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Savidge, T. C.

Publications and source records attributed to Savidge, T. C..

2 recordsLinked to original sources

Developing a standardized but extendable framework to increase the findability of infectious disease datasets

Biomedical datasets are increasing in size, stored in many repositories, and face challenges in FAIRness (findability, accessibility, interoperability, reusability). As a Consortium of infectious disease researchers from 15 Centers, we aim to adopt open science practices to promote transparency, encourage reproducibility, and accelerate research advances through data reuse. To improve FAIRness of our datasets and computational tools, we evaluated metadata standards across established biomedical data repositories. The vast majority do not adhere to a single standard, such as Schema.org, which is widely-adopted by generalist repositories. Consequently, datasets in these repositories are not findable in aggregation projects like Google Dataset Search. We alleviated this gap by creating a reusable metadata schema based on Schema.org and catalogued nearly 400 datasets and computational tools we collected. The approach is easily reusable to create schemas interoperable with community standards, but customized to a particular context. Our approach enabled data discovery, increased the reusability of datasets from a large research consortium, and accelerated research. Lastly, we discuss ongoing challenges with FAIRness beyond discoverability.

bioinformatics↗

Systematic Analysis of Mobile Genetic Elements Mediating β-lactamase Gene Amplification in Non-Carbapenemase-Producing Carbapenem Resistant Enterobacterales Bloodstream Infections

Non-carbapenemase-producing carbapenem resistant Enterobacterales (non-CP-CRE) are increasingly recognized as important contributors to prevalent carbapenem resistant Enterobacterales (CRE) infections. However, there is limited understanding of mechanisms underlying non-CP-CRE causing invasive disease. Long- and short-read whole genome sequencing (WGS) was used to elucidate carbapenem non-susceptibility determinants in Enterobacterales bloodstream isolates at MD Anderson Cancer Center in Houston, Texas. We investigated carbapenem non-susceptible Enterobacterales (CNSE) mechanisms through a combination of phylogenetic analysis, antimicrobial resistant (AMR) gene detection/copy number quantification, porin assessment, and mobile genetic element (MGE) characterization. Most CNSE isolates sequenced were non-CP-CRE (41/79; 51.9%) whereas 25.3% (20/79) were carbapenem intermediate Enterobacterales (CIE) and 22.8% (18/79) were carbapenemase producing Enterobacterales (CPE). Statistically significant copy number variants (CNVs) of extended-spectrum {beta}-lactamase (ESBL) genes (Wilcoxon Test; p-value < 0.001) were present in both non-CP-CR E. coli (median CNV = 2.6X; n= 17) and K. pneumoniae (median CNV = 3.2X, n = 17). All non-CP-CR E. coli and K. pneumoniae had predicted reduced expression of at least one outer membrane porin gene (i.e., ompC/ompF or ompK36/ompK35). Completely resolved CNSE genomes revealed that IS26 and ISEcp1 structures harboring blaCTX-M variants along with other AMR elements were the primary drivers of gene amplification, occurring in mostly IncFIB/IncFII plasmid contexts. MGE mediated {beta}-lactamase gene amplifications resulted in either tandem arrays, primarily mediated by IS26 translocatable units, or segmental duplication, typically due to ISEcp1 transposition units. Non-CP-CRE strains were the most prevalent cause of CRE bacteremia with carbapenem non-susceptibility driven by concurrent porin loss and MGE-mediated amplification of blaCTX-M genes. IMPORTANCECarbapenem resistant Enterobacterales (CRE) are considered urgent antimicrobial resistance (AMR) threats. The vast majority of CRE research has focused on carbapenemase producing Enterobacterales (CPE) even though non-carbapenemase-producing CRE (non-CP-CRE) comprise 50% or more of isolates in some surveillance studies. Thus, carbapenem resistance mechanisms in non-CP-CRE remain poorly characterized. To address this problem, we applied a combination of short- and long-read sequencing technologies to a cohort of CRE bacteremia isolates and used these data to unravel complex mobile genetic element structures mediating {beta}- lactamase gene amplification. By generating complete genomes of 65 carbapenem non-susceptible Enterobacterales (CNSE) covering a genetically diverse array of isolates, our findings both generate novel insights into how non-CP-CRE overcome carbapenem treatments and provide researchers scaffolds for characterization of their own non-CP-CRE isolates. Improved recognition of mechanisms driving development of non-CP-CRE could assist with design and implementation of future strategies to mitigate the impact of these increasingly recognized AMR pathogens.

genomics↗