An empirical evaluation of multifarious outcomes in pharmacogenetics: beta-2 adrenoceptor gene polymorphisms in asthma treatment

Abstract

Objective: Pharmacogenetics promises to individualize therapeutics. Concerns, however, exist about the lack of replication of discoveries. Selective use of different endpoints, times of assessment, types of interventions and genetic groups across studies may lead to spurious results. Here, we examined the variability of definitions of endpoints and analyses reported across studies addressing the association of the Arg16Gly and/or Gln27Glu polymorphisms of the beta2-adrenergic receptor gene with clinical response to beta2-agonist therapy in asthma.

Methods: We systematically calculated the number and type of endpoints and analyses reported across studies and recorded the appraisal of their statistical significance.

Results: Across 21 studies, the total number of probed and reported associations was 487 when the multiple endpoints and types of comparisons presented by multiple comparisons were considered (337 for Arg16Gly, 98 for Gln27Glu and 52 for their haplotypes): 465 (95%) were probed only once; only six associations were probed twice and two associations were probed five times, for the same endpoint, time of assessment, type of interventions and genetic group. Most studies (17/21) claimed at least one significant association. Overall, however, 243/487 (49.9%) probed and reported associations were not statistically significant, 120 (24.6%) were of unspecified statistical significance, 86 (17.7%) were statistically significant only for specific selected genetic contrasts and only 38 (7.8%) were genuinely statistically significant for the comparison between all available genetic groups.

Conclusions: The multifarious outcomes in this literature are inconsistent across studies and susceptible to selective reporting. The lack of standardization hinders the evaluation of replication validity for reported discoveries.