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Genetic variants have potential influence on DNA methylation and thereby regulate mRNA expression. This study aimed to comprehensively reveal the relationships among SNP, methylation and mRNA, and identify methylation‐mediated regulation patterns in human peripheral blood mononuclear cells (PBMCs). Based on in‐house multi‐omics datasets from 43 Chinese Han female subjects, genome‐wide association trios were constructed by simultaneously testing the following three association pairs: SNP‐methylation, methylation‐mRNA and SNP‐mRNA. Causal inference test (CIT) was used to identify methylation‐mediated genetic effects on mRNA. A total of 64,184 significant cis‐methylation quantitative trait loci (meQTLs) were identified (FDR < 0.05). Among the 745 constructed trios, 464 trios formed SNP‐methylation‐mRNA regulation chains (CIT). Network analysis (Cytoscape 3.3.0) constructed multiple complex regulation networks among SNP, methylation and mRNA (eg a total of 43 SNPs simultaneously connected to cg22517527 and further to PRMT2, DIP2A and YBEY). The regulation chains were supported by the evidence from 4DGenome database, relevant to immune or inflammatory related diseases/traits, and overlapped with previous eQTLs from dbGaP and GTEx. The results provide new insights into the regulation patterns among SNP, DNA methylation and mRNA expression, especially for the methylation‐mediated effects, and also increase our understanding of functional mechanisms underlying the established associations.

We contribute to debate about causal inferences in educational research in two ways. First, we quantify how much bias there must be in an estimate to invalidate an inference. Second, we utilize Rubins causal model to interpret the bias necessary to invalidate an inference in terms of sample replacement. We apply our analysis to an inference of a positive effect of Open Court Curriculum on reading achievement from a randomized experiment, and an inference of a negative effect of kindergarten retention on reading achievement from an observational study. We consider details of our framework, and then discuss how our approach informs judgment of inference relative to study design. We conclude with implications for scientific discourse.

Evaluating blocked randomized experiments from a potential outcomes perspective has two primary branches of work. The first focuses on larger blocks, with multiple treatment and control units in each block. The second focuses on matched pairs, with a single treatment and control unit in each block. These literatures not only provide different estimators for the standard errors of the estimated average impact, but they are also built on different sets of assumptions. Neither literature handles cases with blocks of varying size that contain singleton treatment or control units, a case which can occur in a variety of contexts, such as with different forms of matching or poststratification. In this article, we reconcile the literatures by carefully examining the performance of variance estimators under several different frameworks. We then use these insights to derive novel variance estimators for experiments containing blocks of different sizes.

Here, we present a joint-tissue imputation (JTI) approach and a Mendelian randomization framework for causal inference, MR-JTI. JTI borrows information across transcriptomes of different tissues, leveraging shared genetic regulation, to improve prediction performance in a tissue-dependent manner. Notably, JTI includes the single-tissue imputation method PrediXcan as a special case and outperforms other single-tissue approaches (the Bayesian sparse linear mixed model and Dirichlet process regression). MR-JTI models variant-level heterogeneity (primarily due to horizontal pleiotropy, addressing a major challenge of transcriptome-wide association study interpretation) and performs causal inference with type I error control. We make explicit the connection between the genetic architecture of gene expression and of complex traits and the suitability of Mendelian randomization as a causal inference strategy for transcriptome-wide association studies. We provide a resource of imputation models generated from GTEx and PsychENCODE panels. Analysis of biobanks and meta-analysis data, and extensive simulations show substantially improved statistical power, replication and causal mapping rate for JTI relative to existing approaches. MR-JTI, a unified framework for joint-tissue imputation and Mendelian randomization, improves prediction performance in a tissue-dependent manner when applied to large-scale biobanks and meta-analysis data.

This article systematically reviews what is known empirically about the association between executive function and student achievement in both reading and math and critically assesses the evidence for a causal association between the two. Using meta-analytic techniques, the review finds that there is a moderate unconditional association between executive function and achievement that does not differ by executive function construct, age, or measurement type but finds no compelling evidence that a causal association between the two exists.

Applied researchers are increasingly interested in whether and how treatment effects vary in randomized evaluations, especially variation that is not explained by observed covariates. We propose a model-free approach for testing for the presence of such unexplained variation. To use this randomization-based approach, we must address the fact that the average treatment effect, which is generally the object of interest in randomized experiments, actually acts as a nuisance parameter in this setting. We explore potential solutions and advocate for a method that guarantees valid tests in finite samples despite this nuisance. We also show how this method readily extends to testing for heterogeneity beyond a given model, which can be useful for assessing the sufficiency of a given scientific theory. We finally apply our method to the National Head Start impact study, which is a large-scale randomized evaluation of a Federal preschool programme, finding that there is indeed significant unexplained treatment effect variation.

We investigate the problem of testing whether d possibly multivariate random variables, which may or may not be continuous, are jointly (or mutually) independent. Our method builds on ideas of the two-variable Hilbert–Schmidt independence criterion but allows for an arbitrary number of variables. We embed the joint distribution and the product of the marginals in a reproducing kernel Hilbert space and define the d-variable Hilbert–Schmidt independence criterion dHSIC as the squared distance between the embeddings. In the population case, the value of dHSIC is 0 if and only if the d variables are jointly independent, as long as the kernel is characteristic. On the basis of an empirical estimate of dHSIC, we investigate three non-parametric hypothesis tests: a permutation test, a bootstrap analogue and a procedure based on a gamma approximation. We apply non-parametric independence testing to a problem in causal discovery and illustrate the new methods on simulated and real data sets.

Causal inference is a central topic in education research, although oftentimes it relies on observational studies, which makes causal identification methodologically challenging. This manuscript introduces causal graphs as a powerful language for elucidating causal theories and an effective tool for causal identification analysis. It discusses graphical criteria for causal identification, which provide principled approaches for removing bias and assessing causal identification given a causal theory. Through illustrative examples, this manuscript demonstrates the application of causal graphs and adjustment criterion for covariate selection in the context of education research, exemplifying their key advantages particularly in scenarios where randomized experiments are impractical. This manuscript aims to acquaint researchers with causal graphs as an effective tool for causal inference, thereby facilitating theory-based causal inquiries in applied education research.

Several branches of the potential outcome causal inference literature have discussed the merits of blocking versus complete randomization. Some have concluded it can never hurt the precision of estimates, and some have concluded it can hurt In this article, we reconcile these apparently conflicting views, give a more thorough discussion of what guarantees no harm, and discuss how other aspects of a blocked design can cost, all in terms of estimator precision. We discuss how the different findings are due to different sampling models and assumptions of how the blocks were formed. We also connect these ideas to common misconceptions; for instance, we show that analyzing a blocked experiment as if it were completely randomized, a seemingly conservative method, can actually backfire in some cases. Overall, we find that blocking can have a price but that this price is usually small and the potential for gain can be large. It is hard to go too far wrong with blocking.

With climate change threatening agricultural productivity and global food demand increasing, it is important to better understand which farm management practices will maximize crop yields in various climatic conditions. To assess the effectiveness of agricultural practices, researchers often turn to randomized field experiments, which are reliable for identifying causal effects but are often limited in scope and therefore lack external validity. Recently, researchers have also leveraged large observational datasets from satellites and other sources, which can lead to conclusions biased by confounding variables or systematic measurement errors. Because experimental and observational datasets have complementary strengths, in this paper we propose a method that uses a combination of experimental and observational data in the same analysis. As a case study, we focus on the causal effect of crop rotation on corn (maize) and soybean yields in the Midwestern United States. We find that, in terms of root mean squared error, our hybrid method performs 13% better than using experimental data alone and 26% better than using the observational data alone in the task of predicting the effect of rotation on corn yield at held-out experimental sites. Further, the causal estimates based on our method suggest that benefits of crop rotations on corn yield are lower in years and locations with high temperatures whereas the benefits of crop rotations on soybean yield are higher in years and locations with high temperatures. In particular, we estimated that the benefit of rotation on corn yields (and soybean yields) was 0.85 t ha −1 (0.24 t ha −1 ) on average for the top quintile of temperatures, 1.03 t ha −1 (0.21 t ha −1 ) on average for the whole dataset, and 1.19 t ha −1 (0.16 t ha −1 ) on average for the bottom quintile of temperatures. This association between temperatures and rotation benefits is consistent with the hypothesis that the benefit of the corn-soybean rotation on soybean yield is largely driven by pest pressure reductions while the benefit of the corn-soybean rotation on corn yields is largely driven by nitrogen availability.