Generalized causal mediation analysis

The goal of mediation analysis is to assess direct and indirect effects of a treatment or exposure on an outcome. More generally, we may be interested in the context of a causal model as characterized by a directed acyclic graph (DAG), where mediation via a specific path from exposure to outcome may involve an arbitrary number of links (or "stages"). Methods for estimating mediation (or pathway) effects are available for a continuous outcome and a continuous mediator related via a linear model, while for a categorical outcome or categorical mediator, methods are usually limited to two-stage mediation. We present a method applicable to multiple stages of mediation and mixed variable types using generalized linear models. We define pathway effects using a potential outcomes framework and present a general formula that provides the effect of exposure through any specified pathway. Some pathway effects are nonidentifiable and their estimation requires an assumption regarding the correlation between counterfactuals. We provide a sensitivity analysis to assess the impact of this assumption. Confidence intervals for pathway effect estimates are obtained via a bootstrap method. The method is applied to a cohort study of dental caries in very low birth weight adolescents. A simulation study demonstrates low bias of pathway effect estimators and close-to-nominal coverage rates of confidence intervals. We also find low sensitivity to the counterfactual correlation in most scenarios.     

Estimation of Parameters for Macroparasite Population Evolution Using Approximate Bayesian Computation

Summary We estimate the parameters of a stochastic process model for a macroparasite population within a host using approximate Bayesian computation (ABC). The immunity of the host is an unobserved model variable and only mature macroparasites at sacrifice of the host are counted. With very limited data, process rates are inferred reasonably precisely. Modeling involves a three variable Markov process for which the observed data likelihood is computationally intractable. ABC methods are particularly useful when the likelihood is analytically or computationally intractable. The ABC algorithm we present is based on sequential Monte Carlo, is adaptive in nature, and overcomes some drawbacks of previous approaches to ABC. The algorithm is validated on a test example involving simulated data from an autologistic model before being used to infer parameters of the Markov process model for experimental data. The fitted model explains the observed extra‐binomial variation in terms of a zero‐one immunity variable, which has a short‐lived presence in the host.     

Complementarity of statistical treatments to reconstruct worldwide routes of invasion: the case of the Asian ladybird Harmonia axyridis

Inferences about introduction histories of invasive species remain challenging because of the stochastic demographic processes involved. Approximate Bayesian computation (ABC) can help to overcome these problems, but such method requires a prior understanding of population structure over the study area, necessitating the use of alternative methods and an intense sampling design. In this study, we made inferences about the worldwide invasion history of the ladybird Harmonia axyridis by various population genetics statistical methods, using a large set of sampling sites distributed over most of the species’ native and invaded areas. We evaluated the complementarity of the statistical methods and the consequences of using different sets of site samples for ABC inferences. We found that the H. axyridis invasion has involved two bridgehead invasive populations in North America, which have served as the source populations for at least six independent introductions into other continents. We also identified several situations of genetic admixture between differentiated sources. Our results highlight the importance of coupling ABC methods with more traditional statistical approaches. We found that the choice of site samples could affect the conclusions of ABC analyses comparing possible scenarios. Approaches involving independent ABC analyses on several sample sets constitute a sensible solution, complementary to standard quality controls based on the analysis of pseudo‐observed data sets, to minimize erroneous conclusions. This study provides biologists without expertise in this area with detailed methodological and conceptual guidelines for making inferences about invasion routes when dealing with a large number of sampling sites and complex population genetic structures.     

Rapid increase in southern elephant seal genetic diversity after a founder event

Genetic diversity provides the raw material for populations to respond to changing environmental conditions. The evolution of diversity within populations is based on the accumulation of mutations and their retention or loss through selection and genetic drift, while migration can also introduce new variation. However, the extent to which population growth and sustained large population size can lead to rapid and significant increases in diversity has not been widely investigated. Here, we assess this empirically by applying approximate Bayesian computation to a novel ancient DNA dataset that spans the life of a southern elephant seal (Mirounga leonina) population, from initial founding approximately 7000 years ago to eventual extinction within the past millennium. We find that rapid population growth and sustained large population size can explain substantial increases in population genetic diversity over a period of several hundred generations, subsequently lost when the population went to extinction. Results suggest that the impact of diversity introduced through migration was relatively minor. We thus demonstrate, by examining genetic diversity across the life of a population, that environmental change could generate the raw material for adaptive evolution over a very short evolutionary time scale through rapid establishment of a large, stable population.     

Extensive population decline in the Tasmanian devil predates European settlement and devil facial tumour disease

The Tasmanian devil (Sarcophilus harrisii) was widespread in Australia during the Late Pleistocene but is now endemic to the island of Tasmania. Low genetic diversity combined with the spread of devil facial tumour disease have raised concerns for the species’ long-term survival. Here, we investigate the origin of low genetic diversity by inferring the species'' demographic history using temporal sampling with summary statistics, full-likelihood and approximate Bayesian computation methods. Our results show extensive population declines across Tasmania correlating with environmental changes around the last glacial maximum and following unstable climate related to increased ‘El Niño–Southern Oscillation’ activity.     

Influence of drift and admixture on population structure of American black bears (Ursus americanus) in the Central Interior Highlands,USA, 50 years after translocation

Bottlenecks, founder events, and genetic drift often result in decreased genetic diversity and increased population differentiation. These events may follow abundance declines due to natural or anthropogenic perturbations, where translocations may be an effective conservation strategy to increase population size. American black bears (Ursus americanus) were nearly extirpated from the Central Interior Highlands, USA by 1920. In an effort to restore bears, 254 individuals were translocated from Minnesota, USA, and Manitoba, Canada, into the Ouachita and Ozark Mountains from 1958 to 1968. Using 15 microsatellites and mitochondrial haplotypes, we observed contemporary genetic diversity and differentiation between the source and supplemented populations. We inferred four genetic clusters: Source, Ouachitas, Ozarks, and a cluster in Missouri where no individuals were translocated. Coalescent models using approximate Bayesian computation identified an admixture model as having the highest posterior probability (0.942) over models where the translocation was unsuccessful or acted as a founder event. Nuclear genetic diversity was highest in the source (A_R = 9.11) and significantly lower in the translocated populations (A_R = 7.07–7.34; P = 0.004). The Missouri cluster had the lowest genetic diversity (A_R = 5.48) and served as a natural experiment showing the utility of translocations to increase genetic diversity following demographic bottlenecks. Differentiation was greater between the two admixed populations than either compared to the source, suggesting that genetic drift acted strongly over the eight generations since the translocation. The Ouachitas and Missouri were previously hypothesized to be remnant lineages. We observed a pretranslocation remnant signature in Missouri but not in the Ouachitas.     

Computation of pH evolution versus ionic products concentration in a fermentation broth

An algorithm developed for pH computation has been tested to calculate the theoretical pH changes in a culture medium during the course of a fermentation. A divergence between the computed pH value and the value measured with the electrode allows us to highlight the presence of undetected ionic products. The calculation with the algorithm by means of a computer requires only the knowledge of the ionic properties of the substrates and detected products and existing thermodynamic constants. (c) 1993 Wiley & Sons, Inc.     

Population genetic diversity and structure of Rhinogobius candidianus (Gobiidae) in Taiwan: Translocation and release

Rhinogobius candidianus is a freshwater goby distributed in north, northwest, west, and south Taiwan, but this species has been introduced to east Taiwan and became dominant. To investigate its native population genetic diversity and structure and evaluate the sources and diversity of translocated populations, the mitochondrial DNA control region and cytochrome b gene (1981 bp) from 220 specimens were analyzed. These results indicated that (1) the east populations originated from two sources in west Taiwan; (2) translocated populations exist in east Taiwan and south Taiwan; (3) many populations have likely been moved secondarily by human intervention; (4) the effective size of the populations had declined greatly; (5) within the native populations, the ancestral populations colonized Taiwan during the land bridge phase in the Pleistocene through north Taiwan; (6) the landform changes in Taiwan shaped the population structure; and (7) the landforms of the coastline during glaciation also shaped the native range. The low‐level genetic diversity, high population differentiation, and population decline greatly suggest the need for resource management and conservation interventions. Four clades (α–δ) should be managed as four distinct evolutionarily significant units, while the translocated populations should be managed as separate management units. Moreover, the translocated populations in east Taiwan should be evaluated and monitored carefully.     

Size-Dependent Increase in RNA Polymerase II Initiation Rates Mediates Gene Expression Scaling with Cell Size

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