Randomization-based joint central limit theorem and efficient covariate adjustment in stratified 2K2^K factorial experiments

Stratified factorial experiments are widely used in industrial engineering, clinical trials, and social science to measure the joint effects of several factors on an outcome. Researchers often use a linear model and analysis of covariance to analyze experimental results; however, few studies have addressed the validity and robustness of the resulting inferences because assumptions for a linear model might not be justified by randomization. In this paper, we establish the finite-population joint central limit theorem for usual (unadjusted) factorial effect estimators in stratified $2^K$ factorial experiments. Our theorem is obtained under randomization-based inference framework, making use of an extension of the vector form of the Wald--Wolfowitz--Hoeffding theorem for a linear rank statistic. It is robust to model misspecification, arbitrary numbers of strata, stratum sizes, and propensity scores across strata. To improve the estimation and inference efficiency, we propose three covariate adjustment methods and show that under mild conditions, the resulting covariate-adjusted factorial effect estimators are consistent, jointly asymptotically normal, and generally more efficient than the unadjusted estimator. In addition, we propose Neyman-type conservative estimators for the asymptotic variances to facilitate valid inferences. Simulation studies demonstrate the benefits of covariate adjustment methods. Finally, we apply the proposed methods to analyze a real dataset from a clinical trial to evaluate the effects of the addition of bevacizumab and/or carboplatin on pathologic complete response rates in patients with stage II to III triple-negative breast cancer

Mendelian randomization supports genetic liability to hospitalization for COVID-19 as a risk factor of pre-eclampsia

BackgroundPre-eclampsia and eclampsia are among the major threats to pregnant women and fetuses, but they can be mitigated by prevention and early screening. Existing observational research presents conflicting evidence regarding the causal effects of coronavirus disease 2019 (COVID-19) on pre-eclampsia risk. Through Mendelian randomization (MR), this study aims to investigate the causal effect of three COVID-19 severity phenotypes on the risk of pre-eclampsia and eclampsia to provide more rigorous evidence.MethodsTwo-sample MR was utilized to examine causal effects. Summary-level data from genome-wide association studies (GWAS) of individuals of European ancestry were acquired from the GWAS catalog and FinnGen databases. Single-nucleotide polymorphisms associated with COVID-19 traits at p < 5 × −8 were obtained and pruned for linkage disequilibrium to generate instrumental variables for COVID-19. Inverse variance weighted estimates were used as the primary MR results, with weighted median and MR-Egger as auxiliary analyses. The robustness of the MR findings was also evaluated through sensitivity analyses. Bonferroni correction was applied to primary results, with a p < 0.0083 considered significant evidence and a p within 0.083–0.05 considered suggestive evidence.ResultsCritical ill COVID-19 [defined as hospitalization for COVID-19 with either a death outcome or respiratory support, OR (95% CI): 1.17 (1.03–1.33), p = 0.020] and hospitalized COVID-19 [defined as hospitalization for COVID-19, OR (95% CI): 1.10 (1.01–1.19), p = 0.026] demonstrated suggestive causal effects on pre-eclampsia, while general severe acute respiratory syndrome coronavirus 2 infection did not exhibit a significant causal effect on pre-eclampsia. None of the three COVID-19 severity phenotypes exhibited a significant causal effect on eclampsia.ConclusionsOur investigation demonstrates a suggestive causal effect of genetic susceptibility to critical ill COVID-19 and hospitalized COVID-19 on pre-eclampsia. The COVID-19 severity exhibited a suggestive positive dose–response relationship with the risk of pre-eclampsia. Augmented attention should be paid to pregnant women hospitalized for COVID-19, especially those needing respiratory support

The role of the autonomic nervous system in polycystic ovary syndrome

This article reviewed the relationship between the autonomic nervous system and the development of polycystic ovary syndrome (PCOS). PCOS is the most common reproductive endocrine disorder among women of reproductive age. Its primary characteristics include persistent anovulation, hyperandrogenism, and polycystic ovarian morphology, often accompanied by disturbances in glucose and lipid metabolism. The body’s functions are regulated by the autonomic nervous system, which consists mainly of the sympathetic and parasympathetic nervous systems. The autonomic nervous system helps maintain homeostasis in the body. Research indicates that ovarian function in mammals is under autonomic neural control. The ovaries receive central nervous system information through the ovarian plexus nerves and the superior ovarian nerves. Neurotransmitters mediate neural function, with acetylcholine and norepinephrine being the predominant autonomic neurotransmitters. They influence the secretion of ovarian steroids and follicular development. In animal experiments, estrogen, androgens, and stress-induced rat models have been used to explore the relationship between PCOS and the autonomic nervous system. Results have shown that the activation of the autonomic nervous system contributes to the development of PCOS in rat. In clinical practice, assessments of autonomic nervous system function in PCOS patients have been gradually employed. These assessments include heart rate variability testing, measurement of muscle sympathetic nerve activity, skin sympathetic response testing, and post-exercise heart rate recovery evaluation. PCOS patients exhibit autonomic nervous system dysfunction, characterized by increased sympathetic nervous system activity and decreased vagal nerve activity. Abnormal metabolic indicators in PCOS women can also impact autonomic nervous system activity. Clinical studies have shown that various effective methods for managing PCOS regulate patients’ autonomic nervous system activity during the treatment process. This suggests that improving autonomic nervous system activity may be an effective approach in treating PCOS

Table2_Mendelian randomization supports genetic liability to hospitalization for COVID-19 as a risk factor of pre-eclampsia.xlsx

BackgroundPre-eclampsia and eclampsia are among the major threats to pregnant women and fetuses, but they can be mitigated by prevention and early screening. Existing observational research presents conflicting evidence regarding the causal effects of coronavirus disease 2019 (COVID-19) on pre-eclampsia risk. Through Mendelian randomization (MR), this study aims to investigate the causal effect of three COVID-19 severity phenotypes on the risk of pre-eclampsia and eclampsia to provide more rigorous evidence.MethodsTwo-sample MR was utilized to examine causal effects. Summary-level data from genome-wide association studies (GWAS) of individuals of European ancestry were acquired from the GWAS catalog and FinnGen databases. Single-nucleotide polymorphisms associated with COVID-19 traits at p −8 were obtained and pruned for linkage disequilibrium to generate instrumental variables for COVID-19. Inverse variance weighted estimates were used as the primary MR results, with weighted median and MR-Egger as auxiliary analyses. The robustness of the MR findings was also evaluated through sensitivity analyses. Bonferroni correction was applied to primary results, with a p ResultsCritical ill COVID-19 [defined as hospitalization for COVID-19 with either a death outcome or respiratory support, OR (95% CI): 1.17 (1.03–1.33), p = 0.020] and hospitalized COVID-19 [defined as hospitalization for COVID-19, OR (95% CI): 1.10 (1.01–1.19), p = 0.026] demonstrated suggestive causal effects on pre-eclampsia, while general severe acute respiratory syndrome coronavirus 2 infection did not exhibit a significant causal effect on pre-eclampsia. None of the three COVID-19 severity phenotypes exhibited a significant causal effect on eclampsia.ConclusionsOur investigation demonstrates a suggestive causal effect of genetic susceptibility to critical ill COVID-19 and hospitalized COVID-19 on pre-eclampsia. The COVID-19 severity exhibited a suggestive positive dose–response relationship with the risk of pre-eclampsia. Augmented attention should be paid to pregnant women hospitalized for COVID-19, especially those needing respiratory support.</p

Table4_Mendelian randomization supports genetic liability to hospitalization for COVID-19 as a risk factor of pre-eclampsia.xlsx

BackgroundPre-eclampsia and eclampsia are among the major threats to pregnant women and fetuses, but they can be mitigated by prevention and early screening. Existing observational research presents conflicting evidence regarding the causal effects of coronavirus disease 2019 (COVID-19) on pre-eclampsia risk. Through Mendelian randomization (MR), this study aims to investigate the causal effect of three COVID-19 severity phenotypes on the risk of pre-eclampsia and eclampsia to provide more rigorous evidence.MethodsTwo-sample MR was utilized to examine causal effects. Summary-level data from genome-wide association studies (GWAS) of individuals of European ancestry were acquired from the GWAS catalog and FinnGen databases. Single-nucleotide polymorphisms associated with COVID-19 traits at p −8 were obtained and pruned for linkage disequilibrium to generate instrumental variables for COVID-19. Inverse variance weighted estimates were used as the primary MR results, with weighted median and MR-Egger as auxiliary analyses. The robustness of the MR findings was also evaluated through sensitivity analyses. Bonferroni correction was applied to primary results, with a p ResultsCritical ill COVID-19 [defined as hospitalization for COVID-19 with either a death outcome or respiratory support, OR (95% CI): 1.17 (1.03–1.33), p = 0.020] and hospitalized COVID-19 [defined as hospitalization for COVID-19, OR (95% CI): 1.10 (1.01–1.19), p = 0.026] demonstrated suggestive causal effects on pre-eclampsia, while general severe acute respiratory syndrome coronavirus 2 infection did not exhibit a significant causal effect on pre-eclampsia. None of the three COVID-19 severity phenotypes exhibited a significant causal effect on eclampsia.ConclusionsOur investigation demonstrates a suggestive causal effect of genetic susceptibility to critical ill COVID-19 and hospitalized COVID-19 on pre-eclampsia. The COVID-19 severity exhibited a suggestive positive dose–response relationship with the risk of pre-eclampsia. Augmented attention should be paid to pregnant women hospitalized for COVID-19, especially those needing respiratory support.</p

Image3_Mendelian randomization supports genetic liability to hospitalization for COVID-19 as a risk factor of pre-eclampsia.pdf

BackgroundPre-eclampsia and eclampsia are among the major threats to pregnant women and fetuses, but they can be mitigated by prevention and early screening. Existing observational research presents conflicting evidence regarding the causal effects of coronavirus disease 2019 (COVID-19) on pre-eclampsia risk. Through Mendelian randomization (MR), this study aims to investigate the causal effect of three COVID-19 severity phenotypes on the risk of pre-eclampsia and eclampsia to provide more rigorous evidence.MethodsTwo-sample MR was utilized to examine causal effects. Summary-level data from genome-wide association studies (GWAS) of individuals of European ancestry were acquired from the GWAS catalog and FinnGen databases. Single-nucleotide polymorphisms associated with COVID-19 traits at p −8 were obtained and pruned for linkage disequilibrium to generate instrumental variables for COVID-19. Inverse variance weighted estimates were used as the primary MR results, with weighted median and MR-Egger as auxiliary analyses. The robustness of the MR findings was also evaluated through sensitivity analyses. Bonferroni correction was applied to primary results, with a p ResultsCritical ill COVID-19 [defined as hospitalization for COVID-19 with either a death outcome or respiratory support, OR (95% CI): 1.17 (1.03–1.33), p = 0.020] and hospitalized COVID-19 [defined as hospitalization for COVID-19, OR (95% CI): 1.10 (1.01–1.19), p = 0.026] demonstrated suggestive causal effects on pre-eclampsia, while general severe acute respiratory syndrome coronavirus 2 infection did not exhibit a significant causal effect on pre-eclampsia. None of the three COVID-19 severity phenotypes exhibited a significant causal effect on eclampsia.ConclusionsOur investigation demonstrates a suggestive causal effect of genetic susceptibility to critical ill COVID-19 and hospitalized COVID-19 on pre-eclampsia. The COVID-19 severity exhibited a suggestive positive dose–response relationship with the risk of pre-eclampsia. Augmented attention should be paid to pregnant women hospitalized for COVID-19, especially those needing respiratory support.</p

Table1_Mendelian randomization supports genetic liability to hospitalization for COVID-19 as a risk factor of pre-eclampsia.xlsx

BackgroundPre-eclampsia and eclampsia are among the major threats to pregnant women and fetuses, but they can be mitigated by prevention and early screening. Existing observational research presents conflicting evidence regarding the causal effects of coronavirus disease 2019 (COVID-19) on pre-eclampsia risk. Through Mendelian randomization (MR), this study aims to investigate the causal effect of three COVID-19 severity phenotypes on the risk of pre-eclampsia and eclampsia to provide more rigorous evidence.MethodsTwo-sample MR was utilized to examine causal effects. Summary-level data from genome-wide association studies (GWAS) of individuals of European ancestry were acquired from the GWAS catalog and FinnGen databases. Single-nucleotide polymorphisms associated with COVID-19 traits at p −8 were obtained and pruned for linkage disequilibrium to generate instrumental variables for COVID-19. Inverse variance weighted estimates were used as the primary MR results, with weighted median and MR-Egger as auxiliary analyses. The robustness of the MR findings was also evaluated through sensitivity analyses. Bonferroni correction was applied to primary results, with a p ResultsCritical ill COVID-19 [defined as hospitalization for COVID-19 with either a death outcome or respiratory support, OR (95% CI): 1.17 (1.03–1.33), p = 0.020] and hospitalized COVID-19 [defined as hospitalization for COVID-19, OR (95% CI): 1.10 (1.01–1.19), p = 0.026] demonstrated suggestive causal effects on pre-eclampsia, while general severe acute respiratory syndrome coronavirus 2 infection did not exhibit a significant causal effect on pre-eclampsia. None of the three COVID-19 severity phenotypes exhibited a significant causal effect on eclampsia.ConclusionsOur investigation demonstrates a suggestive causal effect of genetic susceptibility to critical ill COVID-19 and hospitalized COVID-19 on pre-eclampsia. The COVID-19 severity exhibited a suggestive positive dose–response relationship with the risk of pre-eclampsia. Augmented attention should be paid to pregnant women hospitalized for COVID-19, especially those needing respiratory support.</p

Image2_Mendelian randomization supports genetic liability to hospitalization for COVID-19 as a risk factor of pre-eclampsia.pdf

BackgroundPre-eclampsia and eclampsia are among the major threats to pregnant women and fetuses, but they can be mitigated by prevention and early screening. Existing observational research presents conflicting evidence regarding the causal effects of coronavirus disease 2019 (COVID-19) on pre-eclampsia risk. Through Mendelian randomization (MR), this study aims to investigate the causal effect of three COVID-19 severity phenotypes on the risk of pre-eclampsia and eclampsia to provide more rigorous evidence.MethodsTwo-sample MR was utilized to examine causal effects. Summary-level data from genome-wide association studies (GWAS) of individuals of European ancestry were acquired from the GWAS catalog and FinnGen databases. Single-nucleotide polymorphisms associated with COVID-19 traits at p −8 were obtained and pruned for linkage disequilibrium to generate instrumental variables for COVID-19. Inverse variance weighted estimates were used as the primary MR results, with weighted median and MR-Egger as auxiliary analyses. The robustness of the MR findings was also evaluated through sensitivity analyses. Bonferroni correction was applied to primary results, with a p ResultsCritical ill COVID-19 [defined as hospitalization for COVID-19 with either a death outcome or respiratory support, OR (95% CI): 1.17 (1.03–1.33), p = 0.020] and hospitalized COVID-19 [defined as hospitalization for COVID-19, OR (95% CI): 1.10 (1.01–1.19), p = 0.026] demonstrated suggestive causal effects on pre-eclampsia, while general severe acute respiratory syndrome coronavirus 2 infection did not exhibit a significant causal effect on pre-eclampsia. None of the three COVID-19 severity phenotypes exhibited a significant causal effect on eclampsia.ConclusionsOur investigation demonstrates a suggestive causal effect of genetic susceptibility to critical ill COVID-19 and hospitalized COVID-19 on pre-eclampsia. The COVID-19 severity exhibited a suggestive positive dose–response relationship with the risk of pre-eclampsia. Augmented attention should be paid to pregnant women hospitalized for COVID-19, especially those needing respiratory support.</p

Image1_Mendelian randomization supports genetic liability to hospitalization for COVID-19 as a risk factor of pre-eclampsia.pdf

BackgroundPre-eclampsia and eclampsia are among the major threats to pregnant women and fetuses, but they can be mitigated by prevention and early screening. Existing observational research presents conflicting evidence regarding the causal effects of coronavirus disease 2019 (COVID-19) on pre-eclampsia risk. Through Mendelian randomization (MR), this study aims to investigate the causal effect of three COVID-19 severity phenotypes on the risk of pre-eclampsia and eclampsia to provide more rigorous evidence.MethodsTwo-sample MR was utilized to examine causal effects. Summary-level data from genome-wide association studies (GWAS) of individuals of European ancestry were acquired from the GWAS catalog and FinnGen databases. Single-nucleotide polymorphisms associated with COVID-19 traits at p −8 were obtained and pruned for linkage disequilibrium to generate instrumental variables for COVID-19. Inverse variance weighted estimates were used as the primary MR results, with weighted median and MR-Egger as auxiliary analyses. The robustness of the MR findings was also evaluated through sensitivity analyses. Bonferroni correction was applied to primary results, with a p ResultsCritical ill COVID-19 [defined as hospitalization for COVID-19 with either a death outcome or respiratory support, OR (95% CI): 1.17 (1.03–1.33), p = 0.020] and hospitalized COVID-19 [defined as hospitalization for COVID-19, OR (95% CI): 1.10 (1.01–1.19), p = 0.026] demonstrated suggestive causal effects on pre-eclampsia, while general severe acute respiratory syndrome coronavirus 2 infection did not exhibit a significant causal effect on pre-eclampsia. None of the three COVID-19 severity phenotypes exhibited a significant causal effect on eclampsia.ConclusionsOur investigation demonstrates a suggestive causal effect of genetic susceptibility to critical ill COVID-19 and hospitalized COVID-19 on pre-eclampsia. The COVID-19 severity exhibited a suggestive positive dose–response relationship with the risk of pre-eclampsia. Augmented attention should be paid to pregnant women hospitalized for COVID-19, especially those needing respiratory support.</p

Image4_Mendelian randomization supports genetic liability to hospitalization for COVID-19 as a risk factor of pre-eclampsia.pdf

BackgroundPre-eclampsia and eclampsia are among the major threats to pregnant women and fetuses, but they can be mitigated by prevention and early screening. Existing observational research presents conflicting evidence regarding the causal effects of coronavirus disease 2019 (COVID-19) on pre-eclampsia risk. Through Mendelian randomization (MR), this study aims to investigate the causal effect of three COVID-19 severity phenotypes on the risk of pre-eclampsia and eclampsia to provide more rigorous evidence.MethodsTwo-sample MR was utilized to examine causal effects. Summary-level data from genome-wide association studies (GWAS) of individuals of European ancestry were acquired from the GWAS catalog and FinnGen databases. Single-nucleotide polymorphisms associated with COVID-19 traits at p −8 were obtained and pruned for linkage disequilibrium to generate instrumental variables for COVID-19. Inverse variance weighted estimates were used as the primary MR results, with weighted median and MR-Egger as auxiliary analyses. The robustness of the MR findings was also evaluated through sensitivity analyses. Bonferroni correction was applied to primary results, with a p ResultsCritical ill COVID-19 [defined as hospitalization for COVID-19 with either a death outcome or respiratory support, OR (95% CI): 1.17 (1.03–1.33), p = 0.020] and hospitalized COVID-19 [defined as hospitalization for COVID-19, OR (95% CI): 1.10 (1.01–1.19), p = 0.026] demonstrated suggestive causal effects on pre-eclampsia, while general severe acute respiratory syndrome coronavirus 2 infection did not exhibit a significant causal effect on pre-eclampsia. None of the three COVID-19 severity phenotypes exhibited a significant causal effect on eclampsia.ConclusionsOur investigation demonstrates a suggestive causal effect of genetic susceptibility to critical ill COVID-19 and hospitalized COVID-19 on pre-eclampsia. The COVID-19 severity exhibited a suggestive positive dose–response relationship with the risk of pre-eclampsia. Augmented attention should be paid to pregnant women hospitalized for COVID-19, especially those needing respiratory support.</p