Timing Is Everything. The Importance of Alignment of Time Anchors for Observational Causal Inference Research.
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ABSTRACT:
SUBMITTER: Taylor SP
PROVIDER: S-EPMC8086541 | biostudies-literature | 2021 May
REPOSITORIES: biostudies-literature
Publications
Timing Is Everything. The Importance of Alignment of Time Anchors for Observational Causal Inference Research.
Taylor Stephanie Parks SP Kowalkowski Marc A MA Admon Andrew J AJ
Annals of the American Thoracic Society 20210501 5
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Project description:Randomized controlled trials (RCTs) are the gold standard for making causal inferences, but RCTs are often not feasible in addiction research for ethical and logistic reasons. Observational data from real-world settings have been increasingly used to guide clinical decisions and public health policies. This paper introduces the potential outcomes framework for causal inference and summarizes well-established causal analysis methods for observational data, including matching, inverse probability treatment weighting, the instrumental variable method and interrupted time-series analysis with controls. It provides examples in addiction research and guidance and analysis codes for conducting these analyses with example data sets.
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Project description:BackgroundDNA methylation is a key epigenetic modification in human development and disease, yet there is limited understanding of its highly coordinated regulation. Here, we identify 818 genes that affect DNA methylation patterns in blood using large-scale population genomics data.ResultsBy employing genetic instruments as causal anchors, we establish directed associations between gene expression and distant DNA methylation levels, while ensuring specificity of the associations by correcting for linkage disequilibrium and pleiotropy among neighboring genes. The identified genes are enriched for transcription factors, of which many consistently increased or decreased DNA methylation levels at multiple CpG sites. In addition, we show that a substantial number of transcription factors affected DNA methylation at their experimentally determined binding sites. We also observe genes encoding proteins with heterogenous functions that have widespread effects on DNA methylation, e.g., NFKBIE, CDCA7(L), and NLRC5, and for several examples, we suggest plausible mechanisms underlying their effect on DNA methylation.ConclusionWe report hundreds of genes that affect DNA methylation and provide key insights in the principles underlying epigenetic regulation.
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Project description:BackgroundCardinality matching (CM), a novel matching technique, finds the largest matched sample meeting prespecified balance criteria thereby overcoming limitations of propensity score matching (PSM) associated with limited covariate overlap, which are especially pronounced in studies with small sample sizes. The current study proposes a framework for large-scale CM (LS-CM); and compares large-scale PSM (LS-PSM) and LS-CM in terms of post-match sample size, covariate balance and residual confounding at progressively smaller sample sizes.MethodsEvaluation of LS-PSM and LS-CM within a comparative cohort study of new users of angiotensin-converting enzyme inhibitor (ACEI) and thiazide or thiazide-like diuretic monotherapy identified from a U.S. insurance claims database. Candidate covariates included patient demographics, and all observed prior conditions, drug exposures and procedures. Propensity scores were calculated using LASSO regression, and candidate covariates with non-zero beta coefficients in the propensity model were defined as matching covariates for use in LS-CM. One-to-one matching was performed using progressively tighter parameter settings. Covariate balance was assessed using standardized mean differences. Hazard ratios for negative control outcomes perceived as unassociated with treatment (i.e., true hazard ratio of 1) were estimated using unconditional Cox models. Residual confounding was assessed using the expected systematic error of the empirical null distribution of negative control effect estimates compared to the ground truth. To simulate diverse research conditions, analyses were repeated within 10 %, 1 and 0.5 % subsample groups with increasingly limited covariate overlap.ResultsA total of 172,117 patients (ACEI: 129,078; thiazide: 43,039) met the study criteria. As compared to LS-PSM, LS-CM was associated with increased sample retention. Although LS-PSM achieved balance across all matching covariates within the full study population, substantial matching covariate imbalance was observed within the 1 and 0.5 % subsample groups. Meanwhile, LS-CM achieved matching covariate balance across all analyses. LS-PSM was associated with better candidate covariate balance within the full study population. Otherwise, both matching techniques achieved comparable candidate covariate balance and expected systematic error.ConclusionsLS-CM found the largest matched sample meeting prespecified balance criteria while achieving comparable candidate covariate balance and residual confounding. We recommend LS-CM as an alternative to LS-PSM in studies with small sample sizes or limited covariate overlap.
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Project description:Experiments have long been the gold standard for causal inference in Ecology. As Ecology tackles progressively larger problems, however, we are moving beyond the scales at which randomised controlled experiments are feasible. To answer causal questions at scale, we need to also use observational data -something Ecologists tend to view with great scepticism. The major challenge using observational data for causal inference is confounding variables: variables affecting both a causal variable and response of interest. Unmeasured confounders-known or unknown-lead to statistical bias, creating spurious correlations and masking true causal relationships. To combat this omitted variable bias, other disciplines have developed rigorous approaches for causal inference from observational data that flexibly control for broad suites of confounding variables. We show how ecologists can harness some of these methods-causal diagrams to identify confounders coupled with nested sampling and statistical designs-to reduce risks of omitted variable bias. Using an example of estimating warming effects on snails, we show how current methods in Ecology (e.g., mixed models) produce incorrect inferences due to omitted variable bias and how alternative methods can eliminate it, improving causal inferences with weaker assumptions. Our goal is to expand tools for causal inference using observational and imperfect experimental data in Ecology.
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Project description:This SuperSeries is composed of the SubSeries listed below.
2021-02-22 | GSE144663 | GEO
Project description:Gene regulatory network inference is essential to uncover complex relationships among gene pathways and inform downstream experiments, ultimately enabling regulatory network re-engineering. Network inference from transcriptional time-series data requires accurate, interpretable, and efficient determination of causal relationships among thousands of genes. Here, we develop Bootstrap Elastic net regression from Time Series (BETS), a statistical framework based on Granger causality for the recovery of a directed gene network from transcriptional time-series data. BETS uses elastic net regression and stability selection from bootstrapped samples to infer causal relationships among genes. BETS is highly parallelized, enabling efficient analysis of large transcriptional data sets. We show competitive accuracy on a community benchmark, the DREAM4 100-gene network inference challenge, where BETS is one of the fastest among methods of similar performance and additionally infers whether the causal effects are activating or inhibitory. We apply BETS to transcriptional time-series data of 2,768 differentially-expressed genes from A549 cells exposed to glucocorticoids over a period of 12 hours. We identify a network of 2,768 genes and 31,945 directed edges (FDR <= 0.2). We validate inferred causal network edges using two external data sources: overexpression experiments on the same glucocorticoid system, and genetic variants associated with inferred edges in primary lung tissue in the Genotype-Tissue Expression (GTEx) v6 project. BETS is available as an open source software package at https://github.com/lujonathanh/BETS
2021-02-22 | GSE144662 | GEO
Project description:Gene regulatory network inference is essential to uncover complex relationships among gene pathways and inform downstream experiments, ultimately enabling regulatory network re-engineering. Network inference from transcriptional time-series data requires accurate, interpretable, and efficient determination of causal relationships among thousands of genes. Here, we develop Bootstrap Elastic net regression from Time Series (BETS), a statistical framework based on Granger causality for the recovery of a directed gene network from transcriptional time-series data. BETS uses elastic net regression and stability selection from bootstrapped samples to infer causal relationships among genes. BETS is highly parallelized, enabling efficient analysis of large transcriptional data sets. We show competitive accuracy on a community benchmark, the DREAM4 100-gene network inference challenge, where BETS is one of the fastest among methods of similar performance and additionally infers whether the causal effects are activating or inhibitory. We apply BETS to transcriptional time-series data of 2,768 differentially-expressed genes from A549 cells exposed to glucocorticoids over a period of 12 hours. We identify a network of 2,768 genes and 31,945 directed edges (FDR <= 0.2). We validate inferred causal network edges using two external data sources: overexpression experiments on the same glucocorticoid system, and genetic variants associated with inferred edges in primary lung tissue in the Genotype-Tissue Expression (GTEx) v6 project. BETS is available as an open source software package at https://github.com/lujonathanh/BETS
2021-02-22 | GSE144660 | GEO
Project description:Purpose of reviewWe review the application and limitations of two implementations of the "case-only design" in injury epidemiology with example analyses of Fatality Analysis Reporting System data.Recent findingsThe term "case-only design" covers a variety of epidemiologic designs; here, two implementations of the design are reviewed: (1) studies to uncover etiological heterogeneity and (2) studies to measure exposure effect modification. These two designs produce results that require different interpretations and rely upon different assumptions. The key assumption of case-only designs for exposure effect modification, the more commonly used of the two designs, does not commonly hold for injuries and so results from studies using this design cannot be interpreted. Case-only designs to identify etiological heterogeneity in injury risk are interpretable but only when the case-series is conceptualized as arising from an underlying cohort.SummaryThe results of studies using case-only designs are commonly misinterpreted in the injury literature.
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