Biology subjects

West, T. E.

Publications and source records attributed to West, T. E..

2 recordsLinked to original sources

bioRxiv2023

Genetic diversity, determinants, and dissemination of Burkholderia pseudomallei lineages implicated in melioidosis in northeast Thailand

Melioidosis is an often-fatal neglected tropical disease caused by an environmental bacterium Burkholderia pseudomallei. However, our understanding of the disease-causing bacterial lineages, their dissemination, and adaptive mechanisms remains limited. To address this, we conducted a comprehensive genomic analysis of 1,391 B. pseudomallei isolates collected from nine hospitals in northeast Thailand between 2015 and 2018, and contemporaneous isolates from neighbouring countries, representing the most densely sampled collection to date. Our study identified three dominant lineages with unique gene sets enhancing bacterial fitness, indicating lineage-specific adaptation strategies. Crucially, recombination was found to drive lineage-specific gene flow. Transcriptome analyses of representative clinical isolates from each dominant lineage revealed heightened expression of lineage-specific genes in environmental versus infection conditions, notably under nutrient depletion, highlighting environmental persistence as a key factor in the success of dominant lineages. The study also revealed the role of environmental factors - slope of terrain, altitude, direction of rivers, and the northeast monsoons - in shaping B. pseudomallei geographical dispersal. Collectively, our findings highlight persistence in the environment as a pivotal element facilitating B. pseudomallei spread, and as a prelude to exposure and infection, thereby providing useful insights for informing melioidosis prevention and control strategies.

microbiology↗

bioRxiv2021

Extreme sampling for genetic rare variant association analysis of dichotomous traits with focus on infectious disease susceptibility

As genomic sequencing becomes more accurate and less costly, large cohorts and consortiums of cohorts are providing high power for rare variant association studies for many conditions. When large sample sizes are not attainable and the phenotype under study is continuous, an extreme phenotypes design can provide high statistical power with a small to moderate sample size. We extend the extreme phenotypes design to the dichotomous infectious disease outcome by sampling on extremes of the pathogenic exposure instead of sampling on extremes of phenotype. We use a likelihood ratio test (LRT) to test the significance of association between infection status and presence of susceptibility rare variants. More than 10 billion simulations are studied to assess the method. The method results in high sample enrichment for rare variants affecting susceptibility. Greater than 90% power to detect rare variant associations is attained in reasonable scenarios. The ordinary case-control design requires orders of magnitude more samples to achieve the same power. The Type I error rate of the LRT is accurate even for p-values < 10-7. We find that erroroneous exposure assessment can lead to power loss more severe than excluding the observations with errors. Nevertheless, careful sampling on exposure extremes can make a study feasible by providing adequate statistical power. Limitations of this method are not unique to this design, and the power is never less than that of the ordinary case-control design. The method applies without modification to other dichotomous outcomes that have strong association with a continuous covariate.

genomics↗