Surface antigens of pathogens are commonly targeted by vaccine-elicited antibodies but antigenic variability, notably in RNA viruses such as influenza, HIV and SARS-CoV-2, pose challenges for control by vaccination. For example, influenza A(H3N2) entered the human population in 1968 causing a pandemic and has since been monitored, along with other seasonal influenza viruses, for the emergence of antigenic drift variants through intensive global surveillance and laboratory characterisation. Statistical models of the relationship between genetic differences among viruses and their antigenic similarity provide useful information to inform vaccine development, though accurate identification of causative mutations is complicated by highly correlated genetic signals that arise due to the evolutionary process. Here, using a sparse hierarchical Bayesian analogue of an experimentally validated model for integrating genetic and antigenic data, we identify the genetic changes in influenza A(H3N2) virus that underpin antigenic drift. We show that incorporating protein structural data into variable selection helps resolve ambiguities arising due to correlated signals, with the proportion of variables representing haemagglutinin positions decisively included, or excluded, increased from 59.8% to 72.4%. The accuracy of variable selection judged by proximity to experimentally determined antigenic sites was improved simultaneously. Structure-guided variable selection thus improves confidence in the identification of genetic explanations of antigenic variation and we also show that prioritising the identification of causative mutations is not detrimental to the predictive capability of the analysis. Indeed, incorporating structural information into variable selection resulted in a model that could more accurately predict antigenic assay titres for phenotypically-uncharacterised virus from genetic sequence. Combined, these analyses have the potential to inform choices of reference viruses, the targeting of laboratory assays, and predictions of the evolutionary success of different genotypes, and can therefore be used to inform vaccine selection processes.

It is well recognised that animal and plant pathogens form complex ecological communities of interacting organisms within their hosts, and there is growing interest in the health implications of such pathogen interactions. Although community ecology approaches have been used to identify pathogen interactions at the within-host scale, methodologies enabling robust identification of interactions from population-scale data such as that available from health authorities are lacking. To address this gap, we developed a statistical framework that jointly identifies interactions between multiple viruses from contemporaneous non-stationary infection time series. Our conceptual approach is derived from a Bayesian multivariate disease mapping framework. Importantly, our approach captures within- and between-year dependencies in infection risk while controlling for confounding factors such as seasonality, demographics and infection frequencies, allowing genuine pathogen interactions to be distinguished from simple correlations. We validated our framework using a broad range of synthetic data. We then applied it to diagnostic data available for five respiratory viruses co-circulating in a major urban population between 2005 and 2013: adenovirus, human coronavirus, human metapneumovirus, influenza B virus and respiratory syncytial virus. We found positive and negative covariances indicative of epidemiological interactions among specific virus pairs. This statistical framework enables a community ecology perspective to be applied to infectious disease epidemiology with important utility for public health planning and preparedness.

Vaccines created from closely related viruses are vital for offering protection against newly emerging strains. For Foot-and-Mouth disease virus (FMDV), where multiple serotypes co-circulate, testing large numbers of vaccines can be infeasible. Therefore the development of an in silico predictor of cross-protection between strains is important to help optimise vaccine choice. Here we describe a novel sparse Bayesian variable selection model using spike and slab priors which is able to predict antigenic variability and identify sites which are important for the neutralisation of the virus. We are able to identify multiple residues which are known to be key indicators of antigenic variability. Many of these were not identified previously using Frequentist mixed-effects models and still cannot be found when an L1 penalty is used. We further explore how the Markov chain Monte Carlo (MCMC) proposal method for the inclusion of variables can offer significant reductions in computational requirements, both for spike and slab priors in general, and our hierarchical Bayesian model in particular.

Identifying when past exposure to an infectious disease will protect against newly emerging strains is central to understanding the spread and the severity of epidemics, but the prediction of viral cross-protection remains an important unsolved problem. For foot-and-mouth disease virus (FMDV) research in particular, improved methods for predicting this cross-protection are critical for predicting the severity of outbreaks within endemic settings where multiple serotypes and subtypes commonly co-circulate, as well as for deciding whether appropriate vaccine(s) exist and how much they could mitigate the effects of any outbreak. To identify antigenic relationships and their predictors, we used linear mixed effects models to account for variation in pairwise cross-neutralization titres using only viral sequences and structural data. We identified those substitutions in surface-exposed structural proteins that are correlates of loss of cross-reactivity. These allowed prediction of both the best vaccine match for any single virus and the breadth of coverage of new vaccine candidates from their capsid sequences as effectively as or better than serology. Sub-sequences chosen by the model-building process all contained sites that are known epitopes on other serotypes. Furthermore, for the SAT1 serotype, for which epitopes have never previously been identified, we provide strong evidence--by controlling for phylogenetic structure--for the presence of three epitopes across a panel of viruses and quantify the relative significance of some individual residues in determining cross-neutralization. Identifying and quantifying the importance of sites that predict viral strain cross-reactivity not just for single viruses but across entire serotypes can help in the design of vaccines with better targeting and broader coverage. These techniques can be generalized to any infectious agents where cross-reactivity assays have been carried out. As the parameterization uses pre-existing datasets, this approach quickly and cheaply increases both our understanding of antigenic relationships and our power to control disease.

Female crickets can locate males by phonotaxis to the mating song they produce. The behaviour and underlying physiology has been studied in some depth showing that the cricket auditory system solves this complex problem in a unique manner. We present an analogue very large scale integrated (aVLSI) circuit model of this process and show that results from testing the circuit agree with simulation and what is known from the behaviour and physiology of the cricket auditory system. The aVLSI circuitry is now being extended to use on a robot along with previously modelled neural circuitry to better understand the complete sensorimotor pathway. 1 In t r o d u c t i o n Understanding how insects carry out complex sensorimotor tasks can help in the design of simple sensory and robotic systems. Often insect sensors have evolved into intricate filters matched to extract highly specific data from the environment which solves a particular problem directly with little or no need for further processing [1]. Examples include head stabilisation in the fly, which uses vision amongst other senses to estimate self-rotation and thus to stabilise its head in flight, and phonotaxis in the cricket. Because of the narrowness of the cricket body (only a few millimetres), the Interaural Time Difference (ITD) for sounds arriving at the two sides of the head is very small (1020s). Even with the tympanal membranes (eardrums) located, as they are, on the forelegs of the cricket, the ITD only reaches about 40s, which is too low to detect directly from timings of neural spikes. Because the wavelength of the cricket calling song is significantly greater than the width of the cricket body the Interaural Intensity Difference (IID) is also very low. In the absence of ITD or IID information, the cricket uses phase to determine direction. This is possible because the male cricket produces an almost pure tone for its calling song. * + School of Electrical and Information Engineering, Institute of Perception, Action and Behaviour. Figure 1: The cricket auditory system. Four acoustic inputs channel sounds directly or through tracheal tubes onto two tympanal membranes. Sound from contralateral inputs has to pass a (double) central membrane (the medial septum), inducing a phase delay and reduction in gain. The sound transmission from the contralateral tympanum is very weak, making each eardrum effectively a 3 input system. The physics of the cricket auditory system is well understood [2]; the system (see Figure 1) uses a pair of sound receivers with four acoustic inputs, two on the forelegs, which are the external surfaces of the tympana, and two on the body, the prothoracic or acoustic spiracles [3]. The connecting tracheal tubes are such that interference occurs as sounds travel inside the cricket, producing a directional response at the tympana to frequencies near to that of the calling song. The amplitude of vibration of the tympana, and hence the firing rate of the auditory afferent neurons attached to them, vary as a sound source is moved around the cricket and the sounds from the different inputs move in and out of phase. The outputs of the two tympana match when the sound is straight ahead, and the inputs are bilaterally symmetric with respect to the sound source. However, when sound at the calling song frequency is off-centre the phase of signals on the closer side comes better into alignment, and the signal increases on that side, and conversely decreases on the other. It is that crossover of tympanal vibration amplitudes which allows the cricket to track a sound source (see Figure 6 for example). A simplified version of the auditory system using only two acoustic inputs was implemented in hardware [4], and a simple 8-neuron network was all that was required to then direct a robot to carry out phonotaxis towards a species-specific calling song [5]. A simple simulator was also created to model the behaviour of the auditory system of Figure 1 at different frequencies [6]. Data from Michelsen et al. [2] (Figures 5 and 6) were digitised, and used together with average and "typical" values from the paper to choose gains and delays for the simulation. Figure 2 shows the model of the internal auditory system of the cricket from sound arriving at the acoustic inputs through to transmission down auditory receptor fibres. The simulator implements this model up to the summing of the delayed inputs, as well as modelling the external sound transmission. Results from the simulator were used to check the directionality of the system at different frequencies, and to gain a better understanding of its response. It was impractical to check the effect of leg movements or of complex sounds in the simulator due to the necessity of simulating the sound production and transmission. An aVLSI chip was designed to implement the same model, both allowing more complex experiments, such as leg movements to be run, and experiments to be run in the real world. Figure 2: A model of the auditory system of the cricket, used to build the simulator and the aVLSI implementation (shown in boxes). These experiments with the simulator and the circuits are being published in [6] and the reader is referred to those papers for more details. In the present paper we present the details of the circuits used for the aVLSI implementation.

A large space of different neural models exists from simple mathematical abstractions to detailed biophysical representations with strongly differing levels of complexity and biological relevance. Previous comparisons between models have looked at biological realism or mathematical tractability rather than expressive power. This paper, however, investigates whether more sophisticated models are better suited to a complex sensorimotor control task than simpler ones, or whether the more general nature of groups of the simpler neurons allows them to collectively solve complex tasks better despite their individual simplicity. Many models have been proposed or used for sensorimotor control tasks such as the control of locomotion. Four such neural models with varying levels of complexity were chosen. Controllers made of networks of each neural type were evolved to generate locomotion in a simulated dynamically stable four-legged robot using a genetic algorithm. The problem domain was chosen as one for which no simple solution could be hand crafted and which, with its tight sensorimotor coupling, had strongly time-dependent properties as is common in many biological control tasks. Analysis of the results shows that the most complex and biologically based model is significantly better at walking control, even producing recognizable gaits.

Godot is a mobile robot platform that serves as a testbed for the interface between a sophisticated low-level robot navigation and a symbolic high-level spoken dialogue system. The interesting feature of this combined system is that information flows in two directions: (1) the navigation system. supplies landmark; information from the cognitive map used for the interpretation of the user's utterances in the dialogue system; and (2) the semantic content of utterances analysed by the dialogue system are used to adjust probabilities about the robot's position in the navigation system.