Development of a Pharmacogenetic Predictive Test in asthma: proof of concept

Abstract

Objective: To assess the feasibility of developing a Combined Clinical and Pharmacogenetic Predictive Test, comprised of multiple single nucleotide polymorphisms (SNPs) that is associated with poor bronchodilator response (BDR).

Methods: We genotyped SNPs that tagged the whole genome of the parents and children in the Childhood Asthma Management Program (CAMP) and implemented an algorithm using a family-based association test that ranked SNPs by statistical power. The top eight SNPs that were associated with BDR comprised the Pharmacogenetic Predictive Test. The Clinical Predictive Test was comprised of baseline forced expiratory volume in 1 s (FEV1). We evaluated these predictive tests and a Combined Clinical and Pharmacogenetic Predictive Test in three distinct populations: the children of the CAMP trial and two additional clinical trial populations of asthma. Our outcome measure was poor BDR, defined as BDR of less than 20th percentile in each population. BDR was calculated as the percent difference between the prebronchodilator and postbronchodilator (two puffs of albuterol at 180 microg/puff) FEV1 value. To assess the predictive ability of the test, the corresponding area under the receiver operating characteristic curves (AUROCs) were calculated for each population.

Results: The AUROC values for the Clinical Predictive Test alone were not significantly different from 0.50, the AUROC of a random classifier. Our Combined Clinical and Pharmacogenetic Predictive Test comprised of genetic polymorphisms in addition to FEV1 predicted poor BDR with an AUROC of 0.65 in the CAMP children (n = 422) and 0.60 (n = 475) and 0.63 (n = 235) in the two independent populations. Both the Combined Clinical and Pharmacogenetic Predictive Test and the Pharmacogenetic Predictive Test were significantly more accurate than the Clinical Predictive Test (AUROC between 0.44 and 0.55) in each of the populations.

Conclusion: Our finding that genetic polymorphisms with a clinical trait are associated with BDR suggests that there is promise in using multiple genetic polymorphisms simultaneously to predict which asthmatics are likely to respond poorly to bronchodilators.

Fig. 1

Algorithm for development of the predictive tests. CAMP, Childhood Asthma Management Program; FBAT, family-based association tests; FEV1, forced expiratory volume in 1 s; SNP, single nucleotide polymorphism.

Fig. 2

Receiver operating characteristic (ROC) curves of Clinical and Combined Clinical and Pharmacogenetic Predictive Tests. The middle lines correspond to the Clinical Predictive Test and the top lines correspond to the Combined Clinical and Pharmacogenetic Predictive Test. The bottom lines represent an area under the ROC (AUROC) of 0.50 which would represent a test that has no discriminatory value. (a) Childhood Asthma Management Program (CAMP). The AUROC is 0.55 for the Clinical Predictive Test and is significantly better at 0.65 for the Pharmacogenetic Predictive Test, P=0.038. (b) Effectiveness of Low-Dose Theophylline as Add-on Treatment in Asthma Trial. The AUROC is 0.44 for the Clinical Predictive Test and is significantly better at 0.63 for the Pharmacogenetic Predictive Test, P=0.0037. (c) Asthma Trial conducted by Sepracor. The AUROC is 0.52 for the Clinical Predictive Test and is significantly better at 0.61 for the Pharmacogenetic Predictive Test, P=0.033.