Yihe Yang, Noah Lorincz-Comi, Xiaofeng Zhu
arXiv 12 Jan 2023 · Statistics — Methodology · 2 citations (OpenAlex)
arXiv:2301.05130 · PDF · DOI · OpenAlex · Extracted main text
Mendelian randomization (MR) is an instrumental variable (IV) approach to infer causal relationships between exposures and outcomes with genome-wide association studies (GWAS) summary data. However, the multivariable inverse-variance weighting (IVW) approach, which serves as the foundation for most MR approaches, cannot yield unbiased causal effect estimates in the presence of many weak IVs. To address this problem, we proposed the MR using Bias-corrected Estimating Equation (MRBEE) that can infer unbiased causal relationships with many weak IVs and account for horizontal pleiotropy simultaneously. While the practical significance of MRBEE was demonstrated in our parallel work (Lorincz-Comi (2023)), this paper established the statistical theories of multivariable IVW and MRBEE with many weak IVs. First, we showed that the bias of the multivariable IVW estimate is caused by the error-in-variable bias, whose scale and direction are inflated and influenced by weak instrument bias and sample overlaps of exposures and outcome GWAS cohorts, respectively. Second, we investigated the asymptotic properties of multivariable IVW and MRBEE, showing that MRBEE outperforms multivariable IVW regarding unbiasedness of causal effect estimation and asymptotic validity of causal inference. Finally, we applied MRBEE to examine myopia and revealed that education and outdoor activity are causal to myopia whereas indoor activity is not.
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| Reference | Intensity | Mentions | Sections | Main text | |
|---|---|---|---|---|---|
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| 2 | Burgess, S., S. G. Thompson, and C. C. G. Collaboration (2011) Avoiding bias from weak instruments in mendelian randomization studies | 1.000 | 5 | 3 | 100% |
| 3 | Zhao, Q., J. Wang, G. Hemani, J. Bowden, and D. S. Small (2020) Statistical inference in two-sample summary-data mendelian randomization using robust adjusted profile score | 0.928 | 4 | 3 | 100% |
| 4 | Morrison, J., N. Knoblauch, J. H. Marcus, M. Stephens, and X. He (2020) Mendelian randomization accounting for correlated and uncorrelated pleiotropic effects using genome-wide summary statistics | 0.843 | 3 | 3 | 100% |
| 5 | Verbanck, M., C.-Y. Chen, B. Neale, and R. Do (2018) Detection of widespread horizontal pleiotropy in causal relationships inferred from mendelian randomization between complex trai… | 0.843 | 3 | 3 | 100% |
| 6 | Ye, T., J. Shao, and H. Kang (2021) Debiased inverse-variance weighted estimator in two-sample summary-data mendelian randomization | 0.843 | 3 | 3 | 100% |
| 7 | Yi, G. Y (2017) Statistical analysis with measurement error or misclassification: strategy, method and application | 0.843 | 3 | 3 | 100% |
| 8 | Zhu, X (2020) Mendelian randomization and pleiotropy analysis self | 0.843 | 3 | 3 | 100% |
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| 10 | Vershynin, R (2018) High-dimensional probability: An introduction with applications in data science, Volume 47 | 0.693 | 6 | 3 | 33% |
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