Effects of memory on the shapes of simple outbreak trees

Genomic tools, including phylogenetic trees derived from sequence data, are increasingly used to understand outbreaks of infectious diseases. One challenge is to link phylogenetic trees to patterns of transmission. Particularly in bacteria that cause chronic infections, this inference is affected by variable infectious periods and infectivity over time. It is known that non-exponential infectious periods can have substantial effects on pathogens’ transmission dynamics. Here we ask how this non-Markovian nature of an outbreak process affects the branching trees describing that process, with particular focus on tree shapes. We simulate Crump-Mode-Jagers branching processes and compare different patterns of infectivity over time. We find that memory (non-Markovian-ness) in the process can have a pronounced effect on the shapes of the outbreak’s branching pattern. However, memory also has a pronounced effect on the sizes of the trees, even when the duration of the simulation is fixed. When the sizes of the trees are constrained to a constant value, memory in our processes has little direct effect on tree shapes, but can bias inference of the birth rate from trees. We compare simulated branching trees to phylogenetic trees from an outbreak of tuberculosis in Canada, and discuss the relevance of memory to this dataset

Inferring Epidemic Contact Structure from Phylogenetic Trees

Contact structure is believed to have a large impact on epidemic spreading and consequently using networks to model such contact structure continues to gain interest in epidemiology. However, detailed knowledge of the exact contact structure underlying real epidemics is limited. Here we address the question whether the structure of the contact network leaves a detectable genetic fingerprint in the pathogen population. To this end we compare phylogenies generated by disease outbreaks in simulated populations with different types of contact networks. We find that the shape of these phylogenies strongly depends on contact structure. In particular, measures of tree imbalance allow us to quantify to what extent the contact structure underlying an epidemic deviates from a null model contact network and illustrate this in the case of random mixing. Using a phylogeny from the Swiss HIV epidemic, we show that this epidemic has a significantly more unbalanced tree than would be expected from random mixing

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

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

The evolution of transmission mode

This article reviews research on the evolutionary mechanisms leading to different transmission modes. Such modes are often under genetic control of the host or the pathogen, and often in conflict with each other via trade-offs. Transmission modes may vary among pathogen strains and among host populations. Evolutionary changes in transmission mode have been inferred through experimental and phylogenetic studies, including changes in transmission associated with host-shifts and with evolution of the unusually complex life cycles of many parasites. Understanding the forces that determine the evolution of particular transmission modes presents a fascinating medley of problems for which there is a lack of good data and often a lack of conceptual understanding or appropriate methodologies. Our best information comes from studies that have been focused on the vertical vs. horizontal transmission dichotomy. With other kinds of transitions, theoretical approaches combining epidemiology and population genetics are providing guidelines for determining when and how rapidly new transmission modes may evolve, but these are still in need of empirical investigation and application to particular cases. Obtaining such knowledge is a matter of urgency in relation to extant disease threats

Social Networks Shape the Transmission Dynamics of Hepatitis C Virus

Hepatitis C virus (HCV) infects 170 million people worldwide, and is a major public health problem in Brazil, where over 1% of the population may be infected and where multiple viral genotypes co-circulate. Chronically infected individuals are both the source of transmission to others and are at risk for HCV-related diseases, such as liver cancer and cirrhosis. Before the adoption of anti-HCV control measures in blood banks, this virus was mainly transmitted via blood transfusion. Today, needle sharing among injecting drug users is the most common form of HCV transmission. Of particular importance is that HCV prevalence is growing in non-risk groups. Since there is no vaccine against HCV, it is important to determine the factors that control viral transmission in order to develop more efficient control measures. However, despite the health costs associated with HCV, the factors that determine the spread of virus at the epidemiological scale are often poorly understood. Here, we sequenced partial NS5b gene sequences sampled from blood samples collected from 591 patients in São Paulo state, Brazil. We show that different viral genotypes entered São Paulo at different times, grew at different rates, and are associated with different age groups and risk behaviors. In particular, subtype 1b is older and grew more slowly than subtypes 1a and 3a, and is associated with multiple age classes. In contrast, subtypes 1a and 3b are associated with younger people infected more recently, possibly with higher rates of sexual transmission. The transmission dynamics of HCV in São Paulo therefore vary by subtype and are determined by a combination of age, risk exposure and underlying social network. We conclude that social factors may play a key role in determining the rate and pattern of HCV spread, and should influence future intervention policies

Bayesian mixture models for phylogenetic source attribution from consensus sequences and time since infection estimates

In stopping the spread of infectious diseases, pathogen genomic data can be used to reconstruct transmission events and characterize population-level sources of infection. Most approaches for identifying transmission pairs do not account for the time that passed since divergence of pathogen variants in individuals, which is problematic in viruses with high within-host evolutionary rates. This is prompting us to consider possible transmission pairs in terms of phylogenetic data and additional estimates of time since infection derived from clinical biomarkers. We develop Bayesian mixture models with an evolutionary clock as signal component and additional mixed effects or covariate random functions describing the mixing weights to classify potential pairs into likely and unlikely transmission pairs. We demonstrate that although sources cannot be identified at the individual level with certainty, even with the additional data on time elapsed, inferences into the population-level sources of transmission are possible, and more accurate than using only phylogenetic data without time since infection estimates. We apply the approach to estimate age-specific sources of HIV infection in Amsterdam MSM transmission networks between 2010-2021. This study demonstrates that infection time estimates provide informative data to characterize transmission sources, and shows how phylogenetic source attribution can then be done with multi-dimensional mixture models

An Ecological and Conservation Perspective on Advances in the Applied Virology of Zoonoses

The aim of this manuscript is to describe how modern advances in our knowledge of viruses and viral evolution can be applied to the fields of disease ecology and conservation. We review recent progress in virology and provide examples of how it is informing both empirical research in field ecology and applied conservation. We include a discussion of needed breakthroughs and ways to bridge communication gaps between the field and the lab. In an effort to foster this interdisciplinary effort, we have also included a table that lists the definitions of key terms. The importance of understanding the dynamics of zoonotic pathogens in their reservoir hosts is emphasized as a tool to both assess risk factors for spillover and to test hypotheses related to treatment and/or intervention strategies. In conclusion, we highlight the need for smart surveillance, viral discovery efforts and predictive modeling. A shift towards a predictive approach is necessary in today’s globalized society because, as the 2009 H1N1 pandemic demonstrated, identification post-emergence is often too late to prevent global spread. Integrating molecular virology and ecological techniques will allow for earlier recognition of potentially dangerous pathogens, ideally before they jump from wildlife reservoirs into human or livestock populations and cause serious public health or conservation issues

Tracking external introductions of HIV using phylodynamics reveals a major source of infections in rural KwaZulu-Natal, South Africa

Despite increasing access to antiretrovirals, HIV incidence in rural KwaZulu-Natal remains among the highest ever reported in Africa. While many epidemiological factors have been invoked to explain such high incidence, widespread human mobility and viral movement suggest that transmission between communities may be a major source of new infections. High cross-community transmission rates call into question how effective increasing the coverage of antiretroviral therapy locally will be at preventing new infections, especially if many new cases arise from external introductions. To help address this question, we use a phylodynamic model to reconstruct epidemic dynamics and estimate the relative contribution of local transmission versus external introductions to overall incidence in KwaZulu-Natal from HIV-1 phylogenies. By comparing our results with population-based surveillance data, we show that we can reliably estimate incidence from viral phylogenies once viral movement in and out of the local population is accounted for. Our analysis reveals that early epidemic dynamics were largely driven by external introductions. More recently, we estimate that 35 per cent (95% confidence interval: 20-60%) of new infections arise from external introductions. These results highlight the growing need to consider larger-scale regional transmission dynamics when designing and testing prevention strategies

Bayesian methods for source attribution using HIV deep sequence data

The advent of pathogen deep-sequencing technology provides new opportunities for infec- tious disease surveillance, especially for fast-evolving viruses like human immunodeficiency virus (HIV). In particular, multiple reads per host contain detailed information on viral within- host diversity. This information allows the reconstruction of partial directed transmission networks, where estimates of who is source and who is recipient are directly available from the phylogenetic ordering of the viruses of any two individuals. This is a new approach for phylodynamics, and the topic of my thesis. In this thesis, I present updates to the bioinformatics pipeline used by the Phylogenetics And Networks for Generalised Epidemics in Africa consortium for processing HIV deep sequence data and running the phyloscanner program. I then present a semi-parametric Bayesian Poisson model for inferring infectious disease transmission flows and the sources of infection at the population level. The framework is computationally scalable in high- dimensional flow spaces thanks to Hilbert Space Gaussian process approximations, allows for sampling bias adjustments, and estimation of gender- and age-specific transmission flows at a finer resolution than previously possible. In this sense, the methods that I developed enable us to overcome some problems which have been unable to be solved by conventional phylodynamic approaches. We apply the approach to densely sampled, population-based HIV deep-sequence data from Rakai, Uganda. I focus on characterising age-specific transmission dynamics, and examining the sources of HIV infections in adolescent and young women in particular.Open Acces