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Risk of Bias Assessment in Cross-Sectional Genetic Research: The Impact of Genetic Polymorphisms on Methadone Response

Date and Location




Monday 23 September 2013 - 10:30 - 12:00


Presenting author and contact person

Presenting author

Brittany Dennis

Contact person

Brittany Dennis
Abstract text
Background: The prevalence of genetic association studies in the literature has increased exponentially over the past decade. Most are cross-sectional studies that present unique methodological challenges and risks of bias; they should be appraised accordingly when included in systematic reviews and meta-analyses. Objectives: To develop a method for assessing risk of bias in genetic association studies and demonstrate its use in a review of the association between a genetic polymorphism (CYP2B6*6) and metabolism of a drug (methadone plasma concentration). Methods: We searched Medline, EMBASE, CINAHL, PsycINFO, and Web of Science databases. Two independent reviewers included studies that reported methadone plasma concentration and the CYP2B6*6 polymorphism. Results: We modified the Newcastle-Ottawa Scale to assess the risk of bias in studies of the effect of genetic polymorphisms on drug metabolism. We removed several categories highlighting the comparability of cohort or case/control selection and the importance of adequate follow-up between study groups, while also introducing categories that emphasize explicit outcome and genetic assessment. We identified seven studies assessing the association between methadone plasma concentration and the CYP2B6*6 polymorphism. Five were cross-sectional; two were case-control. Trough (R) methadone plasma concentration was higher in CYP2B6*6 homozygous carriers compared to non-carriers (SMD = 0.53; 95% CI 0.05-1.00; p=0.03; I2=0%). Trough (S) methadone plasma concentration was higher in *6 haplotype homozygotes than in non-carriers, (SMD = 1.44; 95% CI 0.27-2.61; p=0.04; I2=69%). Conclusions: Participants homozygous for the CYP2B6*6 genotype have higher trough (R) and (S) methadone plasma concentrations compared to non-carriers, suggesting that methadone metabolism is significantly slower in *6 homozygous carriers. We developed an instrument to appraise risk of bias in genetic association studies; it rates the evidence in this review to be of moderate quality and cautions our confidence in the estimates of association. This presentation will focus on that instrument and its application.