Dissertations / Theses on the topic 'Vital statistics'

"Longitudinal studies, where data is collected by measuring the same experimental units several times over a relatively long period, are becoming increasingly common. Conventional statistical approaches have limitations when applied to the analysis of longitudinal data ... Practical limitations of longitudinal analysis that relate to missing data and large data set sizes were explored in this thesis with the application of a sampling technique known as Ranked Set Sampling (RSS). We developed this sampling method, which has not previously been applied to longitudinal data, for fixed and mixed-effects models. This thesis also illustrated inference techniques to estimate these models after selecting sample units by RSS."
Doctor of Philosophy

Every year in the UK, tens of thousands of hospital patients suffer adverse events, such as un-planned transfers to Intensive Therapy Units or unexpected cardiac arrests. Studies have shown that in a large majority of cases, significant physiological abnormalities can be observed within the 24-hour period preceding such events. Such warning signs may go unnoticed, if they occur between observations by the nursing staff, or are simply not identified as such. Timely detection of these warning signs and appropriate escalation schemes have been shown to improve both patient outcomes and the use of hospital resources, most notably by reducing patients’ length of stay. Automated real-time early-warning systems appear to be cost-efficient answers to the need for continuous vital-sign monitoring. Traditionally, a limitation of such systems has been their sensitivity to noisy and artefactual measurements, resulting in false-alert rates that made them unusable in practice, or earned them the mistrust of clinical staff. Tarassenko et al. (2005) and Hann (2008) proposed a novelty detection approach to the problem of continuous vital-sign monitoring, which, in a clinical trial, was shown to yield clinically acceptable false alert rates. In this approach, an observation is compared to a data fusion model, and its “normality” assessed by comparing a chosen statistic to a pre-set threshold. The method, while informed by large amounts of training data, has a number of heuristic aspects. This thesis proposes a principled approach to multivariate novelty detection in stochastic time- series, where novelty scores have a probabilistic interpretation, and are explicitly linked to the starting assumptions made. Our approach stems from the observation that novelty detection using complex multivariate, multimodal generative models is generally an ill-defined problem when attempted in the data space. In situations where “novel” is equivalent to “improbable with respect to a probability distribution ”, formulating the problem in a univariate probability space allows us to use classical results of univariate statistical theory. Specifically, we propose a multivariate extension to extreme value theory and, more generally, order statistics, suitable for performing novelty detection in time-series generated from a multivariate, possibly multimodal model. All the methods introduced in this thesis are applied to a vital-sign monitoring problem and compared to the existing method of choice. We show that it is possible to outperform the existing method while retaining a probabilistic interpretation. In addition to their application to novelty detection for vital-sign monitoring, contributions in this thesis to existing extreme value theory and order statistics are also valid in the broader context of data-modelling, and may be useful for analysing data from other complex systems.

The research presented in this thesis is two-fold: on the one hand, major data mining problems are reformulated as mathematical programming problems. These problems should be carefully designed, since from their formulation depends the efficiency, perhaps the existence, of the solvers. On the other hand, optimisation methods are adapted to solve these problems, most of which are nonsmooth and nonconvex. This part is delicate, as the solution is often required to be good and obtained fast. Numerical experiments on real-world datasets are presented and analysed.
Doctor of Philosophy

Objective: The Affordable Care Act (ACA) has influenced increasing interests in population health and population health outcomes. The purpose of this study was to exemplify the importance of using existing vital statistics data for understanding and monitoring health outcomes and consequentially health disparities at the population level. Data from birth records for two geographic regions from 2009-2014 were compared; low birth weight (LBW) and preterm delivery (PD) were used as surrogates for population health outcomes. Methods: A population-based, multi-year, cross-sectional study design using a pooled dataset of birth records from Tennessee (TN) was the framework for the analyses. A sub-population from North East TN (NE TN) was compared to TN. Logistic regression was used to estimate odds ratios. Attributable risks were calculated to translate the findings from conditional associations to population-level associations to help inform public health policy decision-making. Results: Using birth records (vital statistics), we demonstrated that the period prevalence of cigarette smoking before and during pregnancy remained unchanged with approximately one in three women in NE TN (from 37% in 2009 to 32% in 2014) and one in five women in TN (from 23% in 2009 to 20% in 2014) reporting smoking pre-pregnancy. Multivariate analyses demonstrated that mothers who were at each end of the age spectrum, of very low household income level and reported cigarette smoking pre-pregnancy or during pregnancy had increased risk of a LBW or PD infant. During the years of observation, 39 to 50% of the total incidence of LBW in the group of women who smoked cigarettes prior to pregnancy was attributable to smoking cigarettes. Conclusions: Existing data, such as vital statistics data, should be used routinely to identify geographic areas for which programs or policies can be implemented to reach large portions of populations. Reducing prenatal smoking, for example, has the potential to reduce a large fraction of adverse birth outcomes such as LBW and PD. For the geographic area we evaluated, 39 to 50% of LBW could be prevented by devising population-based smoking cessation programs or policies for women of child-bearing age. With recent emphasis on prevention and well-baby care in the ACA, there is potential to increase attention to this problem, implement evidence-based prevention programs and monitor program effectiveness with existing birth record data. Following this model, we can attain population health goals and address health disparities.

Immigrant flows in Greece after 1990 transformed Greece from a country of outwards migration to an inwards migration state. The contribution of immigrants in a globalized world of migration with sub-replacement fertility levels found in developed countries is a particularly interesting topic in demographic studies. The primary aim of this thesis is to discuss the changes of the demographic and socio-economic characteristics of immigrant population in Greece focusing on Albanian and Bulgarian immigrants. In order to answer these research questions, data from the last three national population census of 1991, 2001 and 2011 as well as vital statistics for European and non-European immigrants’ fertility in Greece have been used. The analysis is based on descriptive statistics for the differential age structure of Greek population and immigrant groups. Reasons for immigration to Greece, educational attainment of immigrants, rates of unemployment and employment status of immigrant population have been used to approach the research questions. The results indicated a younger age structure of Albanian and Bulgarian immigrant population. Meanwhile, immigrant population appears to have higher unemployment rates compared to native Greek population. Finally, a substantial decline of general fertility rates for non-European immigrant women in Greece compared to native Greek women has been observed within the years of the economic recession.

Multivariate statistical methods, including recent computing-intensive techniques, are explained and applied in a medical sociology context to study infant death in relation to socioeconomic risk factors of households in Sri Lankan villages. The data analyzed were collected by a team of social scientists who interviewed households in Sri Lanka during 1980-81. Researchers would like to identify characteristics (risk factors) distinguishing those households at relatively high or low risk of experiencing an infant death. Furthermore, they would like to model temporal and structural relationships among important risk factors. Similar statistical issues and analyses are relevant to many sociological and epidemiological studies. Results from such studies may be useful to health promotion or preventive medicine program planning. With respect to an outcome such as infant death, risk groups and discriminating factors or variables can be identified using a variety of statistical discriminant methods, including Fisher's parametric (normal) linear discriminant, logistic linear discrimination, and recursive partitioning (CART). The usefulness of a particular discriminant methodology may depend on distributional properties of the data (whether the variables are dichotomous, ordinal, normal, etc.,) and also on the context and objectives of the analysis. There are at least three conceptual approaches to statistical studies of risk factors. An epidemiological perspective uses the notion of relative risk. A second approach, generally referred to as classification or discriminant analysis, is to predict a dichotomous outcome, or class membership. A third approach is to estimate the probability of each outcome, or of belonging to each class. These three approaches are discussed and compared; and appropriate methods are applied to the Sri Lankan household data. Path analysis is a standard method used to investigate causal relationships among variables in the social sciences. However, the normal multiple regression assumptions under which this method is developed are very restrictive. In this thesis, limitations of path analysis are explored, and alternative loglinear techniques are considered.
Science, Faculty of
Statistics, Department of
Graduate

The study sample was comprised of 18,953 subjects aged 18 years and older who participated in the Third National Health and Nutrition Examination Survey. Preference for diet soda over regular soda was higher in females as compared to males and in Caucasians as compared to other races. Mean alcohol consumption was almost three times higher in males than in females. Undiagnosed hypertension was more common in males than in females, in 65-90 than in 50-64 year olds, and in people with less than high school education compared to those with higher education. Diastolic pressure was correlated with the level of consumption of diet soda, coffee, tea, and alcohol. Diet soda and alcohol consumption had a statistically significant positive relationship with hypertension even after adjusting for demographic variables and body mass index. The study provides useful information of the patterns of beverage uses and the prevalence of hypertension in the United States.

Lung cancer remains the leading cause of cancer deaths in the United States despite public health campaigns aimed at reducing its rate of mortality. Kentucky is the state with the highest lung cancer incidence and mortality. This study aims to assess the impact of misclassification of cause of death from Lung Cancer in Kentucky for the period 1979 to 2002. We will examine the potential competing classification of death for two other smoking-related diseases, Chronic Obstructive Pulmonary Disease (COPD) and Emphysema. Age-adjusted mortality rates for these diseases for white males were obtained from the National Center for Health Statistics. There was little evidence that any misclassification between COPD or Emphysema mortality rates was in agreement with the rising lung cancer rates in Kentucky. The long-term increase in lung cancer mortality in Kentucky is likely because of a combination of risk effects between smoking and other risk-factors for this disease.

Mortality rates in developing countries have shown a rapidly declining trend since the end of World War II. Countries like Malaysia, Taiwan, Mauritius, Jamaica, and Mexico have increased life expectancy at birth at an average of over a year annually between the 1940's and 1960's (Gwatkin, 1980:616). There appeared to be special causes; probably due to control of endemic disease. Many developing countries have recorded life expectancy gains three or more times as great as those achieved in Western Europe at a comparable stage in its mortality transition (Gwatkin, 1980:616).

Gender, minority, and regional-related disparities have been documented in diabetes management. Self-efficacy, the belief in one's ability to carry out the actions mandated by a task, has been identified as a key predictor in glycemic control; however, it has not been investigated in rural, female populations. This cross-sectional, correlation investigation examined the relationships among self-efficacy, depression, and diabetes self-care management in women living in Appalachia with type 2 diabetes. Using Bandura's Social Cognitive Theory, 85 women ages ≥ 21 with type 2 diabetes for a minimum of 6 months who were residents in Appalachia completed the 1) Diabetes Self-Efficacy Scale, 2) Beck Depression Inventory-II, 3)Summary of Diabetes Self-Care Activities, and a 4) Diabetes Health-Related Demographics tool. Descriptive statistics detailed the sample characteristics. ANOVA, chi-square, and independent t-tests were computed for between group differences as they related to depression, various physiologic states, presence of self-efficacy sources, and glycosylated hemoglobin. Pearson correlation coefficients were used to describe the relationships between self-efficacy, depression, and self-care management. Multiple linear regression analyses examined prediction models for glucose control while controlling for potential confounders. Eighty-four Caucasian and one African-American enrolled in the study with a mean age of 61. The mean time since diabetes diagnosis was 7 years with a mean glycosylated hemoglobin value of 6.9% (SD=1.3). Higher self-efficacy scores were associated with a lower glycosylated hemoglobin (r-.30, p=.005) and ability to choose foods best to maintain a healthy eating plan(r-.415, p=.001). The sources of self-efficacy associated with enhanced self-care management were mastery experience and vicarious experience. There were no significant relationships between self-efficacy and depression or depression and glycosylated hemoglobin. The diabetes self-care management regression model resulted in self-efficacy and education accounting for 7.5% of the variance in glycosylated hemoglobin. Study findings support the social cognitive theory and the utility of self-efficacy as a predictor of glycemic control. Depression was not found to be a significant obstacle in this Appalachian population. Comprehending the significant relationship between self-efficacy and diabetes self-care management allows providers to modify their interventions when caring for women type 2 diabetes in the region.

De två viktigaste händelserna i varje man jordliv är födelse och död. Varje av dessa händelser händer en gång i en livtid. Varje individ kommer in i världen på en bestämd tid på en särskild dag. På samma sätt lämnar varje person denna värld på en särskild dag på en bestämd tid. Växelverkan av dessa två viktiga händelser definierar, till en stor grad, totalityen av den globala befolkningen på någon given tidsperiod. Huruvida det finns befolkningboom/explosionen, eller kollapsen i världen beror i sin helhet på dessa två naturliga källor. Några demographers, klassificerar emellertid flyttning (dvs. emigration och invandring eller inflyttning och ut-flyttning) som delen av källorna av befolkningtillväxt.Antecknar dessa händelser, som och, när de uppstår, inte för gyckel eller en avsluta till honom, men ganska som hjälpmedel till en avsluta. Befolkningen påverkar varje aspekt av människoliv, namely: ekonomiskt, politiskt, lagligt, socialt, kulturellt, miljö-, vård-, Etc. Det är för dessa, och annat lika viktigt resonerar att folk av vision liksom John Graunt (1620-1674); Thomas Malthus (1766-1834); Herrn James Steuart (1713-1780); William Godwin (1756-1836); och något liknande sökte, i de tidig sortdagar, att ge erkännande till befolkningen utfärdar. Detta upprättar faktumet att, även om de formella sätter in av demography, är en förhållandevis ny innovation, folk long har angå om storleksanpassa och kännetecknen av deras territoriella befolkningar för mycket en lång tid. Trots dess jättelika betydelse, verkar som om det lite tid och resurser kanaliseras in i befolkningledning i samtidaa tider.I Ghana som i många ett u-land mycket lite uppmärksamhet har givits sätta in av på varandra följande regeringar. Denna low-profile inställning in mot befolkning utfärdar, över åren, har motsatt påverkats landets samhällsekonomiska och politiska framsteg. Jag kan inte vara för fel att förutsätta att riktig utveckling har undsluppit mest afrikanska länder och framkallningsvärlden på stort främst, därför att sammanlagt av dessa länder riktig uppmärksamhet inte har varit fallen föra befolkningmaterier. Är det inte riktigt att brist av den riktiga metoden och resurser är det huvudsakligt orsakar av ledare seemingly care-free inställning in mot befolkning utfärdar i dessa ett u-land i förflutnan? Även om det kan verka, att många bevattnar, har passerat under överbrygga, och, att, saker verkar för att ha stupat apart (Chinua Achibe) där är alltid ett fönster av flykten, när alla dörrar är stängda.Informations- och kommunikationsteknologier (ICTs) är den nya utvecklingen av fönster och flyktruttar ut ur många hitherto oöverstigliga problem. Därför i detta te, skulle jag något liknande för att undersöka och undersöka hur ICTs och det berömda nya/sociala massmedia kan hjälpa att lätta problemet av non-registreringen eller den otillräckliga registreringen av livsviktiga händelser i Ghana.
THE two most important events in every man’s Earth life are birth and death. Each of these events happens once in a life time. Every individual comes into the world at a certain time on one particular day. In the same way, every person leaves this world on one particular day at a certain time. The interaction of these two important events define, to a large extent, the totality of global population at any given time period. Whether there is population boom/ explosion or collapse in the world as a whole depends on these two natural sources. Some demographers, however, classify migration (i.e. emigration and immigration or in-migration and out-migration) as part of the sources of population growth.Recording these events as and when they occur is not for fun or an end to itself, but rather as a means to an end. Population affects every aspect of human life, namely: economic, political, legal, social, cultural, environmental, health, etc. It is for these and other equally important reasons that people of vision such as John Graunt (1620-1674); Thomas Malthus (1766-1834); Sir James Steuart (1713-1780); William Godwin (1756-1836); and the like sought, in those early days, to give recognition to population issues. This establishes the fact that although the formal field of demography is a relatively recent innovation, people have long been concerned about the size and characteristics of their territorial populations for a very long time. In spite of its enormous importance, it appears that little time and resources are channeled into population management in contemporary times.In Ghana, as in many developing countries, very little attention has been given the field by successive governments. This low-profile attitude towards population issues has, over the years, adversely affected the country’s socio-economic and political progress. I may not be too wrong to postulate that true development has eluded most African countries and the developing world at large mainly because in all of these countries proper attention has not been given to population matters. Is it not true that lack of proper method and resources are the main causes of leaders’ seemingly care-free attitude towards population issues in these developing countries in the past? Even though it may seem that many waters have passed under the bridge and that, things seem to have fallen apart (Chinua Achibe) there is always a window of escape when all doors are closed.Information and Communication Technologies (ICTs) are the new generation of windows and escape routes out of many hitherto insurmountable problems. Therefore, in this thesis, I would like to explore and examine how ICTs and the famous new/social media may help alleviate the problem of non-registration or inadequate registration of vital events in Ghana.

The United States continues to be affected by a severe, long-standing nursing shortage that is not projected to resolve within the next 10 or more years. Unsuccessful passage of the National Council Licensure Examination for Registered Nurses (NCLEX-RN) among graduate nurses remains one of several key contributors to the nursing shortage. The goal of this study was to identify if either cumulative fall semester GPA; the overall prenursing science, mathematics, and English GPA; type of high school background; TOEFL score; clinical pass or fail; and on-time program completion best predicted passage of NCLEX-RN. Archived records from the academic years of 2006-2010 of students/graduates of a small, private BSN program were analyzed. A nonconcurrent, prospective design of secondary data was guided by the theoretical implications of the Seidman retention formula that surmises that early identification of academic problems is a necessary precursor to implementations that promote academic success. Significant, positive correlations were found between GPA of prenursing courses and achievement in clinical courses and on-time nursing program completion. Forward and backward, logistic regression procedures revealed that clinical performance was the strongest predictor of NCLEX-RN success but with an inverse relationship. Implications for positive social change include retention of BSN students to improve graduation rates. This ultimately will foster achievement on the NCLEX-RN, resulting in more graduates will be able to competently serve the health care needs of individuals and communities and alleviation of the nursing shortage.

Objetivo: Discutir criticamente, descrever e analisar os dados de óbitos infantis disponibilizados pelos serviços públicos da província de Cabinda-Angola. Método: Foram estudados nascimentos vivos em hospitais da província de Cabinda, e óbitos de menores de um ano de idade, nos anos 2007 e 2008. Como fonte de dados foram utilizados os registrados nos livros de registro dos hospitais municipais, d o hospital provincial e do escritório provincial da OMS de Cabinda. Os dados são contextualizados pela experiência do autor como habitante da região. Resultados: Os resultados deste trabalho mostram que em 2008 morreram mais crianças no primeiro dia de vida (109) que nos 11 meses restantes (97). Contudo, evidencia-se que 200 óbitos (54,64 por cento ) ocorreram em menores de 28 dias de idade em 2007 enquanto que para o mesmo período em 2008 morreram 178 crianças, Quanto às causas básicas de mortes infantis, a malária é destacada como principal causa. Isoladamente a malária responde aproximadamente por uma morte a cada três crianças falecidas. Dentre as doenças evitáveis por vacinação, o tétano responde por cerca de 5 por cento das mortes. Entre as doenças controláveis por saneamento básico, as diarréias ocupam posição de destaque 9,83 por cento em 2007 e 3,27 por cento em 2008. A redução de 65 para 40 óbitos por pneumonia entre as crianças inscreve-a como segunda ou terceira causa mais importante de óbito entre as crianças cabindenses, partilhando espaço com a asfixia neonatal (17,75 por cento em 2007 e 26,90 por cento em 2008). Apesar das dificuldades e limitantes da qualidade das informações encontradas durante a coleta de dados, buscou-se valorizar as existentes e que foram analisa das neste trabalho. Conclusões: Os resultados obtidos indicam que em Cabinda, melhorias na qualidade de assistência pré-natal, ao parto e ao recém-nascido de risco, poderiam reduzir ainda que parcialmente a Mortalidade Infantil. Fatores como condições inadequadas de abastecimento de água, falta de saneamento básico, dentre outros, revelaram ter papel importante como condicionantes da elevada Mortalidade Infantil observada em Cabinda. Apesar de ser atraente priorizar investimentos dos recursos em ações curativas, este trabalho reforça a perspectiva revisitar as políticas locais de Saúde e priorizar as atividades preventivas nos municípios da grande Cabinda. Assim, sugere-se a implantação de uma rede primária de assistência à saúde e um investimento permanente na melhoria da qualidade das informações de Saúde
Objective: To critically discuss, describe and analyze the infant deaths data available for public services in the province of Cabinda-Angola. Method: A total of live births in hospitals in the province of Cabinda, and deaths of children under one year of age, in years 2007 and 2008. The data source were used those recorded on the records of municipal hospitals, the provincial hospital and the provincial office of WHO in Cabinda. The data are contextualized by the author\'s experience as an inhabitant of the region. Results: The results of this study suggested that in 2008 more children died in the first days of life (109) than in the remaining 11 months (97). However, it is clear that 200 deaths (54.64 per cent ) occurred in children younger than 28 day- old in 2007 while for the same period in 2008 died 178 children. As the root causes of child deaths, malaria is highlighted as the main cause. Malaria alone accounts for approximately one death every three children who die. Among the vaccinepreventable diseases, tetanus accounts for about 5 per cent of deaths. Among the diseases controlled by sanitation, diarrhea, occupy a prominent position in 2007, 9.83 per cent and 3.27 per cent in 2008. The reduction from 65 to 40 deaths from pneumonia among children falls as the second or third most important cause of death among children Cabinda, sharing space with neonatal asphyxia (17.75 per cent in 2007 and 26.90 per cent in 2008). Despite the difficulties, limiting the quality of information found during the data collection, we sought to enhance existing ones, which were analyzed in this work. Conclusions: The results indicate that in Cabinda, improvements in quality of prenatal care, childbirth and the newborn at risk, even partially could reduce infant mortality. Factors such as inadequate water supply, poor sanitation, among others, were found to have important role as determinants of high infant mortality observed in Cabinda. Despite being attractive investments prioritize resources on curative actions, this work reinforces the perspective of revisit policies and prioritize local health preventive activities in the great area of Cabinda. Thus, we suggest the establishment of a network of primary health care and an ongoing investment to improve the quality of information on Health

BACKGROUND:Heart failure is sometimes incorrectly listed as the underlying cause of death (UCD) on death certificates, thus compromising the accuracy and comparability of mortality statistics. Statistical redistribution of the UCD has been used to examine the effect of misclassification of the UCD attributed to heart failure, but sex- and race-specific redistribution of deaths on coronary heart disease (CHD) mortality in the United States has not been examined.METHODS:We used coarsened exact matching to infer the UCD of vital records with heart failure as the UCD from 1999 to 2010 for decedents 55years old and older from states encompassing regions under surveillance by the Atherosclerosis Risk in Communities (ARIC) Study (Maryland, Minnesota, Mississippi, and North Carolina). Records with heart failure as the UCD were matched on decedent characteristics (five-year age groups, sex, race, education, year of death, and state) to records with heart failure listed among the multiple causes of death. Each heart failure death was then redistributed to plausible UCDs proportional to the frequency among matched records.RESULTS:After redistribution the proportion of deaths increased for CHD, chronic obstructive pulmonary disease, diabetes, hypertensive heart disease, and cardiomyopathy, P<0.001. The percent increase in CHD mortality after redistribution was the highest in Mississippi (12%) and lowest in Maryland (1.6%), with variations by year, race, and sex. Redistribution proportions for CHD were similar to CHD death classification by a panel of expert reviewers in the ARIC study.CONCLUSIONS:Redistribution of ill-defined UCD would improve the accuracy and comparability of mortality statistics used to allocate public health resources and monitor mortality trends.

Diabetes is a major risk factor for the development of cataract [3,14,20,22]. In this thesis, we create a model that allows us to understand the incidence of one disease in the context of another; in particular, cataract in the presence of diabetes. The World Health Organization's Vision 2020 blindness-prevention initiative administers surgeries to remove cataracts, the leading cause of blindness worldwide [24]. One of the geographic areas most impacted by cataract-related blindness is Sub-Saharan Africa. In order to plan the number of surgeries to administer, the World Health Organization uses data on cataract prevalence. However, an estimation of the incidence of cataract is more useful than prevalence data for the purpose of resource planning. In 2012, Dray and Williams developed a method for estimating incidence based on prevalence data [5]. Incidence estimates can be further refined by considering associated risk factors such as diabetes. We therefore extend the Dray and Williams model to include diabetes prevalence when calculating cataract incidence estimates. We explore two possible approaches to our model construction, one a detailed extension, and the other, a simplification of that extension. We provide a discussion comparing the two approaches.

RESUMO As informações sobre a mortalidade são tradicionalmente uma importante fonte de dados para estudos epidemiológicos, demográficos e para o planejamento em saúde. As estatísticas de mortalidade por causa são usualmente apresentadas segundo a causa básica de morte; a cada óbito corresponde uma só causa. Este método tem sofrido criticas devido a algumas de suas limitações, principalmente em relação às doenças crônicas quando, geralmente, estão presentes várias causas no momento da morte e apenas a básica é selecionada. As estatísticas de mortalidade segundo as causas múltiplas de morte se apresentam como um método alternativo para o estudo das causas de morte. A introdução dos computadores permitiu o desenvolvimento nos Estados Unidos de um sistema automático para classificar além da causa básica todos os demais diagnósticos mencionados nos atestados de óbito. Esse sistema, denominado ACME (Automated Classification of Medical Entities) amplia muito as possibilidades do uso das estatísticas de mortalidade e desde 1983 vem sendo utilizado no processamento de dados sobre os óbitos ocorridos no Estado de São Paulo. O presente trabalho discute a potencialidade do uso das causas múltiplas de morte para o estudo da mortalidade e apresenta algumas formas para a tabulação e a análise destas estatísticas exemplificadas com o arquivo de dados sobre os óbitos ocorridos em 1983 no Estado de São Paulo. Por meio da análise do número de diagnósticos informados na declaração de óbito mostrou-se um número médio maior dos mesmos em relação aos achados em trabalhos acadêmicos realizados com óbitos de períodos anteriores. 0 estudo das menções de todos os diagnósticos permitiu evidenciar a importância relativa maior de certas causas selecionadas como causa básica menos frequentemente. A análise das associações das causas de morte mostrou a importância do inter-relacionamento das doenças na determinação de morte e sugeriu outros usos das causas múltiplas. A distribuição conjunta das causas externas de morte com os dados sobre a natureza da lesão e a análise desta última segundo o sexo e a idade apresentam-se como nova perspectiva para a compreensão das mortes violentas. O levantamento e a discussão de questões metodológicas sugerem novas áreas de investigação para o estudo das causas múltiplas de morte
SUMMARY Informations about mortality are traditionally an important source of data for epidemiologic and demographic studies as well as for health planning. Mortality statistics based on causes have been derived from the underlying cause of death, implying that for each dead person only one cause is presented. These statistics have been criticised on account of their limitations, mainly when chronic diseases are considered and several causes are responsible for the death. Multiple cause mortality statistics represent an alternative method for the study of causes of death. The advent of computers made possible, in the United States, the development of an automated system for selecting the underlying cause of death as well as for coding all the reported conditions on the death certificate. This system, called ACME (Automated Classification of Medical Entities), greatly enlarges the possibilities of mortality statistics and it is used since 1983 to produce mortality data in the State of São Paulo. This thesis discusses the potential use of multiple cause of death for mortality studies and present some ways of its tabulations and analysis through examples which use the data file of death that occurred in 1983 in the State of São Paulo. The tabulation of the number of different diagnoses reported on the death certificate showed that its median number has increased when compared with the results of academic studies undertaken in other periods of time. The study of all mentions of the reported diagnoses depicted the greater importance of some causes of death infrequently selected as the underlying cause of death. The analysis of associations of causes of death revealed the importance of the combination of diseases to the determination of the death and allowed suggestions for other applications of multiple cause data. The cross tabulation of external causes of death with data related to the nature of injury and the analysis of the nature of injury by age and sex enhance new perspectives for the description and understanding of violent deaths. Methodological questions raised and discussed in this thesis suggest new areas of investigation for the study of multiple causes of death

Orientador: Djalma de Carvalho Moreira Filho
Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas
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Resumo: A informação sobre incidência de câncer, obtida através dos registros de câncer de base populacional - RCBP é um componente essencial de qualquer estratégia de controle de câncer. Nos últimos vinte anos o papel dos registros de câncer tem se ampliado, incorporando o planejamento e avaliação das atividades de controle de câncer. Neste cenário, torna-se de fundamental importância a qualidade das informações fornecidas pelos registros. Uma breve revisão das metodologias para realizar o controle de qualidade dos dados nos registros de câncer, das mais tradicionalmente utilizadas às alternativas propostas torna claro que tais processos não são de fácil aplicação. O RCBP de Porto Alegre foi escolhido para verificar a aplicabilidade desta metodologia à realidade dos registros de câncer brasileiros. O Método de Fluxos apresenta-se neste contexto como adaptável a registros de câncer de diferentes padrões, de rápida execução e sem custos financeiros adicionais. O método proposto permite que o registro de câncer estabeleça uma rotina de vigilância de cobertura, segundo variáveis, tais como, localização primária, idade, sexo e área geográfica.
Abstract: Population-based cancer registries are essential to public health and research. The cancer registries provide information on the surveillance of cancer incidence and survival. At the last 20 years, because of the emerging importance of cancer as a health problem, the cancer registries play a important role to evaluate and to frame public health policy to cancer control. A high-quality cancer registration is fundamental to monitoring cancer burden and identifies patterns and trends in various population groups, in different geographic areas, and over time. Cancer registries try to achieve maximum completeness in case-findings procedures in order to ensure that comparative studies are not distorted by variations on efficacy of registry procedures. A brief review about available methods used to estimate completeness of cancer registrations shows that these methodologies are not easy to use, especially in developing countries. The PBCR Porto Alegre was chosen to verify if the method could be applied to Brazilian cancer registries reality. In this context the Flow Method claims to be adaptable to cancer registries with different patterns of registration and can be executed rapidly and inexpensively. The proposed method allows to a cancer registry to provide a routine surveillance of completeness by variables such as tumor site, age, sex and geographic area.
Doutorado
Saude Coletiva
Doutor em Saude Coletiva

The aim of this dissertation was to analyse social and geographical inequalities in mortality in Ecuador, correcting the potential deficiencies found in the mortality registry. For this purpose, four studies were developed. In the first study we found that, at the national and provincial levels, the mortality registry of Ecuador performs poorly both in terms of completeness and quality. In most of the studied areas, indicators were poorer for the mortality registry in women. Moreover, quality and completeness were lower in the Amazon, central Andean, and northern Coastal regions where historically excluded groups have traditionally lived. In the second study, after correcting deficiencies in the completeness and quality of the mortality registry in the country, we observed not only changes in the number of deaths, but also in the geographic patterns of mortality risks due to some of the main causes of death in women and men. In the third study, a clear geographical pattern of material deprivation in the country was evidenced. High levels of material deprivation were found in areas in the northern Coastal, central Andean and Amazonic regions. In the final study of the dissertation, unique patterns of specific cause of death mortality were observed in women and men in the country. Moreover, many of the main causes of death in men and women were positively associated with material deprivation.
El objetivo principal de esta tesis doctoral fue analizar desigualdades sociales y geográficas en la mortalidad en Ecuador, corrigiendo las potenciales deficiencias que se puedan encontrar en el registro de mortalidad. Para conseguir este fin, se realizaron cuatro estudios. En el primer estudio, se encontró que el registro de mortalidad tiene un pobre desempeño tanto en cobertura como en calidad (a nivel nacional y provincial). Los indicadores analizados fueron peores en el registro de mujeres en la mayoría de las áreas estudiadas. Las áreas con peores indicadores de cobertura y calidad se encontraron en la Costa norte, la Sierra central y en la Amazonía. En el segundo estudio observamos que, después de corregir deficiencias en el registro de mortalidad, no sólo hubo importantes cambios en el número de muertes, sino también en los patrones geográficos de los riesgos de mortalidad por algunas de las principales causas en mujeres y hombres. En el tercer estudio, se evidenció un claro patrón geográfico de la privación material en los cantones de Ecuador. Áreas con altos niveles de privación material se concentraron en la Costa norte, Sierra centro y Amazonía. En el estudio final de la tesis doctoral, se pueden observar distintos patrones geográficos de riesgo de mortalidad según causa y sexo. La privación material a nivel cantonal se asocia positivamente con muchas de las principales causas de mortalidad en mujeres, hombres, o en ambos sexos.

Introdução: As estatísticas de mortalidade são usadas pelo mundo inteiro e por isso precisa ter dados confiáveis e comparáveis. Uma das estratégias para melhorar sua qualidade é a automação de etapas do fluxo dos dados. O Iris é um sistema que codifica as causas de morte da declaração de óbito (DO) e seleciona a causa básica de morte. Objetivos: adaptar o software para uso no Brasil, testá-lo e comparar seu uso com a codificação manual e com a seleção do sistema usado na rotina brasileira, o Sistema de Seleção da Causa Básica de Morte (SCB). Métodos: foram utilizadas uma amostra de declarações de óbito de óbitos ocorridos no período de janeiro a junho de 2014 em nove cidades representando as cinco regiões do Brasil. Foram selecionados óbitos pelas causas mais comuns, com menção de doença transmissível, assim como óbitos infantis, maternos e óbitos com menção de causa externa ou cirurgia. A fase 1 visou a conclusão do dicionário e a fase 2 testar e comparar o uso do Iris. Resultados: 1848 DO, com uma média de 3,1 linhas preenchidas por DO. Foram realizadas 618 ajustes ou adições nas tabelas do dicionário ou nas tabelas de padronização. Em 45,9 por cento das DO o Iris codificou todas as causas de morte presente na DO assim como selecionou a causa básica de morte. Das DO que o Iris não conseguiu concluir o processo, a maioria (97,8 por cento) dessas rejeições foi por dificuldade em encontrar ou processar um código da CID. A concordância do Iris com a codificação manual nos níveis de 4 caracteres, 3 caracteres e 1 caractere dos códigos da CID-10 foi de 73,3 por cento, 78,2 por cento e 83,9 por cento respectivamente. Isso representou uma discordância em 49,1 por cento das DO. A concordância da causa básica de morte com o SCB foi de 74,2por cento, 84,3 por cento e 91,8 por cento nos níveis de 4 caracteres, 3 caracteres e 1 caractere dos códigos da CID-10 respectivamente. A principal causa de discordância (71 por cento) foi por codificações diferentes. Após as pequenas correções, o Iris finaliza 66,6 por cento das DO. Conclusão: As discordâncias tiveram como causa os hábitos e rotinas dos codificadores que variam entre eles, enquanto no Iris a codificação de uma causa é sempre a mesma. As tabelas de decisão do SCB precisam ser revistas. Os dados mostram que é possível usar esta ferramenta e que ela vai diminuir o trabalho dos codificadores. O Iris teve uma boa taxa de finalização, semelhante a países que o utilizam na sua rotina.
Introduction: Mortality statistics is used all over the world and therefore needs reliable and comparable data. One of the strategies to improve quality is an automated data collection. Iris is a system that codes the causes of death of the death certificate (DC) and selects the underlying cause of death. Objective: To adapt Iris software to Brazil finalising the Portuguese dictionary, to test Iris and to compare it with manual coding and with the selection of the Basic Death Cause Selection System (Portuguese acronym is SCB). Methods: The sample was death certificates occurred from January to June of 2014 in nine cities representing the five regions of Brazil. Were selected to compose the sample: routine deaths, DC with mention of communicable disease, infant death, maternal death and DC with mention of external cause or surgery. Phase 1 aimed to complete the dictionary and phase 2 aimed to test and compare Iris. Results: The sample was1848 DC, with an average of 3.1 lines filled by DC. There were 618 adjustments or additions to dictionary tables or standardization tables. In 45.9 per cent of DC Iris coded all causes of death and selected the underlying cause of death. Of the DC that Iris was unable to complete the process, the majority (97.8 per cent) of these rejections were due to difficulty in finding or processing an ICD code. Iris agreement with manual coding at the 4-character, 3- character, and 1-character levels of ICD-10 codes was 73.3 per cent, 78.2 per cent and 83.9 per cent, respectively. This represented a disagreement in 49.1 per cent of DC. The concordance of the underlying cause of death with SCB was 74.2 per cent, 84.3 per cent and 91.8 per cent at the 4- character, 3-character and 1-character levels respectively. The main cause of discordance (71 per cent) was by different codes for the same cause of death. After the small corrections, Iris finalised 66.6 per cent of the DC. Conclusion: The disagreements were caused by coders routines that can vary between them, whereas in Iris the codification of a cause is always the same. The SCB decision tables need to be reviewed. The data show that it is possible to use this tool and that it will decrease the work of the coders. Iris had a good finalisation rate, similar to countries that use it in their routine.

Introdução - Uma das formas de se aumentar a qualidade das informações sobre causas de morte é automatizar o processo de sua elaboração. O software Iris é um dos mecanismos disponíveis para esse fim. Suas principais características é que ele segue as regras internacionais de mortalidade e ele é independente de idioma. Objetivo - Elaborar para o Iris um dicionário na língua portuguesa e avaliar a sua completitude para a codificação das causas de morte. Método - O dicionário criado com dados do arquivo eletrônico do volume 1 da CID-10 e com o Tesauro da Classificação Internacional de Atenção Primária. Foi utilizado o Iris V4.0.34 e, como codificação manual, o que o Programa de Aprimoramento das Informações de Mortalidade no Município de São Paulo (PRO-AIM) da Secretaria Municipal de Saúde de São Paulo escreveu nas declarações de óbito. Caso o Iris não codificasse as causas de morte, ajustes eram feitos no dicionário ou na tabela de padronização. Resultado - O Iris é capaz de codificar as causas de morte e selecionar a causa básica de morte, ambas automaticamente, é um software recente que está em constantes adequações, é independente de idioma e para usá-lo em cada país é necessário realizar somente um dicionário de causas de morte. No teste para avaliação da primeira versão do dicionário em português, o Iris apresentou um desempenho satisfatório. Foi capaz de codificar diretamente 50,6 por cento das declarações de óbito e, após ajustes e acréscimos no dicionário e na tabela de padronização, o software codificou todas as linhas em 94,44 por cento das declarações. Das declarações não codificadas completamente 89,19 por cento delas tinham algum diagnóstico contido no capítulo XX da CID-10. O Iris apresentou 63,1 por cento de concordância nas declarações de óbito pareadas considerando todas as causas de morte com códigos completos de 4 caracteres da CID-10. Conclusão - A realização dos ajustes no dicionário ou na padronização faz parte do processo de desenvolvimento do dicionário e que esse processo é continuo. Com as novas versões do Iris e atualizações e aprimoramento da codificação das causas externas, avanços serão feitos para que ele seja mais compatível com a realidade brasileira. Somado a isso, as futuras versões do Iris com um dicionário mais desenvolvido podem satisfazer as necessidades de codificação automática e melhorar a precisão dos dados de causa morte paras estudos de saúde pública.
Introduction - One way to increase the quality of causes-of-death statistics is to use computers for applying the rules systematically. Iris software is an available system for this purpose. Its main characteristics are that it follows international rules of mortality and it is language independent. Objective - Produce a Portuguese dictionary for Iris and assess its completeness of coding of causes of death. Methods - The creation of the dictionary used two sources: the electronic file of volume 1 of ICD-10 and Thesaurus of Classificação Internacional de Atenção Primária. Was used Iris V4.0.34 and for manual coding the codes at the Programa de Aprimoramento das Informações de Mortalidade no Município de São Paulo (PRO-AIM) of Secretaria Municipal de Saúde of São Paulo has written on death certificates. If Iris couldnt codify the causes of death, adjustments were made in the dictionary or standardization table. Results - Iris is able to encode causes of death and select the underlying cause of death, either automatically; is a recent software that is in constant adjustments; is a language independent software and to use it in your country you need only dictionary of causes of death. In the test for evaluation the first version of the Portuguese dictionary Iris showed satisfactory performance. He was able to code directly for 50.6 per cent of death certificates and, after adjustments and additions in the dictionary and standardization table, the software coded all lines in 94.44 per cent of death certificate. The statements do not fully coded 89.19 per cent had a diagnosis contained in Chapter XX of ICD-10. Iris presented 63,1 per cent agreement on paired death certificates considering all causes of death and 4-digit ICD-10 code level. Conclusion - making adjustments in the dictionary or the standardization is part of the development process of the dictionary and that this process is ongoing. With new Iris versions and updates in the management of the coding external causes, progress will be made to make it more compatible with the Brazilian reality. Added to this, future versions of Iris with a dictionary more developed can meet the needs of auto-tagging and improve the accuracy of data causes death to public health studies.

O Serviço de Verificação de Óbitos (SVO) foi criado para elucidar causas de óbitos naturais mal definidas por meio de exames necroscópicos e registrar informações mais completas sobre as causas de morte no Sistema de Informação de Mortalidade (SIM). Desde a criação da rede nacional de SVO, poucos estudos avaliaram a qualidade dos registros de óbitos dos SVO no SIM. Foram estudados 19780 registros de óbitos não fetais de residentes no Estado do Tocantins entre os anos de 2012, 2011 e 2012, obtidos por download do site do DATASUS do Ministério da Saúde. Além de estabelecer o perfil social demográfico dos óbitos, foram estudadas a completude das informações, as cinco principais causas de morte e as causas básicas registradas pelo SVO e demais atestantes dentro do SIM. Óbitos do sexo masculino, cor parda, casados, sem escolaridade, hospitalares de aposentados e maiores de 75 anos predominaram. A incompletude de dados registrados no SIM para o Estado do Tocantins foi superior a 10% e não houve diferença estatística significativa entre a completude de dados registrados pelo SVO e pelos demais atestantes. As doenças do aparelho circulatório foram as principais causas de morte registradas pelos atestantes, exceto pelo IML, onde as causas externas predominaram. 15% dos registros de causas básicas externas não pertenciam ao IML e o SVO apresentou uma grande proporção de registros de causas básicas mal definidas. A qualificação das informações sobre mortalidade, imprescindível à elaboração de políticas públicas sanitárias, persiste desafiadora no Estado do Tocantins. A criação de uma cultura da informação epidemiológica passa pela inserção curricular, educação e sensibilização médica continuada.
The Death Verification Service (SVO) was created to elucidate causes of natural deaths poorly defined by postmortem examinations and record more complete information on the causes of death in the Mortality Information System (SIM). Since the establishment of the national network of SVO, few studies have evaluated the quality of death records of SVO SIM. We studied 19780 no fetal death records of residents in the State of Tocantins between the years 2012, 2011 and 2012, downloaded the DATASUS website of the Ministry of Health. In addition to establishing the demographic social profile of the deaths were studied completeness information, the five leading causes of death and root causes recorded by the SVO and other informers within the SIM. Deaths male, mulatto, married, uneducated, retired hospital and over 75 years predominated. The incompleteness of data in SIM for the State of Tocantins was higher than 10% and there was no statistically significant difference between the completeness of data recorded by the SVO and the other informers. The circulatory diseases were the main causes of death recorded by informers except for IML, where external causes predominated. 15% of the records of external root causes did not belong to the IML and the SVO had a large proportion of ill-defined basic causes records. The qualification of information on mortality, essential to the development of health policies, remains defiant in the State of Tocantins. Creating a culture of epidemiological information passes through curriculum integration, education and continuing medical awareness.

Orientadores: Jose Guilherme Cecatti, Ellen Hardy
Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas
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Resumo: Objetivos: inicialmente o objetivo foi identificar os óbitos registrados como maternos no ¿Sistema de Informações sobre Mortalidade¿ (SIM), os nascimentos no ¿Sistema de Informações sobre Nascidos Vivos¿ (SINASC), obter as Razões de Mortalidade Materna (RMM) e identificar diagnósticos e procedimentos aproximados pelos critérios mais conhecidos de morbidade materna grave, analisando as mortes de mulheres residentes nas capitais brasileiras no ¿Sistema de Informações Hospitalares¿ (SIH) em 2002. Posteriormente o objetivo foi identificar no SIH todos os registros de mulheres no período grávido-puerperal que tivessem informações indicativas de morbidade materna grave; descrever os diagnósticos e procedimentos utilizados, propor a definição de um escore de morbidade materna e identificar as variáveis associadas à morte materna. Método: Estudo descritivo, populacional, análise de dados secundários. Inicialmente utilizaram-se dois sistemas vitais e o hospitalar, para as 26 capitais estaduais e o Distrito Federal do Brasil, em 2002. Para a primeira etapa foram obtidas as RMM e informações básicas das mortes maternas declaradas. A partir dessas mortes relacionou-se probabilisticamente o SIM com o SINASC e, em seguida, com o SIH, utilizando-se o programa ¿Reclink II¿, com estratégia de blocagem em múltiplos passos. Em seguida, realizou-se análise descritiva simples. Para a segunda etapa, as principais variáveis foram o diagnóstico principal e secundário e o procedimento solicitado e realizado durante a internação. Houve uma seleção inicial de registros de mulheres de 10 a 49 anos de idade, seguida de uma seleção daquelas que apresentaram pelo menos um item indicativo de morbidade materna grave (near miss). Para os relacionamentos do SIH com o SIM e do SIH com ele mesmo, estabeleceu-se estratégia de blocagem em três passos independentes. Para a análise dos dados foram calculadas as razões de near miss, descritos os diagnósticos e procedimentos, utilizada a técnica multivariada de componentes principais e ajustado o modelo de regressão logística. Resultados: Foram identificadas 339 mortes maternas em 2002, com RMM oficial e ajustada, respectivamente, de 46,4 e 64,9 (mortes por 100.000 nascidos vivos). Com o primeiro relacionamento foi possível localizar 46,5% das mortes maternas e, com o segundo, localizaram-se 55,2% das mortes. O diagnóstico mais freqüente foi o de infecção (13,9%), e o procedimento com maior porcentagem (39,0%) foi o de admissão à UTI. Para a segunda etapa, a RNM para o total dos municípios foi de 44,3/ 1.000 nascidos vivos. Foram identificadas 154 mortes maternas dentre os registros indicativos de near miss. A análise descritiva apontou como mais freqüentes os critérios graves relativos a infecção, pré-eclâmpsia e hemorragia. A análise por regressão logística resultou em 12 variáveis, entre elas quatro interações significativas. Conclusões: Os diagnósticos e procedimentos relatados no SIH mostraram a gravidade da condição mórbida materna em 66% dos óbitos maternos declarados, apesar das inconsistências entre os diversos sistemas. Para a segunda etapa, conclui-se que, apesar das limitações existentes no SIH, é promissora a perspectiva de utilizá-lo de forma rotineira, mas com esforços no sentido de melhorar a qualidade da AIH
Abstract: Objectives: initially the objective was to identify maternal deaths in the ¿Mortality Information System¿ (SIM), births in the ¿Live Births Information System¿ (SINASC), to obtain the Maternal Mortality Ratios (MMR) and to identify diagnosis and procedures related with the most common criteria of severe maternal morbidity, evaluating the deaths of women living in Brazilian capitals in the ¿Hospital Information System¿ (SIH) in 2002. Sequentially the objective was to identify in SIH all registers from women during pregnancy, delivery and post partum period who had information indicating severe maternal morbidity; to describe the diagnosis and procedures used; to propose a score of maternal morbidity and to identify variables associated to maternal death. Method: A population descriptive study, secondary data analysis. For the first step two vital systems and hospital system for the 26 capitals and the Federal District of Brazil, in 2002, were used. The MMR and basic information on maternal deaths were obtained. Using data available for these deaths, SIM was probabilistically linked with SINASC and after with SIH, using the software ¿Reclink II¿, with a multiple steps blocking strategy. Simple descriptive analysis was then performed. For the second step the main variables were the primary and secondary diagnosis and the requested and performed procedure during hospitalization. Initially there was a selection of registries of women between 10 and 49 years of age, followed by a selection of those presenting at least one criteria indicating severe maternal morbidity (near miss). For the linkages of SIH with SIM and with itself, a three independent steps blockage strategy was established. For data analysis the Near Miss Ratios were calculated and the diagnosis and procedures were described; the multivariate technique of principal components was used and then a logistic regression model was adjusted. Results: 339 maternal deaths were identified in 2002 with an official and adjusted MMR of respectively 46.4 and 64.9 (maternal deaths per 100.000 live births). With the first linkage it was possible to find 46.5% of the maternal deaths and 55.2% with the second one. The most frequent diagnosis was infection (13.9%) and the most frequent procedure was admission to ICU (39.0%). For the second step, the NMR for the total municipalities was 44,3/ 1.000 live births. Among the registries indicating near miss, 154 maternal deaths were identified. The descriptive analysis pointed out as more frequent the severe criteria related to infection, pre-eclampsia and hemorrhage. The analysis with logistic regression resulted in 12 variables, among them four significant interactions. Conclusions: The diagnosis and procedures informed in the SIH showed the severity of maternal morbidity in 66% of the deaths certified as maternal, despite the inconsistencies among the different systems. For the second step, although the existing limitations in the SIH, the perspective of using it routinely is promising, but only with efforts in order to improve the quality of the document which provides information for the registry
Doutorado
Ciencias Biomedicas
Doutor em Tocoginecologia

L'évolution limite la diversité des organismes par la sélection naturelle. Nous construisons ici des modèles théoriques pour étudier l'effet des contraintes évolutives sur deux systèmes biologiques à des échelles différentes : la coévolution virale-immune et l'évolution des protéines. Nous étudions d'abord comment les systèmes immunitaires limitent le parcours évolutif des virus qui tentent constamment d'échapper aux mises à jour de la mémoire immunitaire. Nous commençons par étudier numériquement un modèle agent-based minimal régissant les interactions microscopiques entre les virus et les systèmes immunitaires dans un cadre abstrait. Ces ingrédients couplent des processus biologiques à différentes échelles - réponse immunitaire, épidémiologie, évolution - qui conjointement déterminent le résultat de l'évolution. Nous constatons que la population des systèmes immunitaires pousse les virus vers un ensemble de motifs biologiquement pertinents. Nous caractérisons ces stratégies évolutives en fonction des paramètres du modèle. Ensuite nous étudions une description à gros grains décrivant l'évolution des virus et des récepteurs immunitaires dans l'espace antigénique. Cette approche consistant en un système d'équations différentielles stochastiques couplées permet de clarifier l'interaction entre les différentes échelles qui constituent ce système phylodynamique. Nous obtenons une description analytique de la façon dont les systèmes immunitaires limitent l'évolution des virus dans l'espace antigénique, alors que les virus parviennent à maintenir une dynamique de fuite en régime permanent. Nous validons les prédictions théoriques à l'aide des simulations numériques. Dans la deuxième partie de ce travail, nous exploitons l'énorme quantité de données accessible sur les séquences protéiques pour extraire des informations sur les contraintes évolutives agissant sur les familles de protéines répétées, constituées de nombreuses répétitions de portions conservées d'acides aminés. Nous couplons un schéma d'inférence à des modèles numériques en nous appuyant sur des idées de mécanique statistique à l'équilibre afin caractériser les observables biologiques découlant d'une description probabiliste des séquences de protéines. Nous utilisons ce cadre pour étudier comment les contraintes fonctionnelles réduisent et façonnent l'espace global des séquences protéiques répétées qui survivent à la sélection. Nous obtenons une estimation du nombre de séquences accessibles, et nous caractérisons quantitativement le rôle relatif des différentes contraintes et des effets phylogénétiques dans la réduction de cet espace. Nos résultats suggèrent que les familles de protéines répétées étudiées sont contraintes par un paysage accidenté qui façonne l'espace des séquences accessibles en plusieurs sous-types groupés de la même famille. Nous exploitons ensuite le même cadre pour étudier l'interaction entre les contraintes évolutives et les corrélations phylogénétiques dans les séries de répétitions. Nous déduisons quantitativement les contraintes fonctionnelles, ainsi que l'échelle de temps relative entre les duplications/suppressions des répétitions et les mutations ponctuelles. Nous étudions et caractérisons également les mécanismes évolutifs microscopiques qui peuvent générer des motifs statistiques spécifiques entre répétitions, observés de manière récurrente dans les données. Les résultats préliminaires suggèrent que l'évolution des séries de répétitions est un processus fortement hors équilibre
Evolution constrains organism diversity through natural selection. Here we build theoretical models to study the effect of evolutionary constraints on two natural systems at different scales: viral-immune coevolution and protein evolution. First we study how immune systems constrain the evolutionary path of viruses which constantly try to escape immune memory updates. We start by studying numerically a minimal agent based model with a few simple ingredients governing the microscopic interactions between viruses and immune systems in an abstract framework. These ingredients couple processes at different scales - immune response, epidemiology, evolution - that all together determine the evolutionary outcome. We find that the population of immune systems drives viruses to a set of interesting evolutionary patterns, which can also be observed in nature. We map these evolutionary strategies onto model parameters. Then we study a coarse-grained theoretical model for the evolution of viruses and immune receptors in antigenic space consisting of a system of coupled stochastic differential equations, inspired by the previous agent-based simulations. This study sheds light on the interplay between the different scales constituting this phylodynamic system. We obtain some analytical insights into how immune systems constrain viral evolution in antigenic space while viruses manage to sustain a steady state escape dynamics. We validate the theoretical predictions against numerical simulations. In the second part of this work we exploit the enormous amount of protein sequence data to extract information about the evolutionary constraints acting on repeat protein families, whose elements are proteins made of many repetitions of conserved portions of amino-acids, called repeats. We couple an inference scheme to computational models, which leverage equilibrium statistical mechanics ideas to characterize the macroscopic observables arising from a probabilistic description of protein sequences. We use this framework to address how functional constraints reduce and shape the global space of repeat protein sequences that survive selection. We obtain an estimate of the number of accessible sequences, and we characterize quantitatively the relative role of different constraints and phylogenetic effects in reducing this space. Our results suggest that the studied repeat protein families are constrained by a rugged landscape shaping the accessible sequence space in multiple clustered subtypes of the same family. Then we exploit the same framework to address the interplay between evolutionary constraints and phylogenetic correlations in repeat tandem arrays. As a result we infer quantitatively the functional constraints, together with the relative timescale between repeat duplications/deletions and point mutations. We also investigate and map what microscopic evolutionary mechanisms can generate specific inter-repeats statistical patterns, which are recurrently observed in data. Preliminary results suggest that evolution of repeat tandem arrays is strongly out of equilibrium

Tropical cyclones (TCs) can have devastating social and economic impacts on coastal communities situated all around the globe. The impact of anthropogenic induced climate change on TC activity has attracted widespread scientific interest over the past decade, resulting in the development of a variety of approaches for TC projection in climate models. However, many uncertainties remain, including those associated with the TC detection algorithm and climate model inter-dependencies that impact projection results. This thesis seeks to address these uncertainties, as well as filling several knowledge gaps in the literature such as limited TC projection studies in the Southern Hemisphere and a global need for regional-scale TC track density projections. The independent TC detection and tracking algorithm utilised in this thesis is first evaluated to determine if it can simulate a realistic TC track climatology in reanalysis data. By way of cluster analysis, model-detected and observed TC tracks are compared and objective criteria for a consistent “TC track” definition are established. Regional-scale TC track projections are then examined in each TC basin around the globe. The exact methodology of cluster analysis in each basin is slightly modified to accommodate basin-scale differences in track climatology but generally follows a cluster assessment of TC tracks in observations, historical climate simulations and future climate projections using results from the Coupled Model Intercomparison Project Phase 5 (CMIP5) models. Regional impacts of the El Niño Southern Oscillation (ENSO) on TC tracks are also examined in current- and future-climates. Projection results are found to be supportive of existing studies, especially in the North Pacific and the Southern Hemisphere. Isolation of TC tracks into clusters indicated that the regional dominance of ENSO is well simulated by the CMIP5 models. Several regional changes in TC activity are noted and attributed to projected changes in the large-scale environment, and changes in ENSO-specific conditions.
Doctor of Philosophy

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The present study aimed to evaluate the quality of information (System coverage, completeness of the data fulfillment and reliability of the information) of SINASC in the city of Ribeirão Preto, São Paulo, through the linkage technique, comparing them to the data obtained from the project entitled Etiology factors of pre-term birth and consequences of perinatal factors on children's health , which studies birth cohorts in São Luís-Maranhão and Ribeirão Preto-São Paulo (BRISA cohort); as well as to analyze and compare the temporal trend of completeness of fulfillment of the variables of SINASC in these two Brazilian cities that make up the study of BRISA cohort, in a time series of 1996-2013. Evaluative study that analyzed the following variables: newborn sex, birth weight, Apgar indices, presence of congenital anomaly, race/color, mother's age, education, marital status, number of living children, length of gestation, type of childbirth, type of pregnancy and number of prenatal visits. The degree of concordance (reliability) of the information was evaluated by Kappa and intraclass correlation coefficients (ICC) for categorical variables and by the Bland-Altman method for numerical variables. Completeness referred to the degree of fulfillment of the field analyzed following the scoring system proposed by Romero and Cunha: excellent, when the variable presents less than 5% of incomplete fulfillment; good (5.0 to 9.9%); regular (10.0 to 19.9%); bad (20.0 to 49.9%) and very bad (50.0% or more). The trend analysis was done by estimation of polynomial regression models. In Ribeirão Preto, the estimated coverage of SINASC, in 2010, classified as good, was 88.3% (95% CI; 87.6% to 89.0%), according to the eight hospitals analyzed. In São Paulo city, the variables that showed nearly perfect or excellent agreement were: hospital of birth, newborn sex, type of pregnancy, type of childbirth, birth weight, maternal age and marital status. The variables number of prenatal visits and length of gestation obtained moderate reliability. The following variables had poor/low reliability: presence of congenital anomaly, race/color, Apgar score at 1st and 5th minutes and number of living children. On the completeness, the variables mother's age, marital status, type of pregnancy, type of childbirth, newborn sex, Apgar scores and birth weight had excellent completeness in the both cities studied. The variables congenital anomaly and race/color of the newborn obtained completeness ranging from bad to very in the capital of Maranhão, unlike the city of Ribeirão Preto, where they had a non-fulfillment percentage of less than 5%. The variable length of gestation showed variation in completeness for all time series, achieving excellence in fulfillment between the years 1999-2010. In Ribeirão Preto, this same variable had excellent completeness between 2000-2013. The chosen polynomial regression models pointed upward trend of non-fulfillment for the variable congenital anomaly in the two cities. In São Luís, the variable marital status had a declining trend for incompleteness, which did not occur in Ribeirão Preto. In São Paulo city, the variable maternal education was presented with decreasing trend of non-fulfillment, which was not evidenced in the capital of Maranhão. The other variables had decreasing trend for the incompleteness in the two cities with statistically significant values in the tested models. This research adds to the evidence of the potential of secondary data as an important source for epidemiological research. Although the results can be translated in advance, it is important to continuously invest in training in order to ensure a system capable of subsidizing policies of intervention and organization of maternal and child health.
Este estudo propôs analisar a qualidade das informações do SINASC nas cidades de São Luís- Maranhão e Ribeirão Preto- São Paulo. Em Ribeirão Preto, a técnica linkage foi utilizada para comparar os dados do SINASC com aqueles obtidos do projeto intitulado Fatores etiológicos do nascimento pré-termo e consequências dos fatores perinatais na saúde da criança, que estuda coortes de nascimentos (coorte BRISA) e a tendência temporal da completitude do preenchimento de variáveis do SINASC por modelos de regressão polinomial foi analisada nestas duas cidades brasileiras, numa série cronológica de 1996-2013. As variáveis analisadas foram: sexo do recém-nascido, peso ao nascer, índices Apgar, presença de anomalia congênita, raça/cor, idade da mãe, escolaridade, situação conjugal, número de filhos vivos, duração da gestação, tipo de parto, tipo de gravidez e número de consultas pré-natal. Em Ribeirão Preto, a cobertura estimada do SINASC, em 2010, classificada como boa, foi de 88,3% (IC95%; 87,6% a 89,0%) segundo os oito hospitais analisados. Na cidade paulista, as variáveis que apresentaram concordância quase perfeita ou excelente foram: hospital de nascimento, sexo do recém-nascido, tipo de gravidez, tipo de parto, peso ao nascer, idade da mãe e situação conjugal. As variáveis número de consultas pré-natal e duração da gestação obtiveram confiabilidade moderada. Tiveram confiabilidade sofrível/fraca as variáveis: presença de anomalia congênita, raça/cor, índice de Apgar no 1° e 5° minutos e número de filhos vivos. Sobre a completitude, as variáveis idade da mãe, estado civil, tipo de gravidez, tipo de parto, sexo do recém-nascido, índices de Apgar e peso ao nascer tiveram excelente completitude nas duas cidades estudadas. As variáveis anomalia congênita e raça/cor do RN obtiveram completitude oscilando entre ruim a muito ruim na capital do Maranhão, ao contrário da cidade de Ribeirão Preto, onde as mesmas tiveram percentual de não preenchimento menor que 5%. Em São Luís, a variável duração da gestação apresentou variação na completitude em toda a série temporal, atingindo excelência no preenchimento entre os anos de 1999-2010. Em Ribeirão Preto, esta mesma variável teve excelente completitude entre 2000-2013. A análise temporal do Sistema nas duas cidades por regressão polinomial evidenciou que a variação no preenchimento de todas as variáveis estudadas não seguiu uma ordem linear, ou seja, toda análise indicou modelos erráticos o que representou a escolha da tendência predominante a cada modelo selecionado que melhor explicava a relação entre completitude de cada variável na série de tempo analisada. Os modelos de regressão polinomial escolhidos apontaram tendência ascendente do não preenchimento para a variável anomalia congênita nas duas cidades. Em São Luís, a variável estado civil teve tendência decrescente para a incompletude, o que não ocorreu em Ribeirão Preto. Na cidade paulista, a variável escolaridade da mãe apresentou-se com tendência decrescente do não preenchimento, o que não se evidenciou na capital maranhense. As demais variáveis tiveram tendência decrescente para a incompletude nas duas cidades com valores estatisticamente significantes nos modelos testados. Da pesquisa, concluiu-se no artigo 1: A cobertura do Sistema na cidade de Ribeirão Preto, classificada como boa revela a necessidade da atenção dos gestores em saúde em ampliar estratégias e investimento em treinamento aos profissionais que preenchem a DNV; importantes variáveis da DNV que tiveram confiabilidade e completitude excelente podem ser utilizadas como cálculo de indicadores de saúde; ainda que o acesso aos serviços de saúde pública em Ribeirão Preto sejam de excelência, as informações do SINASC precisam avançar em estruturação e consolidação de dados robustos afim de que se possa garantir completa e adequada avaliação epidemiológica da saúde materno-infantil. Do artigo 2, pôde-se concluir que: Em ambas as cidades estudadas, o SINASC revelou-se em potencial como fonte de informação epidemiológica de nascimentos; a completitude mostrou-se excelente na maioria das variáveis investigadas e a análise da séria temporal sugere predominância em tendência decrescente do não preenchimento de variáveis do SINASC, configurando avanços. Ainda assim, qualificação profissional e supervisão devem ser garantidos, visto que variáveis ainda apresentam-se com limitações no preenchimento e as causas dessas limitações precisam ser mais detalhadas para que se possam efetivar estratégias de melhorias em seu preenchimento.

This research is the incorporation and melding of classical and Bayesian statistical techniques into an iterative methodology aimed at reducing two major confounding issues in Adverse Drug Reactions (ADRs), confounding by association (drug therapy) and confounding by indication (medical condition) to assist in the detection of signals. [...] This study highlights the ability of the STATFILE algorithm to detect drugs that are potential signals. More importantly, it also flags those drugs that are considered to be bystander drugs or noise, consequently reducing confounding by association. [...] This work highlights the significance and viability of an automated signal detection system and its practical application for the Australian spontaneous reporting of ADRs scene and potentially the international scene.
Doctor of Philosophy

Esta tesis tiene como objetivo principal analizar el Estado de Bienestar de la población española mayor de 64 años desde una perspectiva demográfica y social, con el fin de hallar posibles patrones de desigualdad y heterogeneidad entre los individuos. Desde una perspectiva demográfica, se centra en el estudio de la heterogeneidad en la mortalidad para la población mayor, por edad, sexo y estado civil. Como conclusiones generales se obtiene que los individuos casados muestran probabilidades de fallecimiento inferiores a la de los individuos solteros o viudos. En el aspecto financiero, se demuestra que las prestaciones públicas que se perciben en concepto de pensión y dependencia son claramente insuficientes en caso de tener que hacer frente a costes por cuidados de larga duración. Son las mujeres en estado de soltería las que presentan una mayor vulnerabilidad financiera durante la vejez. Desde el punto de vista de la sostenibilidad del sistema público de pensiones, se hace constar el incremento que se producirá en los próximos años en el número de pensionistas concurrentes de jubilación y viudedad, siendo los individuos casados los que causan un mayor coste a la seguridad social por tal concepto, debido a que presentan unas mayores probabilidades de supervivencia y a que son susceptibles a incurrir en concurrencia de pensiones.
The main aim of this thesis is to analyse the Welfare State for the elderly Spanish population from a demographic and social perspective. The work tries to find possible patterns of inequality and heterogeneity among individuals. From a demographic point of view, it focusses on the study of heterogeneity in mortality for the elderly by age, sex, and marital status. As a general conclusion, it could say that married individuals show lower probabilities of death than those who are single or widow/er. According to the financial perspective, it proves that the public benefits received for pensions and dependency are insufficient in the case of having to face costs for long-term care. By sex, single women are more likely to be financially vulnerable during old age than men. From the sustainability of the public pension system, there will be an increase in the number of concurrent pensioners of retirement and widowhood pensions in the coming years. Married individuals will cause a greater cost to the Social Security since they present a higher probability of survival and they are susceptible to incur in concurrence of pension

Thesis (Ph. D.)--Biomedical Engineering, Georgia Institute of Technology, 2006.
Tannenbaum, Allen, Committee Member ; Choi, Jung, Committee Member ; Borodovsky, Mark, Committee Chair ; Voit, Eberhard, Committee Member ; Lee, Eva, Committee Member.

In the past few years we have witnessed an explosion in the viral genomic data available. GenBank alone holds over 80,000 close to complete viral genomes, and numbers are rising fast. For example, since the submission of the first SARS genome in May 2003, over 140 more have been published. With this genomic data at hand we hope to finally be able to improve our understanding of viruses. Several papers have been dedicated to the study of genome annotation and selection on viral genomes, in particular focusing attention on the evolutionary behaviour of overlapping reading frames. This is a feature common to viruses, where due to the three periodicity of the genetic code, up to three genes may be encoded simultaneously in one direction. The constraints placed on a nucleotide involved in such a multiple coding region will naturally have an effect on its mutational behaviour, and as a result the pattern of evolution will be more complex. Additionally, due to their fast evolution time, we observe changes in gene structure between viruses of the same family. Finally, as a result of this high divergence, alignments between two genomes will tend to be unreliable, thus complicating the issue of comparative analysis further. Our goal is to present methods which may deal with the above mentioned complications. We first introduce an ab initio pairwise comparative annotation method, which not only accounts for the presence of overlapping reading frames in genomes, but also for differences in gene structure between the two compared sequences. Secondly, we develop a hidden Markov model for the annotation of selection strengths across a viral genome accommodating for inter- as well as intragenic differences in selection. Thirdly, we investigate the effect of using a fixed alignment on the inference of selection by incorporating statistical alignment into our selection analysis. All three methods presented here improve on their respective equivalents in the field. We investigate the nature of selection in overlapping regions in several studies, in particular on the genomes of Hepatitis B and HIV2. We provide a full annotation of selection strengths on a nucleotide level for both viral sequences, highlighting fast evolving regions such as the gp120 protein. We also analyse the mutational behaviour of overlapping regions in both genomes and find that in Hepatitis B selection seems to be of equal strength for single and double coding regions. In HIV2, however, single coding regions appear to be under twice as stringent selection as double coding regions, with a tendency for a fast evolving region to overlap a slow evolving one. Each chapter of our work relates to one of our publications. We introduce in turn each method, its academic context and its results. We subsequently in chapter 5 discuss for each method its achievements, its shortcomings and future possible extensions and improvements to it.

O Sistema Único de Saúde (SUS) produz excelentes bases de dados, entre as quais, destacam-se o Sistema de Informação sobre Nascidos Vivos (SINASC) e o Sistema de Informação sobre Mortalidade (SIM). O objetivo desta dissertação é apresentar o VITAIS, uma ferramenta baseada nos aplicativos Access® e Excel® que permite disponibilizar, de forma simplificada, os dados desses sistemas, possibilitando a análise da situação de saúde por parte de gestores, profissionais da saúde, comunidade acadêmica e população em geral. Esta ferramenta permite a geração de relatórios e gráficos automáticos e pré-definidos e faz relacionamentos entre as bases do SIM e do SINASC. Como tal, apresenta vantagens significativas em relação ao tabulador TABWIN.
The Brazilian Health System (SUS) produces excellent data bases such as those for live births (SINASC) and mortality (SIM). The objective of this report is to present VITAIS, a tool based on Access® and Excel® applications that permits presentation of data from these systems in manners facilitating analysis of the health situation of the population of states, municipalities and micro-areas by health managers, health professionals, the academic community and the general population. This tool generates automatic reports and charts, and permits linkage between the SIM and SINASC databases. As such, it presents significant advantages over the TABWIN tabulator.

Recent technological advances have made it possible to measure various parameters of biological processes in a genome-wide manner. While traditional molecular biology focusses on individual processes using targeted experiments (reductionistic approach), the field of systems biology utilizes high-throughput experiments to determine the state of a complete system such as a cell at once (holistic approach). Systems biology is not only carried out in wet-lab, but for the most part also requires tailored computational methods. High-throughput experiments are able to produce massive amounts of data, that are often too complex for a human to comprehend directly, that are affected by substantial noise, i.e. random measurement variation, and that are often subject to considerable bias, i.e. systematic deviations of the measurement from the truth. Thus, computer science and statistical methods are necessary for a proper analysis of raw data from such large-scale experiments. The goal of systems biology is to understand a whole system such as a cell in a quantitative manner. Thus, the computational part does not end with analyzing raw data but also involves visualization, statistical analyses, integration and interpretation. One example for these four computational tasks is as follows: Processes in biological systems are often modeled as networks, for instance, gene regulatory networks (GRNs) that represent the interactions of transcription factors (TFs) and their target genes. Experiments can provide both, the identity and wiring of all constituent parts of the network as well as parameters that allow to describe the processes in the system in a quantative manner. A network provides a straight-forward way to visualize the state and processes of a whole system, its statistical analysis can reveal interesting properties of biological systems, it is able to integrate several datasets from various experiments and simulations of the network can aid to interpret the data. In recent years, microRNAs emerged as important contributors to gene regulation in eukaryotes, breaking the traditional dogma of molecular biology, where DNA is transcribed to RNA which is subsequently translated into proteins. MicroRNAs are small RNAs that are not translated but functional as RNAs: They are able to target specific messenger RNAs (mRNA) and typically lead to their downregulation. Thus, in addition to TFs, microRNAs also play important roles in GRNs. Interestingly, not only animal genomes including the human genome encode microRNAs, but microRNAs are also encoded by several pathogens such as viruses. In this work I developed several computational systems biology methods and applied them to high-throughout experimental data in the context of a project about herpes viral microRNAs. Three methods, ALPS, PARma and REA, are designed for the analysis of certain types of raw data, namely short RNA-seq, PAR-CLIP and RIP-Chip data, respectively. All of theses experiments are widely used and my methods are publicly available on the internet and can be utilized by the research community to analyze new datasets. For these methods I developed non-trivial statistical methods (e.g. the EM algorithm kmerExplain in PARma) and implemented and adapted algorithms from traditional computer science and bioinformatics (e.g. alignment of pattern matrices in ALPS). I applied these novel methods to data measured by our cooperation partners in the herpes virus project. I.a., I discovered and investigated an important aspect of microRNA-mediated regulation: MicroRNAs recognize their targets in a context-dependent manner. The widespread impact of context on regulation is widely accepted for transcriptional regulation, and only few examples are known for microRNA-mediated regulation. By integrating various herpes-related datasets, I could show that context-dependency is not restricted to few examples but is a widespread feature in post-transcriptional regulation mediated by microRNAs. Importantly, this is true for both, for human host microRNAs as well as for viral microRNAs. Furthermore, I considered additional aspects in the data measured in the context of the herpes virus project: Alternative splicing has been shown to be a major contributor to protein diversity. Splicing is tightly regulated and possibly important in virus infection. Mass spectrometry is able to measure peptides quantitatively genome-wide in high-throughput. However, no method was available to detect splicing patterns in mass spectrometry data, which was one of the datasets that has been meausred in the project. Thus, I investigated whether mass spectrometry offers the opportunity to identify cases of differential splicing in large-scale. Finally, I also focussed on networks in systems biology, especially on their simulation. To be able to simulate networks for the prediction of the behavior of systems is one of the central goals in computational systems biology. In my diploma thesis, I developed a comprehensive modeling platform (PNMA, the Petri net modeling application), that is able to simulate biological systems in various ways. For highly detailed simulations, I further developed FERN, a framework for stochastic simulation that is not only integrated in PNMA, but also available stand-alone or as plugins for the widely used software tools Cytoscape or CellDesigner. In systems biology, the major bottleneck is computational analysis, not the generation of data. Experiments become cheaper every year and the throughput and diversity of data increases accordingly. Thus, developing new methods and usable software tools is essential for further progress. The methods I have developed in this work are a step into this direction but it is apparent, that more effort must be devoted to keep up with the massive amounts of data that is being produced and will be produced in the future.
Der technische Fortschritt in den letzten Jahren hat ermöglicht, dass vielerlei Parameter von biologischen Prozessen genomweit gemessen werden können. Während die traditionelle Molekularbiologie sich mit Hilfe gezielter Experimente auf individuelle Prozesse konzentriert (reduktionistischer Ansatz), verwendet das Feld der Systembiologie Hochdurchsatz-Experimente um den Zustand eines vollständigen Systems wie einer Zelle auf einmal zu bestimmen (holistischer Ansatz). Dabei besteht Systembiologie nicht nur aus Laborarbeit, sondern benötigt zu einem großen Teil auch speziell zurechtgeschnittene computergestützte Methoden. Hochdurchsatz-Experimente können riesige Mengen an Daten produzieren, welche oft zu komplex sind um von einem Menschen direkt verstanden zu werden, welche beeinträchtigt sind von substantiellem Rauschen, das heißt zufälliger Messvariation, und welche oft beträchtlichem Bias unterliegen, also systematischen Abweichungen der Messungen von der tatsächlichen Größe. Daher sind informatische und statistische Methoden notwendig für eine geeignete Analyse der Rohdaten eines groß angelegten systembiologischen Experiments. Das Ziel der Systembiologoe ist ein ganzen System wie eine Zelle in quantitativer Weise zu verstehen. Daher endet der computergestützte Teil nicht mit der Analyse der Rohdaten, sondern beinhaltet ebenfalls Visualisierung, statistische Analyse, Integration und Interpretation. Ein Beispiel dieser vier rechnergestützten Aufgaben ist wie folgt: Prozesse in biologischen Systemen werden oft in Netzwerken modelliert. Zum Beispiel werden in genregulatorischen Netzwerken (GRNs) die Interaktionen zwischen Transkriptionsfaktoren (TFs) und deren Zielgenen repräsentiert. Mit Experimenten kann man sowohl die Identität und die Vernetzung aller Bestandteile des Netzwerkes messen, wie auch die Parameter, mit denen man die Prozesse des Systems in quantitativer Weise beschreiben kann. Mit Hilfe eines Netzwerkes kann man auf einfache und direkte Weise den Zustand und die Prozesse eines ganzen Systems visualisieren, die statistische Analyse des Netzwerks kann interessante Eigenschaften eines biologischen Systems aufdecken, es bietet die Möglichkeit, verschiedene experimentelle Daten zu integrieren und seine Simulation kann bei der Interpretation der Daten helfen. Erst vor wenigen Jahren stelle sich heraus, dass sogenannte microRNAs die Genregulation in Eukaryonten maßgeblich beeinflussen. Das steht im Widersprich zum traditionellen Dogma der Molekularbiologie, bei dem die genetische Information aus der DNA in RNA transkribiert wird, welche anschließend in Proteine translatiert wird. MicroRNAs hingegen sind kurze RNAs, welche nicht translatiert werden, sondern als RNAs funktional sind. Sie können spezifische messenger RNAs (mRNAs) binden und führen dann typischerweise zu deren Inhibition. Zusätzlich zu Transkriptionsfaktoren spielen also microRNAs eine wichtige Rolle in GRNs. Interessanterweise enkodieren nicht nur tierische Genome, das menschliche Genom eingeschlossen, microRNAs, sondern viele Pathogene wie Viren exprimieren ihre eigenen microRNAs in infizierten Wirtszellen. In dieser Arbeit habe ich mehrere computergestützte Methoden für die Anwendung in der Systembiologie entwickelt und auf Hochdurchsatz-Daten angewendet, die im Kontext eines Projektes über herpesvirale microRNAs vermessen wurden. Drei Methoden, ALPS, PARma und REA, habe ich für die Analyse von bestimmten Typen von Rohdaten entworfen, nämlich jeweils short RNA-seq, PAR-CLIP und RIP-Chip. All diese Experimente sind weit verbreitet im Einsatz und meine Methoden sind im Internet öffentlich verfügbar und können von der Forschungsgemeinschaft zur Analyse der Rohdaten der jeweiligen Experimente verwendet werden. Für diese Methoden entwickelte ich nicht-triviale statistische Methoden (z.B. den EM Algorithmus kmerExplain in PARma) und implementierte und adaptierte Algorithmen aus der traditionellen Informatik wie auch aus der Bioinformatik (z.B. Sequenzalignment der Mustermatrizen in ALPS). Ich wendete diese neuen Methoden auf Daten an, die von unseren Kooperationspartner im Herpesviren Projekt gemessenen wurden. Dabei entdeckte und erforschte ich unter anderem einen wichtigen Aspekt der Regulation durch microRNAs: MicroRNAs erkennen ihre Targets in kontext-abhängiger Weise. Die weitverbreiteten Auswirkungen von Kontext ist weithin akzeptiert für transkriptionelle Regulation und es sind nur wenige Beispiele von kontext-spezifischer microRNA gesteuerte Regulation bekannt. Indem ich mehrere Herpes-relevante Datensätze integriert analysiert habe, konnte ich zeigen, dass Kontext-Abhängigkeit nicht nur auf ein paar Beispiele beschränkt ist, sondern dass es ebenfalls ein weitverbreitetes Merkmal der post-transkriptionellen Regulation gesteuert durch microRNAs ist, dass Zielgene kontext-abhängig erkannt werden. Das gilt sowohl für die menschlichen microRNAs der Wirtszelle wie auch für die exogenen viralen microRNAs. Desweiteren habe ich zusätzliche Aspekte der Daten des Herpesviren-Projektes betrachtet: Es wurde gezeigt, dass alternatives Spleißen maßgeblich zur Diversität von Proteinen beiträgt. Spleißen ist streng reguliert und möglicherweise wichtig bei der Virusinfektion. Massenspektrometrie kann Peptide genomweit in quantitativer Weise messen. Allerdings stand keine Methode zur Verfügung, um Spleiß-Muster in Massenspektrometrie-Daten, wie sie im Projekt gemessen wurden, zu detektieren. Aus diesem Grund habe ich untersucht, ob es mit Massenspektrometrie-Daten möglich ist, Fälle von alternativen Spleißen im großen Umfang zu identifizieren. Letztendlich habe ich mich auch auf systembiologische Netzwerke und im Speziellen auf deren Simulation konzentriert. Netzwerke simulieren zu können um das Verhalten von Systemen vorherzusagen ist eines der zentralen Ziele der rechnergestützten Systembiologie. Bereits in meiner Diplomarbeit habe dafür ich eine umfassende Modellierplatform (PNMA, the Petri net modelling application) entwickelt. Damit ist es möglich, biologische Systeme auf vielerlei Arten zu simulieren. Für sehr detailierte Simulationen habe ich dann FERN entwickelt, ein Framework zur stochastischen Simulation, welches nicht nur in PNMA integriert ist, sondern auch als eigenständige Software wie auch also Plugin für die weitverbreiteten Programme Cytoscape und CellDesigner verfügbar ist. Der Engpass in der Systembiologie ist mehr und mehr die rechnergestützte Analyse der Daten und nicht deren Generierung. Experimente werden jedes Jahr günstiger und der Durchsatz und die Diversität der Daten wächst dementsprechend. Daher is es für den weiteren wissenschaftlichen Fortschritt essentiell, neue Methoden und benutzbare Softwarepakete zu entwickeln. Die Methoden, die ich in dieser Arbeit entwickelt habe, stellen einen Schritt in diese Richtung dar, aber es ist offensichtlich, dass mehr Anstrengungen aufgewendet werden müssen, um Schritt halten zu können mit den riesigen Mengen an Daten die produziert werden und in der Zukunft noch produziert werden.

This thesis addresses the intersection of two important areas in epidemiology and statistics: genetic linkage analysis and missing data methods, respectively. Genetic linkage analysis is a promising method in viral epidemiology which involves learning about transmission patterns by studying clusters of similar gene sequences. For example, similar sequences found in a pair of geographically distinct communities may imply disease transmission between the two locations. However, this analysis is sensitive to missing data, which can introduce substantial bias. This thesis presents a multiple-imputation approach which corrects for much, though not all, of the bias in genetic linkage analysis. It also introduces a novel resampling-based approach that generates a weighted distribution of complete datasets and is even more effective than imputation for reducing bias. This work highlights the importance of missing data in genetic linkage studies and presents ways to provide more accurate epidemiological information by correcting for missing data. The new resampling-based approach presented in this paper is also general enough to be applied to many types of missing-data problems involving complex datasets; such broader applications are a promising avenue for future research.
Applied Mathematics

Fourier Transform Infrared (FTIR) microscopy is a sensitive method for detecting difference in the morphology of biological cells. In this study FTIR spectra were obtained for uninfected cells, and cells infected with two different viruses. The spectra obtained are difficult to discriminate visually. Here we apply advanced statistical methods to the analysis of the spectra, to test if such spectra are useful for diagnosing viral infections in cells. Logistic Regression (LR) and Partial Least Squares Regression (PLSR) were used to build models which allow us to diagnose if spectral differences are related to infection state of the cells. A three-fold, balanced cross-validation method was applied to estimate the shrinkages of the area under the receiving operator characteristic curve (AUC), and specificities at sensitivities of 95%, 90% and 80%. AUC, sensitivity and specificity were used to gauge the goodness of the discrimination methods. Our statistical results shows that the spectra associated with different cellular states are very effectively discriminated. We also find that the overall performance of PLSR is better than that of LR, especially for new data validation. Our analysis supports the idea that FTIR microscopy is a useful tool for detection of viral infections in biological cells.

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Fundação Oswaldo Cruz. Instituto de Tecnologia em Imunobiológicos. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz Rio de Janeiro, RJ, Brasil.
Esta dissertação investiga a aplicação do Controle Estatístico de Processo (CEP) nas principais fases da produção da suspensão viral (SV) da vacina contra febre amarela produzida em Bio-Manguinhos/FIOCRUZ, Brasil. Empregada na formulação do produto final, a SV é preparada em várias etapas, utilizando a tecnologia aperfeiçoada no Brasil (egg passage), desde 1937. O sistema de CEP implantado está baseado em recursos computacionais, perfeitamente adaptados à realidadeda Instituição. Os gráficos de controle foram a principal ferramenta estatística empregada.Sete variáveis relativas às etapas da produção da SV foram estudadas: perdas de ovos no transporte; ovos não embrionados; embriões mortos na primeira incubação; perdas na inoculação; embriões mortos na segunda incubação; perdas na coleta de embriões e rendimento na coleta de embriões. Dentre as variáveis investigadas, perdas por transporte e fertilidade dos ovos não sofrem interferência direta da produção, porém são de fundamental importância para as fases seguintes e, por esse motivo, foram estudadas. Os resultados mostraram que seis variáveis, das sete analisadas, apresentaram resultados sob controle, ainda que duas delas não tenham atendido a uma das regras sensibilizantes estabelecidas: ovos não embrionados e perdas na coleta. A variável rendimento ficou caracterizada como não controlada.Em relação à capacidade, os processos de transporte de ovos e ovos não embrionados foram classificados como processos incapazes (Cpk< 1,00). Os processos com as variáveis embriões mortos na primeira incubação e perdas na inoculação foram considerados como relativamentecapazes (1,00 ≤Cpk < 1,33) e, finalmente, os processos com variáveis embriões mortos na segunda incubação e perdas na coleta foram considerados capazes (Cpk ≥1,33). Pela análise do conjunto, os resultados indicam a necessidade de ajustes, intensificação e controle contínuo dos processos que estão sendo praticados.
This work deals with the application of Statistical Control Process (SCP) to the main parts of the production of Viral Suspension (VS) ofthe yellow fever vaccine manufactured by Bio-Manguinhos/FIOCRUZ, Brazil. The VS is used in the formulation of the final product and is prepared in several steps, using a technology (egg passage), which has been being improved in Brazil since 1937. The SCP system used is based on computational resources that are well adapted to the Institution reality. Control graphs were the main statistical tools employed. Seven variables related to the productionof the VS were investigated: transporting losses of eggs; non-germinated eggs; dead embryos during the first incubation; losses during inoculation; dead embryos during the second incubation; losses during embryo collect and efficiency in collecting embryo. Among the studied variables, transporting losses and fertility of eggs do not relate directly to the production, but are of fundamental importance for the subsequent steps, and were also studied for this reason. The results showed that six out of seven analyzed variables were under control, although two of them did not attend one of the established sensitivity rules: non germinated eggs and losses in collecting. Efficiency ended up characterized as a non-controlled variable. As far as capacity is concerned, transporting of eggs and non-germinated eggs were classified as uncapable processes (Cpk < 1,00). Dead embryos during the first incubation and losses during inoculation were considered as relatively capable processes (1,00 ≤Cpk < 1,33). Finally, dead embryos during the second incubation and losses in collecting embryo were considered capable processes (Cpk ≥1,33). The results, thus, show a necessity of adjustments,intensification and continuous control of the currently used processes.

L'elaborato, dopo un cenno introduttivo circa la composizione del mercato degli alcolici e delle strategie di marketing, passa all'analisi delle patologie alco-correlate. A tal proposito vengono analizzati argomenti quali: la religione, gli anziani, la tassazione, gli infortuni sul lavoro, gli incidenti stradali ecc. Particolare approfondimento è stato effettuato in riferimento ai giovani e ai fenomeni che hanno creato per massimizzare lo sballo post abuso di alcol. Il testo prosegue con l'analisi mediante somministrazione di un questionario tra i ragazzi residenti nelle diverse province venete. Il test è stato sottoposto in due modalità: tramite intervista diretta presso il locale Motivi cafè di Piombino Dese (PD) e tramite il social network Facebook. I risultati, tenuti volontariamente separati, sono stati poi confrontati tra loro e successivamente comparati con i dati ottenuti dall'indagine multiscopo sulle famiglie effettuata dall'Istat. Dato il fatto che il questionario tratta domande in rifermento agli aperitivi, doveroso era il richiamo allo spritz e al mito sociale e culturale dell'happy hour.

Viruses are submicroscopic biological entities that need to infect a host cell in order to replicate. In their simplest form viruses are constituted by an infective genetic material and a protein shell (the capsid) that protects the viral genome. In this thesis we try to elucidate the general physical principles playing a major role in the morphology, stability, and assembly of viral capsids. Therefore, in the first part of the thesis, we develop a general theory that characterizes spherical and bacilliform (or prolate) capsids based on icosahedral symmetry under the same geometrical framework. In addition, we demonstrate that the structures derived in this geometrical study are obtained spontaneously from the free energy minimization of a very generic interaction among the viral capsomers of the capsid. In the second part of the thesis, we analyze the role of the discrete nature of capsids and the organization of capsomers in the actual mechanical properties of shells. We show that the icosahedral class P influences the stability and mechanical response of the quasi-spherical capsids. We also determine that under expansion, spherical shells tend to produce polyhedral structures (buckling), which are more resistant, and it is in consonance with the maturation process observed in some viruses. We also unveil the existence of built-in stress in the empty procapsids of the elongated bacteriophage φ29. This phenomenon is intimately related to the discrete nature of the structure, and reinforces the mechanical properties of the shell inverting the classical anisotropic response expected from continuum elasticity theory. In the last part of the thesis, we show that viral assembly and disassembly are activated processes controlled by nucleation barrier, which can be explained adapting classical nucleation theory (CNT). We focus on the case of spherical shells and confirm that the underlying assumptions of CNT are surprisingly good in characterizing the assembly of discrete shells, using the physical model introduced in the previous parts. Finally, we also unveil an interesting closure mechanism during the assembly of capsids.

I pazienti con malattia renale allo stadio terminale (ESRD) sono caratterizzati da una mortalità molto elevata ed in particolare, è stato dimostrato, che il rischio di mortalità tende ad aumentare nei pazienti sedentari. Gli effetti positivi dell’attività fisica riscontrati nella popolazione generale possono essere molto rilevanti per i pazienti con ESRD. Oltre ad una potenziale riduzione del rischio cardiovascolare, l’esercizio fisico può incrementare la funzionalità fisica migliorando di conseguenza la qualità di vita. Diversi studi riguardanti l’esercizio fisico in emodialisi suggeriscono che l’incremento dell’attività fisica di questi pazienti migliora le prestazioni fisiologiche ed i risultati clinici. Infatti, mentre un’attività fisica di resistenza determina un aumento della massa muscolare e della forza, un’attività fisica aerobica è associata ad un maggior consumo di ossigeno, ad una riduzione della depressione e quindi, ad un miglioramento delle funzioni cognitive. Purtroppo, nonostante i potenziali benefici che un programma di esercizio personalizzato apporterebbe ai pazienti in dialisi, tra i trattamenti di routine della maggior parte delle Unità Operative di Nefrologia e Dialisi non rientrano né una valutazione accurata di performance fisica del paziente né una consulenza specifica che possa indirizzare il paziente sedentario verso un percorso allenante specifico.
Patients with end-stage renal disease (ESRD) are characterized by very high mortality and in particular, it has been demonstrated that the risk of mortality tends to increase in sedentary patients. The positive effects of physical activity in the general population may be very significant for patients with ESRD. In addition to a potential reduction in cardiovascular risk, exercise can increase physical functionality, thus improving the quality of life. Several studies on exercise in hemodialysis suggest that increased physical activity of these patients improves physiological performance and clinical outcomes. In fact, while physical activity of resistance results in increased muscle mass and strength, physical aerobic activity is associated with increased oxygen consumption, reduced depression, and hence improved cognitive function. Unfortunately, despite the potential benefits of a personalized exercise program to dialysis patients, routine treatments of most Nephrology and Dialysis Operations Units do not include a thorough assessment of the patient's physical performance or specific advice that could direct the sedentary patient to a specific training course.

L'obiettivo di questo elaborato é quello di mettere in evidenza una categoria critica dei rifiuti: i pannolini usa e getta. Essi, infatti, consumano una quantità ingente di risorse ed energia ed inoltre producono un enorme impatto ambientale connesso allo smaltimento finale. Si pensi che quest'ultimi rappresentano circa il 5% del totale dei rifiuti prodotti: 2 miliardi di pannolini solo in Italia che impiegano più di 500 anni per decomporsi in discarica. Per studiare questo fenomeno si è presa in considerazione una cooperativa sociale bolognese che ha molto a cuore la salvaguardia dell'ambiente e che, attraverso un suo progetto, il progetto Lavanda, ha istituito una lavanderia che si occupa di fornire attraverso il noleggio pannolini lavabili agli asili del territorio: la cooperativa Eta Beta. Inoltre, recentemente, essa ha deciso di utilizzare anche pannolini compostabili, forniti dall'azienda IES Gas, per ridurre ulteriormente le emissioni nell'ambiente. Infatti il motore principale della cooperativa è quello di coniugare la raccolta differenziata alla riduzione dei rifiuti, concetto che dovrebbe essere alla base di ogni azienda, ogni famiglia, ogni persona ma che in Italia risulta di difficile realizzazione.Utilizzando i dati dalla Cooperativa e contattando le cooperative che collaborano con essa (Cadiai e Karabak) ed anche gli asili affiliati si è deciso di effettuare un'analisi statistico - gestionale per individuare il numero medio di pannolini utilizzati da un bambino in un anno scolastico andando a considerare diverse variabili come la tipologia di asilo, l'età dei bambini o le presenze. Dopo questa parentesi 'gestionale', lo studio ha ripreso un'impronta 'ambientale': infatti si è andato a studiare il processo anaerobico e aerobico per lo smaltimento dei pannolini compostabili attraverso un esperimento svolto presso il laboratorio di Chimica e di Processo del DICAM, facoltà di Ingegneria, Alma Mater Studiorum di Bologna

Il tumore alla prostata (PCa) è il secondo tumore più comune negli uomini in tutto il mondo. L'approccio standard non chirurgico per il PCa localizzato è la radioterapia (RT), ma uno dei limiti della RT ad alte dosi è il potenziale aumento delle tossicità gastrointestinali e genito-urinarie. Vi presentiamo il protocollo dello studio Microstyle, uno studio clinico multicentrico randomizzato crossover a due bracci. L'outcome primario sarà valutato al termine di un intervento di 6 mesi, misurando il cambiamento nell'aderenza ad uno stile di vita sano. L'ipotesi è che il cambiamento nello stile di vita modificherà il microbioma, migliorerà la qualità della vita e diminuirà gli effetti collaterali della RT. I partecipanti allo studio saranno reclutati tra gli uomini sottoposti a RT in due centri italiani (Milano e Napoli). Prevediamo di randomizzare 300 pazienti in due bracci di intervento: gruppo di intervento (GI) e gruppo di controllo (GC). I partecipanti assegnati al GI incontreranno un dietista e un fisioterapista prima della RT per ricevere consigli personalizzati su dieta ed esercizio fisico, in base al loro stato di salute, per migliorare lo stile di vita generale e ridurre gli effetti collaterali (problemi intestinali e/o urinari). A tutti i partecipanti (GI) verrà fornito un dispositivo contapassi (contapassi) al fine di monitorare e spronare i partecipanti ad aumentare l'attività fisica e ridurre la sedentarietà. I partecipanti inclusi nel GC riceveranno consigli generali di base e materiali disponibili per i pazienti sottoposti a RT. Secondo il disegno incrociato, il GC passerà all’intervento dopo 6 mesi, per migliorare attivamente la compliance verso le raccomandazioni di stile di vita suggerite per tutti i pazienti. Questo studio è innovativo nel suo designo perché proponiamo un intervento sullo stile di vita durante la RT, che include sia la consulenza dietetica che quella sull'attività fisica, nonché il monitoraggio dei cambiamenti nel microbioma e nei biomarcatori sierici. La promozione di un comportamento sano verrà avviata prima dell'inizio delle cure standard, per ottenere effetti di lunga durata, controllare gli effetti collaterali, far fronte a sentimenti di ansia e depressione e migliorare l'efficacia della RT.
Prostate cancer (PCa) is the second most common cancer in men worldwide. The standard non-surgical approach for localized PCa is radiotherapy (RT), but one of the limitations of high-dose RT is the potential increase in gastrointestinal and genitourinary toxicities. We present the protocol of the Microstyle study, a multicenter randomized two-arm crossover clinical trial. The primary outcome will be assessed at the end of a 6-month intervention, by measuring the change in adherence to a healthy lifestyle. The hypothesis is that change in lifestyle will modify microbiome, improve quality of life and decrease the side effects of RT. Study participants will be recruited among men undergoing RT in two Italian centers (Milan and Naples). We foresee to randomize 300 patients in two intervention arms: Intervention Group (IG) and Control Group (CG). Participants allocated to the IG will meet a dietitian and a physiotherapist before RT to receive personalized diet and exercise recommendations, according to their health status, to improve overall lifestyle and reduce side effects (bowel and/or urinary problems). All participants (IG) will be given a pedometer device (steps counter) in order to monitor and to spur participants to increase physical activity and reduce sedentary behavior. Participants included in the CG will receive baseline general advice and materials available for patients undergoing RT. According to the cross-over design, the CG will cross to the intervention approach after 6 months, to actively enhance compliance towards suggested lifestyle recommendations for all patients. This trial is innovative in its design because we propose a lifestyle intervention during RT, which includes both dietary and physical activity counselling, as well as monitoring changes in microbiome and serum biomarkers. The promotion of healthy behavior will be initiated before initiation of standard care, to achieve long lasting effects, control side effects, cope with feelings of anxiety and depression and improve efficacy of RT.

Il lavoro di ricerca qui proposto si inserisce nel filone delle ricerche sulla mobilità intragenerazionale appena esposto. Questo tema è ampiamente affrontato negli studi che si occupano dell’analisi del mercato del lavoro e dei suoi cambiamenti avvenuti nel corso del secolo scorso. Tuttavia, la gran parte della letteratura si concentra sull’ingresso o sull’uscita delle donne dal mondo lavorativo tralasciando lo studio delle loro effettive possibilità di sperimentare un cambiamento di posizione occupazionale. Rispetto agli studi già condotti in questo ambito, riteniamo possa essere interessante aggiungere all’analisi delle carriere femminili anche altri aspetti. Un primo ambito di analisi è l’influenza della posizione occupazionale dei mariti e dei padri sulla carriera delle donne. Un altro ambito riguarda l’influenza di due eventi familiari di particolare rilevanza, quali il matrimonio e la nascita di un figlio, sull’abbandono del mondo del lavoro e sulla chance di cambiamento della posizione occupazionale delle donne. Con il primo interrogativo di ricerca, ci proponiamo di indagare se, nel corso del ventesimo secolo, si siano modificati i modelli di mobilità di carriera in Italia. La seconda domanda di ricerca cercherà invece di capire come gli eventi familiari - matrimonio e nascita di un figlio - influiscano sulla partecipazione delle donne al mercato del lavoro. Infine, con la terza domanda di ricerca, ci chiediamo come gli eventi sopra esposti influenzino le opportunità di carriera delle stesse. Per rispondere agli interrogativi indicati, prenderemo in considerazione lo studio sia dei fattori inerenti la dimensione individuale, sia di quelli specifici riguardanti l’ambito strutturale. L’analisi di questa ultima sfera permetterà di porre attenzione sui cambiamenti che hanno interessato, a partire dagli anni cinquanta del secolo scorso, il sistema produttivo italiano e le modifiche riguardanti i meccanismi di regolamentazione nei rapporti di impiego. Per quanto riguarda, invece, la dimensione individuale, ci si propone di studiare in profondità alcune caratteristiche sociodemografiche dei soggetti, come il genere, la coorte di nascita e il titolo di studio: quelle che gli studiosi di questo ambito ritengono fondamentali per capire come si strutturano le disuguaglianze. Per raggiungere il nostro obiettivo è stata presa in considerazione l'Indagine Longitudinale delle Famiglie Italiane (ILFI 1997-2005) e sono stati utilizzati una pluralità di strumenti statistici, quali tavole di mobilità, tecniche di event history analysis, modelli log-lineari e modelli di regressione logistica. Rispetto al primo interrogativo di ricerca, il quadro che emerge dalle nostre analisi mostra che nel nostro paese sono presenti contenuti tassi di mobilità  di carriera e che nel corso delle coorti sia possibile rilevare solo una lieve variazione rispetto alle opportunità  di cambiamento di classe per gli individui. Prendendo in considerazione il secondo interrogativo proposto, abbiamo potuto constatare come siano soprattutto le donne maggiormente istruite a rimanere nel mercato del lavoro, anche in occasione del matrimonio e della nascita di un figlio. La possibilità  di lavorare solo per una parte della giornata (usufruendo, quindi, di contratti part-time) sembra leggermente favorire la conciliazione tra famiglia e lavoro. All'opposto, abbiamo riscontrato una maggiore propensione all'abbandono nei casi in cui le garanzie legislative del lavoro vengono a mancare. La posizione lavorativa del partner ha mostrato di avere un importante ruolo. Così, il vantaggio relativo del marito sulla moglie porta quest'ultima ad abbandonare il mercato del lavoro per occuparsi, con molte probabilità, al lavoro domestico. Infine è apparso evidente che la nascita del primo figlio ha una forte spinta a uscire dal mercato.

Il lavoro di ricerca qui proposto si inserisce nel filone delle ricerche sulla mobilità intragenerazionale appena esposto. Questo tema è ampiamente affrontato negli studi che si occupano dell’analisi del mercato del lavoro e dei suoi cambiamenti avvenuti nel corso del secolo scorso. Tuttavia, la gran parte della letteratura si concentra sull’ingresso o sull’uscita delle donne dal mondo lavorativo tralasciando lo studio delle loro effettive possibilità di sperimentare un cambiamento di posizione occupazionale. Rispetto agli studi già condotti in questo ambito, riteniamo possa essere interessante aggiungere all’analisi delle carriere femminili anche altri aspetti. Un primo ambito di analisi è l’influenza della posizione occupazionale dei mariti e dei padri sulla carriera delle donne. Un altro ambito riguarda l’influenza di due eventi familiari di particolare rilevanza, quali il matrimonio e la nascita di un figlio, sull’abbandono del mondo del lavoro e sulla chance di cambiamento della posizione occupazionale delle donne. Con il primo interrogativo di ricerca, ci proponiamo di indagare se, nel corso del ventesimo secolo, si siano modificati i modelli di mobilità di carriera in Italia. La seconda domanda di ricerca cercherà invece di capire come gli eventi familiari - matrimonio e nascita di un figlio - influiscano sulla partecipazione delle donne al mercato del lavoro. Infine, con la terza domanda di ricerca, ci chiediamo come gli eventi sopra esposti influenzino le opportunità di carriera delle stesse. Per rispondere agli interrogativi indicati, prenderemo in considerazione lo studio sia dei fattori inerenti la dimensione individuale, sia di quelli specifici riguardanti l’ambito strutturale. L’analisi di questa ultima sfera permetterà di porre attenzione sui cambiamenti che hanno interessato, a partire dagli anni cinquanta del secolo scorso, il sistema produttivo italiano e le modifiche riguardanti i meccanismi di regolamentazione nei rapporti di impiego. Per quanto riguarda, invece, la dimensione individuale, ci si propone di studiare in profondità alcune caratteristiche sociodemografiche dei soggetti, come il genere, la coorte di nascita e il titolo di studio: quelle che gli studiosi di questo ambito ritengono fondamentali per capire come si strutturano le disuguaglianze. Per raggiungere il nostro obiettivo è stata presa in considerazione l'Indagine Longitudinale delle Famiglie Italiane (ILFI 1997-2005) e sono stati utilizzati una pluralità di strumenti statistici, quali tavole di mobilità, tecniche di event history analysis, modelli log-lineari e modelli di regressione logistica. Rispetto al primo interrogativo di ricerca, il quadro che emerge dalle nostre analisi mostra che nel nostro paese sono presenti contenuti tassi di mobilità  di carriera e che nel corso delle coorti sia possibile rilevare solo una lieve variazione rispetto alle opportunità  di cambiamento di classe per gli individui. Prendendo in considerazione il secondo interrogativo proposto, abbiamo potuto constatare come siano soprattutto le donne maggiormente istruite a rimanere nel mercato del lavoro, anche in occasione del matrimonio e della nascita di un figlio. La possibilità  di lavorare solo per una parte della giornata (usufruendo, quindi, di contratti part-time) sembra leggermente favorire la conciliazione tra famiglia e lavoro. All'opposto, abbiamo riscontrato una maggiore propensione all'abbandono nei casi in cui le garanzie legislative del lavoro vengono a mancare. La posizione lavorativa del partner ha mostrato di avere un importante ruolo. Così, il vantaggio relativo del marito sulla moglie porta quest'ultima ad abbandonare il mercato del lavoro per occuparsi, con molte probabilità, al lavoro domestico. Infine è apparso evidente che la nascita del primo figlio ha una forte spinta a uscire dal mercato.

Influenza is a viral infection that affects global health and economy with its endemic and sometimes pandemic spread. Rapid detection of Influenza viruses enables antiviral use and can bring financial savings. It is also essential for the global surveillance of prevalent Influenza strains. RT-PCR is considered the most specific and sensitive method for detection of Influenza, but Influenza mutates at a high rate and it is therefore crucial that RT-PCR methods are updated regularly. In 2014, Cepheid released their Xpert Flu/RSV XC assay, which can detect Influenza A and B and RSV by multiplex RT-PCR in approximately one hour. The aim of this study was to evaluate this assay at Laboratoriemedicin Västernorrland by using the laboratory’s previous PCR assay for detection of Influenza viruses as reference method. Real-time RT-PCR was used to compare Xpert Flu/RSV XC to the reference method. A dilution series was performed to estimate the methods’ PCR efficiencies and precision was calculated from quadruplicates of a positive control sample. Clinical specimens (n=42) were used to evaluate the diagnostic sensitivity and specificity of Xpert Flu/RSV XC. Objective statistical analysis of PCR data was performed and discussed. The Xpert Flu/RSV XC was equivalent to the reference method and demonstrated high diagnostic sensitivity and specificity. Estimated PCR efficiencies were however low. With the introduction of Xpert Flu/RSV XC to the laboratory follows many potential benefits, primarily in form of a simplified pre analytical procedure and a shortened analysis time. The Xpert Flu/RSV XC assay enables fast diagnosis of Influenza infection.

Introduction/background: Epidemics of infectious diseases (ID) are re-occurring now more often and spreads faster into many different parts of the world due to globalization. The increasing evidence of climate change and man-made events have shown impacts to increase the emergency and re-emerging of animal- borne IDs. Studies claims that background factors of these IDs are biological, environmental and human-lifestyle related changes. The pathogen Lassa fever virus (LASV) is a zoonotic organismthat circulates in rodent reservoirs, and the animal´s hosts are rodent species (rats) of the genus Mastomys natalensis. Mastomys natalensis is primarily the reservoir species of the animal-borne disease of Lassa fever (LF) which is most prevalent in west Africa, particularly in Nigeria. Lassa fever (LF) has limited information with under-documented cases, its health effect on pregnant women especially in Nigeria is within the rural areas of Edo, Ondo, Delta, Ebony, Bauchi, Taraba and Plateau states where maternal mortalities are higher.  Aim: The overarching aim of this thesis is to analyse and discuss the health effects of Lassa fever occurrence and outcomes on pregnant women in Nigeria, with emphasis on the maternal mortality and fatality during pregnancy. Method: A statistical and systematic review was performed from retrospective studies of case series, case-control, observational and cohort studies of patients in Nigeria (pregnant women with gestation ages of pregnancy from 2 weeks –32 weeks) that tested positive to LASV. Publication status and publication date was applied for the inclusion of respective studies by electronic searches via Web of Science, Google scholar, MEDLINE and PubMed. Preferred Reporting Items for Systematic reviews and Meta-Analysis guidelines (PRISMA) was used to illustrate the flow of relevant articles in my study. R-commander and R-Studio software was used to analyze the data and to find the causal significant relationship between LF and maternal mortality using “Linear regression and linear model plot”. Result: The total number of full-text and Peer-view publications on Lassa fever virus cases was 1 609 articles. 94 articles out of the 1 609 articles were eligible for full text revision. Exclusion criteria finally yielded 6 studies that were relatively relevant to my study. However, 3 out of the 6 articles were statistically reviewed to know the influence of Lassa fever and the risk of maternal mortality during pregnancy.  Conclusion: Lassa fever occurrence have significantly shown potential increase in the severity of maternal mortality, and is predominant among pregnant women from 39 - 45 years old in Nigeria especially within the risk endemic areas of Ondo, Edo, Ebony and Bauchi states showing significant long-term diseases on LF affected pregnant women, such as encephalopathy, acute kidney dysfunction and acute kidney failure that leads to further health problems or complications like coma and sensorineural deafness.

Trotz Fortschritte in den letzten Dekaden ist das Langzeitüberleben von Nierentransplantaten unzureichend. Die Personalisierung der Behandlung kann dabei zu erheblichen Verbesserungen führen. Vor diesem Hintergrund wurde eine Kohorte von 587 Patienten im ersten Jahr nach der Transplantation untersucht und ein breites Spektrum von Markern zur langfristigen Prognose etabliert. In dieser Dissertation beschreibe ich in vier Manuskripten und zwei Kapiteln meine Arbeit zur personalisierten Transplantationsmedizin. Der klinische Verlauf von Patienten nach Nierentransplantation wurde untersucht. Die wichtigen Komplikationen standen im Vordergrund: Virusreaktivierungen – insbesondere die BK- und Cytomegalieviren – und akute Abstoßung. Folgende Analysen wurden durchgeführt: (i) Systematische Analyse der Assoziationen zwischen Virusreaktivierungen und deren Einfluss auf das Transplantationsergebnis; (ii) Bewertung der Auswirkungen antiviraler Behandlungsstrategien auf die Transplantationsergebnisse; (iii) Entwicklung eines Tools zur Prätransplantations-Risikoeinschätzung der Abstoßung und (iv) Erstellung eines mathematischen Modells für die personalisierte Charakterisierung der Immunantwort gegen das BK-Virus. Zusammengenommen haben die vier Studien das Potenzial, (i) die Patientenversorgung zu verbessern, (ii) die Überwachung von Virusreaktivierungen zu optimieren, (iii) Präventionsstrategien gegen virale Reaktivierungen zu stratifizieren, (iv) die Behandlung der Patienten an das individuelle Risiko akuter Abstoßung anzupassen, und (v) zur Personalisierung der Immuntherapie beizutragen. Die Studien zeigen, wie das große Datenvolumen einer klinischen Studie zur Weiterentwicklung der personalisierten Medizin unter Einsatz effektiver Strategien für Datenmanagement, Analyse und Interpretation genutzt werden kann. Es ist zu erwarten, dass diese Ergebnisse die klinische Praxis beeinflussen und so das langfristige Überleben und die Lebensqualität der Patienten verbessern.
In spite of the developments in the last decades, long-term graft survival rates in kidney transplantation are still poor: Personalization of treatment can thereby lead to a drastic improvement in long-term outcomes. With this goal, a cohort of 587 patients was characterized for a wide range of markers during the first post-transplantation year to assess their long-term prognosis. Here, I describe along four manuscripts and two chapters my work on personalized medicine for renal transplantation. In detail, we have studied the clinical evolution of patients with emphasis on two most relevant complications: viral reactivations – particularly those of BK virus and cytomegalovirus – and acute rejection. We have analysed in depth these phenomena by (i) exhaustively analysing the associations between different viral reactivations and their influence on transplantation outcome, (ii) evaluating the effects of antiviral treatment strategies on viral reactivation and other transplantation outcomes with emphasis on sex-associated differences, (iii) developing a tool for the pre-transplantation risk assessment of acute cellular rejection, and (iv) creating a mathematical model for the personalized characterization of the immune response against the BK virus under immunosuppression. Taken together, these studies have the potential of improving patient care, optimizing monitoring of viral reactivations, stratifying antiviral prevention strategies, tailoring immunosuppression and monitoring to the individual risk of acute rejection, and contributing to personalization of immunotherapy. They demonstrate how the large volume of data obtained within a clinical study can be employed to further the development of personalized medicine, employing effective data management, analysis and interpretation strategies. We expect these results to eventually inform clinical practice, thereby improving long-term survival and quality of life after kidney transplantation.