Risk of bias assessment in cross-sectional genetic research: the impact of genetic polymorphisms on methadone response

Poster
2013 Québec City
Dennis B1, Bawor M2, Sohani Z3, Thabane L4, Guyatt GH5, Samaan Z6
1Department of Clinical Epidemiology and Biostatistics - McMaster University, Population Genomics Program - McMaster University, Canada
2McMaster Integrative Neuroscience Discovery & Study (MiNDS) Program - McMaster University, Population Genomics Program - McMaster University, Canada
3Department of Clinical Epidemiology and Biostatistics - McMaster University, Population Genomics Program - McMaster University, Population Health Research Institute - Hamilton Health Sciences, Canada
4Department of Clinical Epidemiology and Biostatistics - McMaster University, Departments of Paediatrics and Anesthesia - McMaster University, Centre for Evaluation ofMedicine, Biostatistics Unit, Father Sean O’Sullivan Research Centre - St. Joseph’s Health Care Hamilton, Population Health Research Institute - Hamilton Health Sciences, Canada
5Department of Clinical Epidemiology and Biostatistics - McMaster University, Canada
6Department of Psychiatry and Behavioral Neurosciences - McMaster University, Population Genomics Program - McMaster University, Department of Clinical Epidemiology and Biostatistics - McMaster University, Population Health Research Institute - Hamilton Health Sciences, Canada

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.