Testing Mediation Effects in High-Dimensional Microbiome Data with False Discovery Rate Control

Background: Understanding whether and which microbes played a mediating role between an exposure and a disease outcome are essential for researchers to develop clinical interventions to treat the disease by modulating the microbes. Existing methods for mediation analysis of the microbiome are often limited to a global test of community-level mediation or selection of mediating microbes without control of the false discovery rate (FDR). Further, while the null hypothesis of no mediation at each microbe is a composite null that consists of three types of null (no exposure-microbe association, no microbe-outcome association given the exposure, or neither), most existing methods for the global test such as MedTest and MODIMA treat the microbes as if they are all under the same type of null. Results: We propose a new approach based on inverse regression that regresses the (possibly transformed) relative abundance of each taxon on the exposure and the exposure-adjusted outcome to assess the exposure-taxon and taxon-outcome associations simultaneously. Then the association p-values are used to test mediation at both the community and individual taxon levels. This approach fits nicely into our Linear Decomposition Model (LDM) framework, so our new method is implemented in the LDM and enjoys all the features of the LDM, i.e., allowing an arbitrary number of taxa to be tested, supporting continuous, discrete, or multivariate exposures and outcomes as well as adjustment of confounding covariates, accommodating clustered data, and offering analysis at the relative abundance or presence-absence scale. We refer to this new method as LDM-med. Using extensive simulations, we showed that LDM-med always controlled the type I error of the global test and had compelling power over existing methods; LDM-med always preserved the FDR of testing individual taxa and had much better sensitivity than alternative approaches. In contrast, MedTest and MODIMA had severely inflated type I error when different taxa were under different types of null. The flexibility of LDM-med for a variety of mediation analyses is illustrated by the application to a murine microbiome dataset, which identified a plausible mediator.Conclusions: Inverse regression coupled with the LDM is a strategy that performs well and is capable of handling mediation analysis in a wide variety of microbiome studies.

Hierarchical Bayesian classification methods to identify topics by journal quartile with an application in biological sciences

This manuscript builds on a novel, automatic, freely-available Bayesian approach to extract information in abstracts and titles to classify research topics by quartile. This approach is demonstrated for all N= 149,129 ISI-indexed publications in biological sciences journals during 2017. A Bayesian multinomial inverse regression approach is used to extract rankings of topics without the need of a pre-defined dictionary. Bigrams are used for extraction of research topics across manuscripts, and rankings of research topics are constructed by quartile. Worldwide and local results (e.g., comparison between two peer/aspirational research institutions in Colombia) are provided, and differences are explored both at the global and local levels. Some topics persist across quartiles, while the relevance of others is quartile-specific. Challenges in sustainable development appear as more prevalent in top quartile journals across institutions, while the two Colombian institutions favour plant and microorganism research. This approach can reduce information inequities, by allowing young/incipient researchers in biological sciences, especially within lower income countries or universities with limited resources, to freely assess the state of the literature and the relative likelihood of publication in higher impact journals by research topic. This can also serve institutions of higher education to identify missing research topics and areas of competitive advantage.

Globalized parametric optimization of microwave components by means of response features and inverse metamodels

Simulation-based optimization of geometry parameters is an inherent and important stage of microwave design process. To ensure reliability, the optimization process is normally carried out using full-wave electromagnetic (EM) simulation tools, which entails significant computational overhead. This becomes a serious bottleneck especially if global search is required (e.g., design of miniaturized structures, dimension scaling over broad ranges of operating frequencies, multi-modal problems, etc.). In pursuit of mitigating the high-cost issue, this paper proposes a novel algorithmic approach to rapid EM-driven global optimization of microwave components. Our methodology incorporates a response feature technology and inverse regression metamodels to enable fast identification of the promising parameter space regions, as well as to yield a good quality initial design, which only needs to be tuned using local routines. The presented technique is illustrated using three microstrip circuits optimized under challenging scenarios, and demonstrated to exhibit global search capability while maintaining low computational cost of the optimization process of only about one hundred of EM simulations of the structure at hand on the average. The performance is shown to be superior in terms of efficacy over both local algorithms and nature-inspired global methods.

A New Approach to Testing Mediation of the Microbiome using the LDM

Background: Understanding whether and which microbes played a mediating role between an exposure and a disease outcome are essential for researchers to develop clinical interventions to treat the disease by modulating the microbes. Existing methods for mediation analysis of the microbiome are often limited to a global test of community-level mediation or selection of mediating microbes without control of the false discovery rate (FDR). Further, while the null hypothesis of no mediation at each microbe is a composite null that consists of three types of null (no exposure-microbe association, no microbe-outcome association given the exposure, or neither), most existing methods for the global test such as MedTest and MODIMA treat the microbes as if they are all under the same type of null. Methods: We propose a new approach based on inverse regression that regresses the (possibly transformed) relative abundance of each taxon on the exposure and the exposure-adjusted outcome to assess the exposure-taxon and taxon-outcome associations simultaneously. Then the association p-values are used to test mediation at both the community and individual taxon levels. This approach fits nicely into our Linear Decomposition Model (LDM) framework, so our new method is implemented in the LDM and enjoys all the features of the LDM, i.e., allowing an arbitrary number of taxa to be tested, supporting continuous, discrete, or multivariate exposures and outcomes as well as adjustment of confounding covariates, accommodating clustered data, and offering analysis at the relative abundance or presence-absence scale. We refer to this new method as LDM-med. Results: Using extensive simulations, we showed that LDM-med always controlled the type I error of the global test and had compelling power over existing methods; LDM-med always preserved the FDR of testing individual taxa and had much better sensitivity than alternative approaches. In contrast, MedTest and MODIMA had severely inflated type I error when different taxa were under different types of null. The flexibility of LDM-med for a variety of mediation analyses is illustrated by the application to a murine microbiome dataset. Availability and Implementation: Our new method has been added to our R package LDM, which is available on GitHub at https://github.com/yijuanhu/LDM.