An Evidence‐Based Framework for Evaluating Pharmacogenomics Knowledge for Personalized Medicine

Abstract

Clinical annotations are one of the most popular resources available on the Pharmacogenomics Knowledgebase (PharmGKB). Each clinical annotation summarizes the association between variant‐drug pairs, shows relevant findings from the curated literature, and is assigned a level of evidence (LOE) to indicate the strength of support for that association. Evidence from the pharmacogenomic literature is curated into PharmGKB as variant annotations, which can be used to create new clinical annotations or added to existing clinical annotations. This means that the same clinical annotation can be worked on by multiple curators over time. As more evidence is curated into PharmGKB, the task of maintaining consistency when assessing all the available evidence and assigning an LOE becomes increasingly difficult. To remedy this, a scoring system has been developed to automate LOE assignment to clinical annotations. Variant annotations are scored according to certain attributes, including study size, reported P value, and whether the variant annotation supports or fails to find an association. Clinical guidelines or US Food and Drug Administration (FDA)‐approved drug labels which give variant‐specific prescribing guidance are also scored. The scores of all annotations attached to a clinical annotation are summed together to give a total score for the clinical annotation, which is used to calculate an LOE. Overall, the system increases transparency, consistency, and reproducibility in LOE assignment to clinical annotations. In combination with increased standardization of how clinical annotations are written, use of this scoring system helps to ensure that PharmGKB clinical annotations continue to be a robust source of pharmacogenomic information.

Insights into the Genetic Variations of Human Cytochrome P450 2C9: Structural Analysis, Characterization and Comparison

“…In the clinical context, the current pharmacogenomics annotations indicates that the patients carrying the CYP2C9*8 allele in combination with another decreased functional allele may demonstrate reduced metabolism of losartan compared to the patients possessing two WT or normal function alleles [ 30 ]. However, clear evidence regarding the impact on the metabolism of losartan and the role of *8 allele (*8/*8) and in combination with a WT allele (*1/*8) compared to patients with two normal function alleles is scant, with the exception of a study in 2004 [ 14 ].…”

Genetic Factors Associated With Tardive Dyskinesia: From Pre-clinical Models to Clinical Studies

“…All the available published information regarding the impact of human genetic variations on drug response is compiled and publicly available from the Pharmacogenomics Knowledge Base (PharmGKB) ( Relling and Klein 2011 ; Whirl-Carrillo et al, 2012 , Whirl-Carrillo et al, 2021 ). The database provides clinically actionable gene-drug and genotype-phenotype associations and pharmacogenomic guidelines for a variety of drugs ( https://www.pharmgkb.org/ ).…”

Treatment Response to SGLT2 Inhibitors: From Clinical Characteristics to Genetic Variations

“…Common functional polymorphisms in genes coding for these CYPs and UGTs were already shown to play a major role in the large interindividual variability in the pharmacokinetics, pharmacodynamics, and treatment response of several clinically important drugs [50]. For more than 100 gene-drug pairs, there is already a sufficient level of evidence that guidelines for personalized drug treatment tailored to an individual's genetic makeup were prepared and published by professional societies such as the Clinical Pharmacogenetics Implementation Consortium [51,52] (CPIC), the Dutch Pharmacogenetics Working Group [53,54] (DPWG), and others.…”