Table 2.

Levels of evidence

Level of evidence	Standard scoring range	Rare variant scoring rangea	Description
1A	≥ 80	≥ 80	High level of evidence for the association. Level 1A clinical annotations describe variant‐drug combinations that have variant‐specific prescribing guidance in a current clinical guideline annotation or an FDA‐approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g., CYP2C9*3, HLA‐B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must be supported by at least one variant annotation in addition to a clinical guideline or drug label annotation with variant‐specific prescribing guidance.
1B	25–79.9375	10–79.9375	High level of evidence for the association. Level 1B clinical annotations describe variant‐drug combinations with a high level of evidence supporting the association but no variant‐specific prescribing guidance in an annotated clinical guideline or FDA drug label. Level 1B clinical annotations must be supported by variant annotations from at least two independent publications.
2A	8–24.9375 variant in a tier 1 VIP	3–9.9375 variant in a tier 1 VIP	Moderate level of evidence for the association. Variants in level 2A clinical annotations are found in PharmGKB’s tier 1 VIPs. These variants are in known pharmacogenes, implying causation of drug phenotype is more likely. Level 2 clinical annotations describe variant‐drug combinations with a moderate level of evidence supporting the association. For example, the association may be found in multiple cohorts, but there may be a minority of variant annotations that do not support the majority assertion. Level 2 clinical annotations must be supported by variant annotations from at least two independent publications.
2B	8–24.9375	3–9.9375	Moderate level of evidence for the association. Variants in level 2B clinical annotations are not in PharmGKB’s tier 1 VIPs. Level 2 clinical annotations describe variant‐drug combinations with a moderate level of evidence supporting the association. For example, the association may be found in multiple cohorts, but there may be a minority of variant annotations that do not support the majority assertion. Level 2 clinical annotations must be supported by variant annotations from at least two independent publications.
3	0–7.9375	0–2.9375	Low level of evidence for the association. Level 3 clinical annotations describe variant‐drug combinations with a low level of evidence supporting the association. This association may be based on a single publication annotated in PharmGKB, or there may be several variant annotations that failed to replicate the association. The annotation may also be based on preliminary evidence (e.g., a case report, nonsignificant study, or in vitro, molecular, or functional assay evidence), resulting in a lower calculated score.
4	< 0	< 0	Association is unsupported. Level 4 clinical annotations describe variant‐drug combinations where the total score is negative, and the evidence does not support an association between the variant and the drug phenotype.

FDA, US Food and Drug Administration; PharmGKB, Pharmacogenomics Knowledgebase; VIP, very important pharmacogene.

^a A separate scoring range is used for clinical annotations on rare variants.²⁰