Centre For Infectious Disease - Research Highlights Archive http://www.idrec.ac.nz/research-highlights-archive.html en-uk 2022-12-09T18:09:14+01:00 Exploring the evolution of Campylobacter http://www.idrec.ac.nz/research-highlights-archive,listing,,,41,exploring-the-evolution-of-campylobacter.html SHOUKAI YU PhD Candidate mEpiLab The genus Campylobacter is a major cause of human gastroenteritis worldwide; therefore, understanding the evolution of Campylobacter could have important implications. My doctoral studies took a multidisciplinary approach to investigating the evolution of Campylobacter by focusing on the factors which affect genetic exchange. To do this I combined the latest developments from the fields of statistics, genetics, bioinformatics and computer science The importance of recombination In order to understand how Campylobacter evolves, I proposed a mathematical method to estimate the relative rates of recombination and mutation in the generation of new alleles that lead to single locus variants (SLVs). This work revealed that the process of recombination provides a far stronger driving force than mutation in the evolution of Campylobacter jejuni and Campylobacter coli. Furthermore, this model demonstrated that purifying selection also plays an important role in the evolution of Campylobacter. For comparison, I also used this model to examine the role played by recombination in the evolution of other bacteria, which confirmed that recombination is an important process for creating diversity in closely related isolates. Phylogenetics and geographical isolation I also applied a range of phylogenetic and population genetic tools to investigate the effect of geographical isolation on the evolution of Campylobacter by comparing datasets from two geographically separated countries: New Zealand and the United Kingdom. This is the first time this has been attempted. Analysing sequence data at different levels of resolution provided evidence that geographical isolation affects the evolution of Campylobacter genotypes over short time-scales, but that this effect diminishes over longer time-scales. Furthermore, this analysis estimated the time for divergence of NZ-specific lineages of Campylobacter strains. Figure 1. A Neighbour Net of a 1-PSI matrix for sequence type (ST) frequency. The isolates have been grouped by host species and country of origin, with the number after each host source representing sample size. The thick blue line shows the genetic separation between isolates from New Zealand and those from the UK; and the thin blue line demonstrates genetic differences in the isolates originating from ruminant hosts compared to those originating from human and poultry host sources. New Zealand-specific Campylobacter Campylobacter jejuni sequence type 474 (ST-474) is responsible for more than a quarter of human campylobacteriosis notifications in New Zealand, but intriguingly this strain has been rarely identified in other countries. Understanding the clonal relationships of ST-474 strains is helpful for inferring the origin and the evolutionary mechanisms of Campylobacter. In this piece of work, I accessed the full genome sequences of 59 isolates of Campylobacter. I applied a range of phylogenetic tools to a targeted gene reference set to compare estimations of the clonal genealogy inferred for Campylobacter datasets. The implications of my work The findings of my doctoral studies have implications for: identifying the origin of Campylobacter; developing effective disease intervention strategies; predicting the emergence of pathogens; and reducing the occurrence of campylobacteriosis in the food supply chain. Shoukai Yu is in the final stages of writing her doctoral thesis. She was supervised by Professor Nigel French and Dr Patrick Biggs (IDReC), Dr Barbara Holland (University of Tasmania), and Professor Paul Fearnhead (Lancaster University). A link to the first paper to be published from her doctoral studies is available here: Yu S, Fearnhead P, Holland B, Biggs P, Maiden M, French N. Estimating the Relative Roles of Recombination and Point Mutation in the Generation of Single Locus Variants in Campylobacter jejuni and Campylobacter coli. Journal of Molecular Evolution 74, 273-80, 2012 During her doctoral studies Shoukai was awarded a 3-month secondment to the World Health Organisation where she worked with the independent Expert Review Group (iERG). Shoukai has now left New Zealand for Nashville, Tennessee where she is starting as a Postdoctoral Researcher at Vanderbilt University. Her research will be focusing upon identification of genes involved in human diseases. We wish Shoukai every success and look forward to watching her own career evolve.   http://www.idrec.ac.nz/research-highlights-archive,listing,,,41,exploring-the-evolution-of-campylobacter.html Spatial and Spatiotemporal Point Process Modelling in Epidemiology http://www.idrec.ac.nz/research-highlights-archive,listing,,,33,spatial-and-spatiotemporal-point-process-modelling-in-epidemiology.html TILMAN M. DAVIES PhD candidate, Dept. of Statistics. Epidemiologists often deal with data sets comprised of point locations of the disease(s) being studied in order to gain an insight into the spatial variation and/or correlation of infections over a given geographical region. A critical component of this process is the availability of sound statistical methods able to cope with the complex trends and dependence structures typically present in such datasets. My research has dealt with the appraisal and refinement of certain point process methodologies with a view to improved modelling of epidemiologically-flavoured problems. Kernel-Smoothed Density-Ratios An expression of the ‘risk' of infection is a useful statistic commonly employed by epidemiologists. Spatially, this can be achieved by nonparametrically estimating the 2-dimensional probability density functions related to the recorded ‘case' and ‘control' location data via kernel smoothing, and evaluating their ratio. We improved the method by considering variable smoothing in the estimates, and developing computationally efficient methods of highlighting statistically significant sub-regions of risk. Figure 1.  A surface plot showing the relative risk of liver disease in North East England. Spatial Point Processes Models A more detailed investigation into the behaviour of the observed point patterns can be achieved if we consider the presence of inter-point correlation. We investigated the particularly powerful class of models known as ‘log-Gaussian Cox processes,' (LGCP) capable of tracking the evolution of the spatiotemporal disease intensities. This work highlighted the potential the LGCP has in epidemiological applications, and established novel numerical results related to the fitting and conditional simulation of these models. We also look at shot noise process models, which allow simulation of putative centres of heightened risk. Animation 1. Video of Metropolis-Hastings birth -death algorithm performing spatial simulation of possible locations of centres of disease risk. Note that disease need not always develop close to such centres. http://youtu.be/TXZpzJx8xOg Computer software The lack of accessibility to some of the more complicated statistical methods can often be a problem in terms of encouraging their use. Alongside the theoretical and empirical work completed with respect to the kernel density-ratio and LGCP, we developed and released freely available software (LGCP package developed in collaboration with leading researchers at Lancaster University, UK) for use with the statistical computing environment ‘R' to perform operations related to the above topics. The availability of these software packages has already yielded interesting collaborative work with epidemiologists and other scientists around the globe. The R packages that Tilman has helped to develop are available on the links below: Spatial relative risk - sparr log-Gaussian Cox process - lgcp Tilman has recently been examined on his doctoral thesis and has taken a lectureship post within the Maths and Statistics Department at the University of Otago. Congratulations Tilman, and we wish you the best for this next stage of your career. http://www.idrec.ac.nz/research-highlights-archive,listing,,,33,spatial-and-spatiotemporal-point-process-modelling-in-epidemiology.html Shiga Toxin-Producing E. coli at the Cattle-Human Interface http://www.idrec.ac.nz/research-highlights-archive,listing,,,27,shiga-toxin-producing-e-coli-at-the-cattle-human-interface.html PATRICIA JAROS PhD candiate, mEpiLab. My research is focused on the pathogenic bacterium E. coli O157:H7 and other non-O157 related Shiga toxin-producing E. coli  (STECs), which are alternatively known as Verotoxin-producing E. coli (VTECs). These are pathogens of great concern to the food producing industry worldwide as they can cause serious illnesses in humans such as diarrhoea, haemorrhagic colitis, and haemolytic uraemic syndrome. Over the past decade, New Zealand has reported an increase in STEC infections in humans. In 2010, 128 STEC cases were recorded (3.1 cases per 100,000 people). THE RUMINANT RESERVOIR Ruminants shed STEC in their faeces and cattle in particular are considered to be an important reservoir of these pathogens. However, very little is known about the levels of STEC pathogens entering the food chain via slaughtered livestock in New Zealand. My PhD is composed of four epidemiological studies, which aim to investigate the epidemiology of this disease in both the cattle reservoir and the human host population. Initially, I conducted a two-year study across four New Zealand abattoirs, which showed that a higher proportion of bobby calves (4-7 days of age) were shedding E. coli O157:H7 and O26 compared to adult cattle. I then followed groups of calves from "high" and "low" risk farms to investigate the effect of transportation and holding in yards prior to slaughter on the level of carcase contamination with E. coli O157:H7 and O26. THE HUMAN CASES In order to estimate the proportion of human cases that are likely to be associated with the exposure to STEC from cattle, the E. coli strains isolated from cattle in those studies have been genetically typed and will be compared to E. coli strains from human cases in New Zealand. Alongside this, a case-control study will be undertaken to provide a better understanding of the sources of human illness and, in particular, to investigate whether cattle are a significant source of STEC infections for humans in New Zealand. Taken together, my research findings are providing valuable epidemiological data that will both help to assess the risks there may be to consumers of red meat produced in New Zealand and to appropriately target future control strategies for protecting human health.   http://www.idrec.ac.nz/research-highlights-archive,listing,,,27,shiga-toxin-producing-e-coli-at-the-cattle-human-interface.html