arXiv subjects

Youpeng Su

Publications and source records attributed to Youpeng Su.

4 recordsLinked to original sources

arXiv2026

The Modified Egger Intercept Tests for Detecting Horizontal Pleiotropy in Two-Sample Summary-Data Mendelian Randomization

The Egger intercept (EI) test is a widely used tool to detect horizontal pleiotropy in two-sample summary-data Mendelian randomization. A significant EI test suggests that either the average pleiotropic effect differs from zero (i.e., directional pleiotropy) or the InSIDE (Instrument Strength Independent of Direct Effect) assumption is violated (i.e., correlated pleiotropy) or both. As such, the EI test provides an assessment of the validity of the instrumental variable assumptions, with a non-zero EI indicating that the commonly used inverse-variance weighted (IVW) estimator will be biased. However, the EI test may exhibit inaccurate type one error rates due to biased estimation in Egger regression caused by the measurement error and winner's curse. In this article, we propose a modified EI (MEI) test based on a bias-corrected EI estimator under the null hypothesis of no directional or correlated pleiotropy, leveraging the recently developed rerandomized IVW estimator. We then prove the asymptotic properties of the MEI test under realistic conditions. Like the EI test, we find that the power of the MEI test is also affected by the orientation of SNPs. To enhance the robustness of power, we further combine the MEI test statistics obtained under two specific allele coding schemes. Both simulation and real data studies show that the combined test outperforms the EI test in terms of type one error control and power.

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arXiv2026

Simultaneously accounting for the winner's curse and sample structure in Mendelian randomization: bivariate rerandomized inverse variance weighted estimator

The recently developed rerandomized inverse variance weighted (RIVW) estimator provides a simple and efficient framework to break the winner's curse in two-sample Mendelian randomization (MR). However, this method does not account for sample structure (e.g., residual population stratification and sample overlap), a common source of confounding in MR studies. Sample structure can not only distort SNP-exposure and SNP-outcome association estimates but also induce correlation between them, leading exposure-side instrument selection to propagate bias to the outcome side. To address this challenge, we propose the bivariate RIVW (BRIVW) estimator to simultaneously account for the winner's curse and sample structure. The BRIVW estimator extends the RIVW framework by modeling the joint distribution of SNP-exposure and SNP-outcome association estimates, first adjusting their covariance matrix via linkage disequilibrium score regression to account for sample structure and then applying randomized instrument selection and bivariate Rao-Blackwellization to obtain unbiased post-selection association estimates together with an estimator of their covariance matrix. Under mild conditions, we show that the BRIVW estimator is consistent and asymptotically normal. The finite-sample performance of the proposed estimator is evaluated through extensive simulations and real data analyses.

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arXiv2025

Correction for Weak IV Bias and Winner's Curse in Mendelian Randomization Egger Regression: Rerandomized Egger estimator

In two-sample Mendelian randomization (MR), Egger regression is widely used as a sensitivity analysis when directional pleiotropy is detected. However, the increasing complexity of modern MR studies, characterized by many weak instruments, renders the original Egger method less efficient. We first identify the source of weak instrument bias in Egger regression and introduce a debiased Egger (dEgger) estimator that restores consistency and asymptotic normality under substantially weaker conditions. To boost statistical power and ensure the validity of results, we then embed a random instrument selection procedure and present the rerandomized Egger (REgger) estimator along with an associated directional pleiotropy test. Recognizing the challenge of obtaining closed-form variances, we derive simple regression-residual-based variance estimators by truncating higher-order terms. The REgger estimator simultaneously removes the weak instrument bias and winner's curse while retaining robustness to directional pleiotropy, and is asymptotically normal when the effective sample size and post-selection instrument count are sufficiently large. Under balanced pleiotropy, REgger matches the rerandomized inverse-variance-weighted estimator, differing only in having marginally wider confidence intervals; under directional pleiotropy, it achieves substantially greater precision. Extensive simulations and real-data analyses confirm REgger's superior statistical properties, making it a valuable addition to two-sample MR sensitivity analyses.

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arXiv2024

A modified debiased inverse-variance weighted estimator in two-sample summary-data Mendelian randomization

Mendelian randomization uses genetic variants as instrumental variables to make causal inferences about the effects of modifiable risk factors on diseases from observational data. One of the major challenges in Mendelian randomization is that many genetic variants are only modestly or even weakly associated with the risk factor of interest, a setting known as many weak instruments. Many existing methods, such as the popular inverse-variance weighted (IVW) method, could be biased when the instrument strength is weak. To address this issue, the debiased IVW (dIVW) estimator, which is shown to be robust to many weak instruments, was recently proposed. However, this estimator still has non-ignorable bias when the effective sample size is small. In this paper, we propose a modified debiased IVW (mdIVW) estimator by multiplying a modification factor to the original dIVW estimator. After this simple correction, we show that the bias of the mdIVW estimator converges to zero at a faster rate than that of the dIVW estimator under some regularity conditions. Moreover, the mdIVW estimator has smaller variance than the dIVW estimator.We further extend the proposed method to account for the presence of instrumental variable selection and balanced horizontal pleiotropy. We demonstrate the improvement of the mdIVW estimator over the dIVW estimator through extensive simulation studies and real data analysis.

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