APOE ε4 and late-life cognition: mediation by structural brain imaging markers

European Journal of Epidemiology - The apolipoprotein E allele 4 (APOE-ε4) is established as a major genetic risk factor for cognitive decline and late-onset Alzheimer’s disease....     

Validation of data from electronic data warehouse in diabetic ketoacidosis: Caution is needed

Aims

This study validated enterprise data warehouse (EDW) data for a cohort of hospitalized patients with a primary diagnosis of diabetic ketoacidosis (DKA).

New metrics for meta-analyses of heterogeneous effects

We provide two simple metrics that could be reported routinely in random-effects meta-analyses to convey evidence strength for scientifically meaningful effects under effect heterogeneity (ie, a nonzero estimated variance of the true effect distribution). First, given a chosen threshold of meaningful effect size, meta-analyses could report the estimated proportion of true effect sizes above this threshold. Second, meta-analyses could estimate the proportion of effect sizes below a second, possibly symmetric, threshold in the opposite direction from the estimated mean. These metrics could help identify if (1) there are few effects of scientifically meaningful size despite a “statistically significant” pooled point estimate, (2) there are some large effects despite an apparently null point estimate, or (3) strong effects in the direction opposite the pooled estimate also regularly occur (and thus, potential effect modifiers should be examined). These metrics should be presented with confidence intervals, which can be obtained analytically or, under weaker assumptions, using bias-corrected and accelerated bootstrapping. Additionally, these metrics inform relative comparison of evidence strength across related meta-analyses. We illustrate with applied examples and provide an R function to compute the metrics and confidence intervals.     

The identification of synergism in the sufficient-component-cause framework

Various concepts of interaction are reconsidered in light of a sufficient-component-cause framework. Conditions and statistical tests are derived for the presence of synergism within sufficient causes. The conditions derived are sufficient but not necessary for the presence of synergism. In the context of monotonic effects, the conditions derived are closely related to effect modification on the risk difference scale; however, this is not the case without the assumption of monotonic effects.     

A mapping between interactions and interference: implications for vaccine trials

In this paper, we discuss relationships between causal interactions within the counterfactual framework and interference in which the exposure of one person may affect the outcomes of another. We show that the empirical tests for causal interactions can, in fact, all be adapted to empirical tests for particular forms of interference. In the context of interference, by recoding the response as some function of the outcomes of the various persons within a cluster, a wide range of different forms of interference can potentially be detected. The correspondence between causal interactions and forms of interference extends to encompass n-way causal interactions, interference between n persons within a cluster, and multivalued exposures. The theory for causal interactions provides a complete conceptual apparatus for assessing interference as well. The results are illustrated using data from a hypothetical vaccine trial to reason about specific forms of interference and spillover effects that may be present in this vaccine setting. We discuss the implications of this correspondence for our conceptualizations of interaction and for application to vaccine trials and many other settings in which spillover effects may be present.     

Genetic variants on 15q25.1, smoking, and lung cancer: an assessment of mediation and interaction

Genome-wide association studies have identified variants on chromosome 15q25.1 that increase the risks of both lung cancer and nicotine dependence and associated smoking behavior. However, there remains debate as to whether the association with lung cancer is direct or is mediated by pathways related to smoking behavior. Here, the authors apply a novel method for mediation analysis, allowing for gene-environment interaction, to a lung cancer case-control study (1992-2004) conducted at Massachusetts General Hospital using 2 single nucleotide polymorphisms, rs8034191 and rs1051730, on 15q25.1. The results are validated using data from 3 other lung cancer studies. Tests for additive interaction (P = 2 × 10(-10) and P = 1 × 10(-9)) and multiplicative interaction (P = 0.01 and P = 0.01) were significant. Pooled analyses yielded a direct-effect odds ratio of 1.26 (95% confidence interval (CI): 1.19, 1.33; P = 2 × 10(-15)) for rs8034191 and an indirect-effect odds ratio of 1.01 (95% CI: 1.00, 1.01; P = 0.09); the proportion of increased risk mediated by smoking was 3.2%. For rs1051730, direct- and indirect-effect odds ratios were 1.26 (95% CI: 1.19, 1.33; P = 1 × 10(-15)) and 1.00 (95% CI: 0.99, 1.01; P = 0.22), respectively, with a proportion mediated of 2.3%. Adjustment for measurement error in smoking behavior allowing up to 75% measurement error increased the proportions mediated to 12.5% and 9.2%, respectively. These analyses indicate that the association of the variants with lung cancer operates primarily through other pathways.