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The microbiome-gut-brain-axis field is multidisciplinary, benefiting from the expertise of microbiology, ecology, psychiatry, computational biology, and epidemiology amongst other disciplines. As the field matures and moves beyond a basic demonstration of its relevance, it is critical that study design and analysis are robust and foster reproducibility. In this companion piece to Bugs as Features (part I), we present techniques from adjacent and disparate fields to enrich and inform the analysis of microbiome-gut-brain-axis data. Emerging techniques built specifically for the microbiome-gut-brain axis are also demonstrated. All of these methods are contextualised to inform several common challenges: how do we establish causality? How can we integrate data from multiple 'omics techniques? How might we account for the dynamicism of host-microbiome interactions? This perspective is offered to experienced and emerging microbiome scientists alike, to assist with these questions and others, at the study conception, design, analysis and interpretation stages of research., Comment: For main text: 20 pages, 2 figures; for supplementary analysis: 31 pages and 6 figures. Supplementary analysis generated using Rmarkdown by Thomaz F. S. Bastiaanssen. arXiv admin note: substantial text overlap with arXiv:2207.12475

Motivation: Studies including more than one type of 'omics data sets are becoming more prevalent. Integrating these data sets can be a way to solidify findings and even to make new discoveries. However, integrating multi-omics data sets is challenging. Typically, data sets are integrated by performing an all-vs-all correlation analysis, where each feature of the first data set is correlated to each feature of the second data set. However, all-vs-all association testing produces unstructured results that are hard to interpret, and involves potentially unnecessary hypothesis testing that reduces statistical power due to false discovery rate (FDR) adjustment. Implementation: Here, we present the anansi framework, and accompanying R package, as a way to improve upon all-vs-all association analysis. We take a knowledge-based approach where external databases like KEGG are used to constrain the all-vs-all association hypothesis space, only considering pairwise associations that are a priori known to occur. This produces structured results that are easier to interpret, and increases statistical power by skipping unnecessary hypothesis tests. In this paper, we present the anansi framework and demonstrate its application to learn metabolite-function interactions in the context of host-microbe interactions. We further extend our framework beyond pairwise association testing to differential association testing, and show how anansi can be used to identify associations that differ in strength or degree based on sample covariates such as case/control status. Availability: https://github.com/thomazbastiaanssen/anansi, Comment: 12 pages, 3 figures, 7 equations

There has been a growing acknowledgement of the involvement of the gut microbiome - the collection of microbes that reside in our gut - in regulating our mood and behaviour. This phenomenon is referred to as the microbiome-gut-brain axis. While our techniques to measure the presence and abundance of these microbes have been steadily improving, the analysis of microbiome data is non-trivial. Here, we present a perspective on the concepts and foundations of data analysis and interpretation of microbiome experiments with a focus on the microbiome-gut-brain axis domain. We give an overview of foundational considerations prior to commencing analysis alongside the core microbiome analysis approaches of alpha diversity, beta diversity, differential feature abundance and functional inference. We emphasize the compositional data analysis (CoDA) paradigm. Further, this perspective features an extensive and heavily annotated microbiome analysis in R in the supplementary materials, as a resource for new and experienced bioinformaticians alike., Comment: For main text: 23 pages, 3 figures; for supplementary demonstration analysis: 31 pages and 12 figures. Supplementary demonstration analysis generated using Rmarkdown by Thomaz F. S. Bastiaanssen. Part I of a two-part piece