Estimation of Bias in Nongenetic Observational Studies Using “Mendelian Triangulation”

Purpose Phenotype–disease odds ratios calculated from the effect of a genotype on its phenotype and on disease risk (“Mendelian triangulation”) can be used as a standard to assess bias on the corresponding odds ratio from nongenetic studies. Statistical tests are commonly used to compare these odds ratios. We propose a method to estimate the magnitude of the bias and judge the validity of the phenotype–disease association. Methods For four published examples, we obtained 10,000 random values from distributions of the odds ratios from both genetic and nongenetic studies. A range of values compatible with an unbiased odds ratio was then calculated from the empirical distribution of the differences between both odds ratios. Results We show that estimating a range of likely values for an unbiased odds ratio is useful to judge the effect of the phenotype and identify cases for which information from genetic studies adds little to the evaluation of the phenotype–disease association. Conversely, statistical tests could be misleading. Conclusions Estimating a range of values for an unbiased odds ratio is more informative and appropriate than statistical tests when using the Mendelian triangulation approach for assessment of bias in phenotype–disease association studies.