Over the past few decades, various computational and mathematical methodologies have been proposed for forecasting seasonal epidemics. In recent years, the deadly effects of enormous pandemics such as the H1N1 influenza virus, Ebola, and Zika, have compelled scientists to find new ways to improve the reliability and accuracy of epidemic forecasts. The improvement and variety of these prediction methods are undeniable. Nevertheless, many challenges remain unresolved in the path of forecasting the outbreaks using surveillance data. Obtaining the clean real-time data has always been an obstacle. Moreover, the surveillance data is usually noisy and handling the uncertainty of the observed data is a major issue for forecasting algorithms. Correct modeling assumptions regarding the nature of the infectious disease is another dilemma. Oversimplified models could lead to inaccurate forecasts, whereas more complicated methods require additional computational resources and information. Without those, the model may not be able to converge to a unique optimum solution. Through the last decade, there has been a significant effort towards achieving better epidemic forecasting algorithms. However, the lack of standard, well-defined evaluating metrics impedes a fair judgment on the proposed methods. This dissertation is divided into two parts. In the first part, we present a Bayesian particle filter calibration framework integrated with an agent-based model to forecast the epidemic trend of diseases like flu and Ebola. Our approach uses Bayesian statistics to estimate the underlying disease model parameters given the observed data and handle the uncertainty in the reasoning. An individual-based model with different intervention strategies could result in a large number of unknown parameters that should be properly calibrated. As particle filter could collapse in very large-scale systems (curse-of-dimensionality problem), achieving the optimum solution becomes more challenging. Our proposed particle filter framework utilizes machine learning concepts to restrain the intractable search space. It incorporates a smart analyzer in the state dynamics unit that examines the predicted and observed data using machine learning techniques to guide the direction and amount of perturbation of each parameter in the searching process. The second part of this dissertation focuses on providing standard evaluation measures for evaluating epidemic forecasts. We present an end-to-end framework that introduces epidemiologically relevant features (Epi-features), error measures, and ranking schema as the main modules of the evaluation process. Lastly, we provide the evaluation framework as a software package named Epi-Evaluator and demonstrate the potentials and capabilities of the framework by applying it to the output of different forecasting methods. / PHD / Epidemics impose substantial costs to societies by deteriorating the public health and disrupting economic trends. In recent years, the deadly effects of wide-spread pandemics such as H1N1, Ebola, and Zika, have compelled scientists to find new ways to improve the reliability and accuracy of epidemic forecasts. The reliable prediction of future pandemics and providing efficient intervention plans for health care providers could prevent or control disease propagations. Over the last decade, there has been a significant effort towards achieving better epidemic forecasting algorithms. The mission, however, is far from accomplished. Moreover, there has been no significant leap towards standard, well-defined evaluating metrics and criteria for a fair performance judgment between the proposed methods. This dissertation is divided into two parts. In the first part, we present a Bayesian particle filter calibration framework integrated with an agent-based model to forecast the epidemic trend of diseases like flu and Ebola. We model the disease propagation via a large scale agent-based model that simulates the disease spread across the contact network of people. The contact network consists of millions of nodes and is constructed based on demographic information of individuals achieved from the census data. The agent-based model’s configurations are mostly unknown parameters that should be properly calibrated. We present a Bayesian particle filter calibration approach to estimate the underlying disease model parameters given the observed data and handle the uncertainty in the reasoning. As particle filter could collapse in very large-scale systems, achieving the optimum solution becomes more challenging. Our proposed particle filter framework utilizes machine learning concepts to restrain the intractable search space. It incorporates a smart analyzer unit that examines the predicted and observed data using machine learning techniques to guide the direction and amount of perturbation of each parameter in the searching process. The second part of this dissertation focuses on providing standard evaluation measures for evaluating and comparing epidemic forecasts. We present a framework that introduces epidemiologically relevant features (Epi-features), error measures, and ranking schema as the main modules of the evaluation process. Lastly, we provide the evaluation framework as a software package named Epi-Evaluator and demonstrate the potentials and capabilities of the framework by applying it to the output of different forecasting methods.

This dissertation examines equilibria in epidemics and introduces novel approaches to epidemic modeling, consisting of two separate but closely related chapters. In Chapter 2, we develop an optimizing epidemic model within a dynamic urn-SIR framework, accommodating generic offspring distributions, and derive a trajectory convergence theorem. We study the mean-field equilibrium through numerical simulations. Our findings reveal two key features often overlooked in existing literature: substantial variation in epidemic outcomes despite homogeneous individual behavior, and the potential for resurgence in the number of infections. We demonstrate that the offspring distribution of infections significantly impacts epidemic dynamics, with negative binomial distributions leading to more dispersed outcomes and higher probabilities of minor outbreaks compared to geometric distributions. These results highlight the importance of stochastic modeling in epidemic forecasting and public health policy. Chapter 3 proposes and examines static and dynamic urn-SIR models, a novel approach to epidemic modeling that addresses key limitations of traditional stochastic SIR models. We focus on the critical issue of heterogeneity in individual infectiousness, which is not adequately captured by the geometric offspring distribution inherent in the continuous-time Markov chain SIR models. Our urn-SIR models accommodates generic offspring distributions, including the empirically supported negative binomial distribution. We formally formulate the static and dynamic urn-SIR models. The static model focuses on the end of the epidemic, where primary variables are the epidemic size and the total number of contacts, while the dynamic model captures the dynamic process of the disease progression. The cornerstone of our work is a proven threshold limit theorem, characterizing the asymptotic behavior of the epidemic size as the population approaches infinity. This theorem extends beyond early-stage branching process approximations in the existing literature that considers generic offspring distribution. Moreover, we also show that in the dynamic model, the trajectories of epidemic processes converges in probability to a corresponding deterministic system, allowing comprehensive analysis of entire epidemic courses. Our work bridges crucial gaps in existing literature, providing a more realistic representation of disease spread while maintaining analytical tractability. The findings have significant implications for epidemiology, public health, and related fields, informing more effective strategies for disease control and prevention.

Magister Administrationis - MAdmin / HIV and TB are major problems in the South African context and the burden of these diseases is proving detrimental to the development of the country. These diseases have been evident in the country for many years and in recent times the infection rates of TB and HIV has been alarming. The World Health Organization (WHO) classified TB as a problem and the world was to actively implement strategies to combat this epidemic. The issue with TB control strategies is the emergence of HIV which has been the largest contributing factor to the increase in the TB burden in South Africa and many countries like it. South Africa has made great strides in the control of HIV in areas such as mother to child transmission, awareness programs, initiation of ARVs and medical male circumcision which have proven to be successful. In contrast, the TB burden does not share the same fate. The number of deaths caused by TB is continuously rising, as well as the number of new Multi-drug resistant TB cases. Furthermore the emergence of Extreme –drug resistant TB is seen as a sign of a failing health system. Policy makers are now faced with fact that the Directly Observed Therapy Short course (DOTS) program for the prevention of TB is inadequate in an area with a high HIV prevalence, which is what South Africa is faced with. The research objectives are therefore to identify if knowledge from South African TB policies are being disseminated to people who suffer from TB, also to measure if a lack of knowledge may have an impact on treatment success. A policy analysis was done of 5 South African TB policies to identify areas of the policies which are patient specific. The TB policies emphasized a patient-centred approach and the researcher used this concept to motivate that patient-specific areas must be known by the patients. The specific areas identified were: TB specific areas, Treatment specific areas, Adherence specific areas and information/education specific areas. Based on the policy analysis a case study was conducted at Brooklyn Chest Hospital to measure implementation of the policies on the ground. The study found that education was adequate in areas around TB diagnosis, treatment length, signs and symptoms, and family education. The participants lacked knowledge in areas such as TB contacts, monitoring of TB disease, education of TB prior to diagnosis and a high prevalence of non-adherence and multiple cases of TB were found among the participants. Also, the Chi-Square test found no statistical significance between the length of admission to hospital and treatment outcome. The result also shows that of the participants studied, over 30% of the study had not adhered to TB treatment after discharge. The study finds that there are significant shortfalls in the knowledge of participants based on South African TB policies, with a high non-adherence rate before and after discharge. The study shows a lack in the implementation of policy directives on education, following a patient-centred approach, which is evident in the lack of knowledge found in the participants in many facets of the TB disease and the processes to control TB.

A research report submitted to The Faculty of Health Sciences, University of Witwatersrand, in fulfillment of the requirements for the degree Of Masters in Public Health Johannesburg 2005 / ABSTRACT Swaziland is currently faced with a deepening HIV/AIDS epidemic. A systemic review of available information concerning the economic impact of HIV/AIDS on Swaziland was undertaken to collate data and document this impact in order to inform decision makers and planners. The methodology for the systematic review was based on the guidelines described in the Cochrane Reviewers’ handbook. HIV/AIDS has significantly increased the vulnerability of affected Swaziland rural households to environmental shocks. There is an increased burden of orphans due to HIV/AIDS, reduced household labour and income as adults die of AIDS. HIV/AIDS has reduced farm productivity leading to worsening of food insecurity and poverty in affected households. Due to HIV/AIDS, absenteeism in Swaziland organizations has increased by 20- fold. HIV/AIDS is currently the leading cause of death accounting for over 60 percent of all employee deaths. Organisations that have implemented HIV/AIDS workplace responses have been less affected. The micro-sector is the worst affected and it is recommended that policy makers ensure that this sector is protected from the negative impact of HIV/AIDS. The epidemic of negative impacts of HIV/AIDS in Swaziland has not yet reached the peak.

As early as in 1915, 1931 and 1942, there were serious outbreaks of dengue fever occurred to the entire island of Taiwan. In 1942, there were five million people in the whole Taiwan infected with dengue fever. After the significant outbreaks of dengue fever in the entire Kaohsiung District of Taiwan Island in 1987 and 1988, except that the regional epidemics occurred in three places of Northern and Central Taiwan, namely Jhonghe City of Taipei County, Taichung City and Taipei City, all other regional outbreaks of dengue fever mostly occurred in Kaohsiung County or City, Tainan City and Pingtung County. Apparently, the epidemic situation of dengue fever has become an epidemic disease of Southern Taiwan, and gradually developed as a ¡§community disease¡¨ or ¡§environmental disease.¡¨ Coincidently, the year of 2006 was a peak period for the propagation of dengue fever. Under the circumstances that the number of dengue fever patients was getting higher and higher, both the government and the competent authorities took compulsory measures or epidemic prevention acts (such administrative acts as insecticide spraying against mosquitoes in residences after forceful unlocking of doors, emergency public spraying of chemicals against mosquitoes, taking blood tests, and so on). It seemed so obvious that the liberty of living, liberty of property and personal liberty, which are the basic rights of civilians under the protection of the Constitution, were involved. Besides, whenever dengue fever is epidemic, it is common to see conflicts (arguments) over the door unlocking and insecticide spraying problems frequently happened between the citizens and the government departments concerned. In the legal aspect, it is necessary to review whether these acts comply with the provisions of the Constitution. Apart from collecting the related local and foreign literatures to investigate the change of the administrative system of epidemic control, the study introduces the details of the three major directions in taking epidemic prevention measures against dengue fever in Taiwan, including such administrative and management acts as the preventive measures to be taken during the ordinary days, the epidemic control measures after receiving the report of dengue fever cases, and the epidemic prevention measures after the confirmation of dengue fever cases. In addition, regarding the various compulsory epidemic control measures taken by the health administrative authorities, such as the problems of forceful unlocking of doors for intrusion of residences, forceful (emergency) spraying of insecticide, and the compensation for the loss of property rights after the death of real estate owners¡¦ animals or plants caused by the chemical spraying, etc., the study reviews the reference of laws and the proper legal procedures to be complied with. It includes the theories and principles of the Constitution that Taiwan government should comply with. Although the paper encounters limitations in the studying process, it is still hoped that from the limited literatures with limited information, major directions can be found out as a reference for the competent authorities or scholars to improve or solve the abovementioned problems in the later days. It is also expected that the later researchers can have further understanding of the implementation or practical aspects of the epidemic prevention measures of dengue fever, and finally achieve in-depth development and breakthrough in the studies of the solutions. Keywords: dengue fever, basic human rights, epidemic prevention measures

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In this thesis we discuss deterministic compartmental epidemic models. We study the asymp- totic stability of the disease-free solution of models with pulse vaccination campaigns. The main contributions of this thesis are to extend the literature of pulse vaccination models with delay. We take results for ordinary differential equation models and extend them to models with delay differential equations. Model generalizations include the use of a general incidence term as an upper bound for the actual incidence, and the use of switch parameters to approximate time-varying parameters. In particular, we look at contact rate parameters which are piecewise constant or time-varying. We extend literature results for non-delay general incidence models to find uniform asymptotic stability of the disease-free solution which helps us to add delay. We find an upper bound for the susceptible population under pulse vaccination and use this bound to tighten results for eradication thresholds: that is, we use this upper bound to find sufficient conditions for the uniform asymptotic stability of the disease-free solution of delayed pulse vaccination models. We extend literature results for constant contact rate bilinear incidence delay models to models with periodic time-varying contact rate, and determine conditions under which the disease-free solution is uniformly asymptotically stable for small delay. We also find conditions for disease permanence in the corresponding non-delay, time-varying-parameter pulse vaccination model. For piecewise- constant contact rate bilinear incidence models we again find thresholds which guarantee uniform asymptotic stability under small delay. We additionally discuss the effects of time-varying total population on our results, through a change of variables to population fractions. The total population is commonly held constant in the literature, for analytical simplicity, so we survey the methods for time-varying total population and the effects of such variation on the pulse vaccination schemes. We retain thresholds for eradication by considering the compartment populations as fractions of the total, instead of population numbers. The result is also applied to constant-population delay systems. When changing from standard incidence to bilinear incidence in delay systems, we discuss a way to estimate the effect of time-varying N. We support our theory with simulation results.

Viruses are microscopic biological organisms offensive in nature. Human beings have been combating viruses since times remote. Some battles were won, but never the war. One of the most eminent and destructive epidemics throughout human history is the bubonic plague, better known as the Black Death. Since its first attack on human beings, the casualty count produced by the bubonic plague has been astronomical. The epidemics not only inflict damage physically, but also psychologically on human beings. It is remarkable how such nearly invisible agents can instill so much fear in humans. Daniel Defoe¡¦s A Journal of the Plague Year is a masterpiece in journalistic fiction which brings literature, microbiology, and human behavioral psychology together. The book simply describes scenes from the 1665 London bubonic plague attack through the eyes of a narrator amidst the turmoil. However, it also serves as a guide book to human behavior in desperate times. Defoe vividly describes the plague, the suffering, the horror, and most importantly, the society, the people, and their reactions. With the Journal, Defoe blurred the line between factual and fictitious writing. He wrote a fiction based on factual data which very probably served as a warning aimed at public awareness towards epidemics. Some suspect that the Journal was merely an instrument of government propaganda; whichever the case, this book still constitutes as a milestone in epidemic literature as well as journalistic fiction. This thesis aims mainly at analyzing the relationship between the plague and humans. It is interesting to observe how the plague changed human behavior and induced some of the most common flaws in human character out of deep fear: mutual distrust, paranoia, superstition, opportunism, madness, anger, and hostility. The fragility and vulnerability of the human psyche are exposed in epidemic times such as in the recent SARS outbreak. Unavoidably, the destructiveness of the plague makes it evil in human eyes. However, it is possible to discover the positive and constructive sides of the plague instead of just the negative attributes. People tend to rely on religion in seeking comfort, explanation, and spiritual support. There are people who devote themselves to religion as well as those who choose a different path. At the end of the discussion, we take a look at how religion plays an important role in counteracting the epidemics¡¦ delirious effect on human beings.

Viruses are common causative agents of ocular infection among humans. Epidemic keratoconjuntivitis (EKC) is a severe and contagious ocular disease with reported outbreaks worldwide. It is estimated that this disease affects 20-40 million individuals every year, which leads to huge socioeconomic costs for the affected countries. EKC is characterized by keratitis and conjunctivitis but is also associated with pain, edema, lacrimation, and decreased vision that can prolong for months after the infection and in rare cases years. This disease is caused by human adenoviruses (HAdVs), which belong to the family of Adenoviridae. Currently, there is no available treatment against EKC. EKC is mainly caused by HAdV-8, HAdV-19, HAdV-37, HAdV-53, HAdV-54, and HAdV-56, which belong to species D HAdVs. HAdV-8, HAdV-19 and HAdV-37 have previously been shown to use sialic acid (SA)-containing glycans as cellular receptors to bind to and infect human corneal epithelial (HCE) cells. To characterize the receptor in more detail, we performed a glycan array, which included SA-containing glycans. A branched hexasaccharide terminating with SA in each arm was identified as a candidate receptor. This glycan corresponds to the glycan motif found on a ganglioside, GD1a. By performing a series of biological and biochemical experiments we confirmed the function of the GD1a glycan as a cellular receptor for EKC-causing HAdVs. However, the glycan used as a receptor was linked to plasma membrane protein(s) through O-glycosidic bonds, rather than to a lipid (as in the ganglioside). X-ray crystallography analysis showed that the two terminal SA:s interacted with two of the three previously identified SA-binding sites on the knob domain of the HAdV-37 capsid protein known as the fiber. Based on the structural features of the GD1a:HAdV-37 knob interaction, we assumed that a three-armed molecule with each arm terminating with SA would be an efficient inhibitor. Such molecules were designed, synthesized and found to efficiently prevent HAdV-37 binding to and infection of corneal cells. These results indicate that trisialic acids-containing compounds may be used for treatment of EKC. After binding to its primary receptor, most HAdVs have been shown to interact with αVβ3 and αVβ5 integrins to enter human cells. This interaction occurs through the RGD (arginine-alanine-aspartic acid) motif in the capsid protein known as the penton base. However, it was not clear if corneal epithelial cells express αVβ3 and αVβ5 integrins. Thus, to better understand additional early steps of infection by EKC-causing HAdVs, we performed binding and infection competition experiments using human corneal epithelial cells and siRNA, integrin specific antibodies, peptides and RGD-containing ligands indicating that α3, αV, β1 affected HAdV-37 infection of but not binding to HCE cells. We could also see that HAdV-37 co-localize with α3 and αV at after entry into HCE cells. In situ histochemistry confirmed that the expression of α3 and αV in human corneal tissue. Overall, our results suggest that αV and α3 integrins are important for HAdV-37 infection of corneal cells. Altogether, these results provide further insight into the biology of HAdVs and open up for development of novel antiviral drugs.

In the fall of 1892, fear of cholera was pervasive in North America. Ten years into the fifth international cholera epidemic -- that lasted from 1881 to 1896 -- cholera had been raging in the Middle East, India, and Europe, but the disease had yet to cross the Atlantic Ocean. The maritime traffic of immigrants from Europe was continuous, and each migrant ship potentially carried the disease. Doctors, government officials, and politicians were not asking 'will cholera come?', but rather when. While no one got sick or died of cholera in the city of Toronto in 1892, the crisis and fear of imminent cholera was very real. Drawing on archival research, this dissertation maps how a cholera crisis was shaped by urgency, immediacy, and speculation on the future. My argument will show how the geography of an epidemic is not limited to the presence of a disease. If crises are times of profound activity, how does this event need to be substantiated in order to produce change? This dissertation follows how cholera was integral to producing an object called proliferating life that held together: migrating populations, growing cities, and degeneration; marshland as the source of disease; the medical theory of zymosis that explained how disease outbreaks got out of control; and Malthusian 'laws' of population. Health experts used correlation and synecdoche to visualize these relations. However, these experts needed a stable institutional base to articulate both their fears and their recommendations, which included: professionalized expanding health boards, as social infrastructures; reclaiming Toronto’s marshland of Ashbridge's Bay; and a health ideology built upon the fear of future epidemics, immigration, and a growing economic rationale for health. By the early 20th century, state health became instrumental to a "national vitality", a practice of government intervention that I frame as bureaucratic bio-economy.