To Replicate or Not to Replicate: The Case of Pharmacogenetic Studies
Have Pharmacogenomics Failed, or Do They Just Need Larger-Scale Evidence and More Replication?
Over the last 2 decades, pharmacogenetics and, subsequently, pharmacogenomics have generated a highly prolific literature with thousands of promising markers that may be associated with diverse aspects of treatment response (efficacy or harms) of many different drugs. Initial expectations that have been continuously fueled by more editorials and opinion pieces have insisted that research in this area can become the frontrunner and catalyst of personalized, individualized, precision medicine, as drug choice, schedule, dosage, and combination with other drugs could be guided by pharmacogenomics.
Response by Aslibekyan et al on p 418
Despite these promises, it is currently recognized that the large majority of proposed genetic associations (including pharmacogenetics) made in the past, mostly with candidate gene approaches, have not been replicated with larger-scale evidence and stringent statistical criteria.1,2 The old proposed associations were based on weak statistical rules, which are currently considered to select almost entirely false-positives. Certainly, the large majority of them have failed to reach stringent genome-wide significance (P<5×10−8), and most of them have effect sizes close to the null when tested in larger studies. Even with the advent of genome-wide association studies (GWAS), extending also into whole-genome sequencing in the last few years, the yield of new replicated pharmacogenomic markers has been very limited. Is this a sign of failure of pharmacogenomics or simply a reflection of the lack of large-scale evidence with stringent replication in the field?
In a recent review3 of the literature of GWAS until June 15, 2012, there were 139 meta-analyses of GWAS on diverse phenotypes where the total discovery sample exceeded 10 000 participants. None of them pertained to a pharmacogenomic phenotype. An evaluation of the National Human Genome Research Institute catalog of GWAS4,5 as of March 20, 2013, shows that among the most …