Multiscale Immune Selection and the Transmission-Diversity Feedback in Antigenically Diverse Pathogen Systems

This is the final version of the article. Available from University of Chicago Press via the DOI in this record.Antigenic diversity is commonly used by pathogens to enhance their transmission success. Within-host clonal antigenic variation helps to maintain long infectious periods, whereas high levels of allelic diversity at the population level significantly expand the pool of susceptible individuals. Diversity, however, is not necessarily a static property of a pathogen population but in many cases is generated by the very act of infection and transmission, and it is therefore expected to respond dynamically to changes in transmission and immune selection. We hypothesized that this coupling creates a positive feedback whereby infection and disease transmission promote the generation of diversity, which itself facilitates immune evasion and further infections. To investigate this link in more detail, we considered the human malaria parasite Plasmodium falciparum, one of the most important antigenically diverse pathogens. We developed an individual-based model in which antigenic diversity emerges as a dynamic property from the underlying transmission processes. Our results show that the balance between stochastic extinction and the generation of new antigenic variants is intrinsically linked to within-host and between-host immune selection. This in turn determines the level of diversity that can be maintained in a given population. Furthermore, the transmission-diversity feedback can lead to temporal lags in the response to natural or intervention-induced perturbations in transmission rates. Our results therefore have important implications for monitoring and assessing the effectiveness of disease control efforts

Searching, Sorting, and Cake Cutting in Rounds

We study sorting and searching in rounds motivated by a cake cutting problem. The search problem we consider is: we are given an array $x = (x_1, \ldots, x_n)$ and an element $z$ promised to be in the array. We have access to an oracle that answers comparison queries: "How is $x_i$ compared to $x_j$?", where the answer can be "$$". The goal is to find the location of $z$ with success probability at least $p \in [0,1]$ in at most $k$ rounds of interaction with the oracle. The problem is called ordered or unordered search, depending on whether the array $x$ is sorted or unsorted, respectively. For ordered search, we show the expected query complexity of randomized algorithms is $\Theta\bigl(k\cdot p \cdot n^{1/k}\bigr)$ in the worst case. In contrast, the expected query complexity of deterministic algorithms searching for a uniformly random element is $\Theta\bigl(k\cdot p^{1/k} \cdot n^{1/k}\bigr)$. The uniform distribution is the worst case for deterministic algorithms. For unordered search, the expected query complexity of randomized algorithms is $np\bigl(\frac{k+1}{2k}\bigr) \pm 1$ in the worst case, while the expected query complexity of deterministic algorithms searching for a uniformly random element is $np \bigl(1 - \frac{k-1}{2k}p \bigr) \pm 1$. We also discuss the connections of these search problems to the rank query model, where the array $x$ can be accessed via queries of the form "Is rank$(x_i) \leq k$?". Unordered search is equivalent to Select with rank queries (given $q$, find $x_i$ with rank $q$) and ordered search to Locate with rank queries (given $x_i$, find its rank). We show an equivalence between sorting with rank queries and proportional cake cutting with contiguous pieces for any number of rounds, as well as an improved lower bound for deterministic sorting in rounds with rank queries.Comment: 33 pages, 4 figure

Assessing dengue vaccination impact: Model challenges and future directions.

In response to the sharp rise in the global burden caused by dengue virus (DENV) over the last few decades, the WHO has set out three specific key objectives in its disease control strategy: (i) to estimate the true burden of dengue by 2015; (ii) a reduction in dengue mortality by at least 50% by 2020 (used as a baseline); and (iii) a reduction in dengue morbidity by at least 25% by 2020. Although various elements will all play crucial parts in achieving this goal, from diagnosis and case management to integrated surveillance and outbreak response, sustainable vector control, vaccine implementation and finally operational and implementation research, it seems clear that new tools (e.g. a safe and effective vaccine and/or effective vector control) are key to success. The first dengue vaccine was licensed in December 2015, Dengvaxia® (CYD-TDV) developed by Sanofi Pasteur. The WHO has provided guidance on the use of CYD-TDV in endemic countries, for which there are a variety of considerations beyond the risk-benefit evaluation done by regulatory authorities, including public health impact and cost-effectiveness. Population-level vaccine impact and economic and financial aspects are two issues that can potentially be considered by means of mathematical modelling, especially for new products for which empirical data are still lacking. In December 2014 a meeting was convened by the WHO in order to revisit the current status of dengue transmission models and their utility for public health decision-making. Here, we report on the main points of discussion and the conclusions of this meeting, as well as next steps for maximising the use of mathematical models for vaccine decision-making

Investigating the trade-off between the effectiveness and efficiency of process modeling

Despite recent efforts to improve the quality of process models, we still observe a significant dissimilarity in quality between models. This paper focuses on the syntactic condition of process models, and how it is achieved. To this end, a dataset of 121 modeling sessions was investigated. By going through each of these sessions step by step, a separate ‘revision’ phase was identified for 81 of them. Next, by cutting the modeling process off at the start of the revision phase, a partial process model was exported for these modeling sessions. Finally, each partial model was compared with its corresponding final model, in terms of time, effort, and the number of syntactic errors made or solved, in search for a possible trade-off between the effectiveness and efficiency of process modeling. Based on the findings, we give a provisional explanation for the difference in syntactic quality of process models

Assessing the burden of pregnancy-associated malaria under changing transmission settings

BACKGROUND: The clinical presentation of pregnancy-associated malaria, or PAM, depends crucially on the particular epidemiological settings. This can potentially lead to an underestimation of its overall burden on the female population, especially in regions prone to epidemic outbreaks and where malaria transmission is generally low. METHODS: Here, by re-examining historical data, it is demonstrated how excess female mortality can be used to evaluate the burden of PAM. A simple mathematical model is then developed to highlight the contrasting signatures of PAM within the endemicity spectrum and to show how PAM is influenced by the intensity and stability of transmission. RESULTS: Both the data and the model show that maternal malaria has a huge impact on the female population. This is particularly pronounced in low-transmission settings during epidemic outbreaks where excess female mortality/morbidity can by far exceed that of a similar endemic setting. CONCLUSION: The results presented here call for active intervention measures not only in highly endemic regions but also, or in particular, in areas where malaria transmission is low and seasonal

Analysis of symmetries in models of multi-strain infections

In mathematical studies of the dynamics of multi-strain diseases caused by antigenically diverse pathogens, there is a substantial interest in analytical insights. Using the example of a generic model of multi-strain diseases with cross-immunity between strains, we show that a significant understanding of the stability of steady states and possible dynamical behaviours can be achieved when the symmetry of interactions between strains is taken into account. Techniques of equivariant bifurcation theory allow one to identify the type of possible symmetry-breaking Hopf bifurcation, as well as to classify different periodic solutions in terms of their spatial and temporal symmetries. The approach is also illustrated on other models of multi-strain diseases, where the same methodology provides a systematic understanding of bifurcation scenarios and periodic behaviours. The results of the analysis are quite generic, and have wider implications for understanding the dynamics of a large class of models of multi-strain diseases

The IT-CMF: A Practical Application of Design Science

The IT-Capability Maturity Model [IT-CMF] is a high-level process capability maturity framework for managing the IT function within an organization. The purpose of this paper is to explore and explain the IT-CMF as a “ method meta-model” for IT management, emphasizing the novel approach to addressing the application of design processes and design artifacts by means of a very structured use of engaged scholarship and open innovation techniques to the ongoing challenge of managing organization’s IT capability