE is available here.