Stochastic Simulation Models of Plasmodium Falciparum Malaria\ud Epidemiology and Control

Every year malaria causes an estimated 1.3–3 million deaths and around half a billion clinical episodes. The majority of deaths occur in children under the age ofyears. Malaria today occurs mostly in tropical and subtropical countries, particularly in subSaharan Africa and Southeast Asia. In developing countries malaria may account for as much as 40% of public health expenditure, 30-50% of hospital admissions, and up to 50% of outpatient visits to health facilities. Malaria is a vector borne disease caused by the protozoan parasites of the genus Plasmodium. Plasmodium falciparum causes the most severe form of the disease, and is responsible for half of the clinical cases and 90% of the deaths from malaria. Malaria control interventions in countries where the disease is endemic currently include personal protection against mosquito bites, vector control, and prophylactic drugs. There is currently no registered malaria vaccine, but this is an active field of research. The vaccine that is furthest advanced in clinical development is called RTS,S/AS02A. This is a preerythrocytic vaccine, which aims to kill the parasites before they enter the red blood cells. Predictive models can provide a rational basis for decisions on how to allocate resources for malaria control. Mathematical modeling of malaria has a long history, starting with the first models of malaria transmission dynamics by Ross a century ago. At the Swiss Tropical Institute, a malaria modeling project has generated algorithms for rational planning of malaria control. This model is implemented as an individual-based discrete-time simulation model. The behaviors and state changes of simulated human individuals are governed by a minimal set of sub-models that are considered crucial for making quantitative predictions of the impact of malaria control interventions. The integrated model includes components that capture relevant aspects of malaria transmission and epidemiology in the absence of control: the relationship between the entomologic inoculation rate and the force of infection; epidemiologic models for acute illness, severe morbidity, and mortality; infectiousness of human population. Another central model component, for natural immunity to asexual blood stages of P. falciparum, is described in this thesis. The use of the model for making quantitative predictions requires reliable estimates of the values of the parameters of the mathematical functions. The different model components were therefore fitted to a number of datasets from studies in various ecological settings and for various epidemiologic outcomes using a simulated annealing algorithm. Comparison of the model predictions with field data show that the model appears to reproduce reasonably well the parasitologic patterns seen in malariologic surveys in endemic areas. Epidemiologic patterns can be modified by control interventions. Because of the individualbased approach chosen, a number of different simulated interventions can be introduced by making assumptions on how they modify the processes described above. This thesis describes a model for case management to predict the impact of improved case management on incidence of clinical episodes and mortality while incorporating effects on persistence of parasites and transmission. It allows the simulation of different rates of treatment coverage and parasitologic cure rates, and makes it possible to look at how variations in transmission intensity might affect the impact of changes in the health system. It also defines a baseline environment that can be used the predict the impact of other control interventions. The second part of the thesis focuses on the prediction of the impact of a pre-erythrocytic stage vaccine. Different assumptions about how such a vaccine may lead to a measured reduction in the incidence of new infections in vaccinated individuals are discussed. The vaccine profile was chosen to match data from clinical trials of RTS,S/AS02A. The results demonstrate that an adequate simulation of the first two RTS,S/AS02A trials published can be achieved by assuming that vaccination completely blocks a certain fraction of infections that would otherwise reach the erythrocytic stages. The impact that such a vaccine would have on the epidemiology if introduced via the Expanded Program on Immunization (EPI) is then predicted. This is the first major attempt to combine dynamic modeling of malaria transmission and control with predictions of parasitologic and clinical outcome. The results suggest a significant impact on morbidity and mortality for a range of assumptions about the vaccine characteristics, but only small effects on transmission intensities. To make predictions of the cost-effectiveness of such a vaccination program, costing data are incorporated into a model of a health system that is currently in place in a low-income country context, based largely on data from Tanzania. Depending on the assumed vaccine characteristics and cost, the predicted cost-effectiveness ratios would make vaccination campaigns an attractive choice for health planners compared with other malaria control interventions. In addition to making quantitative predictions, the model points to data that may be important to make accurate predictions. In order to make mid- to longterm predictions, more data on the clinical epidemiology of malaria in adolescents and adults would be desirable. The work reported here creates a sound foundation for measuring the effects of introducing new antimalarial interventions, or scaling-up those that are already known to be efficacious and cost-effective. A challenge that remains is to make a comprehensive set of model predictions available to a non-modeler audience so it can be valuable both for informing malaria control strategies and research funding policy

Relationship between the entomologic inoculation rate and the force of infection for Plasmodium falciparum malaria.

We propose a stochastic model for the relationship between the entomologic inoculation rate (EIR) for Plasmodium falciparum malaria and the force of infection in endemic areas. The model incorporates effects of increased exposure to mosquito bites as a result of the growth in body surface area with the age of the host, naturally acquired pre-erythrocytic immunity, and the reduction in the proportion of entomologically assessed inoculations leading to infection, as the EIR increases. It is fitted to multiple datasets from field studies of the relationship between malaria infection and the EIR. We propose that this model can account for non-monotonic relationships between the age of the host and the parasite prevalence and incidence of disease. It provides a parsimonious explanation for the faster acquisition of natural immunity in adults than in children exposed to high EIRs. This forms one component of a new stochastic model for the entire transmission cycle of P. falciparum that we have derived to estimate the potential epidemiologic impact of malaria vaccines and other malaria control interventions

Design of trials for interrupting the transmission of endemic pathogens

Many interventions against infectious diseases have geographically diffuse effects. This leads to contamination between arms in cluster-randomized trials (CRTs). Pathogen elimination is the goal of many intervention programs against infectious agents, but contamination means that standard CRT designs and analyses do not provide inferences about the potential of interventions to interrupt pathogen transmission at maximum scale-up.; A generic model of disease transmission was used to simulate infections in stepped wedge cluster-randomized trials (SWCRTs) of a transmission-reducing intervention, where the intervention has spatially diffuse effects. Simulations of such trials were then used to examine the potential of such designs for providing generalizable causal inferences about the impact of such interventions, including measurements of the contamination effects. The simulations were applied to the geography of Rusinga Island, Lake Victoria, Kenya, the site of the SolarMal trial on the use of odor-baited mosquito traps to eliminate Plasmodium falciparum malaria. These were used to compare variants in the proposed SWCRT designs for the SolarMal trial.; Measures of contamination effects were found that could be assessed in the simulated trials. Inspired by analyses of trials of insecticide-treated nets against malaria when applied to the geography of the SolarMal trial, these measures were found to be robust to different variants of SWCRT design. Analyses of the likely extent of contamination effects supported the choice of cluster size for the trial.; The SWCRT is an appropriate design for trials that assess the feasibility of local elimination of a pathogen. The effects of incomplete coverage can be estimated by analyzing the extent of contamination between arms in such trials, and the estimates also support inferences about causality. The SolarMal example illustrates how generic transmission models incorporating spatial smoothing can be used to simulate such trials for a power calculation and optimization of cluster size and randomization strategies. The approach is applicable to a range of infectious diseases transmitted via environmental reservoirs or via arthropod vectors

Modeling the public health impact of malaria vaccines for developers and policymakers

Efforts to develop malaria vaccines show promise. Mathematical model-based estimates of the potential demand, public health impact, and cost and financing requirements can be used to inform investment and adoption decisions by vaccine developers and policymakers on the use of malaria vaccines as complements to existing interventions. However, the complexity of such models may make their outputs inaccessible to non-modeling specialists. This paper describes a Malaria Vaccine Model (MVM) developed to address the specific needs of developers and policymakers, who need to access sophisticated modeling results and to test various scenarios in a user-friendly interface. The model's functionality is demonstrated through a hypothetical vaccine.; The MVM has three modules: supply and demand forecast; public health impact; and implementation cost and financing requirements. These modules include pre-entered reference data and also allow for user-defined inputs. The model includes an integrated sensitivity analysis function. Model functionality was demonstrated by estimating the public health impact of a hypothetical pre-erythrocytic malaria vaccine with 85% efficacy against uncomplicated disease and a vaccine efficacy decay rate of four years, based on internationally-established targets. Demand for this hypothetical vaccine was estimated based on historical vaccine implementation rates for routine infant immunization in 40 African countries over a 10-year period. Assumed purchase price was $5 per dose and injection equipment and delivery costs were$0.40 per dose.; The model projects the number of doses needed, uncomplicated and severe cases averted, deaths and disability-adjusted life years (DALYs) averted, and cost to avert each. In the demonstration scenario, based on a projected demand of 532 million doses, the MVM estimated that 150 million uncomplicated cases of malaria and 1.1 million deaths would be averted over 10 years. This is equivalent to 943 uncomplicate cases and 7 deaths averted per 1,000 vaccinees. In discounted 2011 US dollars, this represents $11 per uncomplicated case averted and$1,482 per death averted. If vaccine efficacy were reduced to 75%, the estimated uncomplicated cases and deaths averted over 10 years would decrease by 14% and 19%, respectively.; The MVM can provide valuable information to assist decision-making by vaccine developers and policymakers, information which will be refined and strengthened as field studies progress allowing further validation of modeling assumptions

Sécurité alimentaire et urbanisation : enjeux pour l'agriculture intra et péri-urbaine

Quelle peut être la contribution de l'agriculture intra et péri-urbaine à la sécurité alimentaire dans un contexte d'urbanisation rapide ? Ce papier vise à répondre à cette question en quatre points: la contribution aux approvisionnements alimentaires; aux emplois et revenus urbains; l'intérêt des produits de cette agriculture dans un contexte de transition nutritionnelle; et le caractère réducteur de l'anxiété qu'assure la proximité de ce système de production et d'échange dans un contexte de distanciation des rapports entre les citadins et leur alimentation. Dans la plupart des pays, l'agriculture urbaine et péri-urbaine contribue à l'approvisionnement des villes en quelques produits frais et très périssables comme certains légumes. Mais les produits de base proviennent de zones rurales plus éloignées connectées aux marchés urbains. Les activités urbaines du secteur primaire et du commerce direct associé fournissent des emplois et des revenus à des migrants récents, sans qualifications particulières autres que celles de l'agriculture. Mais c'est plutôt dans le secteur de la transformation agro-alimentaire artisanale que l'on observe la plus forte dynamique de création d'emplois urbains en particulier pour les femmes avec peu de qualifications formelles. En revanche la fourniture de légumes frais par le maraîchage péri-urbain représente un enjeu important dans le contexte de la transition nutritionnelle qui atteint désormais la plupart des villes des pays du sud. La consommation soutenue de tels produits à faible densité énergétique, riches en fibres et en anti-oxydant présente plusieurs avantages nutritionnels pour prévenir les maladies de pléthore - obésité, diabète type II, maladies cardio et cérébro-vasculaires et certains cancers - qui se développent en ville. Enfin, s'appuyant sur une grille d'analyse de l'acceptabilité des risques, ce papier montre l'intérêt d'une alimentation de proximité pour rassurer des consommateurs inquiets du fait de la distanciation que l'urbanisation opère dans leurs relations à l'agriculture et au delà, à la nature. (Résumé d'auteur

Computing floating-point logarithms with fixed-point operations

International audienceElementary functions from the mathematical library input and output floating-point numbers. However it is possible to implement them purely using integer/fixed-point arithmetic. This option was not attractive between 1985 and 2005, because mainstream processor hardware supported 64-bit floating-point, but only 32-bit integers. Besides, conversions between floating-point and integer were costly. This has changed in recent years, in particular with the generalization of native 64-bit integer support. The purpose of this article is therefore to reevaluate the relevance of computing floating-point functions in fixed-point. For this, several variants of the double-precision logarithm function are implemented and evaluated. Formulating the problem as a fixed-point one is easy after the range has been (classically) reduced. Then, 64-bit integers provide slightly more accuracy than 53-bit mantissa, which helps speed up the evaluation. Finally, multi-word arithmetic, critical for accurate implementations, is much faster in fixed-point, and natively supported by recent compilers. Novel techniques of argument reduction and rounding test are introduced in this context. Thanks to all this, a purely integer implementation of the correctly rounded double-precision logarithm outperforms the previous state of the art, with the worst-case execution time reduced by a factor 5. This work also introduces variants of the logarithm that input a floating-point number and output the result in fixed-point. These are shown to be both more accurate and more efficient than the traditional floating-point functions for some applications