Indirect estimation of the comparative treatment effect in pharmacogenomic subgroups

Abstract

Evidence of clinical utility is a key issue in translating pharmacogenomics into clinical practice. Appropriately designed randomized controlled trials generally provide the most robust evidence of the clinical utility, but often only data from a pharmacogenomic association study are available. This paper details a method for reframing the results of pharmacogenomic association studies in terms of the comparative treatment effect for a pharmacogenomic subgroup to provide greater insight into the likely clinical utility of a pharmacogenomic marker, its' likely cost effectiveness, and the value of undertaking the further (often expensive) research required for translation into clinical practice. The method is based on the law of total probability, which relates marginal and conditional probability. It takes as inputs: the prevalence of the pharmacogenomic marker in the patient group of interest, prognostic effect of the pharmacogenomic marker based on observational association studies, and the unstratified comparative treatment effect based on one or more conventional randomized controlled trials. The critical assumption is that of exchangeability across the included studies. The method is demonstrated using a case study of cytochrome P450 (CYP) 2C19 genotype and the anti-platelet agent clopidogrel. Indirect subgroup analysis provided insight into relationship between the clinical utility of genotyping CYP2C19 and the risk ratio of cardiovascular outcomes between CYP2C19 genotypes for individuals using clopidogrel. In this case study the indirect and direct estimates of the treatment effect for the cytochrome P450 2C19 subgroups were similar. In general, however, indirect estimates are likely to have substantially greater risk of bias than an equivalent direct estimate.

Figure 1. Relationships between subgroup treatment effects, association study results and unstratified RCT study results.

CYP2C19 genotype and clopidogrel is used here as an example to illustrate the groups of individuals (based on treatment and pharmacogenomics marker status) involved in the indirect subgroup analysis and the relationships between the groups (both known and unknown). Values in the brackets represent the 95% confidence intervals for the estimate. CYP2C19: cytochrome P450 2C19, LoF: loss-of-function.

Figure 2. One way deterministic sensitivity analysis for indirect estimates of treatment effect.

The indirect estimates of the treatment effect (relative risk for comparison of ticagrelor and clopidogrel) for subgroups based on cytochrome P450 2C19 (CYP2C19) genotype are displayed as a function of the size of the association study estimate. LoF = subgroup with a CYP2C19 loss-of-function allele, LoF′ = subgroup without a CYP2C19 loss-of-function allele.