title: Meta-analysis of genetic studies using Mendelian randomization--a multivariate approach.
abstract: In traditional epidemiological studies the association between phenotype (risk factor) and disease is often biased by confounding and reverse causation. As a person's genotype is assigned by a seemingly random process, genes are potentially useful instrumental variables for adjusting for such bias. This type of adjustment combines information on the genotype-disease association and the genotype-phenotype association to estimate the phenotype-disease association and has become known as Mendelian randomization. The information on genotype-disease and genotype-phenotype may well come from a meta-analysis. In such a synthesis, a multivariate approach needs to be used whenever some studies provide evidence on both the genotype-phenotype and genotype-disease associations. This paper presents two multivariate meta-analytical models, which differ in their treatment of the heterogeneities (between-study variances). Heterogeneities on the genotype-phenotype and genotype-disease associations may be highly correlated, but a multivariate model that parameterizes the heterogeneity directly is difficult to fit because that correlation is poorly estimated. We advocate an alternative model that treats the heterogeneities on genotype-phenotype and phenotype-disease as being independent. This model fits readily and implicitly defines the correlation between the heterogeneities on genotype-phenotype and genotype-disease. We show how either maximum likelihood or a Bayesian approach with vague prior distributions can be used to fit the alternative model.
authors.affiliation: Department of Health Sciences, Centre for Biostatistics and Genetic Epidemiology, University of Leicester, 22-28 Princess Rd West, Leicester, LE1 6TP, U.K. john.thompson@le.ac.uk
authors.forename: John R
authors.initials: JR
authors.lastname: Thompson
authors.forename: Cosetta
authors.initials: C
authors.lastname: Minelli
authors.forename: Keith R
authors.initials: KR
authors.lastname: Abrams
authors.forename: Martin D
authors.initials: MD
authors.lastname: Tobin
authors.forename: Richard D
authors.initials: RD
authors.lastname: Riley
mesh_terms: D003327:Coronary Disease / Q000235:genetics; D006710:Homocysteine / Q000097:blood / Q000235:genetics; D015201:Meta-Analysis as Topic; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D008957:Models, Genetic; D015233:Models, Statistical; D015999:Multivariate Analysis; D011110:Polymorphism, Genetic
chemical_list: D006710:Homocysteine; D042965:Methylenetetrahydrofolate Reductase (NADPH2)