Longitudinal assessments are crucial in evaluating the disease state and trajectory in patients of neurodegenerative diseases. Neuropsychological outcomes measured over time often have a non-linear trajectory with autocorrelated residuals and skewed distributions. Due to these issues, statistical analysis and interpretation involving longitudinal cognitive outcomes can be a difficult and controversial task, thus hindering most convenient transformations (e.g. logarithmic) to avoid the assumption violations of common statistical modelling techniques. We propose the Adjusted Local Linear Trend (ALLT) model, an extended state space model in lieu of the commonly-used linear mixed-effects model (LMEM) in modeling longitudinal neuropsychological outcomes. Our contributed model has the capability to utilize information from the stochasticity of the data while accounting for subject-specific trajectories with the inclusion of covariates and unequally-spaced time intervals. The first step of model fitting involves a likelihood maximization step to estimate the unknown variances in the model before parsing these values into the Kalman Filter and Kalman Smoother recursive algorithms. Results from simulation studies showed that the ALLT model is able to attain lower bias, lower standard errors and high power, particularly in short longitudinal studies with equally-spaced time intervals, as compared to the LMEM. The ALLT model also outperforms the LMEM when data is missing completely at random (MCAR), missing at random (MAR) and, in certain cases, even in data with missing not at random (MNAR). In terms of model selection, likelihood-based inference is applicable for the ALLT model. Although a Chi-Square distribution with k degrees of freedom, where k is the number of parameter lost during estimation, was not the asymptotic distribution in the case of ALLT, we were able to derive an asymptotic distribution approximation of the likelihood ratio test statistics using the power transformation method for the utility of a Gaussian distribution to facilitate model selections for ALLT. In light of these findings, we believe that our proposed model will shed light into longitudinal data analysis not only in the neuropsychological data realm but also on a broader scale for statistical analysis of longitudinal data. / 2023-10-05T00:00:00Z

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<p>Hypercholesterolemia is the presence of high levels of cholesterol in the blood, and it is one of the major factors for the development of long-term complications in T1D patients.</p> <p>In the thesis, we studied 1303 Caucasians with type 1 diabetes in the Diabetes Control and Complications Trial (DCCT). With the experience of diabetes study, many factors are associated with diabetes complications, they are age, gender, cohort, treatment, diabetes duration, body mass index (BMI), exercise, insulin dose, etc. We mainly focus on which factors are associated with total cholesterol (CHL) analysis in the thesis.</p> <p>Many measures were collected monthly, quarterly or yearly for average 6.5 years from 1983 to 1993. We used annually lipid measures of DCCT because of their values are sufficient and complete, and they belong to longitudinal data.</p> <p>Different methods are discussed in the study, and linear mixed effect models are the appropriate approach to the study. The details of model selection with CHL model analysis are shown, which includes fixed effect selection, random effects selection, and residual correlation structure selection. Then the SNPs were added on three models individually in GWAS. We found locus (rs7412) is not only genome-wide associated with CHL, but also genome-wide associated with LDL.</p> <p>We will assess whether these SNPs are diabetes-specific in the future, and we will add dietary data in the three models to identify locus are associated with the interaction of diet and SNPs.</p> / Master of Science (MSc)

The Forest Vegetation Simulator (FVS) is a growth and yield modeling system widely-used for predicting stand and tree-level attributes for management and planning applications in North American forests. The accuracy of FVS predictions for a range of tree and stand level attributes depends a great deal on the performance of the diameter increment model and its predictions of change in diameter at breast height (DBH) over time. To address the challenge of predicting growth in highly variable and geographically expansive forest systems, FVS was designed to include an internal calibration algorithm that makes use of growth observations, when available, from permanent inventory plots. The basic idea is that observed growth rates on a collection of remeasured trees are used to adjust or "calibrate" FVS diameter growth predictions. Therefore, DBH modeling was the focus of this investigation. Five methods were proposed for local calibration of individual tree DBH growth predictions and compared to two sets of results generated without calibration. Data from the US Forest Service's Forest Inventory and Analysis (FIA) program were used to test the methods for eleven widely-distributed forest tree species in Virginia. Two calibration approaches were based on median prediction errors from locally-observed DBH increments spanning a five year average time interval. Two were based on simple linear regression models fitted to the locally-observed prediction errors, and one method employed a mixed effects regression model with a random intercept term estimated from locally-observed DBH increments. Data witholding, specifically a leave-one-out cross-validation was used to compare results of the methods tested. Results showed that any of the calibration approaches tested in general led to improved accuracy of DBH growth predictions, with either of the median-based methods or regression based methods performing better than the random-effects-based approach. Equivalence testing showed that median or regression-based local calibration methods met error tolerances within ± 12% of observed DBH increments for all species with the random effects approach meeting a larger tolerance of ± 17%. These results showed improvement over uncalibrated models, which failed to meet tolerances as high as ± 30% for some species in a newly-fitted DBH growth model for Virginia, and as high as ± 170% for an existing model fitted to data from a much larger region of the Southeastern United States. Local calibration of regional DBH increment models provides an effective means of substantially reducing prediction errors when a relatively small set of observations are available from local sources such as permanent forest inventory plots, or the FIA database. / MS / The Forest Vegetation Simulator (FVS) is a growth and yield model widely-used for predicting stand dynamics, management and decision support in North American forests. Diameter increment is a major component in modeling tree growth. The system of integrated analytical tools in FVS is primarily based on the performance of the diameter increment model and the subsequent use of predicted in diameter at breast height (DBH) over time in forecasting tree attributes. To address the challenge of predicting growth in highly variable and geographically expansive forest systems, FVS was designed to include an internal calibration algorithm that makes use of growth observations, when available, from permanent inventory plots. The basic idea was that observed growth rates on a small set of remeasured trees are used to adjust or “calibrate” FVS growth predictions. The FVS internal calibration was the subject being investigated here. Five alternative methods were proposed attributed to a specific site or stand of interest and compared to two sets of results, which were based on median prediction errors, generated without calibration. Results illustrated that median-based methods or regression based methods performed better than the random-effects-based approach using independently observed growth data from Forest Service FIA re-measurements in Virginia. Local calibration of regional DBH increment models provides an effective means of substantially reducing prediction errors. The results of this study should also provide information to evaluate the efficiency of FVS calibration alternatives and a possible method for future implementation.

Os experimentos agronômicos que envolvem somente um fator longitudinal são bastante comuns. No entanto, existem casos em que as observações são tomadas considerando dois ou mais desses fatores, como nos casos em que são feitas medidas de uma variável resposta em profundidades diferentes ao longo do tempo, por exemplo. Admite-se que essas observações, tomadas de modo sistemático em cada unidade experimental, sejam correlacionadas e as variâncias nos diferentes níveis do fator longitudinal sejam heterogêneas. Com o uso de modelos mistos, essa correlação entre medidas repetidas e a heterogeneidade de variâncias podem ser modeladas convenientemente. Para que esses modelos sejam ajustados a um conjunto de dados envolvendo presença de dois fatores longitudinais, existe a necessidade de se adaptarem algumas estruturas de variâncias e covariâncias que são comuns em experimentos com somente um fator longitudinal. O objetivo do presente trabalho é utilizar a classe dos modelos lineares mistos para estudar a massa seca de raiz no solo de uma plantação de cana-de-açúcar. O experimento foi casualizado em blocos e as parcelas receberam quatro doses de nitrogênio. Foram feitas medidas repetidas ao longo de dois fatores longitudinais, sendo um qualitativo ordinal (profundidades) e um quantitativo (distâncias da linha de plantio). Por meio dos testes de razão de verossimilhanças, de Wald e utilizando os critérios de informação AIC e BIC, selecionou-se uma estrutura de covariâncias parcimoniosa e outra estrutura para explicar o comportamento médio das respostas. A verificação do ajuste foi feita por meio de gráficos de diagnósticos de resíduos. / Agronomic experiments involving only one longitudinal factor are quite common. However, there are cases that the observations are made by considering two or more of these factors such as where measurements are made in a response variable at different depths along the time, for example. It is admitted that these observations, taken in a systematic way in each experimental unit are correlated and variances are heterogeneous in different levels of longitudinal factor. Using mixed models, this correlation between repeated measures and heterogeneity of variances can be modeled conveniently. To fit these models to data set involving presence of two longitudinal factors, there is need to adapt some variance and covariance structures that are common in experiments with only one longitudinal factor. The objective of this work is to use the class of linear mixed models to study the dry root mass in the soil of a plantation of cane sugar. The experiment was the randomized complete blocks design and parcels received four doses of nitrogen. Repeated measurements were made along two longitudinal factors being one ordinal qualitative (depths) and one quantitative (distances from the row). With the aid of likelihood ratio, Wald tests and using the AIC and BIC information criteria, we selected a parsimonious covariance structure and another structure to explain the average behavior of the responses. Checking the fit was made using diagnostic graphics of residuals.

Os experimentos agronômicos que envolvem somente um fator longitudinal são bastante comuns. No entanto, existem casos em que as observações são tomadas considerando dois ou mais desses fatores, como nos casos em que são feitas medidas de uma variável resposta em profundidades diferentes ao longo do tempo, por exemplo. Admite-se que essas observações, tomadas de modo sistemático em cada unidade experimental, sejam correlacionadas e as variâncias nos diferentes níveis do fator longitudinal sejam heterogêneas. Com o uso de modelos mistos, essa correlação entre medidas repetidas e a heterogeneidade de variâncias podem ser modeladas convenientemente. Para que esses modelos sejam ajustados a um conjunto de dados envolvendo presença de dois fatores longitudinais, existe a necessidade de se adaptarem algumas estruturas de variâncias e covariâncias que são comuns em experimentos com somente um fator longitudinal. O objetivo do presente trabalho é utilizar a classe dos modelos lineares mistos para estudar a massa seca de raiz no solo de uma plantação de cana-de-açúcar. O experimento foi casualizado em blocos e as parcelas receberam quatro doses de nitrogênio. Foram feitas medidas repetidas ao longo de dois fatores longitudinais, sendo um qualitativo ordinal (profundidades) e um quantitativo (distâncias da linha de plantio). Por meio dos testes de razão de verossimilhanças, de Wald e utilizando os critérios de informação AIC e BIC, selecionou-se uma estrutura de covariâncias parcimoniosa e outra estrutura para explicar o comportamento médio das respostas. A verificação do ajuste foi feita por meio de gráficos de diagnósticos de resíduos. / Agronomic experiments involving only one longitudinal factor are quite common. However, there are cases that the observations are made by considering two or more of these factors such as where measurements are made in a response variable at different depths along the time, for example. It is admitted that these observations, taken in a systematic way in each experimental unit are correlated and variances are heterogeneous in different levels of longitudinal factor. Using mixed models, this correlation between repeated measures and heterogeneity of variances can be modeled conveniently. To fit these models to data set involving presence of two longitudinal factors, there is need to adapt some variance and covariance structures that are common in experiments with only one longitudinal factor. The objective of this work is to use the class of linear mixed models to study the dry root mass in the soil of a plantation of cane sugar. The experiment was the randomized complete blocks design and parcels received four doses of nitrogen. Repeated measurements were made along two longitudinal factors being one ordinal qualitative (depths) and one quantitative (distances from the row). With the aid of likelihood ratio, Wald tests and using the AIC and BIC information criteria, we selected a parsimonious covariance structure and another structure to explain the average behavior of the responses. Checking the fit was made using diagnostic graphics of residuals.

1 AbstraktEN The diploma thesis deals with linear mixed effects models. In the first chap- ter, we discuss parameter estimation and hypothesis testing in the linear mixed effects models. The second chapter is dedicated to graphical diagnostics. We look at the suitable diagnostic plots for residuals and random effects estimates. It is closely described, how the violations of assumptions affect the diagnostic plots. In the third chapter we have consequences of the violations of assumptions on the parameter estimates and results of hypothesis testing for fixed effects. 1

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In longitudinal studies, data collected within a subject or cluster are somewhat correlated by their very nature and special cares are needed to account for such correlation in the analysis of data. Under the framework of longitudinal studies, three topics are being discussed in this thesis. In chapter 2, the joint modelling of multivariate longitudinal process consisting of different types of outcomes are discussed. In the large cohort study of UK north Stafforshire osteoarthritis project, longitudinal trivariate outcomes of continuous, binary and ordinary data are observed at baseline, year 3 and year 6. Instead of analysing each process separately, joint modelling is proposed for the trivariate outcomes to account for the inherent association by introducing random effects and the covariance matrix G. The influence of covariance matrix G on statistical inference of fixed-effects parameters has been investigated within the Bayesian framework. The study shows that by joint modelling the multivariate longitudinal process, it can reduce the bias and provide with more reliable results than it does by modelling each process separately. Together with the longitudinal measurements taken intermittently, a counting process of events in time is often being observed as well during a longitudinal study. It is of interest to investigate the relationship between time to event and longitudinal process, on the other hand, measurements taken for the longitudinal process may be potentially truncated by the terminated events, such as death. Thus, it may be crucial to jointly model the survival and longitudinal data. It is popular to propose linear mixed-effects models for the longitudinal process of continuous outcomes and Cox regression model for survival data to characterize the relationship between time to event and longitudinal process, and some standard assumptions have been made. In chapter 3, we try to investigate the influence on statistical inference for survival data when the assumption of mutual independence on random error of linear mixed-effects models of longitudinal process has been violated. And the study is conducted by utilising conditional score estimation approach, which provides with robust estimators and shares computational advantage. Generalised sufficient statistic of random effects is proposed to account for the correlation remaining among the random error, which is characterized by the data-driven method of modified Cholesky decomposition. The simulation study shows that, by doing so, it can provide with nearly unbiased estimation and efficient statistical inference as well. In chapter 4, it is trying to account for both the current and past information of longitudinal process into the survival models of joint modelling. In the last 15 to 20 years, it has been popular or even standard to assume that longitudinal process affects the counting process of events in time only through the current value, which, however, is not necessary to be true all the time, as recognised by the investigators in more recent studies. An integral over the trajectory of longitudinal process, along with a weighted curve, is proposed to account for both the current and past information to improve inference and reduce the under estimation of effects of longitudinal process on the risk hazards. A plausible approach of statistical inference for the proposed models has been proposed in the chapter, along with real data analysis and simulation study.

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