Integrating host population contact structure and pathogen whole-genome sequence data to understand the epidemiology of infectious diseases : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy, Massey University, Manawatū, New Zealand

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With advances in high-throughput sequencing technologies, computational biology, and evolutionary modelling, pathogen sequence data is increasingly being used to inform infectious disease outbreak investigations; supporting inferences on the timing and directionality of transmission as well as providing insights into pathogen evolutionary dynamics and the development of antimicrobial resistance. This thesis focuses on the application of pathogen whole-genome sequence data in conjunction with social network analysis to investigate the transmission dynamics of two important pathogens; Campylobacter jejuni and Staphylococcus aureus. The first four studies centre around the recent emergence of an antimicrobial-resistant C. jejuni strain that was found to have rapidly spread throughout the New Zealand commercial poultry industry. All four studies build on the results of an industry survey that were not only used to determine the basic farm demographics and biosecurity practices of all poultry producers, but also to construct five contact networks representing the on- and off-farm movement patterns of goods and services. Contact networks were used in study one to investigate the relationship between farm-level contact risk pathways and the reported level of biosecurity. However, despite many farms having a number of contact risk pathways, no relationship was found due to the high level of variability in biosecurity practices between producers. In study two the contact risk between commercial poultry, backyard poultry, and wild birds was investigated by examining the spatial overlap between the commercial contact networks and (i) all poultry transactions made through the online auction website TradeMe® and, (ii) all wild bird observations made through the online citizen science bird monitoring project, eBird, with study results suggesting that the greatest risk is due to the growing number of online trades made over increasingly long distances and shorter timespans. Study three further uses the commercial contact networks to investigate the role of multiple transmission pathways on the genetic relatedness of 167 C. jejuni isolates sampled from across 30 commercial poultry farms. Permutational multivariate analysis of variance and distance-based linear models were used to explore the relative importance of network distances as potential determinants of the pairwise genetic relatedness between the C. jejuni isolates, with study results highlighting the importance of transporting feed vehicles in addition to the geographical proximity of farms and the parent company in the spread of disease. In the last of the four C. jejuni studies, a compartmental disease transmission model was developed to simulate both the spread and sequence mutations across an outbreak within the commercial poultry industry. Simulated sequences were used in an analysis mirroring the methods used in study three in order to validate the approaches examining the contribution of local contacts and network contacts towards disease transmission. An additional analysis is also performed in which the simulated sequence data is used to infer a transmission tree and explore the use of pathogen phylogenies in determining who-infected-whom across different model systems. A further study, motivated by the application of whole-genome sequence data to infer transmission, investigated the spread of S. aureus within the New Zealand dairy industry. This study demonstrated how whole-genome sequence data can be used to investigate pathogen population and evolutionary dynamics at multiple scales: from local to national and international. For this study, the genetic relatedness between 57 bovine-derived S. aureus isolates sampled from across 17 New Zealand dairy herds were compared with 59 S. aureus isolates that had been previously sampled and characterised from humans and domestic pets from across New Zealand and 103 S. aureus isolates extracted from GenBank that included both human and livestock isolates sampled from across 19 countries. Results from this study not only support evidence showing that the movement of live animals is an important risk factor for the spread of S. aureus, but also show that using cattle-tracing data alone may not be enough to fully capture the between farm transmission dynamics of S. aureus. Overall, by using these two pathogen examples, this thesis demonstrates the potential use of pathogen whole-genome sequence data alongside contact network data in an epidemiological investigation, whilst highlighting the limitations and future challenges that must be considered in order to continue to develop robust methods that can be used to reliably infer the transmission and evolutionary dynamics across a range of infectious diseases.