A Versatile and Efficient Novel Approach for Mendelian Randomization Analysis with Application to Assess the Causal Effect of Fetal Hemoglobin on Anemia in Sickle Cell Anemia

Mendelian randomization (MR) is increasingly employed as a technique to assess the causation of risk factor on an outcome using observational data. The two-stage least-squares (2SLS) procedure commonly used examine genetic variants instrument variables. validity 2SLS relies representative sample randomly selected from study cohort or population for genome-wide association (GWAS), which not always true in practice. For example, extreme phenotype sequencing (EPS) design widely investigate determinants GWAS it bears many advantages such efficiency, low genotyping cost, and large power detecting involvement rare disease etiology. In this paper, we develop novel, versatile, efficient approach, namely MR analysis under Extreme random Phenotype Sampling (MREPS), one-sample based samples drawn through either sampling nonrandom EPS design. simulations, MREPS provides unbiased estimates causal effects, correct type I errors effect testing. Furthermore, robust different designs has high power. These results demonstrate superiority over standard approach. We applied highlight total fetal hemoglobin anemia patients with sickle cell two independent studies. A user-friendly Shiny app web interface was implemented professionals easily explore MREPS.