Many important scientific questions can not be studied properly using a single measurement as a response. For example, many phenotypes of interest in recent clinical research may be difficult to characterize due to their inherent complexity. It may be difficult to determine the presence or absence of disease based on a single measurement, or even a few measurements, or the phenotype may only be defined based on a series of symptoms. Similarly, a set of related phenotypes or measurements may be studied together in order to detect a shared etiology. In this work, we propose methods for studying complex phenotypes of these types, where the phenotype may be characterized either longitudinally or by a diverse set of continuous, discrete, or not fully observed components. In chapter 1, we seek to identify predictors that are related to multiple components of diverse outcomes. We take up specifically the question of identifying a multiple regulator, where we seek a genetic marker that is associated with multiple biomarkers for autoimmune disease. To do this, we propose sparse multiple regulation testing (SMRT) both to estimate the relationship between a set of predictors and diverse outcomes and to provide a testing framework in which to identify which predictors are associated with multiple elements of the outcomes, while controlling error rates. In chapter 2, we seek to identify risk profiles or risk scores for diverse outcomes, where a risk profile is a linear combination of predictors. The risk profiles will be chosen to be highly correlated to latent traits underlying the outcomes. To do this, we propose semiparametric canonical correlation analysis (sCCA), an updated version of the classical canonical correlation analysis. In chapter 3, the scientific question of interest pertains directly to the progression of disease over time. We provide a testing framework in which to detect the association between a set of genetic markers and the progression of disease in the context of a GWAS. To test for this association while allowing for highly nonlinear longitudinal progression of disease, we propose functional principal variance component (FPVC) testing.

Methods of estimating parametric and nonparametric components, as well as properties of the corresponding estimators, have been examined in partially linear models by Wahba [1987], Green et al. [1985], Engle et al. [1986], Speckman [1988], Hu et al. [2004], Charnigo et al. [2015] among others. These models are appealing due to their flexibility and wide range of practical applications including the electricity usage study by Engle et al. [1986], gum disease study by Speckman [1988], etc., wherea parametric component explains linear trends and a nonparametric part captures nonlinear relationships. The compound estimator (Charnigo et al. [2015]) has been used to estimate the nonparametric component of such a model with multiple covariates, in conjunction with linear mixed modeling for the parametric component. These authors showed, under a strict orthogonality condition, that parametric and nonparametric component estimators could achieve what appear to be (nearly) optimal rates, even in the presence of subject-specific random effects. We continue with research on partially linear models with subject-specific random intercepts. Inspired by Speckman [1988], we propose estimators of both parametric and nonparametric components of a partially linear model, where consistency is achievable under an orthogonality condition. We also examine a scenario without orthogonality to find that bias could still exist asymptotically. The random intercepts accommodate analysis of individuals on whom repeated measures are taken. We illustrate our estimators in a biomedical case study and assess their finite-sample performance in simulation studies. Jump points have often been found within the domain of nonparametric models (Muller [1992], Loader [1996] and Gijbels et al. [1999]), which may lead to a poor fit when falsely assuming the underlying mean response is continuous. We study a specific type of change-point where the underlying mean response is continuous on both left and right sides of the change-point. We identify the convergence rate of the estimator proposed in Liu [2017] and illustrate the result in simulation studies.

We are concerned with testing for differential expression and consider three different aspects of such testing procedures. First, we develop an exact ANOVA type model for discrete gene expression data, produced by technologies such as a Massively Parallel Signature Sequencing (MPSS), Serial Analysis of Gene Expression (SAGE) or other next generation sequencing technologies. We adopt two Bayesian hierarchical models—one parametric and the other semiparametric with a Dirichlet process prior that has the ability to borrow strength across related signatures, where a signature is a specific arrangement of the nucleotides. We utilize the discreteness of the Dirichlet process prior to cluster signatures that exhibit similar differential expression profiles. Tests for differential expression are carried out using non-parametric approaches, while controlling the false discovery rate. Next, we consider ways to combine expression data from different studies, possibly produced by different technologies resulting in mixed type responses, such as Microarrays and MPSS. Depending on the technology, the expression data can be continuous or discrete and can have different technology dependent noise characteristics. Adding to the difficulty, genes can have an arbitrary correlation structure both within and across studies. Performing several hypothesis tests for differential expression could also lead to false discoveries. We propose to address all the above challenges using a Hierarchical Dirichlet process with a spike-and-slab base prior on the random effects, while smoothing splines model the unknown link functions that map different technology dependent manifestations to latent processes upon which inference is based. Finally, we propose an algorithm for controlling different error measures in a Bayesian multiple testing under generic loss functions, including the widely used uniform loss function. We do not make any specific assumptions about the underlying probability model but require that indicator variables for the individual hypotheses are available as a component of the inference. Given this information, we recast multiple hypothesis testing as a combinatorial optimization problem and in particular, the 0-1 knapsack problem which can be solved efficiently using a variety of algorithms, both approximate and exact in nature.

京都大学 / 0048 / 新制・課程博士 / 博士(経済学) / 甲第18763号 / 経博第514号 / 新制||経||273(附属図書館) / 31714 / 京都大学大学院経済学研究科経済学専攻 / (主査)教授 西山 慶彦, 准教授 奥井 亮, 講師 末石 直也 / 学位規則第4条第1項該当 / Doctor of Economics / Kyoto University / DGAM

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Neste trabalho apresentamos os modelos lineares parciais generalizados com uma variável explicativa contínua tratada de forma não paramétrica e os modelos lineares parciais aditivos generalizados com no mínimo duas variáveis explicativas contínuas tratadas de tal forma. São utilizados os P-splines para descrever a relação da variável resposta com as variáveis explicativas contínuas. Sendo assim, as funções de verossimilhança penalizadas, as funções escore penalizadas e as matrizes de informação de Fisher penalizadas são desenvolvidas para a obtenção das estimativas de máxima verossimilhança penalizadas por meio da combinação do algoritmo backfitting (Gauss-Seidel) e do processo iterativo escore de Fisher para os dois tipos de modelo. Em seguida, são apresentados procedimentos para a estimação do parâmetro de suavização, bem como dos graus de liberdade efetivos. Por fim, com o objetivo de ilustração, os modelos propostos são ajustados à conjuntos de dados reais. / In this work we present the generalized partial linear models with one continuous explanatory variable treated nonparametrically and the generalized additive partial linear models with at least two continuous explanatory variables treated in such a way. The P-splines are used to describe the relationship among the response and the continuous explanatory variables. Then, the penalized likelihood functions, penalized score functions and penalized Fisher information matrices are derived to obtain the penalized maximum likelihood estimators by the combination of the backfitting (Gauss-Seidel) algorithm and the Fisher escoring iterative method for the two types of model. In addition, we present ways to estimate the smoothing parameter as well as the effective degrees of freedom. Finally, for the purpose of illustration, the proposed models are fitted to real data sets.

Made available in DSpace on 2016-06-02T20:06:09Z (GMT). No. of bitstreams: 1 6004.pdf: 835734 bytes, checksum: b9cae4e00b44525ff06f6dfea7cfe687 (MD5) Previous issue date: 2014-03-28 / Universidade Federal de Sao Carlos / Correlated data sets with nonlinear structure are common in many areas such as biostatistics, pharmacokinetics and longitudinal studies. Nonlinear mixed-effects models are useful tools to analyse those type of problems. In this dissertation, a generalization to this models is proposed, namely by semiparametric partially nonlinear mixed-effects model (MMSPNL), with a nonparametric function to model the mean of the response variable. It assumes that the mean of the interest variable is explained by a nonlinear function, which depends on fixed effects parameters and explanatory variables, and by a nonparametric function. Such nonparametic function is quite flexible, allowing a better adequacy to the functional form that underlies the data. The random effects are included linearly to the model, which simplify the expression of the response variable distribution and enables the model to take into account the within-group correlation structure. It is assumed that the random errors and the random effects jointly follow a multivariate normal distribution. Relate to the nonparametric function, it is deal with the P-splines smoothing technique. The methodology to obtain the parameters estimates is penalized maximum likelihood method. The random effects may be obtained by using the Empirical Bayes method. The goodness of the model and identification of potencial influent observation is verified with the local influence method and a residual analysis. The pharmacokinetic data set, in which the anti-asthmatic drug theophylline was administered to 12 subjects and serum concentrations were taken at 11 time points over the 25 hours (after being administered), was re-analysed with the proposed model, exemplifying its uses and properties. / Dados correlacionados com estrutura não linear são comuns em bioestatística, estudos farmacocinéticos e longitudinais. Modelos mistos não lineares são ferramentas úteis para se analisar esses tipos de problemas. Nesta dissertação, propõe-se uma generalização desses modelos, chamada de modelo misto semiparamétrico parcialmente não linear (MMSPNL), com uma função não paramétrica para se modelar a média da variável resposta. Assume-se que a média da variável de interesse é explicada por uma função não linear, que depende de parâmetros de efeitos fixos e variáveis explicativas, e por uma função não paramétrica. Tal função não paramétrica possui grande flexibilidade, permitindo uma melhor adequação à forma funcional que subjaz aos dados. Os efeitos aleatórios são incluídos linearmente ao modelo, o que simplifica a expressão da distribuição da variável resposta e permite considerar a estrutura de correlação intra grupo. É assumido que os erros aleatórios e efeitos aleatórios conjuntamente seguem uma distribuição normal multivariada. Em relação a função não paramétrica, utiliza-se a técnica de suavização com P-splines. A metodologia para se obterem as estimativas dos parâmetros é o método de máxima verossimilhança penalizada. Os efeitos aleatórios podem ser obtidos usando-se o método de Bayes empírico. A qualidade do modelo e a identificação de observações aberrantes é verificada pelo método de influência local e por análise de resíduos. O conjunto de dados farmacocinéticos, em que o antiasmático theophylline foi administrado a 12 sujeitos e concentrações séricas foram tomadas em 11 instantes de tempo durante as 25 horas (após ser administrado), foi reanalisado com o modelo proposto, exemplificando seu uso e propriedades.

Neste trabalho apresentamos os modelos lineares parciais generalizados com uma variável explicativa contínua tratada de forma não paramétrica e os modelos lineares parciais aditivos generalizados com no mínimo duas variáveis explicativas contínuas tratadas de tal forma. São utilizados os P-splines para descrever a relação da variável resposta com as variáveis explicativas contínuas. Sendo assim, as funções de verossimilhança penalizadas, as funções escore penalizadas e as matrizes de informação de Fisher penalizadas são desenvolvidas para a obtenção das estimativas de máxima verossimilhança penalizadas por meio da combinação do algoritmo backfitting (Gauss-Seidel) e do processo iterativo escore de Fisher para os dois tipos de modelo. Em seguida, são apresentados procedimentos para a estimação do parâmetro de suavização, bem como dos graus de liberdade efetivos. Por fim, com o objetivo de ilustração, os modelos propostos são ajustados à conjuntos de dados reais. / In this work we present the generalized partial linear models with one continuous explanatory variable treated nonparametrically and the generalized additive partial linear models with at least two continuous explanatory variables treated in such a way. The P-splines are used to describe the relationship among the response and the continuous explanatory variables. Then, the penalized likelihood functions, penalized score functions and penalized Fisher information matrices are derived to obtain the penalized maximum likelihood estimators by the combination of the backfitting (Gauss-Seidel) algorithm and the Fisher escoring iterative method for the two types of model. In addition, we present ways to estimate the smoothing parameter as well as the effective degrees of freedom. Finally, for the purpose of illustration, the proposed models are fitted to real data sets.