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Research in human-associated microbiomes often involves the analysis of taxonomic count tables generated via high-throughput sequencing. It is difficult to apply statistical tools as the data is high-dimensional, sparse, and compositional. An approachable way to alleviate high-dimensionality and sparsity is to aggregate variables into pre-defined sets. Set-based analysis is ubiquitous in the genomics literature and has demonstrable impact on improving interpretability and power of downstream analysis. Unfortunately, there is a lack of sophisticated set-based analysis methods specific to microbiome taxonomic data, where current practice often employs abundance summation as a technique for aggregation. This approach prevents comparison across sets of different sizes, does not preserve inter-sample distances, and amplifies protocol bias. Here, we attempt to fill this gap with a new single-sample taxon enrichment method that uses a novel log-ratio formulation based on the competitive null hypothesis commonly used in the enrichment analysis literature. Our approach, titled competitive balances for taxonomic enrichment analysis (CBEA), generates sample-specific enrichment scores as the scaled log-ratio of the subcomposition defined by taxa within a set and the subcomposition defined by its complement. We provide sample-level significance testing by estimating an empirical null distribution of our test statistic with valid p-values. Herein, we demonstrate, using both real data applications and simulations, that CBEA controls for type I error, even under high sparsity and high inter-taxa correlation scenarios. Additionally, CBEA provides informative scores that can be inputs to downstream analyses such as prediction tasks.

Background The infant intestinal microbiome plays an important role in metabolism and immune development with impacts on lifelong health. The linkage between the taxonomic composition of the microbiome and its metabolic phenotype is undefined and complicated by redundancies in the taxon-function relationship within microbial communities. To inform a more mechanistic understanding of the relationship between the microbiome and health, we performed an integrative statistical and machine learning-based analysis of microbe taxonomic structure and metabolic function in order to characterize the taxa-function relationship in early life. Results Stool samples collected from infants enrolled in the New Hampshire Birth Cohort Study (NHBCS) at approximately 6-weeks ( n  = 158) and 12-months ( n  = 282) of age were profiled using targeted and untargeted nuclear magnetic resonance (NMR) spectroscopy as well as DNA sequencing of the V4-V5 hypervariable region from the bacterial 16S rRNA gene. There was significant inter-omic concordance based on Procrustes analysis (6 weeks: p  = 0.056; 12 months: p  = 0.001), however this association was no longer significant when accounting for phylogenetic relationships using generalized UniFrac distance metric (6 weeks: p  = 0.376; 12 months: p  = 0.069). Sparse canonical correlation analysis showed significant correlation, as well as identifying sets of microbe/metabolites driving microbiome-metabolome relatedness. Performance of machine learning models varied across different metabolites, with support vector machines (radial basis function kernel) being the consistently top ranked model. However, predictive R 2 values demonstrated poor predictive performance across all models assessed (avg: − 5.06% -- 6 weeks; − 3.7% -- 12 months). Conversely, the Spearman correlation metric was higher (avg: 0.344–6 weeks; 0.265–12 months). This demonstrated that taxonomic relative abundance was not predictive of metabolite concentrations. Conclusions Our results suggest a degree of overall association between taxonomic profiles and metabolite concentrations. However, lack of predictive capacity for stool metabolic signatures reflects, in part, the possible role of functional redundancy in defining the taxa-function relationship in early life as well as the bidirectional nature of the microbiome-metabolome association. Our results provide evidence in favor of a multi-omic approach for microbiome studies, especially those focused on health outcomes.

Vietnam is experiencing an epidemiologic transition with an increased prevalence of non-communicable diseases. The country needs novel, large-scale, and sustainable interventions to improve hypertension control. We report the 12 month follow-up results of a cluster randomized feasibility trial in Hung Yen province, Vietnam, which evaluated the feasibility and acceptability of two community-based interventions to improve hypertension control: a \"storytelling\" and a didactic intervention. The storytelling intervention included stories in the patients' own words about coping with hypertension and didactic content about the importance of healthy lifestyle behaviors in controlling elevated blood pressure levels. The didactic intervention included only didactic content, which were general recommendations for managing several important risk factors for hypertension and other non-communicable diseases. The storytelling intervention was delivered by two DVDs three months apart; the didactic intervention included only one DVD. The trial was conducted in patients with poorly controlled hypertension from 4 communes (communities), which were equally randomized to the two interventions. The mean age of the 160 patients was 66 years and 54% were men. Between baseline enrollment and the 12 month follow-up, mean systolic blood pressure declined by 10.8 mmHg (95% CI: 6.5-14.9) in the storytelling group and by 5.8 mmHg (95% CI: 1.6-10.0) in the didactic content group. The storytelling group also experienced more improvement in several health behaviors, including increased levels of physical activity and reduced consumption of salt and alcohol. We observed considerable long-term beneficial effects of both interventions, especially of our storytelling intervention, among patients with inadequately controlled hypertension. A large scale randomized trial should more systematically compare the short and long-term effectiveness of the two interventions in controlling hypertension. ClinicalTrials.gov: NCT02483780.

Background Prenatal exposure to arsenic has been linked to a range of adverse health conditions in later life. Such fetal origins of disease are frequently the result of environmental effects on the epigenome, leading to long-term alterations in gene expression. Several studies have demonstrated effects of prenatal arsenic exposure on DNA methylation; however the impact of arsenic on the generation and decoding of post-translational histone modifications (PTHMs) is less well characterized, and has not been studied in the context of prenatal human exposures. Methods In the current study, we examined the effect of exposure to low-to-moderate levels of arsenic in a US birth cohort, on the expression of 138 genes encoding key epigenetic regulators in the fetal portion of the placenta. Our candidate genes included readers, writers and erasers of PTHMs, and chromatin remodelers. Results Arsenic exposure was associated with the expression of 27 of the 138 epigenetic genes analyzed. When the cohort was stratified by fetal sex, arsenic exposure was associated with the expression of 40 genes in male fetal placenta, and only 3 non-overlapping genes in female fetal placenta. In particular, we identified an inverse relationship between arsenic exposure and expression of the gene encoding the histone methyltransferase, PRDM6 ( p  < 0.001). Mutation of PRDM6 has been linked to the congenital heart defect, patent ductus arteriosus. Conclusions Our findings suggest that prenatal arsenic exposure may have sex-specific effects on the fetal epigenome, which could plausibly contribute to its subsequent health impacts.

We examine how operational changes in customer flows in retail stores affect the rate of COVID-19 transmission. We combine a model of customer movement with two models of disease transmission: direct exposure when two customers are in close proximity and wake exposure when one customer is in the airflow behind another customer. We find that the effectiveness of some operational interventions is sensitive to the primary mode of transmission. Restricting customer flow to one-way movement is highly effective if direct exposure is the dominant mode of transmission. In particular, the rate of direct transmission under full compliance with one-way movement is less than one-third the rate under two-way movement. Directing customers to follow one-way flow, however, is not effective if wake exposure dominates. We find that two other interventions—reducing the speed variance of customers and throughput control—can be effective whether direct or wake transmission is dominant. We also examine the trade-off between customer throughput and the risk of infection to customers, and we show how the optimal throughput rate drops rapidly as the population prevalence rises.

BackgroundYoung children are frequently exposed to antibiotics, with the potential for collateral consequences to the gut microbiome. The impact of antibiotic exposures to off-target microbes (i.e., bacteria not targeted by treatment) and antibiotic resistance genes (ARGs) is poorly understood.MethodsWe used metagenomic sequencing data from paired stool samples collected prior to antibiotic exposure and at 1 year from over 200 infants and a difference-in-differences approach to assess the relationship between subsequent exposures and the abundance or compositional diversity of microbes and ARGs while adjusting for covariates.ResultsBy 1 year, the abundance of multiple species and ARGs differed by antibiotic exposure. Compared to infants never exposed to antibiotics, Bacteroides vulgatus relative abundance increased by 1.72% (95% CI: 0.19, 3.24) while Bacteroides fragilis decreased by 1.56% (95% CI: −4.32, 1.21). Bifidobacterium species also exhibited opposing trends. ARGs associated with exposure included class A beta-lactamase gene CfxA6. Among infants attending day care, Escherichia coli and ARG abundance were both positively associated with antibiotic use.ConclusionNovel findings, including the importance of day care attendance, were identified through considering microbiome data at baseline and post-intervention. Thus, our study design and approach have important implications for future studies evaluating the unintended impacts of antibiotics.ImpactThe impact of antibiotic exposure to off-target microbes and antibiotic resistance genes in the gut is poorly defined.We quantified these impacts in two cohort studies using a difference-in-differences approach. Novel to microbiome studies, we used pre/post-antibiotic data to emulate a randomized controlled trial.Compared to infants unexposed to antibiotics between baseline and 1 year, the relative abundance of multiple off-target species and antibiotic resistance genes was altered.Infants who attended day care and were exposed to antibiotics within the first year had a higher abundance of Escherichia coli and antibiotic resistance genes; a novel finding warranting further investigation.

Background Vietnam is experiencing an epidemiologic transition with an increased prevalence of non-communicable diseases. Novel, large-scale, effective, and sustainable interventions to control hypertension in Vietnam are needed. We report the results of a cluster-randomized feasibility trial at 3 months follow-up conducted in Hung Yen province, Vietnam, designed to evaluate the feasibility and acceptability of two community-based interventions to improve hypertension control: a “storytelling” intervention, “We Talk about Our Hypertension,” and a didactic intervention. Methods The storytelling intervention included stories about strategies for coping with hypertension, with patients speaking in their own words, and didactic content about the importance of healthy lifestyle behaviors including salt reduction and exercise. The didactic intervention included only didactic content. The storytelling intervention was delivered by two DVDs at 3-month intervals; the didactic intervention included only one installment. The trial was conducted in four communes, equally randomized to the two interventions. Results The mean age of the 160 study patients was 66 years, and 54% were men. Most participants described both interventions as understandable, informative, and motivational. Between baseline and 3 months, mean systolic blood pressure declined by 8.2 mmHg (95% CI 4.1–12.2) in the storytelling group and by 5.5 mmHg (95% CI 1.4–9.5) in the didactic group. The storytelling group also reported a significant increase in hypertension medication adherence. Conclusions Both interventions were well accepted in several rural communities and were shown to be potentially effective in lowering blood pressure. A large-scale randomized trial is needed to compare the effectiveness of the two interventions in controlling hypertension. Trial registration ClinicalTrials.gov, NCT02483780

Following publication of the original article [1], The author found that there was a minor error in Fig. 2 that needed to be corrected. In the Storytelling intervention group, one patient lost to follow up should be at 3 month, not at 1 month. The corrected Fig. 2 is included below. Fig. 2 CONSORT flow diagram for the feasibility cluster-randomized controlled trial

The human gut microbiome is a complex and dynamic ecosystem, featuring a multitude of microbes all interacting with their hosts in an elaborate manner. Even though this exchange is often mediated through microbial metabolic and functional outputs, such as the production of certain metabolites, environmental exposures, and host lifestyle are highly influential in shaping the presence of microbial species irrespective of their individual roles. As such, a comprehensive understanding of the microbiome requires researchers to examine the relationship between taxonomic abundance and function simultaneously. Assessing microbial contributions to important ecosystem services can enable identification of robust functions supported by a variety of species, or to identify important keystone taxa that are associated with a disease-causing biochemical pathway. The primary objective of this thesis is to assess different approaches for investigating the taxa-function relationship and evaluate its value in providing unique biological insights. First, we leveraged densely collected multi-omics data from the New Hampshire Birth Cohort Study to identify genus-metabolite pairs that are core to infant gut microbiomes. Second, we developed a novel statistical method that enables integrating taxa-function relationships in epidemiological studies. Third, we assessed microbial phenotypic traits as a potential source for defining interpretable and human-centric microbiome functions