Assessment of pharmacogenetic tests: presenting measures of clinical validity and potential population impact in association studies

The Pharmacogenomics Journal (2017) 17, 386–392 OPEN www.nature.com/tpj ORIGINAL ARTICLE Assessment of pharmacogenetic tests: presenting measures of clinical validity and potential population impact in association studies ECM Tonk1, D Gurwitz2, A-H Maitland-van der Zee3 and ACJW Janssens1,4 The progressing discovery of genetic variants associated with drug-related adverse events has raised expectations for pharmacogenetic tests to improve drug efficacy and safety. To further the use of pharmacogenetics in health care, tests with sufficient potential to improve efficacy and safety, as reflected by good clinical validity and population impact, need to be identified. The potential benefit of pharmacogenetic tests is often concluded from the strength of the association between the variant and the adverse event; measures of clinical validity are generally not reported. This paper describes measures of clinical validity and potential population health impact that can be calculated from association studies. We explain how these measures are influenced by the strength of the association and by the frequencies of the variant and the adverse event. The measures are illustrated using examples of testing for HLA-B*5701 associated with abacavir-induced hypersensitivity and SLCO1B1 c.521T4C (*5) associated with simvastatin-induced adverse events. The Pharmacogenomics Journal (2017) 17, 386–392; doi:10.1038/tpj.2016.34; published online 10 May 2016 INTRODUCTION Genetic variants associated with drug response or drug-related adverse events can potentially be used to improve the efficacy and safety of drugs.1–3 Pharmacogenetic tests are generally thought to be useful when the association between the genetic variant and the drug response or adverse event is strong.4 However, the ability of a pharmacogenetic test to improve drug efficacy and safety depends on more than just the association between the genetic variant and drug response or the adverse event. For that reason, the assessment of pharmacogenetic tests goes beyond quantification of association alone. Reporting measures of clinical validity and population impact in addition to measures of association allows a more informative evaluation of pharmacogenetic tests. The clinical validity of a pharmacogenetic test indicates the test’s ability to predict the occurrence of the adverse event of interest. Clinical validity is determined by the strength of the association between the genetic variant and the adverse event, but also by the frequencies of the genetic variant and the adverse event. Therefore, a strong association is essential but not a sufficient condition to ensure good clinical validity. The clinical validity subsequently impacts the clinical utility of the test, which is the ability of the test to prevent adverse effects through differentiation in treatments based on the test results.5 The population impact indicates the potential benefit of a pharmacogenetic test and differentiation in treatments and can be expressed as the expected reduction in adverse events or the number of patients that need a different treatment. 1 Evaluations of pharmacogenetic tests often report measures of association without considering clinical validity and population impact.4,6,7 For example, measures of clinical validity are included in the Clinical Pharmacogenetics Implementation Consortium guidelines for drug/gene pairs when this information is available from empirical studies, which is the case for only 5 of the 35 drugs.8 The reasons for this are that pharmacogenetic studies frequently investigate intermediate continuous end points instead of adverse events, such as drug plasma concentrations and biochemical markers of toxicity. Also, studies that investigate adverse events are often observational studies with a case–control design, which by design have a different proportion of cases than in the population of interest. Because of that, case–control studies do allow calculation of the pharmacogenetic association (odds ratio (OR)) but not of all measures of clinical validity. In this paper we explain how measures of clinical validity and potential population impact can be calculated in pharmacogenetic association studies. Additionally, we demonstrate how the measures are impacted by variations in ORs, adverse event frequency and variant frequency, and illustrate their use in the assessment of pharmacogenetic testing for HLA-B*5701, which is associated with abacavir-induced hypersensitivity9 and SLCO1B1 c.521T4C (*5) associated with simvastatin-induced adverse events.10,11 Measures of clinical validity Clinical validity refers to the ability of a test to correctly identify or predict an outcome of interest, which, in pharmacogenetics, indicates the ability of the test to predict adverse events such as Department of Clinical Genetics/EMGO Institute for Health and Care Research, Section Community Genetics, VU University Medical Center, Amsterdam, The Netherlands; Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; 3Utrecht Institute of Pharmaceutical Sciences, Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht University, Utrecht, The Netherlands and 4Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA. Correspondence: Professor ACJW Janssens, Department of Epidemiology, Rollins School of Public Health, Emory University, 1518 Clifton Road NE, Atlanta, GA 30322, USA. E-mail: Received 24 August 2015; revised 24 December 2015; accepted 26 February 2016; published online 10 May 2016 2 Assessment of pharmacogenetic tests ECM Tonk et al 387 Box 1. Examples Abacavir Abacavir is a nucleoside reverse transcriptase inhibitor indicated for treatment of HIV infection. Treatment with abacavir is generally well tolerated, but 5–8% of the patients experience hypersensitivity reactions that can be life threatening and warrant immediate discontinuation of the drug. Hypersensitivity reactions can be clinically diagnosed based on symptoms only or be immunologically confirmed using patch testing. Multiple studies revealed a strong association between carriage of HLAB*5701 and abacavir hypersensitivity in Caucasians and Hispanics.9,44–46 Figure 1. Calculation of clinical validity and potential population impact measures from 2 × 2 contingency tables reporting adverse event by genetic variant subgroups. Contingency tables can be constructed using empirical data or using hypothetical data calculated from summary statistics and association measures, such as odds ratios derived from observational studies with a case– control design in combination with the frequencies of the genetic variant and the adverse event (see Supplementary Information). toxicity or lack of treatment efficacy. Clinical validity is indicated by measures of discriminative accuracy and predictive value. The discriminative accuracy refers to the ability of a test to di (...truncated)