In this paper we consider the problem of constructing confidence intervals and lower bounds forthe intraclass correlation coefficient in an interrater reliability study where the raters are randomly selected from a population of raters.The likelihood function of the interrater reliability is derived and simplified, and the profile likelihood based approach is readily available for computing the confidence intervals of the interrater reliability. Unfortunately, the confidence intervals computed by using the profile likelihood function are in general too narrow to have the desired coverage probabilities. From the point view of practice, a conservative approach, if is at least as precise as any existing method, is preferred sinceit gives the correct results with a probability higher than claimed. Under this rationale, we propose the so-called modified likelihood approach in this paper. Simulation study shows that, the proposed method in general has better performance than currently used methods.

Retinal pigment epithelium (RPE) is a principal site of pathogenesis in age-related macular de-generation (AMD). AMD is a main source of vision loss even blindness in the elderly and there is no effective treatment right now. Our aim is to describe the relationship between the morphology of RPE cells and the age and genotype of the eyes. We use principal component analysis (PCA) or functional principal component method (FPCA), support vector machine (SVM), and random forest (RF) methods to analyze the morphological data of RPE cells in mouse eyes to classify their age and genotype. Our analyses show that amongst all morphometric measures of RPE cells, cell shape measurements (eccentricity and solidity) are good for classification. But combination of cell shape and size (perimeter) provide best classification.

The clinical trial is the most import study for the development of successful novel drugs. The aim of this dissertation is to develop innovative statistical methods to overcome the three main obstacles in clinical trials: (1) lengthy trial duration and inaccurate maximum tolerated dose (MTD) in phase I trials; (2) heterogeneity in drug effect when patients are given the same prescription and same dose; and (3) high failure rates of expensive phase III confirmatory trials due to the discrepancy in the endpoints adopted in phase II and III trials. Towards overcoming the first obstacle, we originally develop a hybrid design for the time-to-event dose escalation method with overdose control using a normalized equivalent toxicity score (NETS) system. This hybrid design can substantially reduce sample size, shorten study length, and estimate accurate MTD by employing a parametric model and adaptive Bayesian approach. Toward overcoming the second obstacle, we propose a new approach to incorporate patients’ characteristic using our proposed design in phase I clinical trials which considers the personalized information for patients who participant in the trials. To conquer the third obstacle, we propose a novel two-stage screening design for phase II trials whereby the endpoint of percent change in of tumor size is used in an initial screening to select potentially effective agents within a short time interval followed by a second screening stage where progression free survival is estimated to confirm the efficacy of agents. These research projects will substantially benefit both cancer patients and researchers by improving clinical trial efficiency and reducing cost and trial duration. Moreover, they are of great practical meaning since cancer medicine development is of paramount importance to human health care.

In this dissertation we study the algebraic properties of the intersection algebra of two ideals I and J in a Noetherian ring R. A major part of the dissertation is devoted to the finite generation of these algebras and developing methods of obtaining their generators when the algebra is finitely generated. We prove that the intersection algebra is a finitely generated R-algebra when R is a Unique Factorization Domain and the two ideals are principal, and use fans of cones to find the algebra generators. This is done in Chapter 2, which concludes with introducing a new class of algebras called fan algebras. Chapter 3 deals with the intersection algebra of principal monomial ideals in a polynomial ring, where the theory of semigroup rings and toric ideals can be used. A detailed investigation of the intersection algebra of the polynomial ring in one variable is obtained. The intersection algebra in this case is connected to semigroup rings associated to systems of linear diophantine equations with integer coefficients, introduced by Stanley. In Chapter 4, we present a method for obtaining the generators of the intersection algebra for arbitrary monomial ideals in the polynomial ring.

We are examining iteratively regularized methods for solving nonlinear inverse problems. Of particular interest for these types of methods are application problems which are unstable. For these application problems, special methods of numerical analysis are necessary, since classical algorithms tend to be divergent.

The variance is the measure of spread from the center. Therefore, how to accurately estimate variance has always been an important topic in recent years. In this paper, we consider a linear regression model which is the most popular model in practice. We use jackknife empirical likelihood method to obtain the interval estimate of variance in the regression model. The proposed jackknife empirical likelihood ratio converges to the standard chi-squared distribution. The simulation study is carried out to compare the jackknife empirical likelihood method and standard method in terms of coverage probability and interval length for the confidence interval of variance from linear regression models. The proposed jackknife empirical likelihood method has better performance. We also illustrate the proposed methods using two real data sets.

In statistics it is of interest to find a better interval estimator of the absolute mean deviation. In this thesis, we focus on using the jackknife, the adjusted and the extended jackknife empirical likelihood methods to construct confidence intervals for the mean absolute deviation of a random variable. The empirical log-likelihood ratio statistics is derived whose asymptotic distribution is a standard chi-square distribution. The results of simulation study show the comparison of the average length and coverage probability by using jackknife empirical likelihood methods and normal approximation method. The proposed adjusted and extended jackknife empirical likelihood methods perform better than other methods for symmetric and skewed distributions. We use real data sets to illustrate the proposed jackknife empirical likelihood methods.

This dissertation aims at analyzing complex problems arising in the context of dynamical networks, proteomics, and disease prevention. First, a new graph-based method for proving global stability of synchronization in directed dynamical networks is developed. This method utilizes stability and graph theories to clarify the interplay between individual oscillator dynamics and network topology. Secondly, a graph-theoretical algorithm is proposed to predict Ca2+-binding site in proteins. The new algorithm enables us to identify previously-unknown Ca2+-binding sites, and deepens our understanding towards disease-related Ca2+-binding proteins at a molecular level. Finally, an optimization model and algorithm to solve a disease prevention problem are described at the population level. The new resource allocation model is designed to assist clinical managers to make decisions on identifying at-risk population groups, as well as selecting a screening and treatment strategy for chlamydia and gonorrhea patients under a fixed budget. The resource allocation model and algorithm can have a significant impact on real treatment strategy issues.

Networks of neurons, which form central pattern generators (CPGs), are important for controlling animal behaviors. Of special interest are configurations or CPG motifs composed of reciprocally inhibited neurons, such as half-center oscillators (HCOs). Bursting rhythms of HCOs are shown to include stable synchrony or in-phase bursting. This in-phase bursting can co-exist with anti-phase bursting, commonly expected as the single stable state in HCOs that are connected with fast non-delayed synapses. The finding contrasts with the classical view that reciprocal inhibition has to be slow or time-delayed to synchronize such bursting neurons. Phase-locked rhythms are analyzed via Lyapunov exponents estimated with variational equations, and through the convergence rates estimated with Poincar\'e return maps. A new mechanism underlying multistability is proposed that is based on the spike interactions, which confer a dual property on the fast non-delayed reciprocal inhibition; this reveals the role of spikes in generating multiple co-existing phase-locked rhythms. In particular, it demonstrates that the number and temporal characteristics of spikes determine the number and stability of the multiple phase-locked states in weakly coupled HCOs. The generality of the multistability phenomenon is demonstrated by analyzing diverse models of bursting networks with various inhibitory synapses; the individual cell models include the reduced leech heart interneuron, the Sherman model for pancreatic beta cells, the Purkinje neuron model and Fitzhugh-Rinzel phenomenological model. Finally, hypothetical and experiment-based CPGs composed of HCOs are investigated. This study is relevant for various applications that use CPGs such as robotics, prosthetics, and artificial intelligence.

With new tests being developed and marketed, the comparison of the diagnostic accuracy of two continuous-scale diagnostic tests are of great importance. Comparing the partial areas under the receiver operating characteristic curves (pAUC) is an effective method to evaluate the accuracy of two diagnostic tests. In this thesis, we study the semi-parametric inference for the difference between two pAUCs. A normal approximation for the distribution of the difference between two pAUCs has been derived. The empirical likelihood ratio for the difference between two pAUCs is defined and its asymptotic distribution is shown to be a scaled chi-quare distribution. Bootstrap and empirical likelihood based inferential methods for the difference are proposed. We construct five confidence intervals for the difference between two pAUCs. Simulation studies are conducted to compare the finite sample performance of these intervals. We also use a real example as an application of our recommended intervals.