Mathematics Dissertations

NONPARAMETRIC INFERENCES FOR THE HAZARD FUNCTION WITH RIGHT TRUNCATION

Haci Mustafa Akcin — Tue, 14 May 2013 08:29:57 PDT

Incompleteness is a major feature of time-to-event data. As one type of incompleteness, truncation refers to the unobservability of the time-to-event variable because it is smaller (or greater) than the truncation variable. A truncated sample always involves left and right truncation.

Left truncation has been studied extensively while right truncation has not received the same level of attention. In one of the earliest studies on right truncation, Lagakos et al. (1988) proposed to transform a right truncated variable to a left truncated variable and then apply existing methods to the transformed variable. The reverse-time hazard function is introduced through transformation. However, this quantity does not have a natural interpretation. There exist gaps in the inferences for the regular forward-time hazard function with right truncated data. This dissertation discusses variance estimation of the cumulative hazard estimator, one-sample log-rank test, and comparison of hazard rate functions among finite independent samples under the context of right truncation.

First, the relation between the reverse- and forward-time cumulative hazard functions is clarified. This relation leads to the nonparametric inference for the cumulative hazard function. Jiang (2010) recently conducted a research on this direction and proposed two variance estimators of the cumulative hazard estimator. Some revision to the variance estimators is suggested in this dissertation and evaluated in a Monte-Carlo study.

Second, this dissertation studies the hypothesis testing for right truncated data. A series of tests is developed with the hazard rate function as the target quantity. A one-sample log-rank test is first discussed, followed by a family of weighted tests for comparison between finite $K$-samples. Particular weight functions lead to log-rank, Gehan, Tarone-Ware tests and these three tests are evaluated in a Monte-Carlo study.

Finally, this dissertation studies the nonparametric inference for the hazard rate function for the right truncated data. The kernel smoothing technique is utilized in estimating the hazard rate function. A Monte-Carlo study investigates the uniform kernel smoothed estimator and its variance estimator. The uniform, Epanechnikov and biweight kernel estimators are implemented in the example of blood transfusion infected AIDS data.

New Non-Parametric Methods for Income Distributions

Shan Luo — Mon, 29 Apr 2013 07:05:18 PDT

Low income proportion (LIP), Lorenz curve (LC) and generalized Lorenz curve (GLC) are important indexes in describing the inequality of income distribution. They have been widely used for measuring social stability by governments around the world. The accuracy of estimating those indexes is essential to quantify the economics of a country. Established statistical inferential methods for these indexes are based on an asymptotic normal distribution, which may have poor performance when the real income data is skewed or has outliers. Recent applications of nonparametric methods, though, allow researchers to utilize techniques without giving data the parametric distribution assumption. For example, existing research proposes the plug-in empirical likelihood (EL)-based inferences for LIP, LC and GLC. However, this method becomes computationally intensive and mathematically complex because of the presence of nonlinear constraints in the underlying optimization problem. Meanwhile, the limiting distribution of the log empirical likelihood ratio is a scaled Chi-square distribution. The estimation of the scale constant will affect the overall performance of the plug-in EL method. To improve the efficiency of the existing inferential methods, this dissertation first proposes kernel estimators for LIP, LC and GLC, respectively. Then the cross-validation method is proposed to choose bandwidth for the kernel estimators. These kernel estimators are proved to have asymptotic normality. The smoothed jackknife empirical likelihood (SJEL) for LIP, LC and GLC are defined. Then the log-jackknife empirical likelihood ratio statistics are proved to follow the standard Chi-square distribution. Extensive simulation studies are conducted to evaluate the kernel estimators in terms of Mean Square Error and Asymptotic Relative Efficiency. Next, the SJEL-based confidence intervals and the smoothed bootstrap-based confidence intervals are proposed. The coverage probability and interval length for the proposed confidence intervals are calculated and compared with the normal approximation-based intervals. The proposed kernel estimators are found to be competitive estimators, and the proposed inferential methods are observed to have better finite-sample performance. All inferential methods are illustrated through real examples.

Neural Cartography: Computer Assisted Poincare Return Mappings for Biological Oscillations

Jeremy J. Wojcik — Tue, 17 Jul 2012 07:04:10 PDT

This dissertation creates practical methods for Poincaré return mappings of individual and networked neuron models. Elliptic bursting models are found in numerous biological systems, including the external Globus Pallidus (GPe) section of the brain; the focus for studies of epileptic seizures and Parkinson's disease. However, the bifurcation structure for changes in dynamics remains incomplete. This dissertation develops computer-assisted Poincaré ́maps for mathematical and biologically relevant elliptic bursting neuron models and central pattern generators (CPGs). The first method, used for individual neurons, offers the advantage of an entire family of computationally smooth and complete mappings, which can explain all of the systems dynamical transitions. A complete bifurcation analysis was performed detailing the mechanisms for the transitions from tonic spiking to quiescence in elliptic bursters. A previously unknown, unstable torus bifurcation was found to give rise to small amplitude oscillations. The focus of the dissertation shifts from individual neuron models to small networks of neuron models, particularly 3-cell CPGs. A CPG is a small network which is able to produce specific phasic relationships between the cells. The output rhythms represent a number of biologically observable actions, i.e. walking or running gates. A 2-dimensional map is derived from the CPGs phase-lags. The cells are endogenously bursting neuron models mutually coupled with reciprocal inhibitory connections using the fast threshold synaptic paradigm. The mappings generate clear explanations for rhythmic outcomes, as well as basins of attraction for specific rhythms and possible mechanisms for switching between rhythms.

Jackknife Emperical Likelihood Method and its Applications

Hanfang Yang — Tue, 17 Jul 2012 07:02:55 PDT

In this dissertation, we investigate jackknife empirical likelihood methods motivated by recent statistics research and other related fields. Computational intensity of empirical likelihood can be significantly reduced by using jackknife empirical likelihood methods without losing computational accuracy and stability. We demonstrate that proposed jackknife empirical likelihood methods are able to handle several challenging and open problems in terms of elegant asymptotic properties and accurate simulation result in finite samples. These interesting problems include ROC curves with missing data, the difference of two ROC curves in two dimensional correlated data, a novel inference for the partial AUC and the difference of two quantiles with one or two samples. In addition, empirical likelihood methodology can be successfully applied to the linear transformation model using adjusted estimation equations. The comprehensive simulation studies on coverage probabilities and average lengths for those topics demonstrate the proposed jackknife empirical likelihood methods have a good performance in finite samples under various settings. Moreover, some related and attractive real problems are studied to support our conclusions. In the end, we provide an extensive discussion about some interesting and feasible ideas based on our jackknife EL procedures for future studies.

Statistical Evaluation of Continuous-Scale Diagnostic Tests with Missing Data

Binhuan Wang — Thu, 12 Jul 2012 13:02:24 PDT

The receiver operating characteristic (ROC) curve methodology is the statistical methodology for assessment of the accuracy of diagnostics tests or bio-markers. Currently most widely used statistical methods for the inferences of ROC curves are complete-data based parametric, semi-parametric or nonparametric methods. However, these methods cannot be used in diagnostic applications with missing data. In practical situations, missing diagnostic data occur more commonly due to various reasons such as medical tests being too expensive, too time consuming or too invasive. This dissertation aims to develop new nonparametric statistical methods for evaluating the accuracy of diagnostic tests or biomarkers in the presence of missing data. Specifically, novel nonparametric statistical methods will be developed with different types of missing data for (i) the inference of the area under the ROC curve (AUC, which is a summary index for the diagnostic accuracy of the test) and (ii) the joint inference of the sensitivity and the specificity of a continuous-scale diagnostic test. In this dissertation, we will provide a general framework that combines the empirical likelihood and general estimation equations with nuisance parameters for the joint inferences of sensitivity and specificity with missing diagnostic data. The proposed methods will have sound theoretical properties. The theoretical development is challenging because the proposed profile log-empirical likelihood ratio statistics are not the standard sum of independent random variables. The new methods have the power of likelihood based approaches and jackknife method in ROC studies. Therefore, they are expected to be more robust, more accurate and less computationally intensive than existing methods in the evaluation of competing diagnostic tests.

Stability Analysis of Phase-Locked Bursting in Inhibitory Neuron Networks

Sajiya Jesmin Jalil — Thu, 14 Jun 2012 12:03:11 PDT

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.

Mathematical Methods for Network Analysis, Proteomics and Disease Prevention

Kun Zhao — Fri, 27 Apr 2012 12:15:44 PDT

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.

Statistical Inferences for the Youden Index

Haochuan Zhou — Tue, 06 Dec 2011 07:54:36 PST

In diagnostic test studies, one crucial task is to evaluate the diagnostic accuracy of a test. Currently, most studies focus on the Receiver Operating Characteristics Curve and the Area Under the Curve. On the other hand, the Youden index, widely applied in practice, is another comprehensive measurement for the performance of a diagnostic test. For a continuous-scale test classifying diseased and non-diseased groups, finding the Youden index of the test is equivalent to maximize the sum of sensitivity and specificity for all the possible values of the cut-point. This dissertation concentrates on statistical inferences for the Youden index. First, an auxiliary tool for the Youden index, called the diagnostic curve, is defined and used to evaluate the diagnostic test. Second, in the paired-design study to assess the diagnostic accuracy of two biomarkers, the difference in paired Youden indices frequently acts as an evaluation standard. We propose an exact confidence interval for the difference in paired Youden indices based on generalized pivotal quantities. A maximum likelihood estimate-based interval and a bootstrap-based interval are also included in the study. Third, for certain diseases, an intermediate level exists between diseased and non-diseased status. With such concern, we define the Youden index for three ordinal groups, propose the empirical estimate of the Youden index, study the asymptotic properties of the empirical Youden index estimate, and construct parametric and nonparametric confidence intervals for the Youden index. Finally, since covariates often affect the accuracy of a diagnostic test, therefore, we propose estimates for the Youden index with a covariate adjustment under heteroscedastic regression models for the test results. Asymptotic properties of the covariate-adjusted Youden index estimators are investigated under normal error and non-normal error assumptions.

Treatment Comparison in Biomedical Studies Using Survival Function

Meng Zhao — Thu, 28 Apr 2011 09:48:12 PDT

In the dissertation, we study the statistical evaluation of treatment comparisons by evaluating the relative comparison of survival experiences between two treatment groups. We construct confidence interval and simultaneous confidence bands for the ratio and odds ratio of two survival functions through both parametric and nonparametric approaches.

We first construct empirical likelihood confidence interval and simultaneous confidence bands for the odds ratio of two survival functions to address small sample efficacy and sufficiency. The empirical log-likelihood ratio is developed, and the corresponding asymptotic distribution is derived. Simulation studies show that the proposed empirical likelihood band has outperformed the normal approximation band in small sample size cases in the sense that it yields closer coverage probabilities to chosen nominal levels.

Furthermore, in order to incorporate prognostic factors for the adjustment of survival functions in the comparison, we construct simultaneous confidence bands for the ratio and odds ratio of survival functions based on both the Cox model and the additive risk model. We develop simultaneous confidence bands by approximating the limiting distribution of cumulative hazard functions by zero-mean Gaussian processes whose distributions can be generated through Monte Carlo simulations. Simulation studies are conducted to evaluate the performance for proposed models. Real applications on published clinical trial data sets are also studied for further illustration purposes.

In the end, the population attributable fraction function is studied to measure the impact of risk factors on disease incidence in the population. We develop semiparametric estimation of attributable fraction functions for cohort studies with potentially censored event time under the additive risk model.

Some Topics in Roc Curves Analysis

Xin Huang — Wed, 06 Apr 2011 06:20:54 PDT

The receiver operating characteristic (ROC) curves is a popular tool for evaluating continuous diagnostic tests. The traditional definition of ROC curves incorporates implicitly the idea of "hard" thresholding, which also results in the empirical curves being step functions. The first topic is to introduce a novel definition of soft ROC curves, which incorporates the idea of "soft" thresholding. The softness of a soft ROC curve is controlled by a regularization parameter that can be selected suitably by a cross-validation procedure. A byproduct of the soft ROC curves is that the corresponding empirical curves are smooth.

The second topic is on combination of several diagnostic tests to achieve better diagnostic accuracy. We consider the optimal linear combination that maximizes the area under the receiver operating characteristic curve (AUC); the estimates of the combination's coefficients can be obtained via a non-parametric procedure. However, for estimating the AUC associated with the estimated coefficients, the apparent estimation by re-substitution is too optimistic. To adjust for the upward bias, several methods are proposed. Among them the cross-validation approach is especially advocated, and an approximated cross-validation is developed to reduce the computational cost. Furthermore, these proposed methods can be applied for variable selection to select important diagnostic tests.

However, the above best-subset variable selection method is not practical when the number of diagnostic tests is large. The third topic is to further develop a LASSO-type procedure for variable selection. To solve the non-convex maximization problem in the proposed procedure, an efficient algorithm is developed based on soft ROC curves, difference convex programming, and coordinate descent algorithm.

Three Topics in Analysis: (I) The Fundamental Theorem of Calculus Implies that of Algebra, (II) Mini Sums for the Riesz Representing Measure, and (III) Holomorphic Domination and Complex Banach Manifolds Similar to Stein Manifolds

Panakkal J. Mathew — Fri, 11 Feb 2011 08:58:54 PST

We look at three distinct topics in analysis. In the first we give a direct and easy proof that the usual Newton-Leibniz rule implies the fundamental theorem of algebra that any nonconstant complex polynomial of one complex variable has a complex root. Next, we look at the Riesz representation theorem and show that the Riesz representing measure often can be given in the form of mini sums just like in the case of the usual Lebesgue measure on a cube. Lastly, we look at the idea of holomorphic domination and use it to define a class of complex Banach manifolds that is similar in nature and definition to the class of Stein manifolds.

A Generalization of AUC to an Ordered Multi-Class Diagnosis and Application to Longitudinal Data Analysis on Intellectual Outcome in Pediatric Brain-Tumor Patients

Yi Li — Mon, 08 Feb 2010 17:07:17 PST

Receiver operating characteristic (ROC) curves have been widely used in evaluation of the goodness of the diagnostic method in many study fields, such as disease diagnosis in medicine. The area under the ROC curve (AUC) naturally became one of the most used variables in gauging the goodness of the diagnosis (Mossman, Somoza 1991). Since medical diagnosis often is not dichotomous, the ROC curve and AUC need to be generalized to a multi-dimensional case. The generalization of AUC to multi-class case has been studied by many researchers in the past decade. Most recently, Nakas & Yiannoutsos (2004) considered the ordered d classes ROC analysis by only considering the sensitivities of each class. Hence, their dimension is only d. Cha (2005) considered more types of mis-classification in the ordered multiple-class case, but reduced the dimension of Ferri, at.el. from d(d-1) to 2(d-1). In this dissertation we are trying to adjust and calculate the VUS for an ordered multipleclass with Cha’s 2(d-1)-dimension method. Our methodology of finding the VUS is introduced. We present the method of adjusting and calculating VUS and their statistical inferences for the 2(d-1)-dimension. Some simulation results are included and a real example will be presented. Intellectual outcomes in pediatric brain-tumor patients were investigated in a prospective longitudinal study. The Standard-Binet Intelligence Scale-Fourth Edition (SB-IV) Standard Age Score (SAS) and Composite intelligence quotient (IQ) score are examined as cognitive outcomes in pediatric brain-tumor patients. Treatment factors, patient factors and time since diagnosis are taken into account as the risk factors. Hierarchical linear/quadratic models and Gompertz based hierarchical nonlinear growth models were applied to build linear and nonlinear longitudinal curves. We use PRESS and Volume Under the Surface (VUS) as the criterions to compare these two methods. Some model interpretations are presented in this dissertation.