Biomedical subjects

D T Haydon

Publications and source records attributed to D T Haydon.

At least 19 recordsLinked to original sources

PubMed2003

Neighbourhood control policies and the spread of infectious diseases.

We present a model of a control programme for a disease outbreak in a population of livestock holdings. Control is achieved by culling infectious holdings when they are discovered and by the pre-emptive culling of livestock on holdings deemed to be at enhanced risk of infection. Because the pre-emptive control programme cannot directly identify exposed holdings, its implementation will result in the removal of both infected and uninfected holdings. This leads to a fundamental trade-off: increased levels of control produce a greater reduction in transmission by removing more exposed holdings, but increase the number of uninfected holdings culled. We derive an expression for the total number of holdings culled during the course of an outbreak and demonstrate that there is an optimal control policy, which minimizes this loss. Using a metapopulation model to incorporate local clustering of infection, we examine a neighbourhood control programme in a locally spreading outbreak. We find that there is an optimal level of control, which increases with increasing basic reproduction ratio, R(0); moreover, implementation of control may be optimal even when R(0) < 1. The total loss to the population is relatively insensitive to the level of control as it increases beyond the optimal level, suggesting that over-control is a safer policy than under-control.

Animals↗

PubMed2003

Spatio-temporal dynamics of the grey-sided vole in Hokkaido: identifying coupling using state-based Markov-chain modelling.

Explaining synchronization of cyclical or fluctuating populations over geographical regions presents ecologists with novel analytical challenges. We have developed a method to measure synchrony within spatial-temporal datasets of population densities applicable to both periodic and irregularly fluctuating populations. The dynamics of each constituent population is represented by a discrete Markov model. The state of a population trajectory at each time-point is classified as one of 'increase', 'decrease', 'peak' or 'trough'. The set of populations at any time-point is characterized by the frequency distribution of these different states, and the time-evolution of this frequency distribution used to test the hypothesis that the dynamics of each population proceeds independently of the others. The analysis identifies years in which population coupling results in synchronous states and onto which states the system converges, and identifies those years in which synchrony remains high but is accounted for by coupling observed in previous years. It also enables identification of which pairs of sites show the highest levels of coupling. Applying these methods to populations of the grey-sided vole on Hokkaido reveals them to be fluctuating in greater synchrony than would be expected from independent dynamics, and that this level of synchrony is maintained through intermittent coupling acting in ca. 1 year in four or five. High synchrony occurs between sites with similar vegetation and of similar altitude indicating that coupling may be mediated through shared environmental stimuli. When coupling is indicated, convergence is equally likely to occur on a peak state as a trough, indicating that synchronization may be brought about by the response of populations to a combination of different stimuli rather than by the action of any single process.

Animals↗

PubMed2003

The construction and analysis of epidemic trees with reference to the 2001 UK foot-and-mouth outbreak.

The case-reproduction ratio for the spread of an infectious disease is a critically important concept for understanding dynamics of epidemics and for evaluating impact of control measures on spread of infection. Reliable estimation of this ratio is a problem central to epidemiology and is most often accomplished by fitting dynamic models to data and estimating combinations of parameters that equate to the case-reproduction ratio. Here, we develop a novel parameter-free method that permits direct estimation of the history of transmission events recoverable from detailed observation of a particular epidemic. From these reconstructed 'epidemic trees', case-reproduction ratios can be estimated directly. We develop a bootstrap algorithm that generates percentile intervals for these estimates that shows the procedure to be both precise and robust to possible uncertainties in the historical reconstruction. Identifying and 'pruning' branches from these trees whose occurrence might have been prevented by implementation of more stringent control measures permits estimation of the possible efficacy of these alternative measures. Examination of the cladistic structure of these trees as a function of the distance of each case from its infection source reveals useful insights about the relationship between long-distance transmission events and epidemic size. We demonstrate the utility of these methods by applying them to data from the 2001 foot-and-mouth disease outbreak in the UK.

Algorithms↗

PubMed2003

The implications of virus diversity within the SAT 2 serotype for control of foot-and-mouth disease in sub-Saharan Africa.

SAT 2 is the serotype most often associated with outbreaks of foot-and-mouth disease (FMD) in livestock in southern and western Africa and is the only SAT type to have been recorded outside the African continent in the last decade. Its epidemiology is complicated by the presence of African buffalo (Syncerus caffer), which play an important role in virus maintenance and transmission. To assess the level of genetic complexity of this serotype among viruses associated with both domestic livestock and wildlife, complete VP1 gene sequences of 53 viruses from 17 countries and three different host species were analysed. Phylogenetic analysis revealed eleven virus lineages, differing from each other by at least 20 % in pairwise nucleotide comparisons, four of which fall within the southern African region, two in West Africa and the remaining five in central and East Africa. No evidence of recombination between these lineages was detected, and thus we conclude that these are independently evolving virus lineages which occur primarily in discrete geographical localities in accordance with the FMD virus topotype concept. Applied to the whole phylogeny, rates of nucleotide substitution are significantly different between topotypes, but most individual topotypes evolve in accordance with a molecular clock at an average rate of approximately 0.002 substitutions per site per year. This study provides an indication of the intratypic complexity of the SAT 2 serotype at the continental level and emphasizes the value of molecular characterization of diverse FMD field strains for tracing the origin of outbreaks.

Africa South of the Sahara↗

PubMed2001

Phase coupling and synchrony in the spatiotemporal dynamics of muskrat and mink populations across Canada.

Population ecologists have traditionally focused on the patterns and causes of population variation in the temporal domain for which a substantial body of practical analytic techniques have been developed. More recently, numerous studies have documented how populations may fluctuate synchronously over large spatial areas; analyses of such spatially extended time-series have started to provide additional clues regarding the causes of these population fluctuations and explanations for their synchronous occurrence. Here, we report on the development of a phase-based method for identifying coupling between temporally coincident but spatially distributed cyclic time-series, which we apply to the numbers of muskrat and mink recorded at 81 locations across Canada. The analysis reveals remarkable parallel clines in the strength of coupling between proximate populations of both species--declining from west to east--together with a corresponding increase in observed synchrony between these populations the further east they are located.

Animals↗

PubMed2001

Dynamics of the 2001 UK foot and mouth epidemic: stochastic dispersal in a heterogeneous landscape.

Foot-and-mouth is one of the world's most economically important livestock diseases. We developed an individual farm-based stochastic model of the current UK epidemic. The fine grain of the epidemiological data reveals the infection dynamics at an unusually high spatiotemporal resolution. We show that the spatial distribution, size, and species composition of farms all influence the observed pattern and regional variability of outbreaks. The other key dynamical component is long-tailed stochastic dispersal of infection, combining frequent local movements with occasional long jumps. We assess the history and possible duration of the epidemic, the performance of control strategies, and general implications for disease dynamics in space and time.

Animal Husbandry↗

PubMed2001

The generation and persistence of genetic variation in foot-and-mouth disease virus.

Genetic variation in foot-and-mouth disease virus (FMDV) is of interest for at least two reasons. First, changes to the genes encoding capsid proteins results in antigenic variation, and affects vaccine efficiency and effectiveness of vaccination programs; second, genetic changes can lead to important insights into the transport of virus between countries, regions, herds, and even possibly individuals. Current estimates of RNA virus mutation rates suggest that an average of about one base mis-incorporation is likely to occur each time a single FMDV genome replicates. This should result in the introduction of every possible 1-step mutation from the progenitor genotype into the viraemia of a single infected animal many times a day. In the absence of purifying selection, a single infected animal should therefore generate a genetically very diverse population of virus.Viral-capsid sequences obtained from infected animals sampled over long-term FMDV epidemics suggest that these genetic changes accrue in a remarkably linear 'clock-like' fashion and at rates of around 1% change per year. While such a rate is generally regarded as quite high, it is actually somewhat lower than one might expect based on the rate at which viral diversity could be generated within a single animal. The difference might be explained in a variety of possible ways: (1) the mutation rate has been overestimated; (2) purifying selection is stronger than predicted; (3) only a restricted subset of excreted virus is actually infectious; (4) infected animals only excrete virus from a small partitioned subset of amplified virus, and that most of the generated viral diversity is unable to exit the animal; or (5) only a small fraction of all infected animals participate in the actual disease-transmission process.

Animals↗

PubMed2001

Population biology of multihost pathogens.

The majority of pathogens, including many of medical and veterinary importance, can infect more than one species of host. Population biology has yet to explain why perceived evolutionary advantages of pathogen specialization are, in practice, outweighed by those of generalization. Factors that predispose pathogens to generalism include high levels of genetic diversity and abundant opportunities for cross-species transmission, and the taxonomic distributions of generalists and specialists appear to reflect these factors. Generalism also has consequences for the evolution of virulence and for pathogen epidemiology, making both much less predictable. The evolutionary advantages and disadvantages of generalism are so finely balanced that even closely related pathogens can have very different host range sizes.

Animals↗

PubMed2001

The insect endosymbiont Sodalis glossinidius utilizes a type III secretion system for cell invasion.

Sodalis glossinidius is a maternally transmitted secondary endosymbiont residing intracellularly in tissues of the tsetse flies, Glossina spp. In this study, we have used Tn5 mutagenesis and a negative selection procedure to derive a S. glossinidius mutant that is incapable of invading insect cells in vitro and is aposymbiotic when microinjected into tsetse. This mutant strain harbors Tn5 integrated into a chromosomal gene sharing high sequence identity with a type III secretion system invasion gene (invC) previously identified in Salmonella enterica. With the use of degenerate PCR, we have amplified a further six Sodalis inv/spa genes sharing high sequence identity with type III secretion system genes encoded by Salmonella pathogenicity island 1. Phylogenetic reconstructions based on the inv/spa genes of Sodalis and other members of the family Enterobacteriaceae have consistently identified a well-supported clade containing Sodalis and the enteric pathogens Shigella and Salmonella. These results suggest that Sodalis may have evolved from an ancestor with a parasitic intracellular lifestyle, possibly a latter-day entomopathogen. These observations lend credence to a hypothesis suggesting that vertically transmitted mutualistic endosymbionts evolve from horizontally transmitted parasites through a parasitism-mutualism continuum.

Aedes↗

PubMed2001

Genetic heterogeneity of SAT-1 type foot-and-mouth disease viruses in southern Africa.

Genetic relationships of 50 SAT-1 type foot-and-mouth disease viruses were determined by phylogenetic analysis of an homologous 417 nucleotide region encoding the C-terminal half of the VP1 gene and part of the 2A segment. Viruses obtained from persistently-infected African buffalo populations were selected in order to assess the regional genetic variation within the host species and compared with ten viruses recovered from recent and historical cases of clinical infection. Phylogenetic reconstructions identified three independently evolving buffalo virus lineages within southern Africa, that correspond with the following discrete geographic localities: (1) South Africa and southern Zimbabwe, (2) Namibia, Botswana and western Zimbabwe, and (3) Zambia, Malawi and northern Zimbabwe. This strict geographic grouping of viruses derived from buffalo was shown to be useful for determining the origin of recent SAT-1 epizootics in livestock. The percentage of conserved amino acid sites across the 50 SAT-1 viruses compared in this study was 50%. Most mutations were clustered within three discrete hypervariable regions, which coincide with the immunogenic G-H loop, H-1 loop and C-terminus region of the protein. Despite the high levels of variation within the primary sequence, secondary structural features appear to be conserved.

Africa South of the Sahara↗

PubMed2001

A centuries-long epidemic of scrapie in British sheep?

The apparent persistence of scrapie in British sheep for more than 250 years is difficult to explain. Susceptibility to scrapie is associated with particular alleles at a single locus, the PrP gene. As the only known effect of these alleles is to confer susceptibility to a fatal disease, natural selection is expected to reduce their frequency, as has been observed in practice during scrapie outbreaks in single sheep flocks. Susceptibility alleles, and hence scrapie itself, are therefore expected to become rare, yet the disease remains widespread. We suggest that the paradox of scrapie's persistence can be explained by the exceptionally long time-scales inherent in the epidemiology of the disease. It is proposed that scrapie should be regarded as epidemic in British sheep but, unlike more familiar epidemics, which have time-scales of months or years, the scrapie epidemic has a time-scale of centuries. This interpretation implies that scrapie should eventually disappear from the sheep population.

Animals↗

PubMed2001

Evidence for positive selection in foot-and-mouth disease virus capsid genes from field isolates.

The nature of selection on capsid genes of foot-and-mouth disease virus (FMDV) was characterized by examining the ratio of nonsynonymous to synonymous substitutions in 11 data sets of sequences obtained from six different serotypes of FMDV. Using a method of analysis that assigns each codon position to one of a number of estimated values of nonsynonymous to synonymous ratio, significant evidence of positive selection was identified in 5 data sets, operating at 1-7% of codon positions. Evidence of positive selection was identified in complete capsid sequences of serotypes A and C and in VP1 sequences of serotypes SAT 1 and 2. Sequences of serotype SAT-2 recovered from a persistently infected African buffalo also revealed evidence for positive selection. Locations of codons under positive selection coincide closely with those of antigenic sites previously identified with the use of monoclonal antibody escape mutants. The vast majority of codons are under mild to strong purifying selection. However, these results suggest that arising antigenic variants benefit from a selective advantage in their interaction with the immune system, either during the course of an infection or in transmission to individuals with previous exposure to antigen. Analysis of amino acid usage at sites under positive selection indicates that this selective advantage can be conferred by amino acid substitutions that share physicochemically similar properties.

Amino Acid Sequence↗

PubMed2001

Ehrlichia ruminantium major antigenic protein gene (map1) variants are not geographically constrained and show no evidence of having evolved under positive selection pressure.

In a search for tools to distinguish antigenic variants of Ehrlichia ruminantium, we sequenced the major antigenic protein genes (map1 genes) of 21 different isolates and found that the sequence polymorphisms were too great to permit the design of probes which could be used as markers for immunogenicity. Phylogenetic comparison of the 21 deduced MAP1 sequences plus another 9 sequences which had been previously published did not reveal any geographic clustering among the isolates. Maximum likelihood analysis of codon and amino acid changes over the phylogeny provided no statistical evidence that the gene is under positive selection pressure, suggesting that it may not be important for the evasion of host immune responses.

Amino Acid Sequence↗

PubMed2000

Habitat loss and raptor predation: disentangling long- and short-term causes of red grouse declines.

The number of red grouse (Lagopus lagopus scoticus) shot in the UK has declined by 50% during the 20th century This decline has coincided with reductions in the area of suitable habitat and recoveries in the populations of some avian predators. Here we use long-term records of shooting bags and a large-scale manipulation of raptor density to disentangle the effects of habitat loss and raptor predation on grouse populations. The numbers of grouse harvested on the Eskdale half of Langholm Moor in southern Scotland declined significantly during 1913-1990 and grouse bags from the whole moor from 1950 to 1990 exhibited an almost identical but non-significant trend. Hen harriers (Circus cyaneus) and peregrine falcons (Falco peregrinus) were absent or bred at low densities on this moor throughout this period but heather-dominant vegetation declined by 48% between 1948 and 1988. Harrier and peregrine breeding numbers on Langholm Moor increased to high levels following protection in 1990 whilst grouse density and grouse bags declined year after year until shooting was abandoned in 1998. The prediction of a peak in grouse bags on Langholm Moor in 1996 based on the patterns of bags during 1950-1990 was supported by the observed peaks in 1997 on two nearby moors with few raptors which formerly cycled in synchrony with Langholm Moor. This study demonstrates that, whilst long-term declines in grouse bags were most probably due to habitat loss, high levels of raptor predation subsequently limited the grouse population and suppressed a cycle. This study thus offers support to theoretical models which predict that generalist predators may suppress cycles in prey populations.

Animals↗

PubMed2000

Spatial coupling in cyclic population dynamics: models and data.

We use a dynamic random field to model a spatial collection of coupled oscillators with discrete time stochastic dynamics. At each time step the phase of each cyclic local population is subject to random noise, incremented by a common dynamic, and pulled by a coupling force in the direction of some collective mean phase. We define asynchrony and derive expressions for its measurement in this model. We describe robust methods for phase estimation of cyclic population time series, for estimating strength of coupling between local populations, and for measuring variance of locally acting noise from field data. Proposed methods allow intermittently acting phase synchronizing events operating over large spatial scales to be distinguished from more continuous and possibly locally acting coupling, both of which could result in elevated levels of phase synchronization. We demonstrate the utility of this approach by applying it to classical spatial time series data of Canadian lynx. Analysis confirms findings of previous studies and reveals evidence to suggest that interpopulation coupling was weaker over the 20th century than for the 1800s. Analysis supports the notion that synchrony in these populations is maintained by a continuous and locally acting coupling between adjacent regions with large phase adjustments occurring only infrequently. When this coupling is absent, asynchrony develops between populations.

Animals↗

PubMed1999

Molecular evolution of swine vesicular disease virus.

Phylogenetic analysis was used to examine the evolutionary relationships within a group of coxsackie B viruses that contained representatives of the major serotypes of this group and 45 isolates of swine vesicular disease virus (SVDV) from Asia and Europe. Separate analyses of sequence data from two regions of the viral genomes encoding the VP1 and 3BC genes both revealed that the SVDV belonged to a single monophyletic group which could be clearly distinguished from all other sampled coxsackieviruses. Regression analysis revealed that within the SVDV clade at least 80% of the synonymous variation in evolutionary divergence between isolates was explained by time, indicating the existence of an approximate molecular clock. Calibration of this clock according to synonymous substitutions per year indicated the date of occurrence of a common ancestor for the SVDV clade to be between 1945 and 1965.

Amino Acid Substitution↗

PubMed1998

Immune avoidance strategies in RNA viruses: fitness continuums arising from trade-offs between immunogenicity and antigenic variability.

Highly exposed and protruding amino acid sites on the surface of viral capsids are subject to fewer residue interactions and packing constraints than those buried within protein interiors. Consequently they often experience higher rates of non-synonymous substitution and exhibit greater genetic variability than buried interior sites. However such protrusive surface structures often induce host immune responses and are likely to constitute B cell epitopes. Genetic variation at these surface sites is therefore likely to correspond to antigenic variation. This may be of adaptive value to the virus for two quite different reasons. The first is that antigenic variation arising over the course of a viraemia may result in greater net viral replication, and increased opportunities for viral transmission. The second is that antigenic variation generated rapidly over a single infection or incrementally over several sequential infections may give rise to variants that are sufficiently immunologically distinct that they can reinfect host individuals with previous infection experience of related virus. This would lead to an extension of the susceptible host pool with consequent increase in transmission opportunities. The surface architecture of viral capsid proteins is therefore conceivably subject to two opposing selection pressures: one to minimize the surface area accessible to interaction with elements of the immune system, the other to increase the potential access to antigenic variation by adoption of exposed and unconstrained protein conformations. Therefore, there exists a possible trade-off between the fitness benefits deriving from potential ability to generate antigenic variation, and the increased immunogenicity with which such potential may be associated. We propose that the existence of this trade-off would lead to a continuum of different strategies by which a virus might combat an immune response. We explore this strategy space with simple mathematical models, and show that peak loads of infectious virus particles are proportional to levels of antigenic diversity, and inversely proportional to immunogenicity, thereby creating the potential for a trade-off by which fitness might be maintained with a continuum of strategies. This may remain possible even if the antigenic variants are not transmissible between hosts, so long as immune resources are sufficiently dispersed between antigenic variants. The diversity of possible strategies is discussed with reference to the Picornavirus family.

Antibodies, Viral↗

PubMed1997

The design of veterinary vaccination programmes.

The optimal design of a veterinary vaccination programme depends on both the characteristics of the vaccine and the epidemiology of the pathogen or parasite. Relevant vaccine characteristics are the proportion of those vaccinated that are initially protected, the duration of protection and the coverage achieved by the vaccination programme. The most important epidemiological parameter is the basic reproduction number, R0. Mathematical theory can integrate this information to address such questions as: whether it is possible to eliminate an infection; what proportion of hosts must be vaccinated to achieve this: what age should hosts first be vaccinated; and at what interval should hosts be revaccinated? Examples of rabies in foxes and foot-and-mouth disease in cattle suggest that theory can be used to guide the design of vaccination programmes.

Animals↗