Meta-analysis of genetic studies using Mendelian randomization--a multivariate approach.
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.
Thompson
John R
JR
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
Minelli
Cosetta
C
Abrams
Keith R
KR
Tobin
Martin D
MD
Riley
Richard D
RD
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
D006710:Homocysteine; D042965:Methylenetetrahydrofolate Reductase (NADPH2)