Causal mediation analysis with multiple mediators.

In diverse fields of empirical research-including many in the biological sciences-attempts are made to decompose the effect of an exposure on an outcome into its effects via a number of different pathways. For example, we may wish to separate the effect of heavy alcohol consumption on systolic blood pressure (SBP) into effects via body mass index (BMI), via gamma-glutamyl transpeptidase (GGT), and via other pathways. Much progress has been made, mainly due to contributions from the field of causal inference, in understanding the precise nature of statistical estimands that capture such intuitive effects, the assumptions under which they can be identified, and statistical methods for doing so. These contributions have focused almost entirely on settings with a single mediator, or a set of mediators considered en bloc; in many applications, however, researchers attempt a much more ambitious decomposition into numerous path-specific effects through many mediators. In this article, we give counterfactual definitions of such path-specific estimands in settings with multiple mediators, when earlier mediators may affect later ones, showing that there are many ways in which decomposition can be done. We discuss the strong assumptions under which the effects are identified, suggesting a sensitivity analysis approach when a particular subset of the assumptions cannot be justified. These ideas are illustrated using data on alcohol consumption, SBP, BMI, and GGT from the Izhevsk Family Study. We aim to bridge the gap from "single mediator theory" to "multiple mediator practice," highlighting the ambitious nature of this endeavor and giving practical suggestions on how to proceed

The formal approach to quantitative causal inference in epidemiology: misguided or misrepresented?

Two recent articles, one by Vandenbroucke, Broadbent and Pearce (henceforth VBP) and the other by Krieger and Davey Smith (henceforth KDS), criticize what these two sets of authors characterize as the mainstream of the modern ‘causal inference’ school in epidemiology. The criticisms made by these authors are severe; VBP label the field both ‘wrong in theory’ and ‘wrong in practice’, and KDS—at least in some settings—feel that the field not only ‘bark[s] up the wrong tree’ but ‘miss[es] the forest entirely’. More specifically, the school of thought, and the concepts and methods within it, are painted as being applicable only to a very narrow range of investigations, to the exclusion of most of the important questions and study designs in modern epidemiology, such as the effects of genetic variants, the study of ethnic and gender disparities and the use of study designs that do not closely mirror randomized controlled trials (RCTs). Furthermore, the concepts and methods are painted as being potentially highly misleading even within this narrow range in which they are deemed applicable. We believe that most of VBP’s and KDS’s criticisms stem from a series of misconceptions about the approach they criticize. In this response, therefore, we aim first to paint a more accurate picture of the formal causal inference approach, and then to outline the key misconceptions underlying VBP’s and KDS’s critiques. KDS in particular criticize directed acyclic graphs (DAGs), using three examples to do so. Their discussion highlights further misconceptions concerning the role of DAGs in causal inference, and so we devote the third section of the paper to addressing these. In our Discussion we present further objections we have to the arguments in the two papers, before concluding that the clarity gained from adopting a rigorous framework is an asset, not an obstacle, to answering more reliably a very wide range of causal questions using data from observational studies of many different designs

An Assessment and Extension of the Mechanism-Based Approach to the Identification of Age-Period-Cohort Models.

: Many methods have been proposed to solve the age-period-cohort (APC) linear identification problem, but most are not theoretically informed and may lead to biased estimators of APC effects. One exception is the mechanism-based approach recently proposed and based on Pearl's front-door criterion; this approach ensures consistent APC effect estimators in the presence of a complete set of intermediate variables between one of age, period, cohort, and the outcome of interest, as long as the assumed parametric models for all the relevant causal pathways are correct. Through a simulation study mimicking APC data on cardiovascular mortality, we demonstrate possible pitfalls that users of the mechanism-based approach may encounter under realistic conditions: namely, when (1) the set of available intermediate variables is incomplete, (2) intermediate variables are affected by two or more of the APC variables (while this feature is not acknowledged in the analysis), and (3) unaccounted confounding is present between intermediate variables and the outcome. Furthermore, we show how the mechanism-based approach can be extended beyond the originally proposed linear and probit regression models to incorporate all generalized linear models, as well as nonlinearities in the predictors, using Monte Carlo simulation. Based on the observed biases resulting from departures from underlying assumptions, we formulate guidelines for the application of the mechanism-based approach (extended or not).<br/

The developmental effects of media-ideal internalization and self-objectification processes on adolescents’ negative body-feelings, dietary restraint, and binge eating

Despite accumulated experimental evidence of the negative effects of exposure to media-idealized images, the degree to which body image, and eating related disturbances are caused by media portrayals of gendered beauty ideals remains controversial. On the basis of the most up-to-date meta-analysis of experimental studies indicating that media-idealized images have the most harmful and substantial impact on vulnerable individuals regardless of gender (i.e., “internalizers” and “self-objectifiers”), the current longitudinal study examined the direct and mediated links posited in objectification theory among media-ideal internalization, self-objectification, shame and anxiety surrounding the body and appearance, dietary restraint, and binge eating. Data collected from 685 adolescents aged between 14 and 15 at baseline (47 % males), who were interviewed and completed standardized measures annually over a 3-year period, were analyzed using a structural equation modeling approach. Results indicated that media-ideal internalization predicted later thinking and scrutinizing of one’s body from an external observer’s standpoint (or self-objectification), which then predicted later negative emotional experiences related to one’s body and appearance. In turn, these negative emotional experiences predicted subsequent dietary restraint and binge eating, and each of these core features of eating disorders influenced each other. Differences in the strength of these associations across gender were not observed, and all indirect effects were significant. The study provides valuable information about how the cultural values embodied by gendered beauty ideals negatively influence adolescents’ feelings, thoughts and behaviors regarding their own body, and on the complex processes involved in disordered eating. Practical implications are discussed

In Vivo Time- Resolved Microtomography Reveals the Mechanics of the Blowfly Flight Motor

Dipteran flies are amongst the smallest and most agile of flying animals. Their wings are driven indirectly by large power muscles, which cause cyclical deformations of the thorax that are amplified through the intricate wing hinge. Asymmetric flight manoeuvres are controlled by 13 pairs of steering muscles acting directly on the wing articulations. Collectively the steering muscles account for <3% of total flight muscle mass, raising the question of how they can modulate the vastly greater output of the power muscles during manoeuvres. Here we present the results of a synchrotron-based study performing micrometre-resolution, time-resolved microtomography on the 145 Hz wingbeat of blowflies. These data represent the first four-dimensional visualizations of an organism's internal movements on sub-millisecond and micrometre scales. This technique allows us to visualize and measure the three-dimensional movements of five of the largest steering muscles, and to place these in the context of the deforming thoracic mechanism that the muscles actuate. Our visualizations show that the steering muscles operate through a diverse range of nonlinear mechanisms, revealing several unexpected features that could not have been identified using any other technique. The tendons of some steering muscles buckle on every wingbeat to accommodate high amplitude movements of the wing hinge. Other steering muscles absorb kinetic energy from an oscillating control linkage, which rotates at low wingbeat amplitude but translates at high wingbeat amplitude. Kinetic energy is distributed differently in these two modes of oscillation, which may play a role in asymmetric power management during flight control. Structural flexibility is known to be important to the aerodynamic efficiency of insect wings, and to the function of their indirect power muscles. We show that it is integral also to the operation of the steering muscles, and so to the functional flexibility of the insect flight motor

Transiting Disintegrating Planetary Debris around WD 1145+017

More than a decade after astronomers realized that disrupted planetary material likely pollutes the surfaces of many white dwarf stars, the discovery of transiting debris orbiting the white dwarf WD 1145+017 has opened the door to new explorations of this process. We describe the observational evidence for transiting planetary material and the current theoretical understanding (and in some cases lack thereof) of the phenomenon.Comment: Invited review chapter. Accepted March 23, 2017 and published October 7, 2017 in the Handbook of Exoplanets. 15 pages, 10 figure

Reading faces: differential lateral gaze bias in processing canine and human facial expressions in dogs and 4-year-old children

Sensitivity to the emotions of others provides clear biological advantages. However, in the case of heterospecific relationships, such as that existing between dogs and humans, there are additional challenges since some elements of the expression of emotions are species-specific. Given that faces provide important visual cues for communicating emotional state in both humans and dogs, and that processing of emotions is subject to brain lateralisation, we investigated lateral gaze bias in adult dogs when presented with pictures of expressive human and dog faces. Our analysis revealed clear differences in laterality of eye movements in dogs towards conspecific faces according to the emotional valence of the expressions. Differences were also found towards human faces, but to a lesser extent. For comparative purpose, a similar experiment was also run with 4-year-old children and it was observed that they showed differential processing of facial expressions compared to dogs, suggesting a species-dependent engagement of the right or left hemisphere in processing emotions

An affordable, quality-assured community-based system for high-resolution entomological surveillance of vector mosquitoes that reflects human malaria infection risk patterns.

ABSTRACT: BACKGROUND: More sensitive and scalable entomological surveillance tools are required to monitor low levels of transmission that are increasingly common across the tropics, particularly where vector control has been successful. A large-scale larviciding programme in urban Dar es Salaam, Tanzania is supported by a community-based (CB) system for trapping adult mosquito densities to monitor programme performance. Methodology An intensive and extensive CB system for routine, longitudinal, programmatic surveillance of malaria vectors and other mosquitoes using the Ifakara Tent Trap (ITT-C) was developed in Urban Dar es Salaam, Tanzania, and validated by comparison with quality assurance (QA) surveys using either ITT-C or human landing catches (HLC), as well as a cross-sectional survey of malaria parasite prevalence in the same housing compounds. RESULTS: Community-based ITT-C had much lower sensitivity per person-night of sampling than HLC (Relative Rate (RR) [95% Confidence Interval (CI)] = 0.079 [0.051, 0.121], P < 0.001 for Anopheles gambiae s.l. and 0.153 [0.137, 0.171], P < 0.001 for Culicines) but only moderately differed from QA surveys with the same trap (0.536 [0.406,0.617], P = 0.001 and 0.747 [0.677,0.824], P < 0.001, for An. gambiae or Culex respectively). Despite the poor sensitivity of the ITT per night of sampling, when CB-ITT was compared with QA-HLC, it proved at least comparably sensitive in absolute terms (171 versus 169 primary vectors caught) and cost-effective (153US$versus 187US$ per An. gambiae caught) because it allowed more spatially extensive and temporally intensive sampling (4284 versus 335 trap nights distributed over 615 versus 240 locations with a mean number of samples per year of 143 versus 141). Despite the very low vectors densities (Annual estimate of about 170 An gambiae s.l bites per person per year), CB-ITT was the only entomological predictor of parasite infection risk (Odds Ratio [95% CI] = 4.43[3.027,7. 454] per An. gambiae or Anopheles funestus caught per night, P =0.0373). Discussion and conclusion CB trapping approaches could be improved with more sensitive traps, but already offer a practical, safe and affordable system for routine programmatic mosquito surveillance and clusters could be distributed across entire countries by adapting the sample submission and quality assurance procedures accordingly

Wolbachia and DNA barcoding insects: patterns, potential and problems

Wolbachia is a genus of bacterial endosymbionts that impacts the breeding systems of their hosts. Wolbachia can confuse the patterns of mitochondrial variation, including DNA barcodes, because it influences the pathways through which mitochondria are inherited. We examined the extent to which these endosymbionts are detected in routine DNA barcoding, assessed their impact upon the insect sequence divergence and identification accuracy, and considered the variation present in Wolbachia COI. Using both standard PCR assays (Wolbachia surface coding protein – wsp), and bacterial COI fragments we found evidence of Wolbachia in insect total genomic extracts created for DNA barcoding library construction. When >2 million insect COI trace files were examined on the Barcode of Life Datasystem (BOLD) Wolbachia COI was present in 0.16% of the cases. It is possible to generate Wolbachia COI using standard insect primers; however, that amplicon was never confused with the COI of the host. Wolbachia alleles recovered were predominantly Supergroup A and were broadly distributed geographically and phylogenetically. We conclude that the presence of the Wolbachia DNA in total genomic extracts made from insects is unlikely to compromise the accuracy of the DNA barcode library; in fact, the ability to query this DNA library (the database and the extracts) for endosymbionts is one of the ancillary benefits of such a large scale endeavor – for which we provide several examples. It is our conclusion that regular assays for Wolbachia presence and type can, and should, be adopted by large scale insect barcoding initiatives. While COI is one of the five multi-locus sequence typing (MLST) genes used for categorizing Wolbachia, there is limited overlap with the eukaryotic DNA barcode region

Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms

Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD associations (P &lt; 5 × 10(-8), in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms