The Brisbane Longitudinal Twin Study (BLTS) was being conducted in Australia and was funded by the US National Institute on Drug Abuse (NIDA). Adolescent twins were sampled as a part of this study and surveyed about their substance use as part of the Pathways to Cannabis Use, Abuse and Dependence project. The methods developed in this dissertation were designed for the purpose of analyzing a subset of the Pathways data that includes demographics, cannabis use metrics, personality measures, and imputed genotypes (SNPs) for 493 complete twin pairs (986 subjects.) The primary goal was to determine what combination of SNPs and additional covariates may predict cannabis use, measured on an ordinal scale as: “never tried,” “used moderately,” or “used frequently”. To conduct this analysis, we extended the ordinal Generalized Monotone Incremental Forward Stagewise (GMIFS) method for mixed models. This extension includes allowance for a unpenalized set of covariates to be coerced into the model as well as flexibility for user-specified correlation patterns between twins in a family. The proposed methods are applicable to high-dimensional (genomic or otherwise) data with ordinal response and specific, known covariance structure within clusters.

Made available in DSpace on 2010-04-20T20:48:35Z (GMT). No. of bitstreams: 3 74548.pdf.jpg: 26566 bytes, checksum: 1363b6015e29349551fc03353232c2f6 (MD5) 74548.pdf: 1970291 bytes, checksum: afaf033a3bee5d623cfb2ac4ccc1cef1 (MD5) 74548.pdf.txt: 340191 bytes, checksum: 0b249196cea065834bc87d775c4ff9ae (MD5) Previous issue date: 2005-09-27T00:00:00Z / A determinação e a mensuração da importância das principais fontes de vantagem competitiva, ainda é um tema em discussão na área de Estratégia. Uma linha de pesquisa, iniciada em meados dos anos 80, tem seu foco principal na determinação e quantificação da importância dos fatores que poderiam explicar as diferenças no desempenho de um grupo de empresas, utilizando a decomposição da variância dos valores do desempenho através das técnicas de Regressão Linear ou de Componentes de Variância. Nesta linha de pesquisa, desenvolveram-se uma série de trabalhos empíricos cujo propósito principal é quantificar, entre outros fatores, qual a importância do setor industrial em que a empresa atua, qual a importância do ano, qual a importância de se fazer parte de um grupo econômico e qual a importância dos fatores idiossincráticos da empresa na explicação do desempenho apresentado em determinados períodos. Dos resultados destes trabalhos surgiram discussões importantes sobre o papel da estratégia corporativa e sobre a importância relativa de tais fatores na determinação da vantagem competitiva. Este trabalho se insere nesta linha de pesquisa, cujo objetivo é, utilizando uma base de dados brasileira muito mais abrangente e completa que os estudos anteriores, quer nacionais e internacionais, primeiramente verificar se a realidade apontada nos estudos internacionais se assemelha à do Brasil. Em segundo lugar, contribuir com um refinamento teórico, refazendo estas análises utilizando modelos lineares mistos, mais apropriados para estes conjuntos de dados, que os modelos de componentes de variância. Em terceiro lugar, utilizando dois tipos de matriz de covariância, verifica se o desempenho de um determinado ano influi no desempenho dos anos imediatamente subseqüentes, verificando, assim, a possível existência de medidas repetidas para a variável ano. Finalmente, analisa se parte da variabilidade do desempenho das empresas brasileiras pode ser atribuído ao fato da empresa se localizar em determinada Unidade da Federação / The delimitation of the main sources of competitive advantage and the quantification of their importance, are still relevant issues in the strategy field of studies. At the middle of the 80´s, a new stream of research emerged, focusing in determining and quantifying the importance of the factors which could explain the differences among the performance of a set of firms, through the decomposition of factors variance using linear regression or variance components. In this set of works, there was developed several empirical researches whose main purpose was to quantify the importance of factors as industrial sector, year, corporate affiliation and idiosyncratic issues in explaining the firm performance. From the results presented in these papers several discussions raised about the hole of corporate strategy and about the relative importance of those factors in the determination of the competitive advantage. The investigation developed in this work, which is aligned with this set of researches, uses a broad and complete data base of Brazilians´ firms, first, to verify if the findings about international firms are similar to Brazilian firms. Second, develop new analysis using linear mixed models, which are theoretically more appropriate for this type of analysis. Third, by the use of two types of covariance matrices, test the existence of repeated measures for the variable year, to verify if the results of performance of a year influence the performance of the subsequent years. Finally, it is analyzed if being established in a specific Brazilian State impacts the firm performance.

Um dos estudos observacionais mais difundidos e usados em epidemiologia veterinária é o estudo do tipo transversal. Sua popularidade ocorre por fatores como baixo custo e rapidez comparados com outros tipos de estudos, além de ajudar a estimar a prevalência de uma doença (desfecho) e postular fatores associados com o desfecho, que poderão ser confirmados como fatores causais em outros tipos de estudos epidemiológicos. Porém, este tipo de estudo apresenta dois importantes desafios: a dependência dos dados, muito frequente dada a típica estrutura populacional de animais dentro do mesmo rebanho ou fazenda e a escolha da medida de associação para desfechos binários, tão frequentes neste modelo de estudo. Com o objetivo de contribuir com a compreensão global da epidemiologia do aborto bovino associado à Neospora caninum tendo em conta a estrutura populacional, construiu-se um modelo misto com os dados de um estudo transversal realizado em duas regiões do Rio Grande do Sul. Usaram-se dados de 60 propriedades amostradas em duas regiões (noroeste e sudeste) e 1256 bovinos. A percentagem de aborto dentro de cada rebanho variou entre 1% e 30%. Vacas soropositivas tiveram 6,63 vezes mais chances de ter histórico de aborto (IC 95%: 4,41-13,20). As chances de uma vaca ter histórico de aborto foram 5,18 vezes maiores na região noroeste em relação à região sudeste (IC 95%: 1,83-20,80). Um coeficiente de correlação intraclasse de 16% foi estimado, indicando que 16% da variação da ocorrência de abortamentos não explicados pelos efeitos fixos foram devido as fazendas. Já na segunda parte deste trabalho, uma revisão sistemática foi realizada considerando um conjunto diverso de revistas e jornais com o objetivo de verificar os métodos estatísticos usados e a adequação das interpretações das medidas de associação estimadas em estudos transversais na área de medicina veterinária. Um total de 62 artigos foi avaliado. A revisão mostrou que, independentemente do nível de prevalência relatado no artigo, 96% deles empregou regressão logística e, portanto, estimaram razão de chances (RC). Nos artigos com prevalência superior a 10%, 23 deles fizeram uma interpretação adequada da RC como uma “razão de chances” ou simplesmente não fizeram uma interpretação direta da RC, enquanto 23 artigos interpretaram de forma inadequada a RC, considerando-a como risco ou probabilidade. Entre os artigos com prevalência inferior a 10%, apenas três interpretaram a RC como uma “razão de chances”, cinco interpretaram como risco ou probabilidade e em um, apesar de ter estimado a razão de prevalências (RP), foi interpretado de forma inadequada. Paralelamente, com o objetivo de exemplificar o uso de métodos estatísticos que estimam diretamente a razão de prevalências (RP), medida mais adequada para os estudos transversais, um conjunto de dados obtidos a partir de um estudo transversal sobre a ocorrência de anticorpos (AC) contra o vírus da diarreia viral bovina (BVDV) foi usado. Os AC foram medidos em amostras de tanque de leite de rebanhos leiteiros localizados no estado do Rio Grande do Sul, em que os possíveis fatores associados puderam ser avaliados. Entre os métodos utilizados, as maiores discrepâncias nas medidas de associação estimadas foram observadas com a regressão logística tomando-se como referência a regressão log-binomial. Finalmente, é importante que este tipo de desafio seja atendido pelos pesquisadores que realizam estudos transversais, ou seja, considerar a estrutura das populações nas análises, cuidado ao escolher o tipo de modelo estatístico empregado para desfecho binário e interpretação dos estimadores. / The commonest study design used in veterinary epidemiology is the cross-sectional study. Its popularity lies on the fact of the short time needed and low costs compared with other types of studies; moreover, this type of study estimates prevalence and associated factors, which may be elucidated as causal in another type of epidemiological studies. However, this type of study presents two major challenges: a very common dependence between data given the typical structure of the animal population, i.e., animals within herds or farms and the choice of measure of association for binary outcomes, frequently used in this type of study. In order to contribute to the understanding of the epidemiology of bovine abortion associated with Neospora caninum, a mixed model accounting for the hierarchical structure of cattle population using data from a cross-sectional study conducted in two regions (northwest and southeast) of Rio Grande do Sul was made. Data from 60 dairy herds and 1256 sampled cattle were used. The percentage of abortions in each herd ranged between 1% and 30%. Seropositive cows were 6.63 times more likely to have a history of abortion (95% CI: 4.41 to 13.20). The chances of a cow have a history of abortion were 5.18 times higher in the northwest comparing with the southeast region (95% CI: 1.83 to 20.80). An intraclass correlation coefficient (ICC) of 16% was estimated which means that 16% of the variation in abortion occurrence not explained by the fixed effects is due to farms. In the second part of this work, a systematic review was conducted considering a range of journals and newspapers in order to verify the statistical methods used and the adequacy of the interpretations of the measures of association estimated in cross-sectional studies from the veterinary medicine field. A total of 62 articles were revised. The review showed that, regardless of the reported prevalence, 96% of them employed logistic regression, therefore estimating odds ratio (OR). From the articles that reported prevalence rates above 10%, 23 of them did a proper interpretation of OR as an odds ratio, or simply did not make a direct interpretation of the OR, while 23 articles interpreted improperly the OR as a risk or probability. Among the articles that reported prevalence rates lower than 10%, only three interpreted the OR as an odds ratio, five interpreted as a risk or probability and only one, despite the estimated prevalence ratio (PR), it was improperly interpreted. Meanwhile, in order to exemplify the use of statistical methods to estimate directly the PR, the more appropriate measure of association in cross-sectional studies, a data set obtained from a cross-sectional study to estimate the occurrence of antibodies (AB) against bovine viral diarrhea virus (BVDV) in milk was used; AB were measured in bulk tank samples from dairy herds located in the state of Rio Grande do Sul, Brazil, and also possible associated factors were estimated. Among the methods used, major discrepancies in the measures of association estimated were observed with the logistic regression, comparing with the log-binomial regression. Finally, it is important that such challenges are met by the researchers that undertake cross-sectional studies.

A firma é o principal agente econômico para a produção e distribuição de bens e serviços. Seu constante investimento em melhorias e o aperfeiçoamento de sua capacidade produtiva, visando tornar-se cada vez mais eficiente, transforma-se em um determinante central do bem estar econômico da sociedade. O processo de medir a ineficiência de firmas baseia-se em análises de fronteiras, onde a ineficiência é medida como a distância entre os pontos observados da variável resposta e a função de produção, custo ou lucro verdadeiras, dependendo do modelo assumido para descrever a variável resposta. Existe uma variedade de formas funcionais para essas funções e algumas vezes é difícil julgar qual delas deve ser escolhida, visto que a forma verdadeira é desconhecida e pode ser somente aproximada. Em geral, na literatura, dados de produção são analisados assumindo-se modelos multiplicativos que impõem a restrição de que a produção é estritamente positiva e utiliza-se a transformação logarítmica para linearizar o modelo. Considera-se que o logaritmo do produto dada a ineficiência técnica tem distribuição contínua, independentemente de os dados serem contínuos ou discretos. A tese divide-se em dois artigos: o primeiro utiliza a inferência bayesiana para estimar a eficiência econômica de firmas utilizando os modelos de fronteira estocástica de custo com forma funcional flexível Fourier, que asseguram um bom ajuste para a fronteira, sendo fundamental para o cálculo da ineficiência econômica; o segundo artigo propõem os modelos generalizados de fronteira estocástica, baseando-se nos modelos lineares generalizados mistos com a abordagem bayesiana, para quantificar a ineficiência técnica de firmas (medida de incerteza) utilizando a variável resposta na escala original e distribuições pertencentes à família exponencial para a variável resposta dada a medida de ineficiência. / The firm is the main economic agent for the production and distribution of goods and services. Its constant investment in improvements and enhancement of its productive capacity to make itself more efficient becomes a central determinant of economic welfare of society. The measure process of inefficiency is based on frontier analysis, where inefficiency is measured as the distance between the observed points from variable response and real production, cost or profit function, depending on chosen model to describe the variable response. There are several functional forms to these functions and sometimes it is very difficult to decide which one has to be chosen because the true form is unknown and it can just be approximate. Generally, in the literature, production data are analyzed assuming multiplicative models that impose the restriction of what the production is strictly positive and use the logarithm transformation to turn the model lineal. It is considerate that the product\'s logarithm given the technical inefficiency has distribution continual, independent if the data are continuous or discrete. The papers presented in this thesis are: the first paper uses the bayesian inference to estimate the economic efficiency of firms in the cost stochastic frontier models using the Fourier flexible cost function, that assure a good settlement to the frontier being essential to calculate the economic inefficiency. The second paper proposes a generalized stochastic frontier models, based on generalized linear mixed models with the Bayesian approach, to quantify the inefficiency technical of the firms (uncertainty measures) by using the response variable in the scale original with distributions belonging on the exponential family to the response variable given the measure of inefficiency.

Um dos estudos observacionais mais difundidos e usados em epidemiologia veterinária é o estudo do tipo transversal. Sua popularidade ocorre por fatores como baixo custo e rapidez comparados com outros tipos de estudos, além de ajudar a estimar a prevalência de uma doença (desfecho) e postular fatores associados com o desfecho, que poderão ser confirmados como fatores causais em outros tipos de estudos epidemiológicos. Porém, este tipo de estudo apresenta dois importantes desafios: a dependência dos dados, muito frequente dada a típica estrutura populacional de animais dentro do mesmo rebanho ou fazenda e a escolha da medida de associação para desfechos binários, tão frequentes neste modelo de estudo. Com o objetivo de contribuir com a compreensão global da epidemiologia do aborto bovino associado à Neospora caninum tendo em conta a estrutura populacional, construiu-se um modelo misto com os dados de um estudo transversal realizado em duas regiões do Rio Grande do Sul. Usaram-se dados de 60 propriedades amostradas em duas regiões (noroeste e sudeste) e 1256 bovinos. A percentagem de aborto dentro de cada rebanho variou entre 1% e 30%. Vacas soropositivas tiveram 6,63 vezes mais chances de ter histórico de aborto (IC 95%: 4,41-13,20). As chances de uma vaca ter histórico de aborto foram 5,18 vezes maiores na região noroeste em relação à região sudeste (IC 95%: 1,83-20,80). Um coeficiente de correlação intraclasse de 16% foi estimado, indicando que 16% da variação da ocorrência de abortamentos não explicados pelos efeitos fixos foram devido as fazendas. Já na segunda parte deste trabalho, uma revisão sistemática foi realizada considerando um conjunto diverso de revistas e jornais com o objetivo de verificar os métodos estatísticos usados e a adequação das interpretações das medidas de associação estimadas em estudos transversais na área de medicina veterinária. Um total de 62 artigos foi avaliado. A revisão mostrou que, independentemente do nível de prevalência relatado no artigo, 96% deles empregou regressão logística e, portanto, estimaram razão de chances (RC). Nos artigos com prevalência superior a 10%, 23 deles fizeram uma interpretação adequada da RC como uma “razão de chances” ou simplesmente não fizeram uma interpretação direta da RC, enquanto 23 artigos interpretaram de forma inadequada a RC, considerando-a como risco ou probabilidade. Entre os artigos com prevalência inferior a 10%, apenas três interpretaram a RC como uma “razão de chances”, cinco interpretaram como risco ou probabilidade e em um, apesar de ter estimado a razão de prevalências (RP), foi interpretado de forma inadequada. Paralelamente, com o objetivo de exemplificar o uso de métodos estatísticos que estimam diretamente a razão de prevalências (RP), medida mais adequada para os estudos transversais, um conjunto de dados obtidos a partir de um estudo transversal sobre a ocorrência de anticorpos (AC) contra o vírus da diarreia viral bovina (BVDV) foi usado. Os AC foram medidos em amostras de tanque de leite de rebanhos leiteiros localizados no estado do Rio Grande do Sul, em que os possíveis fatores associados puderam ser avaliados. Entre os métodos utilizados, as maiores discrepâncias nas medidas de associação estimadas foram observadas com a regressão logística tomando-se como referência a regressão log-binomial. Finalmente, é importante que este tipo de desafio seja atendido pelos pesquisadores que realizam estudos transversais, ou seja, considerar a estrutura das populações nas análises, cuidado ao escolher o tipo de modelo estatístico empregado para desfecho binário e interpretação dos estimadores. / The commonest study design used in veterinary epidemiology is the cross-sectional study. Its popularity lies on the fact of the short time needed and low costs compared with other types of studies; moreover, this type of study estimates prevalence and associated factors, which may be elucidated as causal in another type of epidemiological studies. However, this type of study presents two major challenges: a very common dependence between data given the typical structure of the animal population, i.e., animals within herds or farms and the choice of measure of association for binary outcomes, frequently used in this type of study. In order to contribute to the understanding of the epidemiology of bovine abortion associated with Neospora caninum, a mixed model accounting for the hierarchical structure of cattle population using data from a cross-sectional study conducted in two regions (northwest and southeast) of Rio Grande do Sul was made. Data from 60 dairy herds and 1256 sampled cattle were used. The percentage of abortions in each herd ranged between 1% and 30%. Seropositive cows were 6.63 times more likely to have a history of abortion (95% CI: 4.41 to 13.20). The chances of a cow have a history of abortion were 5.18 times higher in the northwest comparing with the southeast region (95% CI: 1.83 to 20.80). An intraclass correlation coefficient (ICC) of 16% was estimated which means that 16% of the variation in abortion occurrence not explained by the fixed effects is due to farms. In the second part of this work, a systematic review was conducted considering a range of journals and newspapers in order to verify the statistical methods used and the adequacy of the interpretations of the measures of association estimated in cross-sectional studies from the veterinary medicine field. A total of 62 articles were revised. The review showed that, regardless of the reported prevalence, 96% of them employed logistic regression, therefore estimating odds ratio (OR). From the articles that reported prevalence rates above 10%, 23 of them did a proper interpretation of OR as an odds ratio, or simply did not make a direct interpretation of the OR, while 23 articles interpreted improperly the OR as a risk or probability. Among the articles that reported prevalence rates lower than 10%, only three interpreted the OR as an odds ratio, five interpreted as a risk or probability and only one, despite the estimated prevalence ratio (PR), it was improperly interpreted. Meanwhile, in order to exemplify the use of statistical methods to estimate directly the PR, the more appropriate measure of association in cross-sectional studies, a data set obtained from a cross-sectional study to estimate the occurrence of antibodies (AB) against bovine viral diarrhea virus (BVDV) in milk was used; AB were measured in bulk tank samples from dairy herds located in the state of Rio Grande do Sul, Brazil, and also possible associated factors were estimated. Among the methods used, major discrepancies in the measures of association estimated were observed with the logistic regression, comparing with the log-binomial regression. Finally, it is important that such challenges are met by the researchers that undertake cross-sectional studies.

Ce travail a pour but de développer des outils statistiques pour l'étude du déclin cognitif général ou précédant le diagnostic de démence, à partir de données de cohorte en tenant compte du risque compétitif de décès et de la censure par intervalle. Le temps de démence est censuré par intervalle dans les études de cohortes car le diagnostic de démence ne peut être établi qu'à l'occasion des visites qui peuvent être espacées de plusieurs années. Ceci induit une sous-estimation du risque de démence à cause du risque compétitif de décès : les sujets déments sont à fort risque de mourir, et peuvent donc décéder avant la visite de diagnostic. Dans la première partie, nous proposons un modèle conjoint à classes latentes pour données longitudinales corrélées à un événement censuré par intervalle, en compétition avec le décès. Appliqué à la cohorte Paquid, ce modèle permet d'identifier des profils de déclin cognitif associés à des risques différents de démence et de décès. En utilisant cette méthodologie, nous comparons ensuite des modèles pronostiques dynamiques pour la démence, traitant la censure par intervalle, basés sur des mesures répétées de marqueurs cognitifs. Dans la seconde partie, nous conduisons une étude comparative afin de clarifier l'interprétation des estimateurs du maximum de vraisemblance des modèles mixtes et conjoints et estimateurs par équations d'estimation généralisées (GEE), couramment utilisés dans le contexte de données longitudinales incomplètes et tronquées par le décès. Les estimateurs de maximum de vraisemblance ciblent le changement individuel chez les individus vivants. Les estimateurs GEE avec matrice de corrélation de travail indépendante, pondérés par l'inverse de la probabilité d'être observé sachant que le sujet est vivant, ciblent la trajectoire moyennée sur la population des survivants à chaque âge. Ces résultats justifient l'utilisation des modèles conjoints dans l'étude de la démence, qui sont des outils prometteurs pour mieux comprendre l'histoire naturelle de la maladie / The purpose of this work is to develop statistical tools to study the general or the prediagnosis cognitive decline, while accounting for the selection by death and interval censoring. In cohort studies, the time-to-dementia-onset is interval-censored as the dementia status is assessed intermittently. This issue can lead to an under-estimation of the risk of dementia, due to the competing risk of death: subjects with dementia are at high risk to die and can thus die prior to the diagnosis visit. First, we propose a joint latent class illness-death model for longitudinal data correlated to an interval-censored time-to-event, competing with the time-to-death. This model is applied on the Paquid cohort to identify profiles of pre-dementia cognitive declines associated with different risks of dementia and death. Using this methodology, we compare dynamic prognostic models for dementia based on repeated measures of cognitive markers, accounting for interval censoring. Secondly, we conduct a simulation study to clarify the interpretation of maximum likelihood estimators of joint and mixed models as well as GEE estimators, frequently used to handle incomplete longitudinal data truncated by death. Maximum likelihood estimators target the individual change among the subjects currently alive. GEE estimators with independent working correlation matrix, weighted by the inverse probability to be observed given that the subject is alive, target the population-averaged change among the dynamic population of survivors. These results justify the use of joint models in dementia studies, which are promising statistical tools to better understand the natural history of dementia

Submitted by Ricardo Cedraz Duque Moliterno (ricardo.moliterno@uefs.br) on 2016-04-06T23:39:59Z No. of bitstreams: 1 Disserta??o Alirio- RGV.pdf: 1134374 bytes, checksum: c5cada877e2f1b7066d7296503b7a9a8 (MD5) / Made available in DSpace on 2016-04-06T23:39:59Z (GMT). No. of bitstreams: 1 Disserta??o Alirio- RGV.pdf: 1134374 bytes, checksum: c5cada877e2f1b7066d7296503b7a9a8 (MD5) Previous issue date: 2016-02-22 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPES / The aims of this study were to evaluate the adaptability and stability of 14 yellow passion fruit plant hybrids and to estimate the genetic components of variance and average via mixed models (REML/BLUP), estimate the phenotypic, genotypic and environmental correlations between passion fruit characteristics in three environments. The selection of genotypes was based on methods of adaptability, as produced by the harmonic mean of genetic values (MHVG); of stability, as produced by the relative performance of genetic values (PRVG); and on a joint selection for both adaptability and stability, as produced by the harmonic mean of the relative performance of the genetic values (MHPRVG). The genetic correlations were estimated (rG), phenotypic (rF) and environment (rE) for each environment. The following traits were evaluated: fruit number (FN); total cumulative productivity (TCP); fruit mass (FM); fruit length (FL); fruit diameter (FD); peel mass (PM); peel thickness (PT); pulp mass (PUM); juice yield (JY); soluble solids (SS); titratable acidity (TA); and SS/TA (RATIO). The estimates for heritability and the genetic gains in the evaluated environments were found to have good perspectives for the selection of superior genotypes, except for traits TCP, SS, and JY. There was a marked effect from the genotype x environment interaction (GxE) for most traits, except for FL, JY, SS, TA, and SS/TA. The most stable and adaptable hybrids in the evaluated environments were BRS Gigante Amarelo (BRS Yellow Giant), HFOP-09, H09-09, GP09-02, GP09-03, and BRS Sol do Cerrado (BRS Sun of Cerrado). In 88.88% of cases the estimates of genotypic correlations were higher than phenotypic in the three environments. In Len??is genotypic correlations between FN x FM, FD, PT, PM, PUM, SS and TA, differed from the other environments. In Dom Basil?o and Rio de Contas to TCP correlated positively with FM, FL, FD and PM. In all environments the selection of fruits with higher FM facilitating higher LF, FD, PM and PUM and the selection of the oval thinner peel fruit shape. In general, for correlations between traits of agronomic importance, such as FN x TCP, SS; FM x FD, PM, PUM, RATIO; FD x FM, PUM, RATIO; FL/FD x PT e FM x RATIO showed the same behavior in the three evaluation environments, except for characteristics FN x FM, FD, PT, PM, PUM e TA in Lenc?is. / Os objetivos deste trabalho foram avaliar a adaptabilidade e estabilidade de 14 h?bridos de maracujazeiro-amarelo, estimar os componentes gen?ticos de vari?ncia e de m?dia via modelos mistos (REML/BLUP), estabelecer as correla??es fenot?picas, genot?picas e ambientais entre caracter?sticas do fruto de maracujazeiro em tr?s ambientes. Foram avaliados 14 gen?tipos de maracujazeiro nos ambientes de Dom Bas?lio-BA, Rio de Contas-BA e Len??is-BA, utilizando o delineamento experimental em blocos casualizados completos, com tr?s repeti??es e nove plantas por parcela. A sele??o gen?tipos baseou-se nos m?todos da adaptabilidade dada pela m?dia harm?nica dos valores gen?ticos (MHVG), estabilidade pela performance relativa dos valores gen?ticos (PRVG) e sele??o conjunta para adaptabilidade e estabilidade dada pela m?dia harm?nica da performance relativa dos valores gen?ticos (MHPRVG). Foram estimadas as correla??o genot?pica (rG), fenot?pica (rF) e de ambiente (rE) para cada ambiente. Foram avaliados os caracteres, n?mero de frutos (NF); produtividade total acumulada (PR); massa do fruto (MF); comprimento de frutos (CF); di?metro do fruto (DF); rela??o CF/DF; massa da casca (MC); espessura de casca (EC); massa da polpa (MP); rendimento de suco (RE); s?lidos sol?veis (SS); acidez titul?vel (AT) e RATIO (SS/AT). As estimativas de herdabilidade e os ganhos gen?ticos nos ambientes avaliados apresentaram boas perspectivas para sele??o de gen?tipos superiores. Houve efeito pronunciado da intera??o GxE para a maioria dos caracteres, exceto CF, RE, SS, AT e SS/AT. De acordo com o crit?rio MHPRVG os h?bridos mais est?veis e adapt?veis nos ambientes de avalia??o foram o BRS Gigante Amarelo, HFOP-09, H09-09, GP09-02, GP09-03 e BRS Sol do Cerrado. Em 88,88% dos casos as estimativas das correla??es genot?picas foram maiores do que as fenot?picas nos tr?s ambientes. Em len??is as correla??es genot?picas foram negativas entre NF x MF, DF, EC, MC, MP, SS e AT, divergindo dos demais ambientes. Nos ambientes de Dom Bas?lio e Rio de Contas a PR correlacionou se positivamente com MF, CF, DF e MC. Em todos os ambientes a sele??o de frutos com maiores MF proporcionar? maiores CF, DF, PC e PP e pela sele??o do formato de frutos ovais menor espessura de casca. De modo geral, para as correla??es entre caracter?sticas de import?ncia agron?mica, como NF x PR, SS; MF x DF, MC, MP, RATIO; DF x MC, MP, RATIO; CF/DF x EC e MC x RATIO apresentaram o mesmo comportamento nos tr?s ambientes de avalia??o, exceto para caracter?sticas NF x MF, DF, EC, MC, MP e AT em Len??is.

L’objectif des essais de phase I en oncologie est d’identifier la dose maximale tolérée (DMT). Le schéma « 3+3 » nécessite d’interrompre les inclusions en attendant l’évaluation d’une cohorte de trois patients pour définir la dose à attribuer aux patients suivants. Les investigateurs d’oncologie pédiatrique ont proposé l’adaptation Rolling 6 pour éviter cette suspension temporaire des inclusions. Dans une étude de simulation, nous avons montré qu’un schéma adaptatif avec attribution des doses basées sur un modèle statistique permettait de pallier ce problème, et identifiait plus fréquemment la DMT. Néanmoins ces trois schémas restent limités pour identifier la DMT, notamment du fait que le critère de jugement est un critère binaire, la survenue de toxicité dose-limitante sur un cycle de traitement. Nous avons proposé un nouveau schéma adaptatif utilisant les données ordinales répétées de toxicité sur l’ensemble des cycles de traitement. La dose à identifier est celle associée au taux de toxicité grave maximal par cycle que l’on juge tolérable. Le grade maximal de toxicité par cycle de traitement, en 3 catégories (grave / modéré / nul), a été modélisé par le modèle mixte à cotes proportionnelles. Le modèle est performant à la fois pour détecter un effet cumulé dans le temps et améliore l’identification de la dose cible, sans risque majoré de toxicité, et sans rallonger la durée des essais. Nous avons aussi étudié l’intérêt de ce modèle ordinal par rapport à un modèle logistique mixte plus parcimonieux. Ces modèles pour données longitudinales devraient être plus souvent utilisés pour l’analyse des essais de phase I étant donné leur pertinence et la faisabilité de leur implémentation. / Phase I dose-finding trials aim at identifying the maximum tolerated dose (MTD). The “3+3” design requires an interruption of enrolment while the evaluation of the previous three patients is pending. In pediatric oncology, investigators proposed the Rolling 6 design to allow for a more continuous enrollment. In a simulation study, we showed that an adaptive dose-finding design, with dose allocation guided by a statistical model not only minimizes accrual suspension as with the rolling 6, and but also led to identify more frequently the MTD. However, the performance of these designs in terms of correct identification of the MTD is limited by the binomial variability of the main outcome: the occurrence of dose-limiting toxicity over the first cycle of treatment. We have then proposed a new adaptive design using repeated ordinal data of toxicities experienced during all the cycles of treatment. We aim at identifying the dose associated with a specified tolerable probability of severe toxicity per cycle. The outcome was expressed as the worst toxicity experienced, in three categories (severe / moderate / no toxicity), repeated at each treatment cycle. It was modeled through a proportional odds mixed model. This model enables to seek for cumulated toxicity with time, and to increase the ability to identify the targeted dose, with no increased risk of toxicity, and without delaying study completion. We also compared this ordinal model to a more parsimonious logistic mixed model.Because of their applicability and efficiency, those models for longitudinal data should be more often used in phase I dose-finding trials.

Chez les patients infectés par le VIH, les traitements antirétroviraux empêchent la réplicationvirale, ce qui est suivi, dans la plupart des cas, par une restauration de la population des lymphocytesT CD4+ (CD4). Néanmoins ce n’est pas le cas pour certains patients appelés patients àfaible réponse immunitaire. Des injections d’interleukine-7 (IL7) exogène, une cytokine impliquéedans l’homéostasie des CD4, sont considérées afin de maintenir les taux de CD4 au-dessus de500 cellules par μL, taux au-dessus duquel les patients ont une espérance de vie comparable auxpersonnes non infectées par le VIH. Les essais INSPIRE ont évalué l’effet d’injections répétéesd’IL7 chez les patients à faible réponse immunologique.Nous présentons plusieurs modèles mécanistes de l’effet des injections d’IL7 sur les CD4, quiincluent des effets aléatoires afin de tenir compte de la variabilité inter-individuelle. En utilisantces modèles avec une approche Bayésienne, les paramètres individuels d’un nouveau patient sontéchantillonnés, ce qui nous permet de faire des prédictions sur sa dynamique de CD4 et donc depersonnaliser le traitement. Nous proposons quatre protocoles adaptatifs permettant de limiter letemps passé sous 500 CD4 par μL, sans pour autant augmenter le nombre d’injections. Ces protocolesont été implémentés dans une application Shiny présentant une interface facile d’utilisation,et pourront être testés lors d’essais cliniques.Le réservoir viral, principalement constitué de CD4 quiescentes infectées, est la première barrièreà l’éradication du VIH. Les injections d’IL7 entrainent une augmentation du nombre deCD4 et donc du réservoir viral ; la question est alors de savoir si les injections provoquent denouvelles infections cellulaires ou si le réservoir augmente de la même façon que les CD4. Nousconcluons que si quelques patients ont présenté des dynamiques de marqueurs compatibles avecla survenue de nouvelles infections de cellules, ce n’est pas le cas de la majorité des patients. Laconfirmation de ces phénomènes et la caractérisation de potentiels patients à risque nécessite desdonnées supplémentaires mesurables dans un essai clinique. / In HIV infected patients, antiretroviral therapy suppresses the viral replication which is followedin most patients by a restoration of the CD4+ T cells (CD4) pool. However, it is not the case forsome patients called low immunological responders. Injections of interleukin-7 (IL7), a cytokineinvolved in the CD4 homeostasis, are considered in order to maintain the CD4 levels above 500cells per μL, the level at which life expectancy is similar to that of the non-infected. INSPIREtrials evaluated the effect of repeated injections of IL7 on low immunological responders.We present a few mechanistic models of the effect of IL7 injections on CD4, which includerandom effects to account for inter-individual variability. Using these models with a Bayesianapproach, the individual parameters of a new patient are sampled, which allows us to makepredictions about its CD4 dynamics and thus to personalize the treatment. We propose fouradaptive protocols that limit the time spent under 500 CD4 per μL, without increasing thenumber of injections. Those protocols are implemented into a Shiny app with an easy to useinterface, and they could be tested during clinical trials.The viral reservoir, mainly made up of quiescent infected CD4, is the main obstacle to HIVeradication. IL7 injections induce an increase of the level of CD4, hence of the viral reservoir ; thequestion is then to determine if the injections induce new cell infections or if the reservoir increasesin the same way as CD4. We conclude that while some patients presented marker dynamicsconsistent with the occurrence of new cell infections, this is not the case for the majority ofpatients. Confirmation of these events and characterization of potential at-risk patients requiresadditional measurable data in a clinical trial.

DNA microarrays are a relatively new technology for assessing the expression levels of thousands of genes simultaneously. Researchers hope to find genes that are differentially expressed by hybridizing cDNA from known treatment sources with various genes spotted on the microarrays. The large number of tests involved in analyzing microarrays has raised new questions in multiple testing. Several approaches for identifying differentially expressed genes have been proposed. This paper considers two: (1) a mixed models approach, and (2) the Signiffcance Analysis of Microarrays.