Dissertations / Theses on the topic 'Epidemiological modelling'

This thesis covers the formulation and analysis of a number of deterministic, continuous models of infection by a disease such as bovine tuberculosis in one species (essentially badgers) and in two mutually infective species (badgers and cattle). We examine the dynamics of the disease in each model and then consider the effects of the application of different badger culling strategies which have the objective of eliminating the disease in cattle.

Thesis (S.M.)--Massachusetts Institute of Technology, Computation for Design and Optimization Program, 2009.
Cataloged from PDF version of thesis.
Includes bibliographical references (p. 69-70).
The purpose of this project is to incorporate a Poisson disease model into the Spatiotemporal Epidemiological Modeler (STEM) and visualize the disease spread on Google Earth. It is done through developing a Poisson disease model plug-in using the Eclipse Modeling Framework (EMF), a modeling framework and code generation facility for building tools and other applications based on a structured data model. The project consists of two stages. First, it develops a disease model plug-in of a Poisson disease model of a homogenous population, which is built as an extension of the implemented SI disease model in the STEM. Next, it proposes an algorithm to port a Poisson disease model of a heterogeneous population into the STEM. The development of the two new diseases plugins explores the maximum compatibility of the STEM and sets model for potential users to flexibly construct their own disease model for simulation.
by Hui Zhang.
S.M.

In this thesis, we consider the problem of long-term persistence in ecological and epidemiological systems. This is important in conservation biology for protecting species at risk of extinction and in epidemiology for reducing disease prevalence and working towards elimination. Understanding how to predict and control persistence is critical for these aims. In Chapter 2, we discuss existing ways of characterising persistence and their relationship with the modelling paradigms employed in ecology and epidemiology. We note that data are often limited to information on the state of particular patches or populations and are modelled using a metapopulation approach. In Chapter 3, we define persistence in relation to a pre-specified time horizon in stochastic single-species and two-species competition models, comparing results between discrete and continuous time simulations. We find that discrete and continuous time simulations can result in different persistence predictions, especially in the case of inter-specific competition. The study also serves to illustrate the shortcomings of defining persistence in relation to a specific time horizon. A more mathematically rigorous interpretation of persistence in stochastic models can be found by considering the quasi-stationary distribution (QSD) and the associated measure of mean time to extinction from quasi-stationarity. In Chapter 4, we investigate the contribution of individual patches to extinction times and metapopulation size, and provide predictors of patch value that can be calculated easily from readily available data. In Chapter 5, we focus directly on the QSD of heterogeneous systems. Through simulation, we investigate possible compressions of the QSD that could be used when standard numerical approaches fail due to high system dimensionality, and provide guidance on appropriate compression choices for different purposes. In Chapter 6, we consider deterministic models and investigate the effect of introducing additional patch states on the persistence threshold. We suggest a possible model that might be appropriate for making predictions that extend to stochastic systems. By considering a family of models as limiting cases of a more general model, we demonstrate a novel approach for deriving quantities of interest for linked models that should help guide modelling decisions. Finally, in Chapter 7, we draw out implications for conservation biology and disease control, as well as for future work on biological persistence.

This study reviews available methods of exposure assessment, examines the effects of exposure misclassification on the ability to identify an association, and focuses on recent progress in subjective exposure modelling. Subjective exposure modelling utilises a framework of parameters identified as likely to control personal exposure levels together with detailed guidance and expert judgement in order to estimate exposure concentrations. As part of a case-control study, the Neurotoxicity of Paint Solvents (NPS) study, the process of evaluating subjects' lifetime exposure to solvents was reviewed. A training program and detailed guidance material was produced and the ability of assessors to reconstruct inhalation exposures from textual data was tested. In the training study, assessors were shown to estimate exposures that were well correlated with measured levels (correlation coefficients for log estimate compared to log measured values ranging from 0.73 to 0.85). The assessors tended to overestimate levels with the estimates ranging from 1.6 to 3.5 times the measured results. A series of painting simulation exercises was carried out to validate the use of certain guidance values for the model parameters. Using different paint application methods and different paint types, the influence of these variables on exposure levels was assessed. The results agreed closely with the guidance produced for the inhalation exposure model. Analysis of the solvent exposure histories of the NPS study group suggested that dermal exposure and uptake of solvents was important. To this end a novel dermal exposure model was developed for spray painting tasks. Using a conceptual model of the process, a method to describe both the likely dermal solvent exposure and solvent uptake through the skin was created. Mechanisms for combining exposures from the dermal and inhalation exposure pathways are described. Using occupational history information together with workplace monitoring records and data from paint manufacturers, both inhalation and dermal exposure to solvents was estimated for the one-hundred and twenty NPS study subjects. Two solvent exposure metrics were calculated. Cumulative exposure was the product of exposure level and time, while average annual intensity was the cumulative exposure figure divided by the number of years in solvent using employment.

A mathematical approach was used to model seasonal variation of cyathostomin faecal egg output, and in simulating anthelmintic control strategy. The model is based on parameters of biological development of cyathostomins and climatic data. A good fit of the model prediction to the field data was obtained after some parameter adjustments. The development rate of ingested larvae to egg laying adults, survival time of adults and the assumption made in modelling the peak pasture larval availability were the main driving forces for the model prediction to fit to the observed data. The apparent fit of the model prediction to the field data obtained after parameter adjustment generally indicated some major differences between donkeys and horse in their reaction to the parasite and/or between cyathostomins of donkeys and horses. The results of the stimulation of the effect of various protocols for the timing and frequency of anthelmintic treatment on the adult cyathostomin worm burden have shown that treating donkeys only once in a year or a combination of once in a year followed by every two or even four years can substantially reduces and maintains the parasite burden far below the pre-treatment level for many years. Generally the study made has revealed that the non-strongyle gastrointestinal parasites of donkeys are highly prevalent and have a high pathogenic potential, and the findings of cestodes and trematodes are not accidental or unusual, as previously suggested.

Background: With an estimated 10.4 million incident tuberculosis (TB) cases in 2015, and the current trajectory of 1.5%/year incidence rate decline, new TB vaccines are urgently needed to help meet the WHO goal of tuberculosis elimination by 2050. However, insufficient epidemiological evidence exists to inform TB vaccine development strategies and to assist clinical trial site selection and design. Research to meet these data needs is critical to accelerate TB vaccine development. To maximise the future impact of new TB vaccines, estimates of the population-level impact of vaccine characteristics and implementation strategies are needed to inform design of TB vaccine target product profiles. To accelerate and de-risk clinical trials, appropriate epidemiological data are required to inform trial site selection, sample size calculations and recruitment strategy. However, data availability at trial sites is limited, and prospective studies are resource-intensive, so new methods are needed to collect appropriate data to inform TB vaccine trial design. To inform data-driven development strategies for new TB vaccines, the aims of this thesis were to 1) estimate the epidemiological impact of new TB vaccine characteristics and implementation in China to inform design of target product profiles; and 2) to develop a novel epidemiological spatial mapping tool capable of informing clinical trial design for new TB vaccines in low-income, high-burden settings. Methods: A deterministic, age-structured, Mycobacterium tuberculosis transmission model was developed and calibrated to age-stratified epidemiological and demographic data from China. This was employed to estimate the population-level epidemiological impact of new TB vaccines over the 2025-2050 time horizon, through an exploration of potential vaccine characteristics and implementation strategies. A new methodology for empirical data collection to determine spatial distribution of TB notifications was developed. The electronic PArticipant Locator application (ePAL app) combined 3,243 community-identified points of interest with high resolution satellite maps, within an electronic tablet-based case report form. The app was integrated in to the National Tuberculosis Programme in Blantyre, Malawi, for collection of demographics, health status and coordinates of place of residence for patients ≥18 years initiating TB treatment. Accuracy of ePAL-recorded co-ordinates was evaluated against GPS coordinates obtained at the participant’s place of residence. Results: Mathematical modelling predicted a shift towards a reactivation-driven, ageing TB epidemic in China by 2050. Vaccines protective against disease, effective post-infection and providing at least 5 years protection were essential for achieving higher levels of impact. Vaccination of older adults provided greater population-level impact than vaccinating adolescents for all equivalent vaccines explored, even if much lower coverage were achieved in older adult vaccination. Recommendations for post-infection vaccines were robust to substantial reductions in efficacy and duration of protection in older adults, whereas for pre-infection vaccines in some of these scenarios adolescent vaccination may be equivalent or preferred. Vaccinating older adults with post-infection vaccines provided substantially higher impact than pre-infection vaccines. 1,899 TB patients were registered using ePAL in the 12-month study period, with high patient acceptance (98.7%, 1,899/1,924). ePAL achieved clinic-based collection of patient location of residence accurate to a median of 84 metres (IQR: 35-317 metres) in a high population density urban setting without a municipal address system. Advantages of the ePAL system included real-time availability of high-resolution spatial data, low set up costs, and ease of use by health staff as part of routine TB registration. Data were used to identify areas with high TB burden, potentially suitable for TB vaccine trials. Conclusions: The research presented in this thesis informs the development of appropriate TB vaccines and target populations to maximise future population-level impact. A prevention of disease vaccine efficacious post-infection and delivered to older adults would contribute towards maximising population-level impact in China. Adolescent-targeted tuberculosis vaccines are likely to have low impact in ageing, reactivation-driven epidemics like China, which suggests a modification of the current strategic focus on adolescents among certain funders. Clinical trials should assess disease endpoints, include M.tb-infected and older adult populations, and extend beyond the usual 2-3 years follow up. To support design of disease endpoint trials, ePAL may provide an accurate, easily implementable, low-cost tool for identification of areas of high TB burden in settings without addresses.

In patologia vegetale, un modello epidemiologico è una rappresentazione semplificata delle relazioni tra patogeno, ospite e ambiente che determinano se, quando e come un’epidemia si sviluppa nel tempo. La presente tesi raccoglie lo sviluppo di modelli meccanicistici, dinamici, guidati da variabili ambientali (weather-driven), che possono essere utilizzati per la difesa di precisione dalle principali malattie di frumento e leguminose in rotazione colture. Tramite l’applicazione dell’analisi dei sistemi alle informazioni contenute nella letteratura scientifica, ogni patosistema è stato analizzato e concettualizzato per lo sviluppo teoretico e matematico del modello. I seguenti patogeni sono stati considerati per lo sviluppo dei modelli: i) Ascochyta rabiei agente causale della rabbia (Ascochyta blight) del cece; ii) Puccinia graminis f.sp. tritici agente causale della ruggine nera del grano; iii) Sclerotinia sclerotiorum, una specie polifaga e agente causale di diverse malattie di leguminose e colture industriali (es. marciume bianco di fagiolo e soia, muffa bianca del colza, sclerotiniosi del girasole). La capacità previsionale dei modelli è stata valutata utilizzando dati reali indipendenti raccolti in diversi condizioni ambientali ed epidemiologiche. Dal confronto tra le predizioni e i dati reali di campo, i modelli si sono rivelati accurati e robusti e, quindi, utilizzabili dagli agricoltori nei processi decisionali per la protezione delle colture. La presente tesi contiene anche i risultati di una revisione della letteratura sulle esigenze termiche del genere Colletotrichum, contenente numerosi agenti causali dell’antracnosi di leguminose e diverse colture industriali. L’effetto della temperatura su quattro processi biologici (crescita miceliale, germinazione delle spore, infezione e sporulazione) è stato modellizzato per i maggiori gruppi filogenetici di Colletotrichum spp.. Questo lavoro getta le basi per lo sviluppo di un modello meccanicistico, dinamico, weather-driven generalizzato per Colletotrichum spp. sulla base delle similarità entro i gruppi filogenetici.
A plant disease model is a simplification of the relationships between pathogen, host, and environment that determine whether and how an epidemic develops over time. The present dissertation aims to develop mechanistic, dynamic, weather-driven models, which are suitable to be applied in precision crop protection, for important diseases affecting wheat and legumes in a crop rotation scenario. By exploitation of literature and application of system analysis, information concerning the pathosystem were acquired and analyzed to conceptualize and develop the model both theoretically and mathematically. The following pathogens were considered: i) Ascochyta rabiei causing Ascochyta blight in chickpea; ii) Puccinia graminis f.sp. tritici causing stem (or black) rust of wheat; iii) Sclerotinia sclerotiorum, a polyphagous specie causing diseases in several legumes and industrial crops (e.g., white mold of white bean and soybean, stem rot of canola, head rot of sunflower). Models were evaluated using independent data for their ability to predict the occurrence and development of epidemics, under different environmental conditions. The comparison of model predictions versus real data observed in fields showed that models could be considered accurate and robust and, therefore, they may be used to help growers in making decisions to efficiently protect their crops. The present dissertation contains also results of a literature review carried out on temperature requirements of Colletotrichum spp., which involves several species causing anthracnose on legumes and several industrial crops. Temperature-dependent equations were developed for four biological processes (mycelial growth, germination of spores, spore infection, and spore production) of major phylogenetic clades of Colletotrichum spp.. This work may lay the foundation for the development of a general, mechanistic, dynamic, weather-driven model for Colletotrichum spp. based on the intra-clade similarities.

Tuberculosis (TB) is an infectious disease that is considered to be the biggest killer of mankind in the history of infectious diseases. There are still more than 10 million new TB cases every year and it causes more than 1.5 million deaths annually, according to World Health Organization estimates. Nigeria, with a persistent incidence of about 219 cases per 100000 inhabitants on 2019, is among the 8 countries that accounted for two-thirds of the new TB cases in 2018. The control of the disease in this country is coordinated by the National Tuberculosis and Leprosy Control Program (NTBLCP). Despite efforts, current estimated prevalence is still similar to that of 1990. Epidemiological models can be used for a more precise diagnosis of TB situation in certain territories, as well as to help on the design and evaluation of control actions. In this project, two modelling approaches have been used to these ends. First, a top-down approach at the country level (Nigeria) by means of the design, testing and fitting of several SEIR-type models, aimed to provide a global picture of the situation and to quantify some of the most relevant parameters. Second, a bottom-up approach to a smaller area (Gombe state) by means of the design, testing and fitting of an agent-based model (ABM), aimed to unravel a particular context and to help on the design and quantification of control actions. In addition, fieldwork was also carried out in order to look for the particular socio-economic factors that are responsible for the epidemiological situation of TB spread; the statistical analysis of the data obtained is the third approach of this project. SEIR-type approach confirmed a dramatic low notification rate that varies from 16 to 20% during the analysed years (2000-2010). This factor revealed to be the bottleneck for the control of the disease in this country. Model’s predictions showed no relevant effects of control actions without a previous increase in the notification rate. Fieldwork was designed in coordination with NTBLCP local authorities with the aim of analysing socio-economic factors that condition such notification rate in Gombe state. It consisted of an initial gathering of epidemiological data, followed by a set of 52 in-depth interviews with TB patients from different health centres. Obtained data and interviews’ outcomes were statistically analysed using inferential statistics and Anova analysis of mean, with the help of machine learning techniques. Results were devastating: none of the patients interviewed had any knowledge of TB symptoms and 90% had no knowledge of TB transmission mechanisms after talking to the health workers. Mean patients’ delay before going to hospital was 9.6 weeks, and only 10% of interviewed patients went to the doctor within the first month of feeling sick. The epidemiological information obtained from the top-down approach and the results derived from the fieldwork were used for adapting an agent-based model (ABM) of TB spreading in the context of Gombe state. The resulting ABM was successfully fitted to the evolution of estimated prevalence and diagnosed cases from 2007 to 2016. Then, it was used to test different interventions aimed to increase the notification rate, decrease the diagnosis delay, and increase the population’s awareness regarding TB transmissible. The multi-approach methodology used in this project revealed to be a robust way of tackling a real problem. It was capable of providing a global and detailed picture of TB situation in a certain area, relating model’s parameters and outcomes with a real socioeconomic context, and generating a useful tool for helping on the design and evaluation of TB control actions.
La tuberculosi (TB) és la malaltia infecciosa que ha causat més morts a la història de la humanitat. Actualment, hi ha més de 10 milions de nous casos de TB cada any i provoca més d’1.5 milions de morts anuals, segons estimacions de l’Organització Mundial de la Salut. Nigèria, amb una incidència persistent d’uns 219 casos per 100.000 habitants l’any 2019, es troba entre els 8 països que van representar dos terços dels nous casos de tuberculosi el 2018. El control de la malaltia d’aquest país està coordinat pel Programa Nacional de Control de la Tuberculosi i la Lepra (NTBLCP). Malgrat els esforços, la prevalença estimada és la mateixa que s’estimava l’any 1990. Es poden utilitzar models per a un diagnòstic més precís de la situació de TB en determinats territoris, així com per ajudar en el disseny i avaluació de les accions de control. En aquest projecte, s’han utilitzat dues estratègies de modelització per fer-ho. En primer lloc, una estratègia top-down a nivell de país (Nigèria) mitjançant el disseny, proves i adequació de diversos models de tipus SEIR, amb l’objectiu de proporcionar una imatge global de la situació i quantificar alguns dels paràmetres més rellevants. En segon lloc, una estratègia bottom-up estudiant una àrea més petita, l’estat de Gombe, mitjançant el disseny, la prova i l’adequació d’un model basat en agents (ABM). El model ABM té per finalitat entendre en detall la situat particular de l’estat de Gombe i ajudar en el disseny i quantificació de possibles accions de control. També es va realitzar un treball de camp per buscar els factors socioeconòmics particulars responsables de la situació epidemiològica de la TB; l’anàlisi estadística de les dades obtingudes és la tercera estratègia de treball d’aquets projecte. L’aproximació mitjançant models top-down va confirmar una taxa de notificació molt baixa que varia del 16 al 20% durant els anys analitzats (2000-2010). Aquest factor es va revelar com el coll d’ampolla per al control de la malaltia en aquest país. Les prediccions del model no mostraven efectes rellevants de les accions de control sense un augment previ de la taxa de notificació. El treball de camp es va dissenyar en coordinació amb les autoritats locals NTBLCP amb l’objectiu d’analitzar els factors socioeconòmics que condicionen aquesta taxa de notificació a l’estat de Gombe. Va consistir en una recollida inicial de dades epidemiològiques, seguida d’un conjunt de 52 entrevistes amb pacients amb TB de diferents centres de salut. Les dades obtingudes i els resultats de les entrevistes es van analitzar mitjançant estadístiques inferencials i Anova, amb l’ajut de tècniques de Machine learning. Els resultats van ser devastadors: cap dels pacients entrevistats no coneixia els símptomes de la TB i el 90% no coneixia els mecanismes de transmissió de la TB després de parlar amb el personal sanitari. El retard mitjà de diagnòstic dels pacients va ser de 9.6 setmanes, i només el 10% dels entrevistats van acudir al metge durant el primer mes de sentir-se malalt. La informació obtinguda amb l’estratègia top-down i els resultats derivats del treball de camp es van utilitzar per adaptar el model ABM en el context de l’estat de Gombe. Es va ajustar amb èxit a l’evolució de la prevalença estimada i els casos diagnosticats del 2007 al 2016. A continuació, es va utilitzar per provar diferents intervencions destinades a augmentar la taxa de notificació, disminuir el retard de diagnòstic i augmentar la consciència de la població respecte a la TB transmissible. La metodologia utilitzant diferents estratègies utilitzada en aquest projecte s’ha mostrat com una forma robusta d’afrontar el problema real. Ha fet possible proporcionar una imatge global i detallada de la situació de la TB en un determinat àmbit, relacionar els paràmetres i els resultats del model amb un context socioeconòmic real i generar una eina útil per ajudar en el disseny i l’avaluació d’accions de control de la tuberculosi.
La tuberculosis (TB) es la enfermedad infecciosa que más muertes ha causado en la historia de las enfermedades infecciosas, conociéndose como the big killer. Es responsable de más de mil millones de muertes en los últimos 200 años. Hoy en día, todavía hay más de 10 millones de casos nuevos de TB cada año y causa más de 1.5 millones de muertes anuales, según las estimaciones de la Organización Mundial de la Salud (OMS). Nigeria, con una incidencia persistente de aproximadamente 219 casos / 105 habitantes para el año 2019, se encuentra entre los 8 países que representaron conjuntamente dos tercios de los nuevos casos de tuberculosis en 2018. El control de la enfermedad en este país está coordinado por el Programa Nacional de Control de Tuberculosis y Lepra (NTBLCP). A pesar de los esfuerzos, que se centran principalmente en la provisión de DOTS gratuitos (tratamiento observado directamente, curso corto) a personas con TB activa que acuden al hospital, la prevalencia estimada es de alrededor de 330 / 105 habitantes, que es aproximadamente igual a la prevalencia estimada de TB en 1990 (323 / 100,000). Los modelos epidemiológicos se pueden utilizar para un diagnóstico más preciso de la situación de TB en ciertos territorios, así como para ayudar en el diseño y evaluación de acciones de control. En este proyecto, se han utilizado dos enfoques de modelización para estos fines. Primero, un enfoque de arriba hacia abajo (top-down) a nivel de país (Nigeria) mediante el diseño, prueba y ajuste de varios modelos tipo SEIR, con el objectivo de proporcionar una imagen global de la situación y cuantificar algunos de los parámetros más relevantes. En segundo lugar, un enfoque de abajo a arriba (bottom-up) en una área más pequeña (estado de Gombe, en el noreste del país) mediante el diseño, prueba y ajuste de un modelo basado en agentes, con el objetivo de desentrañar un contexto particular y ayudar en el diseño y cuantificación de las acciones de control. Además, también se realizó un Trabajo de campo para investigar los factores socioeconómicos particulares que son responsables de la situación epidemiológica de la propagación de la tuberculosis. El análisis estadístico de los datos obtenidos es el tercer enfoque de este proyecto. Se construyeron varios modelos de tipo SEIR en un intento de caracterizar y comprender progresivamente la dinámica de la TB en diferentes contextos. Estos modelos se ajustaron a algunos países seleccionados de alta carga y baja carga en todo el mundo, y en particular a la situación epidemiológica en Nigeria. La división de la población infecciosa (enferma) en dos subpoblaciones, la de personas que se diagnostican (y se tratan) y la de las que no, confirman una tasa de notificación baja dramática que varía entre el 16 y el 20 % durante los años analizados (2000-2010). Este factor reveló ser el cuello de botella para el control de la enfermedad en este país. Las predicciones del modelo no mostraron efectos relevantes de las acciones de control sin un aumento previo en la tasa de notificación. El trabajo de campo se diseñó en coordinación con las autoridades locales de NTBLCP con el objetivo de analizar los factores socioeconómicos que condicionan dicha tasa de notificación en el estado de Gombe. Consistió en una recopilación inicial de datos de la sucursal del estado de NTBLCP Gombe, la Junta de Administración de Hospitales del Estado de Gombe y varios hospitales en el estado de Gombe, seguida de un conjunto de 52 entrevistas en profundidad con pacientes con tuberculosis de diferentes centros de salud. Los datos obtenidos y los resultados de las entrevistas se analizaron estadísticamente utilizando estadísticas inferenciales y análisis de medias de Anova, con la ayuda de técnicas de aprendizaje automático. Los resultados fueron devastadores: ninguno de los pacientes entrevistados conocía los síntomas de la tuberculosis y el 90 % no conocía los mecanismos de transmisión de la tuberculosis después de hablar con el personal sanitario. El retraso medio de los pacientes en acudir al centro médico fue de 9.6 semanas con una desviación estándar de 4.8; solo el 10 % de los pacientes entrevistados acudió al médico dentro del primer mes de sentirse enfermo, el 30 % dentro de 1-2 meses, el 20 % dentro de 2-3 meses y el 40 % después de sentirse enfermo durante más de 3 meses. La información epidemiológica obtenida del enfoque bottom-up y los resultados derivados del trabajo de campo se utilizaron para adaptar un modelo basado en agentes (ABM) de propagación de TB en el contexto del estado de Gombe. El ABM resultante se ajustó con éxito a la evolución de la prevalencia estimada y los casos diagnosticados de 2007 a 2016. Luego, se usó para probar diferentes intervenciones destinadas a aumentar la tasa de notificación, disminuir el retraso del diagnóstico y aumentar la conciencia de la población sobre la TB transmisible. La metodología de enfoque múltiple utilizada en este proyecto reveló ser una forma sólida de abordar un problema real. Fue capaz de proporcionar una imagen global y detallada de la situación de la TB en un área determinada, relacionar los parámetros y resultados del modelo con un contexto socioeconómico real, y generar una herramienta útil para ayudar en el diseño y la evaluación de acciones de control de TB.

Background: The Kingdom of Saudi Arabia faces one of the highest prevalence rates of type 2 diabetes mellitus (T2DM) in the world. However, there are no credible local data on the trends and future projections of the disease, and the relevant international studies underestimated the true prevalence rates. This thesis used epidemiological modelling to study the trends in T2DM prevalence in Saudi Arabia, predicted its future levels, and quantified the impact of reducing some risk factors on the disease prevalence trends. Methods: This thesis developed and validated the “Saudi IMPACT Diabetes Forecast Model”, which integrates data on the population, obesity and smoking prevalence trends in Saudis aged ≥25 years to estimate the trends in T2DM prevalence (1992-2022) using a Markov modelling approach. The model considers different reasonable scenarios of future trends in obesity prevalence, and incorporates a number of parameters to model the disease epidemiology. These parameters include the estimated diabetes incidence, case-fatality, total mortality, relative risk of diabetes if obese, and relative risk of diabetes if a smoker. The model data inputs and parameters were obtained from different sources, including local departments, medical literature and assumptions. The model results were validated against local data from the STEPwise survey in 2005, and against the model of the Global Burden of Disease study, where the model produced reasonably close results to both of these studies. Results: The prevalence of T2DM among the Saudi population aged ≥25 years was estimated to rise substantially during the 30-year period of 1992-2022 from 8.5% to 39.5%, assuming some levelling off of obesity trends (capping), or to 44.1%, assuming uncapped increasing obesity trends. In men, T2DM prevalence was estimated to increase from 8.7% to 39.2% with capped obesity trends, or to 41.3% with continuing linear increase in obesity trends. In women, T2DM prevalence was estimated to increase from 8.2% to 39.8% with capping of obesity trends, or to 47.7% without such a capping. The model showed that if the trends in obesity start to decline by 10% in 12 years (2010-2022), a relative reduction of 13% in diabetes prevalence could be achieved. If the prevalence of obesity was halted at the 2010 levels, a 10% relative reduction in diabetes prevalence could be attained by 2022. ii Conclusion: T2DM is currently a major public health challenge in Saudi Arabia, and this thesis predicted that its burden will increase substantially in the next decade. Intensive and aggressive preventive measures directed to reduce the levels of risk factors, particularly obesity and smoking, can result in reasonable reduction of the disease prevalence, and therefore should be an urgent action.

Tackling antimicrobial resistance (AMR) is a national and global priority. Despite this, much of our understanding of the epidemiology and transmission of AMR outside the hospital, and thus, how we might control it, remains limited. Long term care facilities (LTCFs) play an important role in the care of older people. However, there have been few studies of the epidemiology and transmission of AMR in this setting. LTCF residents present with frequent co-morbidities which increase their risk of hospitalisation and of AMR infection. LTCFs also offer opportunities for transmission of AMR strains due to the long lengths of stay of residents and the lack of strictly applied infection control measures. This thesis focuses on urinary tract infections (UTIs), one of the most common bacterial infections in LTCFs, hospitals and the community. I first present a systematic review of mathematical models of infectious disease transmission set in LTCFs and a critical review of mathematical models evaluating interventions against AMR bacteria in LTCFs. A checklist for good quality models in this area is proposed. Next, using data from routinely collected microbiology samples, the frequency of AMR in urinary tract E. coli and Klebsiella was compared in LTCF residents with that in older people living in their own homes. Residents of LTCFs had more than four times the rate of E. coli and Klebsiella UTI caused by antibiotic-resistant bacteria compared with those living in the community. The seasonality of UTI consultations was also assessed. A September to November peak in UTI consultation incidence was observed for ages 14-69. This seasonality progressively faded in older age groups and no seasonality was found in individuals aged 85 and over. Finally, a stochastic compartmental mathematical model was developed to explore the transmission of trimethoprim-resistant E. coli in LTCFs. Different treatment, importation and transmission scenarios were addressed.

La presente tesi intende esplorare gli effetti della resistenza parziale sulle epidemie di peronospora della vite (Plasmopara viticola). È stato sviluppato un modello di simulazione teorico che comprende lo sviluppo della pianta ospite e le fasi principali della malattia, dalla mobilizzazione dell’inoculo, alla moltiplicazione della malattia sulle foglie, all’infezione dei grappoli. Attraverso esperimenti (monociclici) di inoculazione è stata studiata la risposta alle infezioni di P. Viticola di 16 varietà parzialmente resistenti, analizzando le seguenti componenti: frequenza d’infezione, durata del periodo di latenza, dimensione delle lesioni, produzione di sporangi, durata del periodo infezioso e infettività degli sporangi prodotti sulle lesioni. Queste componenti di resistenza sono state incorporate nel modello, attraverso cui sono stati studiati i loro effetti sull’epidemia (policiclica) in diversi scenari. Le componenti di resistenza hanno mostrato diversi livelli di efficacia nel sopprimere l’epidemia: l’efficienza di infezione e la produzione di sporangi risultano avere un maggiore impatto nella resistenza espressa a livello di pieno campo. Questo approccio è utile per guidare lo studio fenotipico della resistenza dell’ospite e per anticipare le prestazioni di un genotipo a livello di pieno campo, che risulterebbe difficile e dispendioso considerando la natura perenne della vite.
The present dissertation aims to explore the effects of partial resistance on grapevine downy mildew (Plasmopara viticola) epidemics. A theoretical simulation model was developed including host dynamics and main phases of the disease, from inoculum mobilisation to disease multiplication on foliage, and to infection of clusters. The response to P. Viticola infection was studied for 16 grapevine varieties through (monocyclic) inoculation experiments, by measuring components of partial resistance: infection frequency, duration of latent period, size of lesions, production of sporangia, duration of infectious period, and infectivity of sporangia produced on lesion. Components of partial resistance were incorporated into the model and their effects on the (polycyclic) epidemic were investigated accross different scenarios. Components of partial resistance showed different effectiveness on the suppression of epidemics, infection efficiency and spore production having the strongest impact on the overall field resistance response. This approach is an useful tool for phenotyping studies on host plant resistance and for anticipating the performance of a genotype at the field scale, that otherwise is difficult and time requiring due to the perennial nature of grapevine.

La presente tesi intende esplorare gli effetti della resistenza parziale sulle epidemie di peronospora della vite (Plasmopara viticola). È stato sviluppato un modello di simulazione teorico che comprende lo sviluppo della pianta ospite e le fasi principali della malattia, dalla mobilizzazione dell’inoculo, alla moltiplicazione della malattia sulle foglie, all’infezione dei grappoli. Attraverso esperimenti (monociclici) di inoculazione è stata studiata la risposta alle infezioni di P. Viticola di 16 varietà parzialmente resistenti, analizzando le seguenti componenti: frequenza d’infezione, durata del periodo di latenza, dimensione delle lesioni, produzione di sporangi, durata del periodo infezioso e infettività degli sporangi prodotti sulle lesioni. Queste componenti di resistenza sono state incorporate nel modello, attraverso cui sono stati studiati i loro effetti sull’epidemia (policiclica) in diversi scenari. Le componenti di resistenza hanno mostrato diversi livelli di efficacia nel sopprimere l’epidemia: l’efficienza di infezione e la produzione di sporangi risultano avere un maggiore impatto nella resistenza espressa a livello di pieno campo. Questo approccio è utile per guidare lo studio fenotipico della resistenza dell’ospite e per anticipare le prestazioni di un genotipo a livello di pieno campo, che risulterebbe difficile e dispendioso considerando la natura perenne della vite.
The present dissertation aims to explore the effects of partial resistance on grapevine downy mildew (Plasmopara viticola) epidemics. A theoretical simulation model was developed including host dynamics and main phases of the disease, from inoculum mobilisation to disease multiplication on foliage, and to infection of clusters. The response to P. Viticola infection was studied for 16 grapevine varieties through (monocyclic) inoculation experiments, by measuring components of partial resistance: infection frequency, duration of latent period, size of lesions, production of sporangia, duration of infectious period, and infectivity of sporangia produced on lesion. Components of partial resistance were incorporated into the model and their effects on the (polycyclic) epidemic were investigated accross different scenarios. Components of partial resistance showed different effectiveness on the suppression of epidemics, infection efficiency and spore production having the strongest impact on the overall field resistance response. This approach is an useful tool for phenotyping studies on host plant resistance and for anticipating the performance of a genotype at the field scale, that otherwise is difficult and time requiring due to the perennial nature of grapevine.

Since the introduction in 1996 of highly active antiretroviral therapy (HAART) for treating individuals infected with HIV, morbidity and mortality among individuals who access care in a timely fashion have dramatically decreased. As a result, patterns of health services utilization have shifted from hospitalizations and acute care services to outpatient services and medications. An additional implication of increased HAART coverage has been a reduction in HIV-1 viral load amongst treated individuals. Individuals with lower viral load are less likely to transmit HIV infection to uninfected individuals. A resulting hypothesis is that increasing treatment with HAART—either by treating individuals earlier in their infection or by expanding treatment coverage rate to a greater proportion of infected individuals—could potentially lead to reduced rates of HIV transmission. To date, the results of ecological studies and mathematical modelling studies have been consistent with this hypothesis. The objectives in this dissertation were: to build a computational tool that could be used to answer complex questions regarding the economics of HIV during the HAART era in British Columbia (BC), Canada; and to address specific economic questions relevant to the current treatment of HIV in BC. The particular questions of interest included: the monthly costs associated with various categories of health services utilization and the correlation between categories (Chapter 3); the expected long-term incidence and costs associated with hospitalizations after initiation of HAART (Chapter 4); the lifetime direct medical costs associated with an individual infected with HIV during the HAART era (Chapter 5); and the cost-effectiveness of a strategy to increase HAART coverage from 50% to 75% of clinically eligible individuals, accounting for individual-level and population-level effects of HAART (Chapter 6). These questions were addressed using a variety of statistical and mathematical techniques, based on a BC-specific population-based data source. A key finding with important public health relevance was that use of HAART was associated with decreases in other categories of direct medical costs. These cost offsets were due to both an improvement in morbidity resulting in a reduced need for acute health care services and, more importantly, a reduction in HIV incidence.

Bovine tuberculosis is a chronic disease common to a wide range of mammalian specie~ caused by infection with the bacteria Mycobacterium bovis. Eurasian Badgers Meles meles are implicated in the spread of bovine tuberculosis to domestic cattle in the United Kingdom. A long-term study into the epidemiology of bovine tuberculosis in a wild badger population at Woodchester Park in Gloucestershire, England, has been ongoing since 1975. This has given rise to a dataset of more than 15000 observations to date consisting of various de: mographic and biological data on resident badgers in addition to results from tests used to diagnose infection with Mycobacterium bovis. Work presented in this thesis builds on earlier analyses of these data through the inclusion of more recent records and through the application of novel statistical approaches designed to deal with a number of complexities. The present analyses encompass (i) an updated model for population size estimation (ii) a method for estimating bovine tuberculosis prevalence that accounts for uncertainty in results from the diagnostic tests and (iii) a model for spatiotemporal covariance in group-level disease incidence. Finally, elements of the above are synthesised in a single epidemiological model relating the risk of infection to a range of covariates. In this integrated model, efficient use is made of all clinical data in individual badger's life histories. For this and the afore-mentioned analyses, Bayesian methods using Monte Carlo Markov Chain simulation are adopted. Results are compared from this fully developed model and comparable analyses using frequentist methods.

"This report is submitted in partial requirement for the award of the Master of Public Health at the University of Queensland" Thesis (M.P.H.) - University of Queensland, 2004.
Includes bibliography.

This thesis evaluates the cost-effectiveness of eight policies expanding human immunodeficiency virus (HIV) testing in South Africa. All policies entail provider-initiated test offers for primary healthcare users and one of two options across three policy components: (i) consent method, opt-in or opt-out; (ii) test protocol, rapid only or rapid plus acute infection testing; and (iii) linkage-to-care, standard or enhanced. This thesis highlights four methodological issues. First is the challenge of conducting a population-level analysis, projecting the cost-effectiveness of expanded testing for each member of South Africa’s adult African population. To this end, I conducted a retrospective, descriptive study to measure current population-level testing rates and epidemic descriptors in an African community near Cape Town, South Africa. Second, the effects of testing expansion on current testing uptake were estimated by distinguishing testing in the study community likely to cease after testing expansion (baseline testing) from that likely to continue (background testing). Third, because testing alone is an outcome of less interest than health benefits following treatment, study community linkage-to-care probabilities were estimated and models utilized to estimate the efficacy of treatment. Fourth, the methods to convert the study community testing data into inputs for these models’ parameters are outlined. The enhanced linkage-to-care policies proved the most cost-effective, with opt-in testing and a rapid-only test protocol the least expensive cost-effective option at $848 per life year gained (LYG). Adding an opt-out consent method or acute infection test protocol to this policy increased the LYGs, but at higher cost-effectiveness ratios.

[ES] La cuantificación de la incertidumbre está compuesta por una serie de métodos y técnicas computacionales cuyo objetivo principal es describir la aleatoriedad presente en problemas de diversa índole. Estos métodos son de utilidad en la modelización de procesos biológicos, físicos, naturales o sociales, ya que en ellos aparecen ciertos aspectos que no pueden ser determinados de manera exacta. Por ejemplo, la tasa de contagio de una enfermedad epidemiológica o el factor de crecimiento de un volumen tumoral dependen de factores genéticos, ambientales o conductuales. Estos no siempre pueden definirse en su totalidad y por tanto conllevan una aleatoriedad intrínseca que afecta en el desarrollo final. El objetivo principal de esta tesis es extender técnicas para cuantificar la incertidumbre en dos áreas de las matemáticas: el cálculo de ecuaciones diferenciales fraccionarias y la modelización matemática. Las derivadas de orden fraccionario permiten modelizar comportamientos que las derivadas clásicas no pueden, como por ejemplo los efectos de memoria o la viscoelasticidad en algunos materiales. En esta tesis, desde un punto de vista teórico, se extenderá el cálculo fraccionario a un ambiente de incertidumbre, concretamente en el sentido de la media cuadrática. Se presentarán problemas de valores iniciales fraccionarios aleatorios. El cálculo de la solución, la obtención de las aproximaciones de la media y varianza de la solución y la aproximación de la primera función de densidad de probabilidad de la solución son conceptos que se abordarán en los próximos capítulos. Sin embargo, no siempre es sencillo obtener la solución exacta de un problema de valores iniciales fraccionario aleatorio. Por ello en esta tesis también se dedicará un capítulo para describir un procedimiento numérico que aproxime su solución. Por otro lado, desde un punto de vista más aplicado, se desarrollan técnicas computacionales para cuantificar la incertidumbre en modelos matemáticos. Combinando estas técnicas junto con modelos matemáticos apropiados, se estudiarán problemas de dinámica biológica. En primer lugar, se determinará la cantidad de portadores de meningococo en España con un modelo de competencia de Lotka-Volterra fraccionario aleatorio. A continuación, el volumen de un tumor mamario se modelizará mediante un modelo logístico con incertidumbre. Finalmente ayudándonos de un modelo matemático que describe el nivel de glucosa en sangre de un paciente diabético, se pretende dar una recomendación de carbohidratos e insulina que se debe de ingerir para que el nivel de glucosa del paciente esté dentro de una banda de confianza saludable. Es importante subrayar que para poder realizar estos estudios se requieren datos reales, los cuales pueden estar alterados debido a los errores de medición o proceso que se han cometido para obtenerlos. Por este motivo, modelizar correctamente el problema junto con la incertidumbre en los datos es de vital importancia.
[CA] La quantificació de la incertesa està composada per una sèrie de mètodes i tècniques computacionals, l'objectiu principal de les quals és descriure l'aleatorietat present en problemes de diversa índole. Aquests mètodes són d'utilitat en la modelització de processos biològics, físics, naturals o socials, ja que en ells apareixen certs aspectes que no poden ser determinats de manera exacta. Per exemple, la taxa de contagi d'una malaltia epidemiològica o el factor de creixement d'un volum tumoral depenen de factors genètics, ambientals o conductuals. Aquests no sempre poden definir-se íntegrament i per tant, comporten una aleatorietat intrínseca que afecta en el desenvolupament final. L'objectiu principal d'aquesta tesi doctoral és estendre tècniques per a quantificar la incertesa en dues àrees de les matemàtiques: el càlcul d'equacions diferencials fraccionàries i la modelització matemàtica. Les derivades d'ordre fraccionari permeten modelitzar comportaments que les derivades clàssiques no poden, com per exemple, els efectes de memòria o la viscoelasticitat en alguns materials. En aquesta tesi, des d'un punt de vista teòric, s'estendrà el càlcul fraccionari a un ambient d'incertesa, concretament en el sentit de la mitjana quadràtica. Es presentaran problemes de valors inicials fraccionaris aleatoris. El càlcul de la solució, l'obtenció de les aproximacions de la mitjana i, la variància de la solució i l'aproximació de la primera funció de densitat de probabilitat de la solució són conceptes que s'abordaran en els pròxims capítols. No obstant això, no sempre és senzill obtindre la solució exacta d'un problema de valors inicials fraccionari aleatori. Per això en aquesta tesi també es dedicarà un capítol per a descriure un procediment numèric que aproxime la seua solució. D'altra banda, des d'un punt de vista més aplicat, es desenvolupen tècniques computacionals per a quantificar la incertesa en models matemàtics. Combinant aquestes tècniques juntament amb models matemàtics apropiats, s'estudiaran problemes de dinàmica biològica. En primer lloc, es determinarà la quantitat de portadors de meningococ a Espanya amb un model de competència de Lotka-Volterra fraccionari aleatori. A continuació, el volum d'un tumor mamari es modelitzará mitjançant un model logístic amb incertesa. Finalment ajudant-nos d'un model matemàtic que descriu el nivell de glucosa en sang d'un pacient diabètic, es pretén donar una recomanació de carbohidrats i insulina que s'ha d'ingerir perquè el nivell de glucosa del pacient estiga dins d'una banda de confiança saludable. És important subratllar que per a poder realitzar aquests estudis es requereixen dades reals, els quals poden estar alterats a causa dels errors de mesurament o per la forma en que s'han obtés. Per aquest motiu, modelitzar correctament el problema juntament amb la incertesa en les dades és de vital importància.
[EN] Uncertainty quantification collects different methods and computational techniques aimed at describing the randomness in real phenomena. These methods are useful in the modelling of different processes as biological, physical, natural or social, since they present some aspects that can not be determined exactly. For example, the contagious rate of a epidemiological disease or the growth factor of a tumour volume depend on genetic, environmental or behavioural factors. They may not always be fully described and therefore involve uncertainties that affects on the final result. The main objective of this PhD thesis is to extend techniques to quantify the uncertainty in two mathematical areas: fractional calculus and mathematical modelling. Fractional derivatives allow us to model some behaviours that classical derivatives cannot, such as memory effects or the viscoelasticity of some materials. In this PhD thesis, from a theoretical point of view, fractional calculus is extended into the random framework, concretely in the mean square sense. Initial value problems will be studied. The calculus of the analytic solution, approximations for the mean and for the variance and the computation of the first probability density function are concepts we deal with them thought the following chapters. Nevertheless, it is not always possible to obtain the analytic solution of an initial value problem. Therefore, in this dissertation a chapter is addressed to describe a numerical procedure to approximate the solution for an initial value problem. On the other hand, from a modelling point of view, computational techniques to quantify the uncertainty in mathematical models are developed. Merging these techniques with appropriate mathematical models, problems of biological dynamics are studied. Firstly, the carriers of meningococcus in Spain are determined using a competition Lotka-Volterra random fractional model. Then, the volume of breast tumours is modelled by a random logistic model. Finally, taking advantage of a mathematical model which describes the glucose level of a diabetic patient, a recommendation of insulin shots and carbohydrate intakes is proposed to a patient in order to maintain her/his glucose level in a healthy confidence range. An important observation is that to carry out these studies real data is required and they may include uncertainties contained in the measurements on the process to perform the corresponding study. This it is the reason why it is crucial to properly model the problem taking also into account the randomness of the data.
Burgos Simón, C. (2021). Advances on Uncertainty Quantification Techniques for Dynamical Systems: Theory and Modelling [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/166442
TESIS

The last two decades have seen several large-scale epidemics of international impact, including human, animal and plant epidemics. Policy makers face health challenges that require epidemic predictions based on limited information. There is therefore a pressing need to construct models that allow us to frame all available information to predict an emerging outbreak and to control it in a timely manner. The aim of this thesis is to develop an early-warning modelling approach that can predict emerging disease outbreaks. Based on Bayesian techniques ideally suited to combine information from different sources into a single modelling and estimation framework, I developed a suite of approaches to epidemiological data that can deal with data from different sources and of varying quality. The SEIR model, particle filter algorithm and a number of influenza-related datasets were utilised to examine various models and methodologies to predict influenza outbreaks. The data included a combination of consultations and diagnosed influenza-like illness (ILI) cases for five influenza seasons. I showed that for the pandemic season, different proxies lead to similar behaviour of the effective reproduction number. For influenza datasets, there exists a strong relationship between consultations and diagnosed datasets, especially when considering time-dependent models. Individual parameters for different influenza seasons provided similar values, thereby offering an opportunity to utilise such information in future outbreaks. Moreover, my findings showed that when the temperature drops below 14°C, this triggers the first substantial rise in the number of ILI cases, highlighting that temperature data is an important signal to trigger the start of the influenza epidemic. Further probing was carried out among Maltese citizens and estimates on the under-reporting rate of the seasonal influenza were established. Based on these findings, a new epidemiological model and framework were developed, providing accurate real-time forecasts with a clear early warning signal to the influenza outbreak. This research utilised a combination of novel data sources to predict influenza outbreaks. Such information is beneficial for health authorities to plan health strategies and control epidemics.

En esta tesis, se utilizan t ecnicas matem atico-epidemiol ogicas para modelar el rendimiento acad emico en Espa~na (prestando especial atenci on en el fracaso escolar) para comprender mejor los mecanismos detr as de esta importante cuesti on, as como para predecir c omo evolucionar an los resultados acad emicos en el Bachillerato espa~nol en los pr oximos a~nos. El nivel educativo de Bachillerato en Espa~na est a formado por los dos ultimos cursos antes de acceder a la universidad o al mercado de trabajo y corresponde a los estudiantes de 16 18 a~nos. Este nivel educativo es muy importante para la formaci on de los estudiantes ya que representa un periodo en el que deber an tomar importantes decisiones sobre el futuro acad emico y profesional. En primer lugar, en el Cap tulo 2, se presenta un modelo determinista donde se analiza el rendimiento acad emico asumiendo que la actitud negativa de los alumnos de Bachillerato puede ser debida a su comportamiento aut onomo y la in uencia de compa~neros con malos resultados acad emicos. Luego, en el Cap tulo 3, se mejora el modelo basado en la idea de que no s olo los malos h abitos acad emicos se transmiten socialmente sino tambi en los buenos h abitos de estudio. Adem as, descomponemos los par ametros de transmisi on de h abitos acad emicos con el n de analizar con m as detalle qu e grupos de estudiantes son m as susceptibles a ser in uenciados por compa~neros con buenos o malos h abitos acad emicos. El abandono escolar tambi en han sido incluido en este modelo. El enfoque adoptado permite proporcionar predicciones deterministas y con intervalos de con anza de la evoluci on del rendimiento escolar (incluyendo las tasas de abandono) en Bachillerato en Espa~na en los pr oximos a~nos. Este enfoque, adem as, nos permite modelar el rendimiento acad emico en otros niveles educativos del sistema acad emico espa~nol o de fuera de Espa~na tal y como se muestra en el Cap tulo 4, donde el modelo se aplica satisfactoriamente al sistema acad emico actual de la regi on alemana de Renania del Norte-Westfalia. Para concluir esta tesis, proporcionamos una estimaci on de los costes relacionados con el rendimiento acad emico espa~nol basado en nuestras predicciones. Esta estimaci on representa la inversi on en Bachillerato por parte del Gobierno espa~nol y las familias en los pr oximos a~nos, con especial atenci on en los grupos de estudiantes que no promocionan y abandonan en los diferentes cursos acad emicos.
In this dissertation, we use epidemiologic-mathematical techniques to model the academic performance in Spain (paying special attention on the academic underachievement) to understand better the mechanisms behind this important issue as well as to predict how academic results will evolve in the Spanish Bachillerato over the next few years. The Spanish Bachillerato educational level is made up of the last courses before accessing to the university or to the work market and corresponds to students of 16¿18 years old. This educational level is a milestone in the career training of students because it represents a period to make important decisions about academic and professional future. In a rst step, in the Chapter 2 we will present a deterministic model where academic performance is analyzed assuming the negative attitude of Bachillerato students may be due to their autonomous behavior and the in uence of classmates with bad academic results. Then, in the Chapter 3, the model is improved based on the idea that not only the bad academic habits are socially transmitted but also the good study habits. Besides, we decompose the transmission academic habits into good and bad academic habits, in order to analyze with more detail which group of students are more susceptible to be in uenced by good or bad academic students. The consideration of quantifying the abandon rates is also a new issue dealt with in it. The adopted approach allow to provide both punctual and con dence intervals predictions to the evolution of academic performance (including the abandon rates) in Bachillerato in Spain over the next few years. The adopted approach allows us to model academic performance in academic levels other than Bachillerato and/or beyond the Spanish academic system. This issue is assessed in Chapter 4, where the model is satisfactorily applied to the current academic system of the German region of North Rhine-Westphalia. To conclude this dissertation, we provide an estimation of the cost related to the Spanish academic underachievement based on our predictions. This estimation represents the investment in the Spanish Bachillerato from the Spanish Government and families over the next few years, paying special attention on the groups of students who do not promote and abandon during their corresponding academic year.
Sánchez Sánchez, A. (2013). Modelling the evolution dynamics of the academic performance in high school in Spain. Probabilistic predictions of future trends and their economical consequences [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/32280
TESIS

La paratuberculosis (PTB) est une maladie endémique des ruminants causée par Mycobacterium avium subsp. paratuberculosis (Map). Les stratégies de maîtrise actuelles ne sont pas suffisamment efficaces. La réponse à l'exposition à Map varie entre les animaux avec une part de déterminisme génétique. Des marqueurs génétiques pourraient permettre une sélection. L'objectif était d'évaluer par modélisation l'efficacité potentielle attendue de stratégies de maîtrise utilisant la sélection génétique ou la réduction de l'exposition en élevage. Nous avons identifié quatre traits phénotypiques de résistance influençant principalement la propagation de Map à l'échelle du troupeau et montré la valeur ajoutée de leur amélioration simultanée. Nous avons évalué l'effet de l'environnement du troupeau et du système d’élevage sur la propagation et la maîtrise de Map. Nous avons montré une différence d’efficacité des stratégies de maîtrise les plus pertinentes entre deux systèmes d'élevage bovins laitiers contrastés d'Europe: l'ouest de la France et l'Irlande. Nous avons évalué l'efficacité que pourrait apporter la sélection génomique en évaluant le temps nécessaire pour atteindre des niveaux de variation des traits sélectionnés permettant un bon contrôle de l‘infection sous l’hypothèse que des marqueurs de sélection soient disponibles. Nous avons identifié 2 paramètres du modèle de sélection génomique influents sur l’efficacité de la sélection. Notre modèle permet d’intégrer de nouvelles connaissances biologiques sur le déterminisme génétique de la résistance à Map pour évaluer des stratégies de maîtrise complexes comprenant une composante de sélection génomique
Paratuberculosis (PTB) is an endemic disease of ruminants caused by Mycobacterium avium subsp. paratuberculosis (Map). Current control strategies are not effective enough. The response to Map exposure varies between animals with evidence of a partial genetic determinism. Genetic markers could allow selection. The objective was to assess the potential expected effectiveness of control strategies relying on genetic selection or reduction of exposure in herds, using a modelling approach. We identified four phenotypic traits of resistance mainly influencing the spread of Map at the herd scale and showed the added value of their simultaneous improvement. We evaluated the effect of the herd environment and management on the spread and control of Map. We showed a difference in effectiveness of the most relevant control strategies between two contrasting dairy cattle systems in Europe: western France and Ireland. We evaluated the effectiveness of genomic selection by assessing the time required to reach levels of variation in the selected traits allowing to achieve a good control of infection, assuming that associated genomic markers could be available. Effectiveness of selection was mainly influenced by 2 of the parameters of the developed genomic selection model. Our model allows to account for future knowledge about the genetic determinism of cattle resistance to Map in order to assess the effectiveness of complex control strategies including a genomic selection component

La surveillance syndromique est un concept récent en épidémiologie. Fondée sur le suivi automatisé d'indicateurs de santé non spécifiques, cette nouvelle approche offre des perspectives intéressantes pour la détection de phénomènes pathologiques émergents. Nous nous sommes basés sur les données actuellement collectées en France sur la mortalité bovine pour évaluer la faisabilité et la pertinence d'un système de surveillance syndromique basé sur cet indicateur. Nous avons d'abord modélisé le niveau de référence de la mortalité bovine en France puis proposé des méthodes pour identifier et quantifier d'éventuels excès de mortalité. Nous avons d'abord analysé des données réelles pour estimer rétrospectivement les conséquences sur la mortalité de l'épizootie de fièvre catarrhale ovine qui a touché le cheptel bovin français en 2007 et 2008. Nous avons ensuite proposé une méthode visant à identifier des regroupements d'unités spatiales présentant des augmentations inhabituelles de mortalité, et évalué ses performances pour détecter des foyers d'une maladie infectieuse dont nous avons simulé la propagation dans le cheptel bovin. Sur la base de ces travaux, nous discutons finalement de l'intérêt pour la protection de la santé animale d'un système de surveillance non spécifique basé sur la mortalité, et émettons des propositions pour la mise en place opérationnelle d'un tel système.

Main goal of forest diseases’ management is to reduce economic, biological and aesthetic damages and biodiversity loss caused by plant parasites. The many strategies used can be grouped under two main actions, prevention (prophylaxis in some early writings) and therapy (treatment or cure). Prevention is limited primarily by the lack of knowledge of the organisms involved, including host plants. Mathematical models have been used to extend the understanding of plant disease epidemiology on a number of fronts, providing an opportunity for a more rational use of resources on expensive field trials and representing a step towards more sustainable control measures. From a curative point of view, current efforts by scientists have focused on developing diseases management (Pest Management = PM) concepts in order to balance the benefits of pesticides with the ecological concerns of their residues contaminating the environment. In this thesis, the two PM principles were applied from an innovative point of view on two case studies: ash dieback caused by Hymenoscyphus fraxineus, which can be considered the most serious disease for Fraxinus genus in Europe, and chestnut ink disease, caused by Phytophthora cambivora and P. cinnamomi. In the first part of the thesis, the two diseases are introduced, in order to permit the evaluation of similarities and differences (chapter I). Subsequently, from chapter II to chapter V, the experimental trials performed are described. In particular, in chapter II a study of the ecological niche of H. fraxineus, with the characterization of the environmental variables associated with naturally infected zones, is reported. This procedure was realized with Species Distribution Models (SDM), widely utilized in the ecological field and only recently applied to plant pathology. The presence of the pathogen was highly correlated to three summer predictors: abundant precipitation, high soil moisture and low air temperature, in comparison with the averages of the study area. The ensemble forecasting technique was then applied to obtain a prediction of the potential distribution of the pathogen at European scale, considering the distribution maps of Fraxinus excelsior and Fraxinus angustifolia, susceptible to the parasite. At last, an innovative method of network analysis permitted to identify the suitable areas that are not reachable by the pathogen with a natural spread. Chapter III reports a study conducted to evaluate six fungicides for their potential to control ash dieback. Initially, in vitro tests of the active ingredients against five different strains of the pathogen indicated thiabendazole, propiconazole and allicin as the most effective fungicides, with lower median lethal doses than procloraz. In contrast, copper sulphate and potassium phosphite were totally ineffective. Subsequently, the antifungal activities of the best three compounds were investigated in planta against H. fraxineus by trunk injection on European ashes inoculated with an indigenous strain. The test was preceded by preliminary trials to maximize the efficacy of injections; in the experimental conditions highest speed was reached with the addition of 1.2 % acetic acid to the aqueous solution and making treatments in early morning or late afternoon. Considering the results of in planta trial, thiabendazole and allicin significantly slowed down the growth of the necroses in the growing season, in contrast propiconazole injections were impracticable. The studies in chapters IV and V recall the methodologies applied to ash dieback, with application to chestnut ink disease complex. In particular, in chapter IV fuzzy logic theory was applied considering the environmental variables, such as minimum winter temperature, summer drought, slope's aspect, streams' distance and soil's permeability, that mainly can influence the development of the disease. The model was validated with a broad field survey conducted in a chestnut area in Treviso province. Moreover, uncertainty maps (regarding model structure, inputs and parameters) were produced for the correct interpretation of the prediction. Great part of the chestnut area in the study zone resulted as suitable for the development of ink disease, whereas only the 18.8 %, corresponding to higher elevation zones, presented inferior risks. In a second study (chapter V), a comparative efficacy trial on four potassium phosphite formulations by means of endotherapy against chestnut ink disease is performed. P. cinnamomi was isolated with baiting technique from symptomatic chestnuts and was inoculated on 50 asymptomatic trees. As a result of endotherapic treatments, the unique solution that significantly slowed down necroses' growth was potassium phosphite (35 %) with an addition of 0.1 % micronutrient solution. An additional endotherapic trial was conducted in a preliminary way in the chestnut where P. cinnamomi was isolated, with the main aim to evaluate growth stimulation of active growing callus next to the shape flame necroses by the injected solution of potassium phosphite 70 %. In this case, results did not highlight a significant difference between treated trees and water control ones, probably for the need of longer times for older trees. On the base of the achieved results, epidemiological modelling and endotherapic treatments, applied both to ash dieback and chestnut ink disease, can represent fundamental tools in the management of these important diseases and should be applied in an Integrated Pest Management (IPM) approach, together with appropriate cultural techniques to maximize benefits.
Lo scopo principale della gestione delle malattie forestali è la riduzione dei danni economici, biologici ed estetici e delle perdite di biodiversità dovute alle malattie delle piante. Le molteplici strategie usate nella gestione delle malattie possono essere raggruppate in due azioni principali, la prevenzione (anche detta profilassi) e la terapia (trattamento o cura). La prevenzione è principalmente limitata dalla mancanza di conoscenza in merito all'organismo in oggetto e i suoi ospiti. I modelli matematici sono stati utilizzati per approfondire la conoscenza delle malattie delle piante con vari obiettivi. Essi offrono l'opportunità di affrontare un uso razionale delle risorse riguardo ai costosi monitoraggi e rappresentano un passo fondamentale verso misure di controllo più sostenibili. Da un punto di vista curativo, oggigiorno gli sforzi sono focalizzati allo sviluppo di concetti di gestione delle malattie che bilancino i benefici dei pesticidi con le preoccupazioni in merito ai residui che possono contaminare l'ambiente. In questa tesi, i due principi della gestione della malattia sono stati affrontati con due casi studio: il dissecamento del frassino, causata da Hymenoscyphus fraxineus, che può essere considerata la più grave malattia del genere Fraxinus in Europa, e il mal dell'inchiostro del castagno, causata da Phytophthora cambivora (Petri) Buism. and P. cinnamomi Rands. Nella prima parte della tesi sono state introdotte le due malattie, in modo da poterne appurare somiglianze e differenze (Capitolo I). Successivamente, dal capitolo II al capitolo V sono descritte le prove sperimentali effettuate. In particolare, nel capitolo II è stato approntato uno studio della nicchia ecologica di H. fraxineus, con la caratterizzazione di variabili ecologiche e ambientali associate a zone naturalmente infette. Tale procedura è stata effettuata tramite Species Distribution Models (SDM), ampiamente utilizzati in ambito ecologico e da poco tempo anche nell'ambito della patologia vegetale. La presenza del patogeno è risultata fortemente correlata a tre variabili ambientali estive, in particolare abbondanti precipitazioni, alta umidità del suolo e basse temperature, in comparazione con la media dell'area di studio. Successivamente la tecnica dell'ensemble forecasting è stata applicata per ottenere una predizione della distribuzione potenziale del patogeno a scala europea, considerando la distribuzione di F. excelsior e F. angustifolia, ospiti della malattia. Infine, un innovativo metodo di network analysis ha permesso di individuare le aree ecologicamente adatte al patogeno ma non raggiungibili con una diffusione naturale. Nel capitolo III viene descritto uno studio condotto per valutare sei diversi fungicidi contro H. fraxineus. Inizialmente è stata effettuata una prova in vitro dei prodotti commerciali contro cinque ceppi del patogeno. Tiabendazolo, propiconazolo e allicina sono risultati i fungicidi più efficaci, con dose letale mediana più bassa, rispetto, per esempio, al principio attivo procloraz. Al contrario, il solfato di rame e i fosfiti di potassio si sono rilevati completamente inefficaci. Successivamente, i tre migliori fungicidi sono stati applicati in planta tramite trattamenti endoterapici su frassini maggiori inoculati al tronco con un ceppo autoctono. Tale test è stato anticipato da prove preliminari per massimizzare l'efficienza delle iniezioni; nelle condizioni stazionali e climatiche delle prove, maggiori velocità sono state raggiunte con soluzione acquosa addizionata con 1.2 % di acido acetico, effettuando i trattamenti la mattina presto o nel pomeriggio tardo. Considerando i risultati della prova in planta, tiabendazolo e allicina hanno rallentato in maniera significativa la crescita delle necrosi, al contrario non si è riusciti a iniettare la soluzione a base di propiconazolo. I capitoli IV e V riprendono le metodologie applicate contro la patologia del dissecamento del frassino, applicandole al mal dell'inchiostro del castagno. In particolare nel capitolo IV, la teoria fuzzy è stata adottata nello studio del complesso del mal dell'inchiostro, includendo nella costruzione del modello variabili ambientali quali temperatura minima invernale, siccità estiva, esposizione, distanza da corsi d'acqua e permeabilità del suolo, che più possono influire sullo sviluppo della malattia. Il modello è stato validato con un'ampia ricerca sul campo condotta nei castagneti nell'area di Treviso. Inoltre, sono state prodotte delle mappe dell'incertezza (inerenti a struttura, input e parametri del modello) per la corretta interpretazione della previsione. Buona parte dell'area a castagneto nella zona di studio si è rivelata adatta allo sviluppo del mal dell'inchiostro, mentre solo il 18.8 %, corrispondente alle aree più elevate, presentava rischi inferiori. Un secondo studio (capitolo V) ha riguardato una prova comparativa di efficacia di quattro formulazioni di fosfiti di potassio tramite endoterapia. P. cinnamomi è stata isolata con la tecnica del baiting in un castagneto affetto da mal dell'inchiostro ed è stata inoculata su 50 castagni asintomatici. In seguito ai trattamenti endoterapici, l'unica soluzione che ha significativamente rallentato la crescita delle necrosi è stata quella a base di fosfiti di potassio (35 %) addizionata con 0.1 % di soluzione di micronutrienti. Un'ulteriore prova di endoterapia è stata condotta in via preliminare nel castagneto abbandonato in cui era stata isolata P. cinnamomi, al fine di valutare la stimolazione alla crescita del callo cicatriziale da parte della soluzione iniettata fosfiti di potassio 70 %. I risultati ottenuti in questo caso non hanno evidenziato una differenza significativa rispetto ai controlli trattati con acqua, probabilmente per una necessità di tempi più lunghi considerando piante di età maggiore. In base ai risultati raggiunti, la modellistica epidemiologica e i trattamenti endoterapici sperimentati in merito alle patologie del dissecamento del frassino e al mal dell'inchiostro del castagno possono rappresentare degli strumenti fondamentali nella gestione integrata delle malattie considerate, da applicare insieme ad appropriate tecniche colturali per massimizzarne i benefici.

A modelagem epidemiológica é uma importante ferramenta que auxilia os órgãos de saúde no controle de doenças infecciosas, pois permitem analisar e comparar diversas estratégias que facilitam a tomada de decisões e definições de protocolos. A dengue é atualmente a doença viral humana com maior número de casos. Possui índice de mortalidade baixo, entretanto, é endêmica em mais de 100 países e 40% da população mundial está em risco de contrair a infecção. Através dos dados de notificação de dengue no Brasil, evidenciamos que os surtos são sazonais, que há alternância de sorotipos ao longo dos anos e mostramos que a doença é diferente em cada localização, e que somente com uma normalização adequada é possível sugerir um agrupamento coerente de municípios. Neste trabalho, as informações obtidas a partir dos dados são usadas para a estruturação dos modelos matemáticos e para a estimação de parâmetros que validam estes modelos. Comparamos a dinâmica de transmissão de dengue do modelo com um sorotipo, com modelos que permitem a interação de dois, três e quatro sorotipos simultaneamente, além da possibilidade de até quatro infecções sequenciais. Os modelos com múltiplos sorotipos são expandidos do modelo básico que categoriza hospedeiros dentro de uma população como suscetíveis (S), infectados (I) e recuperados (R) e acoplado à dinâmica dos vetores suscetíveis (V) e infectados (Vi). Nossos modelos incluem: um período de imunidade cruzada de forma que o indivíduo adquire imunidade permanente para o sorotipo que já foi infectado e imunidade temporária para os demais; uma forçante de sazonalidade na taxa de nascimento dos vetores; uma assimetria com taxas de transmissão diferentes para cada sorotipo; e o compartimento dos vacinados, com uma vacina tetravalente que confere diferentes imunidades para cada sorotipo. Os resultados mostram que para a reprodução de surtos anuais é necessário a inclusão da forçante de sazonalidade na taxa de nascimento dos vetores, e que o modelo com quatro sorotipos é o que melhor reproduz os dados de incidência de dengue, sendo o mais adequado para analisar estratégias de vacinação com uma vacina tetravalente. Comparamos duas estratégias de vacinação: vacinação aleatória na população e vacinação direcionada para faixas etárias. Neste caso, os resultados demonstram a superioridade da estratégia direcionada e que as escolhas das faixas etárias devem ser definidas por município e não por um protocolo nacional.
Epidemiological modelling is an important tool that assists the health agencies in the control of infectious diseases, since it allows analysing and to compare several strategies that facilitate decision-making and protocol definitions. Dengue is currently the most important vector-borne disease. The mortality rate of dengue is low, however, it is endemic in more than 100 countries and about 40% of the world\'s population is at risk of contracting the infection. Through the dengue notification data in Brazil, we emphasize that the outbreaks are seasonal, there is serotypes alternation over the years and we show that the disease is different in each locality, and that only with a suitable standardization it is possible to propose an appropriate grouping of municipalities. In this work, we use the data information to formulate the mathematical models and for the parameter\'s estimation in order to validate these models. We compare the dynamics of dengue of the one serotype model with the models that allow interaction of two, three and four serotypes simultaneously, including the possibility of at most four sequential infections.The multi-strain models are expanded from the basic model which categorizes the host population as susceptible (S), infected (I), and recovered (R) and coupled with the dynamics of the susceptible (V) and infected (Vi) vectors. Our models include: a period of cross-immunity which means permanent immunity to the serotype of the infection and temporary immunity to the other serotypes; a seasonal forcing in the mosquitoes birth rate; different transmissions rates, so that the models are asymmetric; and the compartment of vaccinated individuals with a tetravalent vaccine which confers different immunities for each serotype. The results show that to reproduce yearly outbreaks it is necessary to include the seasonal forcing in the birth rate of the vectors, and that the four serotypes model is the one that best reproduces the dengue incidence data, being the most suitable model to analyse vaccination strategies with a tetravalent vaccine. We compare two vaccination strategies: random vaccination and vaccination targeted at age groups. In this case, the results demonstrate the superiority of the targeted strategy and that the choices of the age groups should be defined by municipality and not by a national protocol.

La modélisation mathématique est largement utilisée pour effectuer des recherches sur la modélisation des maladies infectieuses. Combler le fossé entre les modèles conceptuels et leurs simulations est l'un des problèmes de la modélisation. Les langages métiers sont souvent utilisés pour addresser ces problèmes en séparant deux aspects de la modélisation : la spécification (modèles conceptuels) et la simulation (modèles informatiques). Dans cette perspective, nous développons un langage métier, appelé KENDRICK, dédié à la modélisation épidémiologique, couplé avec une plate-forme de simulation. Un autre problème de la modélisation en épidémiologie est le mélange des aspects de domaine qui doivent être séparés. Afin de faciliter l'écriture et l'évolution des modèles, il est crucial de pouvoir définir une préoccupation avec aussi peu de dépendances avec d'autres que possible et de pouvoir les combiner aussi librement que possible. Nous abordons ces défis en proposant un méta-modèle mathématique commun qui peut représenter les modèles ainsi que les préoccupations. Nous définissons ensuite les opérateurs qui permettent de combiner des préoccupations ainsi que de les appliquer dans un modèle. Le langage KENDRICK simplifie donc la programmation des simulations épidémiologiques en décomposant un modèle monolithique hautement-couplé en préoccupations modulaires. Cela rend alors plus facile la construction des modèles complexes de l'épidémiologie où plusieurs préoccupations sont considérées en même temps
Mathematical and computational models have become widely used and demanded tools for examining mechanisms of transmission, exploring characteristics of epidemics, predicting future courses of an outbreak and evaluating strategies to find a best control-program. One of the problems of modelling is bridging the gap between conceptual models (i.e compartmental models of epidemiology) and their computer simulation (through deterministic, stochastic or agent-based implementation). Domain Specific Languages (DSLs) are often used to address such difficulties by separating two concerns of modelling, specification (conceptual model) and implementation (computational model). In this perspective, we develop a DSL called KENDRICK targeted to the epidemiological modelling and coupled with a simulation platform that allows the study of such models. The other important issue needs to be addressed in the context of epidemiological modelling is the heterogeneities introduced by separate concerns. In order to facilitate the specification of models and their evolution, it is crucial to be able to define concerns with as few dependencies with each other as possible and to combine them as freely as possible. We address such challenges by proposing a common mathematical meta-model that supports both concerns and models and enabling their compositions by some operators. We then implement our proposal language KENDRICK based on this meta-model. The language simplifies the construction of complex epidemiological models by decomposing them into modular concerns, by which common concerns can be reused across models and can be easily changed

La modélisation mathématique est largement utilisée pour effectuer des recherches sur la modélisation des maladies infectieuses. Combler le fossé entre les modèles conceptuels et leurs simulations est l'un des problèmes de la modélisation. Les langages métiers sont souvent utilisés pour addresser ces problèmes en séparant deux aspects de la modélisation : la spécification (modèles conceptuels) et la simulation (modèles informatiques). Dans cette perspective, nous développons un langage métier, appelé KENDRICK, dédié à la modélisation épidémiologique, couplé avec une plate-forme de simulation. Un autre problème de la modélisation en épidémiologie est le mélange des aspects de domaine qui doivent être séparés. Afin de faciliter l'écriture et l'évolution des modèles, il est crucial de pouvoir définir une préoccupation avec aussi peu de dépendances avec d'autres que possible et de pouvoir les combiner aussi librement que possible. Nous abordons ces défis en proposant un méta-modèle mathématique commun qui peut représenter les modèles ainsi que les préoccupations. Nous définissons ensuite les opérateurs qui permettent de combiner des préoccupations ainsi que de les appliquer dans un modèle. Le langage KENDRICK simplifie donc la programmation des simulations épidémiologiques en décomposant un modèle monolithique hautement-couplé en préoccupations modulaires. Cela rend alors plus facile la construction des modèles complexes de l'épidémiologie où plusieurs préoccupations sont considérées en même temps
Mathematical and computational models have become widely used and demanded tools for examining mechanisms of transmission, exploring characteristics of epidemics, predicting future courses of an outbreak and evaluating strategies to find a best control-program. One of the problems of modelling is bridging the gap between conceptual models (i.e compartmental models of epidemiology) and their computer simulation (through deterministic, stochastic or agent-based implementation). Domain Specific Languages (DSLs) are often used to address such difficulties by separating two concerns of modelling, specification (conceptual model) and implementation (computational model). In this perspective, we develop a DSL called KENDRICK targeted to the epidemiological modelling and coupled with a simulation platform that allows the study of such models. The other important issue needs to be addressed in the context of epidemiological modelling is the heterogeneities introduced by separate concerns. In order to facilitate the specification of models and their evolution, it is crucial to be able to define concerns with as few dependencies with each other as possible and to combine them as freely as possible. We address such challenges by proposing a common mathematical meta-model that supports both concerns and models and enabling their compositions by some operators. We then implement our proposal language KENDRICK based on this meta-model. The language simplifies the construction of complex epidemiological models by decomposing them into modular concerns, by which common concerns can be reused across models and can be easily changed

Le cucurbitacee possono essere attaccate da più di 200 malattie, una corretta gestione è dunque fondamentale per ridurre il rischio di perdite di produzione, sia in termini di quantità sia in termini di qualità. Tra le malattie più importanti che attaccano le cucurbitacee ci sono l’oidio e la peronospora delle cucurbitacee. Podosphaera xanthii e Golovinomyces cichoracearum sono gli agenti causali dell’oidio. È stato studiato l’effetto della temperature sulla germinazione dei conidi in ambiente controllato a 6 temperature costanti (da 10 a 35°C, ad intervalli di 5C°) da 3 a 72 ore. La temperature ottimale per la germinazone, l’infezione e la sporulazione è risultata essere rispettivamente 24.4, 25.7 e 21.3°C per P. xanthii e 17.9, 17.3 e 16.2°C per G. cichoracearum. Un modello meccanicistico è stato sviluppato per il rischio che i due agenti patogeni causassero un attacco di oidio. Il modello simula la germinazione su foglie infettate sulla base delle condizioni ambientali di temperatura e umidità relativa. Le equazioni che calcolano la germinazione delle dei conidi di entrambi i funghi sono state sviluppate sulla base di dati presenti in bibliografia. Un secondo modello meccanicistico è stato sviluppato per Pseudoperonospora cubensis, agente causale della peronospora delle cucurbitacee. Il modello calcola la data di comparsa dei sintomi e la probabilità del superamento di determinate soglie di gravità della malattia, sulla base di sotto-processi dell’infezione. Il passaggio da uno stato dell’infezione al successivo è dipendente dalle condizioni ambientali. Entrambi i modelli sono stati validati confrontando i dati ottenuti dai modelli con dati indipendenti rilevati in coltivazioni del nord Italia.
Cucurbits are potentially affected by more than 200 diseases of diverse etiologies, so a good disease management is crucial to reduce the risk of high yield losses in terms of quantity and quality. Among the more important diseases there are powdery and downy mildew. Podosphaera xanthii and Golovinomyces cichoracearum are the causal agents of cucurbit powdery mildew. The effect of temperature on conidial germination was studied in controlled condition at 6 constant temperature (from 10 to 35°C, step 5°C) for 3 to 72 hours. Optima temperature for conidial germination, infection and sporulation were 24.4, 25.7 and 21.3°C respectively for P. xanthii and 17.9, 17.3 and 16.2°C for G. cichoracearum. A mechanistic model was developed for the risk posed by P. xanthii and G. cichoracearum to cause cucurbit powdery mildew. The model simulates germination on infected leaves on the base of environmental conditions of temperature and relative humidity. Equation regulating spore germination of both fungi were developed using published data. Another mechanistic model was develop also for Pseudoperonospora cubensis, causal agent of cucurbit downy mildew. The model calculates the symptoms appearance and the probability of overtaking severity threshold based on sub-processes of infection. Changes from one state of the infection to the following one depend on environmental conditions. Both models were validated by comparing model outputs with independent data sets collected in fields located in the north of Italy.

Le cucurbitacee possono essere attaccate da più di 200 malattie, una corretta gestione è dunque fondamentale per ridurre il rischio di perdite di produzione, sia in termini di quantità sia in termini di qualità. Tra le malattie più importanti che attaccano le cucurbitacee ci sono l’oidio e la peronospora delle cucurbitacee. Podosphaera xanthii e Golovinomyces cichoracearum sono gli agenti causali dell’oidio. È stato studiato l’effetto della temperature sulla germinazione dei conidi in ambiente controllato a 6 temperature costanti (da 10 a 35°C, ad intervalli di 5C°) da 3 a 72 ore. La temperature ottimale per la germinazone, l’infezione e la sporulazione è risultata essere rispettivamente 24.4, 25.7 e 21.3°C per P. xanthii e 17.9, 17.3 e 16.2°C per G. cichoracearum. Un modello meccanicistico è stato sviluppato per il rischio che i due agenti patogeni causassero un attacco di oidio. Il modello simula la germinazione su foglie infettate sulla base delle condizioni ambientali di temperatura e umidità relativa. Le equazioni che calcolano la germinazione delle dei conidi di entrambi i funghi sono state sviluppate sulla base di dati presenti in bibliografia. Un secondo modello meccanicistico è stato sviluppato per Pseudoperonospora cubensis, agente causale della peronospora delle cucurbitacee. Il modello calcola la data di comparsa dei sintomi e la probabilità del superamento di determinate soglie di gravità della malattia, sulla base di sotto-processi dell’infezione. Il passaggio da uno stato dell’infezione al successivo è dipendente dalle condizioni ambientali. Entrambi i modelli sono stati validati confrontando i dati ottenuti dai modelli con dati indipendenti rilevati in coltivazioni del nord Italia.
Cucurbits are potentially affected by more than 200 diseases of diverse etiologies, so a good disease management is crucial to reduce the risk of high yield losses in terms of quantity and quality. Among the more important diseases there are powdery and downy mildew. Podosphaera xanthii and Golovinomyces cichoracearum are the causal agents of cucurbit powdery mildew. The effect of temperature on conidial germination was studied in controlled condition at 6 constant temperature (from 10 to 35°C, step 5°C) for 3 to 72 hours. Optima temperature for conidial germination, infection and sporulation were 24.4, 25.7 and 21.3°C respectively for P. xanthii and 17.9, 17.3 and 16.2°C for G. cichoracearum. A mechanistic model was developed for the risk posed by P. xanthii and G. cichoracearum to cause cucurbit powdery mildew. The model simulates germination on infected leaves on the base of environmental conditions of temperature and relative humidity. Equation regulating spore germination of both fungi were developed using published data. Another mechanistic model was develop also for Pseudoperonospora cubensis, causal agent of cucurbit downy mildew. The model calculates the symptoms appearance and the probability of overtaking severity threshold based on sub-processes of infection. Changes from one state of the infection to the following one depend on environmental conditions. Both models were validated by comparing model outputs with independent data sets collected in fields located in the north of Italy.

Angiostrongylus cantonensis is a parasitic nematode endemic to tropical and subtropical regions and is the leading cause of human eosinophilic meningitis. The parasite is commonly known as rat lungworm because the primary host in its lifecycle is the rat. A clinical overview of rat lungworm infection is presented, followed by a literature review of rat lungworm epidemiology, risk factors, and surveillance projects. Data collected from previous snail surveys in Florida was considered alongside elevation, population per square kilometer, median household income by zip code territory, and normalized difference vegetation index specific to the geographic coordinates from which the snail samples were retrieved. The parameters of interest were incorporated as possible predictor variables in a Poisson probability regression model and a negative binomial regression model. NDVI and population density were determined to be positively associated with number of snail samples positive for A. cantonensis in a given Miami-based location. A surveillance project was conducted in Hillsborough County, Florida, U.S.A.. Snail samples were collected and tested for A. cantonensis DNA via polymerase chain reaction (PCR) and gel electrophoresis. None of the samples tested positive for A. cantonensis.

Angiostrongylus cantonensis is a parasitic nematode endemic to tropical and subtropical regions and is the leading cause of human eosinophilic meningitis. The parasite is commonly known as rat lungworm because the primary host in its lifecycle is the rat. A clinical overview of rat lungworm infection is presented, followed by a literature review of rat lungworm epidemiology, risk factors, and surveillance projects. Data collected from previous snail surveys in Florida was considered alongside elevation, population per square kilometer, median household income by zip code territory, and normalized difference vegetation index specific to the geographic coordinates from which the snail samples were retrieved. The parameters of interest were incorporated as possible predictor variables in a Poisson probability regression model and a negative binomial regression model. NDVI and population density were determined to be positively associated with number of snail samples positive for A. cantonensis in a given Miami-based location. A surveillance project was conducted in Hillsborough County, Florida, U.S.A.. Snail samples were collected and tested for A. cantonensis DNA via polymerase chain reaction (PCR) and gel electrophoresis. None of the samples tested positive for A. cantonensis.

La maladie de Newcastle (MN) grève lourdement les productions aviaires malgaches, essentielles à l'alimentation et à l'économie familiales. La MN est une dominante pathologique en l'absence de vaccination généralisée. L'objectif de cette thèse est la modélisation, la validation et l'analyse mathématique de modèles de transmission du virus de la MN (VMN) dans les systèmes avicoles villageois en général et à Madagascar en particulier. Nous proposons de nouveaux modèles basés sur les connaissances actuelles de l'histoire naturelle de la transmission du VMN. Ainsi, nous présentons deux modèles mathématiques à compartiments de la transmission du VMN dans une population de poules : un premier modèle avec transmission environnementale et un deuxième modèle où la vaccination contre la maladie est prise en compte. Nous présentons une analyse complète de la stabilité de ces modèles à l'aide des techniques de Lyapunov suivant la valeur du taux de reproduction de base R0. Le travail s'est appuyé sur des enquêtes de terrain pour comprendre les pratiques de vaccination actuelles à Madagascar
Newcastle disease (ND) severely harms Malagasy bird productions, mainly uses to food and family economy. ND is a pathological dominant without general vaccination. The objective of this thesis is modelling the transmission of ND virus (NDV) in smallholder chicken farms in general and, Madagascar in particular. We propose new models based on the state of art and the epidemiology currently known from the transmission of the NDV. Thus, we present two models of the transmission of NDV: a first model with environmental transmission and a second model in which imperfect vaccination of chickens is considered. We present a thorough analysis of the stability of the models using the Lyapunov techniques and obtain the basic reproduction ratio R0. This work is based on field surveys to understand the current vaccination practices in Madagascar

Erysiphe necator (Schwein.) è l’agente causale dell’oidio della vite. Esso è in grado di svernare come ascospore all’interno di corpi fruttiferi, i chasmoteci, oppure come micelio in gemme infette. Le ascospore sono rilasciate nella primavera successiva e causano infezioni primarie che danno origine all’epidemia. Di conseguenza la riduzione dell’inoculo primario svernante potenzialmente riduce le epidemie nella stagione successiva. I primi sei capitoli di questa tesi riguardano nuove conoscenze sulla biologia, epidemiologia e modellistica del patogeno. Due nuovi modelli meccanicistici che simulano, rispettivamente, la maturazione e dispersione dei chasmoteci e le infezioni ascosporiche sono stati sviluppati ed è stata studiata approfonditamente la dinamica di maturazione e dispersione delle ascospore stesse. Nei restanti quattro capitoli il controllo del patogeno è stato riconsiderato in accordo con le linee guida della gestione integrata del vigneto. In particolare è stata valutata l’efficacia di diversi fungicidi, dell’iperparassita Ampelomyces spp. e di un olio minerale nel ridurre il numero di chasmoteci prodotti in autunno, nel distruggere gli stessi durante l’inverno e nel controllare le infezione primarie ascosporiche in primavera.
Erysiphe necator (Schwein.) is the causal agent of grapevine powdery mildew. It survives the winter in two ways: as ascospores in overwintering fruiting bodies, the chasmothecia, and as mycelium in infected buds. Ascospores that are repeatedly released and cause primary infections in the following grapevine growing season and trigger powdery mildew epidemics. Consequently, the reduction of the overwintering inoculum may reduce powdery mildew epidemics in the next season. In order to verify this statement and develop sanitation as a relevant strategy to be used in integrated management of grape powdery mildew, different studies were performed during this Doctorate. The first six chapters of this dissertation pertain to new findings about the biology, epidemiology and modeling of the pathogen. A new mechanistic model predicting maturation and dispersal of chasmothecia was developed, dynamics of ascospore maturation and dispersal were studied and another mechanistic model simulating ascosporic infections was developed. In the last four chapters the control of the pathogen was redrawn according to the Integrated Pest Management concept: the efficacy of fungicides, the hyperparasite Ampelomyces spp., and mineral oil in reducing chasmothecia production in fall, in killing chasmothecia before bud break, and in controlling ascosporic infections in spring was investigated.

Erysiphe necator (Schwein.) è l’agente causale dell’oidio della vite. Esso è in grado di svernare come ascospore all’interno di corpi fruttiferi, i chasmoteci, oppure come micelio in gemme infette. Le ascospore sono rilasciate nella primavera successiva e causano infezioni primarie che danno origine all’epidemia. Di conseguenza la riduzione dell’inoculo primario svernante potenzialmente riduce le epidemie nella stagione successiva. I primi sei capitoli di questa tesi riguardano nuove conoscenze sulla biologia, epidemiologia e modellistica del patogeno. Due nuovi modelli meccanicistici che simulano, rispettivamente, la maturazione e dispersione dei chasmoteci e le infezioni ascosporiche sono stati sviluppati ed è stata studiata approfonditamente la dinamica di maturazione e dispersione delle ascospore stesse. Nei restanti quattro capitoli il controllo del patogeno è stato riconsiderato in accordo con le linee guida della gestione integrata del vigneto. In particolare è stata valutata l’efficacia di diversi fungicidi, dell’iperparassita Ampelomyces spp. e di un olio minerale nel ridurre il numero di chasmoteci prodotti in autunno, nel distruggere gli stessi durante l’inverno e nel controllare le infezione primarie ascosporiche in primavera.
Erysiphe necator (Schwein.) is the causal agent of grapevine powdery mildew. It survives the winter in two ways: as ascospores in overwintering fruiting bodies, the chasmothecia, and as mycelium in infected buds. Ascospores that are repeatedly released and cause primary infections in the following grapevine growing season and trigger powdery mildew epidemics. Consequently, the reduction of the overwintering inoculum may reduce powdery mildew epidemics in the next season. In order to verify this statement and develop sanitation as a relevant strategy to be used in integrated management of grape powdery mildew, different studies were performed during this Doctorate. The first six chapters of this dissertation pertain to new findings about the biology, epidemiology and modeling of the pathogen. A new mechanistic model predicting maturation and dispersal of chasmothecia was developed, dynamics of ascospore maturation and dispersal were studied and another mechanistic model simulating ascosporic infections was developed. In the last four chapters the control of the pathogen was redrawn according to the Integrated Pest Management concept: the efficacy of fungicides, the hyperparasite Ampelomyces spp., and mineral oil in reducing chasmothecia production in fall, in killing chasmothecia before bud break, and in controlling ascosporic infections in spring was investigated.

Orientador: Rodney Carlos Bassanezi
Dissertação (mestrado profissional) - Universidade Estadual de Campinas, Instituto de Matematica, Estatistica e Computação Cientifica
Made available in DSpace on 2018-08-13T04:06:10Z (GMT). No. of bitstreams: 1 SaleseSilva_JoseGilson_M.pdf: 1291910 bytes, checksum: b6f441a8e24badc2915c8f5301ca28ce (MD5) Previous issue date: 2009
Resumo: Apresentamos uma abordagem resumida da epidemiologia matemática, dos modelos epidemiológicos tipo SI, SIS e SIR, bem como um embasamento sobre as equações de diferenças finitas. Utilizamos um modelo matemático determinístico em tempo discreto tipo SI, simplificado, para interpreta¸c¿ao e análise da epidemia de hanseníase do município de Imperatriz-MA, com base em dados relativos ao número de contatos registrados e casos notificados no per'iodo de 1994 a 2007. Apresentamos também uma validação do modelo e histórico da epidemia em Imperatriz.
Abstract: We present an approach summarized from epidemiology mathematics , from the models epidemiological type Oneself SI SS e SIR , as well as a basement on the subject of the equations of differences finite. Uses a model mathematical deterministic in time discreet type SI about to interpretation e analysis from epidemics from hansen'iase of the county of Imperatriz-MA , based on dice relative the number of contacts registered e cases notifying into the period of 1994 the 2007. We present also a validation of the model e historical from epidemics in the Imperatriz.
Mestrado
Biomatematica
Mestre em Matemática

Abstract Cardiovascular disease is currently the leading cause of mortality worldwide. Several factors contribute to its development, including increased body mass index, high blood pressure and smoking. Many genetic and behavioural determinants of these risk factors have been identified, but the interplay between them along the life course is still poorly understood. Life course epidemiology and statistical methods developed for life course studies are required to enhance understanding of the aetiologies of these risk factors for more effective prevention and treatment of cardiovascular disease. In this thesis, structural equation modelling was applied 1) to estimate the effect of variation in the fat mass and obesity-associated gene, FTO, on body mass index over the life course, 2) to identify sensitive periods of growth in influencing adult blood pressure and 3) to identify developmental changes in the effects of two confirmed genetic loci, TTC12-ANKK1-DRD2 and CHRNA5-CHRNA3-CHRNB4, affecting smoking behaviour. Additionally, pleiotropic effects of the variation in CHRNA5-CHRNA3-CHRNB4 on smoking, body mass index and blood pressure were studied. The study population was based on the Northern Finland Birth Cohort 1966 with data available from early gestation until the age of 31 years (N≈6000). The first study indicated that the effect of the FTO variant on body mass index changes over time, with strengthening of the effect by age. The results from the second study demonstrated the important role of both prenatal and postnatal growth in determining adult blood pressure. In the third study, TTC12-ANKK1-DRD2 was shown to influence the initiation of smoking, while CHRNA5-CHRNA3-CHRNB4 was associated with smoking persistence. Finally, some evidence was found for pleiotropic effects of the CHRNA5-CHRNA3-CHRNB4 gene cluster on the three traits of interest. Results from all the studies emphasised the importance of environmental and behavioural factors in determining adult metabolic profile, in addition to genetic predisposition. This study demonstrated the usefulness of life course studies in detecting age-varying genetic effects, and provided new insights into the already identified factors associated with cardiovascular disease risk. The findings also emphasise the importance of early interventions and life style guidance for long-term benefits in health
Tiivistelmä Sydän- ja verisuonitaudit ovat maailman yleisin kuolemansyy. Useat tekijät vaikuttavat näiden tautien kehittymiseen, mukaan lukien ylipaino ja lihavuus, kohonnut verenpaine sekä tupakointi. Useita geneettisiä ja ei-geneettisiä tekijöitä on yhdistetty näihin riskitekijöihin, mutta niiden yhteisvaikutukset elämänkaaren varrella ovat vielä huonosti tunnettuja. Elämänkaariepidemiologiaa ja sitä varten kehitettyjä tilastollisia menetelmiä tarvitaan, jotta saataisiin uutta tietoa riskitekijöiden etiologioista ja voitaisiin tehokkaammin ennaltaehkäistä ja hoitaa sydän- ja verisuonitauteja. Tässä väitöskirjatyössä käytettiin rakenneyhtälömallitusta 1) estimoimaan FTO-geenin yhteyttä painoindeksiin (BMI) elämänkaaren varrella, 2) tunnistamaan kehityksellisesti tärkeitä ajanjaksoja suhteessa aikuisiän verenpaineeseen ja 3) tutkimaan kahden jo ennestään tunnistetun geneettisen lokuksen, TTC12-ANKK1-DRD2:n ja CHRNA5-CHRNA3-CHRNB4:n, vaikutusta tupakointiin eri elämänvaiheissa. Lisäksi tutkittiin CHRNA5-CHRNA3-CHRNB4:n mahdollisia pleiotrooppisia vaikutuksia tupakointiin, painoindeksiin ja verenpaineeseen. Tutkimusväestönä käytettiin Pohjois-Suomen syntymäkohorttia vuodelta 1966, joka sisältää tutkimusaineistoa varhaisraskaudesta aikuisuuteen 31 vuoden ikään saakka (N≈6000). Ensimmäinen osatyö osoitti, että FTO-geenin vaikutus painoindeksiin voimistuu iän kasvaessa. Toisen osatyön tulokset antoivat näyttöä siitä, että raskaudenaikainen ja syntymän jälkeinen kasvu ovat yhteydessä aikuisiän verenpaineeseen. Kolmannessa osatyössä osoitettiin, kuinka TTC12-ANKK1-DRD2 on yhteydessä tupakoinnin aloittamiseen, kun taas CHRNA5-CHRNA3-CHRNB4 vaikuttaa tupakointikäyttäytymisen pysyvyyteen. Viimeinen osatyö antoi näyttöä CHRNA5-CHRNA3-CHRNB4-geeniklusterin pleiotrooppisista vaikutuksista kolmeen tutkittuun fenotyyppiin. Kaikkien osatöiden tuloksissa korostui, geneettisten tekijöiden lisäksi, ei-geneettisten tekijöiden tärkeys aikuisiän metabolisen profiilin kehityksessä. Tämä työ on osoittanut elämänkaarimallituksen hyödyllisyyden, kun pyritään havaitsemaan iän mukaan vaihtelevia geneettisiä efektejä. Se on myös tuonut uutta tietoa liittyen jo aiemmin todettuihin sydän- ja verisuonitautien riskitekijöihin. Lisäksi tulokset korostavat riittävän varhaisten ehkäisytoimien ja elämäntapaohjauksen tärkeyttä pyrittäessä saavuttamaan pitkäaikaisia terveyshyötyjä

Gli obbiettivi di questa tesi di dottorato erano: i) valutare l’effetto di differenti condizioni ambientali sulla biologia ed epidemiologia di isolati di B. cinerea appartenenti alle sub-popolazioni transposa e vacuma, e ii) sviluppare un nuovo modello previsionale per predire il rischio di muffa grigia nei vigneti tra le fasi fenologiche di sviluppo delle infiorescenze e maturazione dei grappoli. Gli effetti della temperatura, durata di bagnatura e umidità relativa sulle infezioni di infiorescenze e bacche di Vitis vinifera sono stati valutati con inoculazioni artificiali di isolati di B. cinerea. Gli effetti della temperatura, attività dell’acqua, umidità relativa e composizione delle bacche di uva sulla germinazione dei conidi, crescita miceliale e produzione di conidi sono stati valutati su substrati artificiali. I risultati evidenziano che la capacità di causare infezioni varia con gli isolati indipendentemente dall’appartenenza alle sub-popolazioni transposa o vacuma. Inoltre, le risposte dei differenti isolati al variare delle condizioni ambientali risultano essere simili. Basandosi sui risultati ottenuti sono state sviluppate equazioni matematiche per spiegare l’effetto dei fattori ambientali sull’incidenza delle infezioni di infiorescenze e bacche, germinazione dei conidi, crescita miceliale e produzione di conidi. Un nuovo modello previsionale è stato sviluppato per predire le infezioni di Botrytis cinerea nei vigneti utilizzando le equazioni sviluppate e seguendo un approccio meccanicistico. Il modello è stato validato per 6 anni (2009-2014) in 13 vigneti localizzati in Italia e Francia. Il nuovo modello risulta essere più completo di quelli proposti finora in letteratura e può essere utilizzato per migliorare le strategie di controllo della muffa grigia nei vigneti.
The aims of this Doctoral work were: i) to investigate the effect of different environmental conditions on biology and epidemiology of B. cinerea strains belonging the two transposon types vacuma and transposa, and ii) develop a new weather-driven mechanistic model in order to predict risk of grey mould in vineyards from early growth of inflorescences to berry ripening. The effect of temperature, wetness duration and relative humidity on infection of Vitis vinifera inflorescences and berries was investigated by artificial inoculation of B. cinerea strains. The effect of temperature, water activity, relative humidity and grape berry composition on conidia germination, colony growth and conidial production was investigated in agar-medium. The results showed that the ability to cause infection was a strain rather than a transposon genotype attribute. Moreover, the general response to different environmental conditions is similar among different B. cinerea strains. Based on these data, equations were developed to account the combined effects of environmental factors on infection incidence, conidia germination, colony growth and conidial production. A new previsional model for Botrytis cinerea infections on grapevine was elaborated using the equations developed and following a mechanistic approach. The model was validated over a 6-year period (2009 to 2014) in 13 vineyards located in different grape-growing areas of Italy and France. The model is more complete than the others proposed in literature and represents an improvement to control grey mould in vineyards.

Gli obbiettivi di questa tesi di dottorato erano: i) valutare l’effetto di differenti condizioni ambientali sulla biologia ed epidemiologia di isolati di B. cinerea appartenenti alle sub-popolazioni transposa e vacuma, e ii) sviluppare un nuovo modello previsionale per predire il rischio di muffa grigia nei vigneti tra le fasi fenologiche di sviluppo delle infiorescenze e maturazione dei grappoli. Gli effetti della temperatura, durata di bagnatura e umidità relativa sulle infezioni di infiorescenze e bacche di Vitis vinifera sono stati valutati con inoculazioni artificiali di isolati di B. cinerea. Gli effetti della temperatura, attività dell’acqua, umidità relativa e composizione delle bacche di uva sulla germinazione dei conidi, crescita miceliale e produzione di conidi sono stati valutati su substrati artificiali. I risultati evidenziano che la capacità di causare infezioni varia con gli isolati indipendentemente dall’appartenenza alle sub-popolazioni transposa o vacuma. Inoltre, le risposte dei differenti isolati al variare delle condizioni ambientali risultano essere simili. Basandosi sui risultati ottenuti sono state sviluppate equazioni matematiche per spiegare l’effetto dei fattori ambientali sull’incidenza delle infezioni di infiorescenze e bacche, germinazione dei conidi, crescita miceliale e produzione di conidi. Un nuovo modello previsionale è stato sviluppato per predire le infezioni di Botrytis cinerea nei vigneti utilizzando le equazioni sviluppate e seguendo un approccio meccanicistico. Il modello è stato validato per 6 anni (2009-2014) in 13 vigneti localizzati in Italia e Francia. Il nuovo modello risulta essere più completo di quelli proposti finora in letteratura e può essere utilizzato per migliorare le strategie di controllo della muffa grigia nei vigneti.
The aims of this Doctoral work were: i) to investigate the effect of different environmental conditions on biology and epidemiology of B. cinerea strains belonging the two transposon types vacuma and transposa, and ii) develop a new weather-driven mechanistic model in order to predict risk of grey mould in vineyards from early growth of inflorescences to berry ripening. The effect of temperature, wetness duration and relative humidity on infection of Vitis vinifera inflorescences and berries was investigated by artificial inoculation of B. cinerea strains. The effect of temperature, water activity, relative humidity and grape berry composition on conidia germination, colony growth and conidial production was investigated in agar-medium. The results showed that the ability to cause infection was a strain rather than a transposon genotype attribute. Moreover, the general response to different environmental conditions is similar among different B. cinerea strains. Based on these data, equations were developed to account the combined effects of environmental factors on infection incidence, conidia germination, colony growth and conidial production. A new previsional model for Botrytis cinerea infections on grapevine was elaborated using the equations developed and following a mechanistic approach. The model was validated over a 6-year period (2009 to 2014) in 13 vineyards located in different grape-growing areas of Italy and France. The model is more complete than the others proposed in literature and represents an improvement to control grey mould in vineyards.

L’ascomicete Guignardia bidwellii, agente causale del marciume nero della vite, è un patogeno economicamente importante in alcuni areali viticoli. La conoscenza, disponibile sul marciume nero dell’uva, è stata recuperata dalla letteratura, analizzata e sintetizzata per sviluppare un modello meccanicistico del ciclo di vita del patogeno, guidata dalle variabili meteorologiche e dalla fenologia della vite, e basata sull'analisi dei sistemi. Il modello è stato poi valutato per la sua capacità di rappresentare il sistema reale e la sua utilità per la comprensione di epidemie di marciume nero su foglie e grappoli in un vigneto del Nord Italia, nel 2013 al 2015. Successivamente, le mancanze di conoscenza sono state analizzate, studiate e quindi colmate attraverso specifici esperimenti. In un primo passo, le dinamiche dell’inoculo primario e dei modelli di dispersione (di entrambi ascospore e conidi) da mummie svernate sono state studiate in un vigneto sperimentale per tre anni. In un secondo passo, l'effetto della temperatura e dell'umidità sulla formazione di picnidi di G. bidwellii e la successiva estrusione di cirri, nelle lesioni su foglia, la produzione e la germinazione dei conidi (inoculo secondario), e la lunghezza del periodo di latenza sono stati studiati sia in condizioni di campo che in ambiente controllato. In un terzo passo, sono stati condotti studi in ambiente controllato per studiare la produzione di conidi di G. bidwellii sulle lesioni di foglie, influenzata da lavaggi ripetuti e alternando periodi di secco ed umido. Il modello epidemiologico sviluppato in questa tesi può essere utilizzata da viticoltori come strumento predittivo per la pianificazione di trattamenti fungicidi nei vigneti.
The ascomycete Guignardia bidwellii, causal agent of black-rot on grapevines, is an economically important pathogen in some viticultural areas. The available knowledge on black-rot of grape was retrieved from literature, analyzed, and synthesized to develop a mechanistic model of the life cycle of the pathogen, driven by weather and vine phenology, and based on the systems analysis. The model was then evaluated for its ability to represent the real system and its usefulness for understanding black-rot epidemics on leaves and bunches in a vineyard of north Italy, in 2013 to 2015. Thereafter, weaknesses in our knowledge were analysed and studied through specific experiments. In a first step, dynamics of primary inoculum and dispersal patterns (both ascospores and conidia) from overwintered grape mummies were investigated in an experimental vineyard during three years. In a second step, the effect of temperature and humidity on the formation of G. bidwellii pycnidia and the extrusion of cirri in grape leaf lesions, production and germination of conidia (secondary inoculum), and the length of the latency period were studied under both environmental and controlled conditions. In a third step, environmental-controlled studies were conducted to investigate the production course of G. bidwellii conidia on grape leaf lesions as influenced by repeated washing events and alternate dry and wet periods. The model developed in this thesis can be used by vinegrowers as a predictive tool for scheduling fungicide sprays in the vineyards.

L’ascomicete Guignardia bidwellii, agente causale del marciume nero della vite, è un patogeno economicamente importante in alcuni areali viticoli. La conoscenza, disponibile sul marciume nero dell’uva, è stata recuperata dalla letteratura, analizzata e sintetizzata per sviluppare un modello meccanicistico del ciclo di vita del patogeno, guidata dalle variabili meteorologiche e dalla fenologia della vite, e basata sull'analisi dei sistemi. Il modello è stato poi valutato per la sua capacità di rappresentare il sistema reale e la sua utilità per la comprensione di epidemie di marciume nero su foglie e grappoli in un vigneto del Nord Italia, nel 2013 al 2015. Successivamente, le mancanze di conoscenza sono state analizzate, studiate e quindi colmate attraverso specifici esperimenti. In un primo passo, le dinamiche dell’inoculo primario e dei modelli di dispersione (di entrambi ascospore e conidi) da mummie svernate sono state studiate in un vigneto sperimentale per tre anni. In un secondo passo, l'effetto della temperatura e dell'umidità sulla formazione di picnidi di G. bidwellii e la successiva estrusione di cirri, nelle lesioni su foglia, la produzione e la germinazione dei conidi (inoculo secondario), e la lunghezza del periodo di latenza sono stati studiati sia in condizioni di campo che in ambiente controllato. In un terzo passo, sono stati condotti studi in ambiente controllato per studiare la produzione di conidi di G. bidwellii sulle lesioni di foglie, influenzata da lavaggi ripetuti e alternando periodi di secco ed umido. Il modello epidemiologico sviluppato in questa tesi può essere utilizzata da viticoltori come strumento predittivo per la pianificazione di trattamenti fungicidi nei vigneti.
The ascomycete Guignardia bidwellii, causal agent of black-rot on grapevines, is an economically important pathogen in some viticultural areas. The available knowledge on black-rot of grape was retrieved from literature, analyzed, and synthesized to develop a mechanistic model of the life cycle of the pathogen, driven by weather and vine phenology, and based on the systems analysis. The model was then evaluated for its ability to represent the real system and its usefulness for understanding black-rot epidemics on leaves and bunches in a vineyard of north Italy, in 2013 to 2015. Thereafter, weaknesses in our knowledge were analysed and studied through specific experiments. In a first step, dynamics of primary inoculum and dispersal patterns (both ascospores and conidia) from overwintered grape mummies were investigated in an experimental vineyard during three years. In a second step, the effect of temperature and humidity on the formation of G. bidwellii pycnidia and the extrusion of cirri in grape leaf lesions, production and germination of conidia (secondary inoculum), and the length of the latency period were studied under both environmental and controlled conditions. In a third step, environmental-controlled studies were conducted to investigate the production course of G. bidwellii conidia on grape leaf lesions as influenced by repeated washing events and alternate dry and wet periods. The model developed in this thesis can be used by vinegrowers as a predictive tool for scheduling fungicide sprays in the vineyards.

LO SCOPO DEL PRESENTE STUDIO E' STATO QUELLO DI APPROFONDIRE I DIVERSI ASPETTI DEL TREMATODE DICROCOELIUM DENDRITICUM, PARASSITA A LOCALIZZAZIONE EPATICA DI DIVERSE SPECIE ANIMALI, UOMO COMPRESO. IN PARTICOLARE, D. DENDRITICUM E' STATO UTILIZZATO COME MODELLO DI INTERAZIONE OSPITE-PARASSITA E COME TALE NE SONO STATI CARATTERIZZATI GLI ASPETTI EPIDEMIOLOGICI, BIOLOGICI, PATOLOGICI E BIOLOGICI. I RISULTATI DI QUESTA TESI HANNO DATO UN IMPORTANTE CONTRIBUTO ALLE CONOSCENZE RELATIVE ALLA EPIDEMIOLOGIA DELLA DICROCOELIOSI IN CAMPANIA ED HANNO CONSENTITO DI CARATTERIZZARE LE REGIONI ITS2 e 28S del rDNA DI DICROCOELIUM DENDRITICUM. INOLTRE HANNO FORNITO DAT PRELIMINARI SUI MECCANISMI MOLECOLARI MEDIATI DALL'INTERAZIONE OSPITE-PARASSITA.

Tese de mestrado, Bioinformática e Biologia computacional (Biologia computacional),Universidade de Lisboa, Faculdade de Ciências, 2015
In recent years our understanding of infectious-disease epidemiology has been greatly increased through mathematical modelling. The major goal of any mathematical study in epidemiology is to develop understanding of the interplay between the variables that determine the course of infection within an individual, and the variables that control the pattern of infections within communities of people. The epidemiology of multi-type pathogen systems, such as dengue, malaria and pneumococcus are notoriously challenging. Direct and indirect interactions between multiple strains shape pathogen population processes, both at the level of a single host and at the population level. Quantifying these interactions is crucial, and the new technologies that are now available to detect multiple infections with different pathogen types are opening new avenues in this endeavour. In this thesis, motivated by the pneumococcus system, we study the colonization dynamics by a multi-type pathogen and focus particularly on co-colonization phenomena, which reflects the simultaneous colonization/infection (terms used in this thesis interchangeably) by two antigenic types of the same pathogen. We pretend to introduce strain ratios, first quantified by Brugger et al. (2010), when modelling the co-colonization phenomena. Therefore, a mathematical epidemiological model is constructed using ordinary differential equations to examine the prevalence and distribution of the co-colonization in the population. Interestingly, we find one scenario where the infection can still persist despite the basic reproduction number R0 being below 1. The phenomena of backward bifurcation is also observed. Moreover, the proportion of each double infected class, at equilibrium, is independent of the size of susceptible or single infected class. Based on a static epidemiological point of view, we also develop an within-host model to study the distribution of co-colonization in an average host. Both models show a clear equal abundance ratio (1:1) prevalence and this seems to be robust despite varying the parameters.
A Epidemiologia é uma ciência que estuda quantitativamente a distribuição dos fenómenos de saúde/doença, e seus factores condicionantes e determinantes, nas populações humanas. Esta permite ainda avaliar a eficácia das intervenções realizadas no âmbito da saúde pública. O fundador da teoria epidemiológica moderna é Ronald Ross cujo estudo no ciclo de vida da malária concedeu-lhe o Nobel em 1902. Este utilizou a modelação matemática para investigar a eficácia das intervenções na prevenção desta doença. No entanto, foi só no final do século XX que a modelação matemática se tornou mais popular. Nos últimos anos o nosso conhecimento relativo à epidemiologia das doenças infecciosas desenvolveu-se bastante devido à modelação matemática. O principal objectivo de qualquer estudo matemático em epidemiologia é melhorar o nosso entendimento relativo às relações das variáveis que determinam o curso de uma infecção quer ao nível do indivíduo como ao nível das comunidades. No entanto, devemos ter sempre em conta que os modelos são sempre abstracções/simplificações dos fenómenos em estudo e os resultados obtidos aproximações do sistema real. A modelação têm sido aplicada para o estudo de diversas doenças infecciosas tal como a sarampo, HIV ou a dengue. Estes modelos revelam-se ferramentas essenciais para compreender a dinâmica das doenças infecciosas e auxiliar no planeamento e controlo das mesmas. Nesta tese, estou interessada em estudar as dinâmicas das doenças infecciosas, mas mais precisamente, explorar através da modelação matemática o fenómeno de co-colonização ou também designado por múltipla colonização. Esta significa a colonização simultânea do hospedeiro por vários microorganismos (da mesma espécie ou diferente). É sabido desde há décadas que a co-colonização é um fenómeno comum na natureza e com importantes consequências para o hospedeiro e parasita. Para o hospedeiro, representa um desafio extra para o seu sistema imunitário. Para o parasita, conduz a interacções directas e indirectas entre as diversas estirpes alterando a sua dinâmica e transmissão. Geralmente este fenómeno agrava o estado de saúde do individuo em comparação com as infecções simples, ou seja, quando o individuo é unicamente colonizado por um parasita. Quantificar a interacção entre as diversas estirpes envolvidas revela-se por isso fundamental, e as novas tecnologias que estão hoje em dia disponíveis para detectar os diferentes patogénios envolvidos, estão a abrir caminho nesta área. Recentemente, Brugger et al. (2010) revelou com os seus estudos na bactéria Streptococcus pneumoniae, também conhecida por pneumoccocus, que a co-colonização tem uma prevalência de 7:9%. Aparentemente, é também mais comum para o hospedeiro apresentar sensivelmente a mesma proporção, usualmente designada por 1:1, entre as duas estirpes da bactéria. Esta prevalência foi também observada independentemente por Valente et al. (2012), mas desta vez em indivíduos saudáveis. Este padrão parece ser, por isso, independente do estado de saúde do indivíduo. O pneumococcus é uma bactéria gram-positiva que normalmente vive assimptomáticamente na nasofaringe e cuja prevalência está aumentada nos primeiros cinco anos de vida de um indivíduo. Ocasionalmente, esta pode migrar para outras regiões do corpo e potencialmente causar uma série de doenças, desde infecções respiratórias ligeiras (otites, etc.) até doenças mais invasivas (pneumonia, septicémia, meningite, etc.). O fenómeno da co-colonização parece também ser um importante factor para a evolução desta espécie, uma vez que representa uma oportunidade para a transferência horizontal de genes. Incorporar esta informação sobre os rácios nos modelos é relevante, uma vez que pode auxiliar na compreensão da sua dinâmica de transmissão e potencialmente prever o impacto de políticas de intervenção, tal como a vacinação. Para um organismo tão diverso como o penumococcus, com mais de 90 estirpes diferentes identificadas, a compreensão da sua biologia está longe de estar completa, e formular modelos reais ainda representa um desafio. Nesta tese foi feito um estudo detalhado acerca do padrão de cocolonização na nasofaringe por múltiplas estirpes do pneumococcus. Mais precisamente, pretendo compreender os factores que justificam a sua prevalência na população e a distribuição dos rácios de cocolonização no caso do hospedeiro apresentar duas estirpes. O principal objectivo deste estudo foi desenhar um modelo matemático que representasse adequadamente a infecção pelo pneumococcus para que o seu output fosse suficientemente preciso para explicar as características da distribuição das estirpes no hospedeiro. Nesse sentido, usei duas abordagens diferentes (mas complementares) para modelar a co-colonização. Em primeiro lugar, usando equações diferenciais ordinárias, construí um modelo epidemiológico determinístico com estrutura nos tipos de co-colonização. Esta abordagem parte da dinâmica de uma população com vista a estudar a distribuição num único indivíduo. Portanto caracteriza-se como uma abordagem topdown. Numa segunda abordagem, criei um modelo probabilístico que a partir da dinâmica da infecção no indivíduo, permite observar a distribuição das estirpes na população. Esta abordagem caracteriza-se como bottom-up. Em ambos os modelos, os resultados que obtive evidenciaram os mecanismos imunitários e estocásticos responsáveis pela distribuição dos rácios de co-colonização. Foi observada uma clara predominância dos rácios 1:1 e este resultado parece ser robusto quando se variam os parâmetros dos modelos. Foram identificados os equilibrios do sistema (trivial e endémico) e avaliada a sua estabilidade. Curiosamente, no modelo epidemiológico, encontrei um cenário em que a infecção pode persistir apesar do número básico de reprodução R0 ser inferior a 1. Este fenómeno tem o nome de backward bifurcation e consiste numa alteração estrutural da estabilidade dos equilíbrios, que deve-se essencialmente ao facto do modelo desenvolvido estruturar os hospedeiros co-colonizados em classes. Estas em média apresentam um número básico de reprodução superior aos hospedeiros colonizados por uma única estirpe. Assim, contribuem em média para uma maior transmissão da infecção na população. Também a proporção de cada classe de hospedeiros duplamente infectados relativamente ao total de hospedeiros infectados, no equilíbrio, é independente da magnitude da classe dos susceptíveis ou dos infectados apenas por uma estirpe. Isto significa que quando o hospedeiro é infectado por uma segunda estirpe tem uma probabilidade fixa de apresentar um determinado rácio. Neste modelo epidemiológico foi também possível verificar, que o mecanismo responsável por desviar a distribuição em torno do rácio 1:1 baseia-se no pressuposto que cada classe de cocolonizados ter taxas de recuperação diferentes, onde umas classes recuperam mais rapidamente que outras. Este rácio traduz como os diferentes patogénios, como um "todo", estão expostos ao sistema imunitário do hospedeiro. Todas as simulações numéricas foram realizadas usando a linguagem de programação Python e o software cientifico Mathematica. Construir modelos epidemiológicos que reflictam o fenómeno de cocolonização é fundamental para melhor compreender determinadas doenças, mas também apresenta muitos desafios técnicos. Nomeadamente, quanto mais factores biológicos forem tidos em conta na modelação, no sentido de os tornar mais realistas, mais parâmetros serão introduzidos e mais complexa será a sua análise. No entanto, seria interessante no futuro incorporar factores como: a identidade das estirpes, a heterogeneidade dos hospedeiros e as variações na sua resposta imunitária. Para além disso, poderíamos ter ainda em conta o fenómeno de co-transmissão, ou seja, a infecção do hospedeiro por mais de um parasita durante o mesmo evento de transmissão. Com isto poderíamos, potencialmente, contribuir para o estudo da evolução da virulência destes patogénios. No entanto, é fundamental que hajam mais resultados experimentais para se fazer uma comparação e validação dos resultados teóricos com vista à criação de modelos biológicos mais representativos da realidade.