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  1. Article ; Online: Permutation-based methods for mediation analysis in studies with small sample sizes

    Miranda E. Kroehl / Sharon Lutz / Brandie D. Wagner

    PeerJ, Vol 8, p e

    2020  Volume 8246

    Abstract: Background Mediation analysis can be used to evaluate the effect of an exposure on an outcome acting through an intermediate variable or mediator. For studies with small sample sizes, permutation testing may be useful in evaluating the indirect effect (i. ...

    Abstract Background Mediation analysis can be used to evaluate the effect of an exposure on an outcome acting through an intermediate variable or mediator. For studies with small sample sizes, permutation testing may be useful in evaluating the indirect effect (i.e., the effect of exposure on the outcome through the mediator) while maintaining the appropriate type I error rate. For mediation analysis in studies with small sample sizes, existing permutation testing methods permute the residuals under the full or alternative model, but have not been evaluated under situations where covariates are included. In this article, we consider and evaluate two additional permutation approaches for testing the indirect effect in mediation analysis based on permutating the residuals under the reduced or null model which allows for the inclusion of covariates. Methods Simulation studies were used to empirically evaluate the behavior of these two additional approaches: (1) the permutation test of the Indirect Effect under Reduced Models (IERM) and (2) the Permutation Supremum test under Reduced Models (PSRM). The performance of these methods was compared to the standard permutation approach for mediation analysis, the permutation test of the Indirect Effect under Full Models (IEFM). We evaluated the type 1 error rates and power of these methods in the presence of covariates since mediation analysis assumes no unmeasured confounders of the exposure–mediator–outcome relationships. Results The proposed PSRM approach maintained type I error rates below nominal levels under all conditions, while the proposed IERM approach exhibited grossly inflated type I rates in many conditions and the standard IEFM exhibited inflated type I error rates under a small number of conditions. Power did not differ substantially between the proposed PSRM approach and the standard IEFM approach. Conclusions The proposed PSRM approach is recommended over the existing IEFM approach for mediation analysis in studies with small sample sizes.
    Keywords Mediation analysis ; Intersection union test ; Permutation under reduced model ; Product of coefficients test ; Permutation under full model ; Medicine ; R ; Biology (General) ; QH301-705.5
    Subject code 310
    Language English
    Publishing date 2020-01-01T00:00:00Z
    Publisher PeerJ Inc.
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: The antibiotic resistance reservoir of the lung microbiome expands with age in a population of critically ill patients

    Victoria T. Chu / Alexandra Tsitsiklis / Eran Mick / Lilliam Ambroggio / Katrina L. Kalantar / Abigail Glascock / Christina M. Osborne / Brandie D. Wagner / Michael A. Matthay / Joseph L. DeRisi / Carolyn S. Calfee / Peter M. Mourani / Charles R. Langelier

    Nature Communications, Vol 15, Iss 1, Pp 1-

    2024  Volume 10

    Abstract: Abstract Antimicrobial resistant lower respiratory tract infections are an increasing public health threat and an important cause of global mortality. The lung microbiome can influence susceptibility of respiratory tract infections and represents an ... ...

    Abstract Abstract Antimicrobial resistant lower respiratory tract infections are an increasing public health threat and an important cause of global mortality. The lung microbiome can influence susceptibility of respiratory tract infections and represents an important reservoir for exchange of antimicrobial resistance genes. Studies of the gut microbiome have found an association between age and increasing antimicrobial resistance gene burden, however, corollary studies in the lung microbiome remain absent. We performed an observational study of children and adults with acute respiratory failure admitted to the intensive care unit. From tracheal aspirate RNA sequencing data, we evaluated age-related differences in detectable antimicrobial resistance gene expression in the lung microbiome. Using a multivariable logistic regression model, we find that detection of antimicrobial resistance gene expression was significantly higher in adults compared with children after adjusting for demographic and clinical characteristics. This association remained significant after additionally adjusting for lung bacterial microbiome characteristics, and when modeling age as a continuous variable. The proportion of adults expressing beta-lactam, aminoglycoside, and tetracycline antimicrobial resistance genes was higher compared to children. Together, these findings shape our understanding of the lung resistome in critically ill patients across the lifespan, which may have implications for clinical management and global public health.
    Keywords Science ; Q
    Subject code 610
    Language English
    Publishing date 2024-01-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Change in circulating proteins during treatment of pulmonary exacerbation in patients with cystic fibrosis

    Brandie D. Wagner / Asem Berkalieva / Monica Borges / Grant Fleming / Noah Graham / Emily Peterson / Xin Jin / Edith T. Zemanick

    Health Science Reports, Vol 4, Iss 1, Pp n/a-n/a (2021)

    2021  

    Keywords Medicine ; R
    Language English
    Publishing date 2021-03-01T00:00:00Z
    Publisher Wiley
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: CANTARE

    Janet C. Siebert / Martine Saint-Cyr / Sarah J. Borengasser / Brandie D. Wagner / Catherine A. Lozupone / Carsten Görg

    BMC Bioinformatics, Vol 22, Iss 1, Pp 1-

    finding and visualizing network-based multi-omic predictive models

    2021  Volume 21

    Abstract: Abstract Background One goal of multi-omic studies is to identify interpretable predictive models for outcomes of interest, with analytes drawn from multiple omes. Such findings could support refined biological insight and hypothesis generation. However, ...

    Abstract Abstract Background One goal of multi-omic studies is to identify interpretable predictive models for outcomes of interest, with analytes drawn from multiple omes. Such findings could support refined biological insight and hypothesis generation. However, standard analytical approaches are not designed to be “ome aware.” Thus, some researchers analyze data from one ome at a time, and then combine predictions across omes. Others resort to correlation studies, cataloging pairwise relationships, but lacking an obvious approach for cohesive and interpretable summaries of these catalogs. Methods We present a novel workflow for building predictive regression models from network neighborhoods in multi-omic networks. First, we generate pairwise regression models across all pairs of analytes from all omes, encoding the resulting “top table” of relationships in a network. Then, we build predictive logistic regression models using the analytes in network neighborhoods of interest. We call this method CANTARE (Consolidated Analysis of Network Topology And Regression Elements). Results We applied CANTARE to previously published data from healthy controls and patients with inflammatory bowel disease (IBD) consisting of three omes: gut microbiome, metabolomics, and microbial-derived enzymes. We identified 8 unique predictive models with AUC > 0.90. The number of predictors in these models ranged from 3 to 13. We compare the results of CANTARE to random forests and elastic-net penalized regressions, analyzing AUC, predictions, and predictors. CANTARE AUC values were competitive with those generated by random forests and penalized regressions. The top 3 CANTARE models had a greater dynamic range of predicted probabilities than did random forests and penalized regressions (p-value = 1.35 × 10–5). CANTARE models were significantly more likely to prioritize predictors from multiple omes than were the alternatives (p-value = 0.005). We also showed that predictive models from a network based on pairwise models with an interaction ...
    Keywords Multi-omic ; Predictive model ; Microbiome ; Metabolome ; Metagenome ; IBD ; Computer applications to medicine. Medical informatics ; R858-859.7 ; Biology (General) ; QH301-705.5
    Subject code 310
    Language English
    Publishing date 2021-02-01T00:00:00Z
    Publisher BMC
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Plasma C-C Chemokine Concentrations in Intermediate Age-Related Macular Degeneration

    Alan G. Palestine / Brandie D. Wagner / Jennifer L. Patnaik / Rebecca Baldermann / Marc T. Mathias / Naresh Mandava / Anne M. Lynch

    Frontiers in Medicine, Vol

    2021  Volume 8

    Abstract: Purpose: To determine the relationship between plasma concentrations of the C-C chemokines CCL2, CCL3, CCL4, and CCL5 and intermediate age-related macular degeneration (iAMD) patients compared with control inidividuals to further define the inflammatory ... ...

    Abstract Purpose: To determine the relationship between plasma concentrations of the C-C chemokines CCL2, CCL3, CCL4, and CCL5 and intermediate age-related macular degeneration (iAMD) patients compared with control inidividuals to further define the inflammatory pathways associated with age-related macular degeneration.Methods: The concentrations of CCL2, CCL3, CCL4, and CCL5 were measured using multiplex assays in plasma collected from 210 patients with iAMD and 102 control individuals with no macular degeneration as defined by multi-modal imaging. Non-inflammatory data included in the analysis were: age, sex, family history of AMD, history of smoking, body mass index, presence of reticular pseudo-drusen and cardiovascular disease. Median concentrations as well as a cutoff value for each chemokine were compared between the two groups.Results: The median concentrations of CCL2 and CCL4 did not differ between control and iAMD groups, however, CCL2 was elevated in iAMD when a cutoff comparison was used (p < 0.05). Median CCL3 and CCL5 concentrations were significantly decreased in the macular degeneration group compared with controls (p < 0.001) as well as when a cutoff value comparison was used. CCL3 and CCL5 were negatively correlated in cases and positively correlated in controls.Conclusions: Plasma CCL3 and CCL5 concentrations were significantly decreased and CCL2 concentrations were increased in patients with iAMD compared with controls, suggesting a role for C-C chemokines in the systemic inflammatory processes associated with disease development.
    Keywords age-related macular degeneration ; inflammation ; chemokines ; CCL2 ; CCL3 ; CCL4 ; Medicine (General) ; R5-920
    Subject code 610
    Language English
    Publishing date 2021-11-01T00:00:00Z
    Publisher Frontiers Media S.A.
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: tidyMicro

    Charlie M. Carpenter / Daniel N. Frank / Kayla Williamson / Jaron Arbet / Brandie D. Wagner / Katerina Kechris / Miranda E. Kroehl

    BMC Bioinformatics, Vol 22, Iss 1, Pp 1-

    a pipeline for microbiome data analysis and visualization using the tidyverse in R

    2021  Volume 13

    Abstract: Abstract Background The drive to understand how microbial communities interact with their environments has inspired innovations across many fields. The data generated from sequence-based analyses of microbial communities typically are of high ... ...

    Abstract Abstract Background The drive to understand how microbial communities interact with their environments has inspired innovations across many fields. The data generated from sequence-based analyses of microbial communities typically are of high dimensionality and can involve multiple data tables consisting of taxonomic or functional gene/pathway counts. Merging multiple high dimensional tables with study-related metadata can be challenging. Existing microbiome pipelines available in R have created their own data structures to manage this problem. However, these data structures may be unfamiliar to analysts new to microbiome data or R and do not allow for deviations from internal workflows. Existing analysis tools also focus primarily on community-level analyses and exploratory visualizations, as opposed to analyses of individual taxa. Results We developed the R package “tidyMicro” to serve as a more complete microbiome analysis pipeline. This open source software provides all of the essential tools available in other popular packages (e.g., management of sequence count tables, standard exploratory visualizations, and diversity inference tools) supplemented with multiple options for regression modelling (e.g., negative binomial, beta binomial, and/or rank based testing) and novel visualizations to improve interpretability (e.g., Rocky Mountain plots, longitudinal ordination plots). This comprehensive pipeline for microbiome analysis also maintains data structures familiar to R users to improve analysts’ control over workflow. A complete vignette is provided to aid new users in analysis workflow. Conclusions tidyMicro provides a reliable alternative to popular microbiome analysis packages in R. We provide standard tools as well as novel extensions on standard analyses to improve interpretability results while maintaining object malleability to encourage open source collaboration. The simple examples and full workflow from the package are reproducible and applicable to external data sets.
    Keywords Microbiome ; Pipeline ; R ; Tidyverse ; Visualization ; Open source ; Computer applications to medicine. Medical informatics ; R858-859.7 ; Biology (General) ; QH301-705.5
    Subject code 004
    Language English
    Publishing date 2021-02-01T00:00:00Z
    Publisher BMC
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Gut microbiota phenotypes of obesity

    Maggie A. Stanislawski / Dana Dabelea / Leslie A. Lange / Brandie D. Wagner / Catherine A. Lozupone

    npj Biofilms and Microbiomes, Vol 5, Iss 1, Pp 1-

    2019  Volume 9

    Abstract: Abstract Obesity is a disease with a complex etiology and variable prevalence across different populations. While several studies have reported gut microbiota composition differences associated with obesity in humans, there has been a lack of consistency ...

    Abstract Abstract Obesity is a disease with a complex etiology and variable prevalence across different populations. While several studies have reported gut microbiota composition differences associated with obesity in humans, there has been a lack of consistency in the nature of the reported changes; it has been difficult to determine whether methodological differences between studies, underlying differences in the populations studied, or other factors are responsible for this discordance. Here we use 16 S rRNA data from previously published studies to explore how the gut microbiota-obesity relationship varies across heterogeneous Western populations, focusing mainly on the relationship between (1) alpha diversity and (2) Prevotella relative abundance with BMI. We provide evidence that the relationship between lower alpha diversity and higher BMI may be most consistent in non-Hispanic white (NHW) populations and/or those with high socioeconomic status, while the relationship between higher Prevotella relative abundance and BMI may be stronger among black and Hispanic populations. We further examine how diet may impact these relationships. This work suggests that gut microbiota phenotypes of obesity may differ with race/ethnicity or its correlates, such as dietary components or socioeconomic status. However, microbiome cohorts are often too small to study complex interaction effects and non-white individuals are greatly underrepresented, creating substantial challenges to understanding population-level patterns in the microbiome-obesity relationship. Further study of how population heterogeneity influences the relationship between the gut microbiota and obesity is warranted.
    Keywords Microbial ecology ; QR100-130
    Language English
    Publishing date 2019-07-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: Factors associated with long-term survival in patients with stroke after coronary artery bypass grafting

    Brandie D. Wagner / Gary K. Grunwald / G. Hossein Almassi / Xinli Li / Frederick L. Grover / A. Laurie W. Shroyer

    Journal of International Medical Research, Vol

    2020  Volume 48

    Abstract: Objective Occurrence of a stroke within 30 days following coronary artery bypass grafting (CABG) is an uncommon, but often devastating, complication. This study aimed to identify factors associated with long-term survival (beyond 30 days) in patients ... ...

    Abstract Objective Occurrence of a stroke within 30 days following coronary artery bypass grafting (CABG) is an uncommon, but often devastating, complication. This study aimed to identify factors associated with long-term survival (beyond 30 days) in patients with stroke after CABG. Methods De-identified patients’ records from the Veterans Affairs Surgical Quality Improvement Program database were used to identify risk factors and perioperative complications associated with survival for up to 20 years in patients with post-CABG stroke. The multivariable Cox proportional hazards model was used for analyzing survival. Results The median survival time for patients with stroke (n = 1422) was 6.7 years. The mortality rate for these patients was highest in the first year post-CABG and was significantly elevated compared with non-stroke patients. Survival rates at 1, 5, and 10 years for stroke versus non-stroke patients were 79% vs. 96%, 58% vs. 83%, and 36% vs. 63%, respectively. High preoperative serum creatinine levels, postoperative occurrence of renal failure, prolonged ventilation, coma, and reoperation for bleeding were important predictors of 1-year mortality of patients with post-CABG stroke. Conclusions Veterans with post-CABG stroke have a considerably higher risk for mortality during the first year compared with patients without stroke.
    Keywords Medicine (General) ; R5-920
    Subject code 610
    Language English
    Publishing date 2020-07-01T00:00:00Z
    Publisher SAGE Publishing
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: Modified PCR protocol to increase sensitivity for determination of bacterial community composition

    Kayla M. Williamson / Brandie D. Wagner / Charles E. Robertson / Mark J. Stevens / Marci K. Sontag / Peter M. Mourani / J. Kirk Harris

    Microbiome, Vol 9, Iss 1, Pp 1-

    2021  Volume 11

    Abstract: Abstract Background The objective of this project was to increase the sensitivity of sequence-based bacterial community determination without impacting community composition or interfering with cluster formation during sequencing. Two PCR protocols ( ... ...

    Abstract Abstract Background The objective of this project was to increase the sensitivity of sequence-based bacterial community determination without impacting community composition or interfering with cluster formation during sequencing. Two PCR protocols (standard and modified) were examined in airway samples where we observed a large range in bacterial load (3.1–6.2 log10 16S rRNA gene copies/reaction). Tracheal aspirate (TA) samples (n = 99) were collected from sixteen children requiring mechanical ventilation at a single center. DNA was extracted, and total bacterial load (TBL) was assessed using qPCR. Amplification of 16S rRNA was attempted with both protocols in all samples. Results PCR product was observed using both protocols in 52 samples and in 24 additional samples only with the modified protocol. TBL, diversity metrics, and prominent taxa were compared for samples in three groups based on success of the two protocols (successful with both, success with modified only, unsuccessful for both). TBL differed significantly across the three groups (p<0.001). Specifically, the modified protocol allowed amplification from samples with intermediate TBL. Shannon diversity was similar between the two protocols, and Morisita-Horn beta diversity index showed high agreement between the two protocols within samples (median value 0.9997, range 0.9947 to 1). We show that both protocols identify similar communities, and the technical variability of both protocols was very low. The use of limited PCR cycles was a key feature to limit impact of background by exclusion of 24% of samples with no evidence of bacterial DNA present in the sample. Conclusion The modified amplification protocol represents a viable approach that increased sensitivity of bacterial community analysis, which is important for study of the human airway microbiome where bacterial load is highly variable. Video abstract
    Keywords 16S rRNA gene ; Microbiome ; Amplicon ; Mechanical ventilation ; Microbial ecology ; QR100-130
    Subject code 500
    Language English
    Publishing date 2021-04-01T00:00:00Z
    Publisher BMC
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  10. Article ; Online: Divergence of bacterial communities in the lower airways of CF patients in early childhood.

    John B O'Connor / Madison M Mottlowitz / Brandie D Wagner / Kathleen L Boyne / Mark J Stevens / Charles E Robertson / Jonathan K Harris / Theresa A Laguna

    PLoS ONE, Vol 16, Iss 10, p e

    2021  Volume 0257838

    Abstract: Rationale Chronic airway infection and inflammation resulting in progressive, obstructive lung disease is the leading cause of morbidity and mortality in cystic fibrosis. Understanding the lower airway microbiota across the ages can provide valuable ... ...

    Abstract Rationale Chronic airway infection and inflammation resulting in progressive, obstructive lung disease is the leading cause of morbidity and mortality in cystic fibrosis. Understanding the lower airway microbiota across the ages can provide valuable insight and potential therapeutic targets. Objectives To characterize and compare the lower airway microbiota in cystic fibrosis and disease control subjects across the pediatric age spectrum. Methods Bronchoalveolar lavage fluid samples from 191 subjects (63 with cystic fibrosis) aged 0 to 21 years were collected along with relevant clinical data. We measured total bacterial load using quantitative polymerase chain reaction and performed 16S rRNA gene sequencing to characterize bacterial communities with species-level sensitivity for select genera. Clinical comparisons were investigated. Measurements and main results Cystic fibrosis samples had higher total bacterial load and lower microbial diversity, with a divergence from disease controls around 2-5 years of age, as well as higher neutrophilic inflammation relative to bacterial burden. Cystic fibrosis samples had increased abundance of traditional cystic fibrosis pathogens and decreased abundance of the Streptococcus mitis species group in older subjects. Interestingly, increased diversity in the heterogeneous disease controls was independent of diagnosis and indication. Sequencing was more sensitive than culture, and antibiotic exposure was more common in disease controls, which showed a negative relationship with load and neutrophilic inflammation. Conclusions Analysis of lower airway samples from people with cystic fibrosis and disease controls across the ages revealed key differences in airway microbiota and inflammation. The divergence in subjects during early childhood may represent a window of opportunity for intervention and additional study.
    Keywords Medicine ; R ; Science ; Q
    Subject code 610
    Language English
    Publishing date 2021-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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