Statistics and Probability Commons^™

Covariance-Enhanced Discriminant Analysis, Peirong Xu, Ji Zhu, Lixing Zhu, Yi Li

The University of Michigan Department of Biostatistics Working Paper Series

Linear discriminant analysis (LDA), a classical method in pattern recognition and machine learning, has been widely used to characterize or separate multiple classes via linear combinations of features. However, the high-dimensionality of the high-throughput features obtained from modern biological experiments, for example, microarray or proteomics, defies traditional discriminant analysis techniques. The possible interfeature correlations present additional challenges and are often under-utilized in modeling. In this paper, by incorporating the possible inter-feature correlations, we propose a Covariance-Enhanced Discriminant Analysis (CEDA) method that simultaneously and consistently selects informative features and identifies the corresponding discriminable classes. We show that, under mild regularity conditions, …

A Phase I Bayesian Adaptive Design To Simultaneously Optimize Dose And Schedule Assignments Both Among And Within Patients, Thomas M. Braun, Jin Zhang

The University of Michigan Department of Biostatistics Working Paper Series

In traditional schedule or dose-schedule finding designs, patients are assumed to receive their assigned dose-schedule combination throughout the trial even though the combination may be found to have an undesirable toxicity profile, which contradicts actual clinical practice. Since no systematic approach exists to optimize intra-patient dose-schedule as- signment, we propose a Phase I clinical trial design that extends existing approaches that optimize dose and schedule solely among patients by incorporating adaptive variations to dose-schedule assignments within patients as the study proceeds. Our design is based on a Bayesian non-mixture cure rate model that incorporates multiple administrations each patient receives with …

Analysis Of Periodontal Data Using Circular Statistics, Samopriyo Maitra, Thomas M. Braun

The University of Michigan Department of Biostatistics Working Paper Series

Periodontal disease is a common cause of tooth loss in adults. The severity of periodontal disease is usually quantified based upon the magnitudes of several tooth-level clinical parameters, the most common of which is clinical attachment level (CAL). Re- cent clinical studies have presented data on the distribution of periodontal disease in hopes of providing information for localized treatments that can reduce the prevalence of periodontal disease. However, these findings have been descriptive without consid- eration of statistical modeling for estimation and inference. To this end, we visualize the mouth as a circle and the teeth as points located on …

The Bayesian Continual Reassessment Method Using A Mixture-Of-Uniforms Prior, Thomas M. Braun

The University of Michigan Department of Biostatistics Working Paper Series

Traditionally, the Bayesian formulation of the Continual Reassessment Method (CRM) is implemented with a one-parameter model describing the association of dose with the probability of dose-limiting toxicity (DLT). Determination of the appropriate value of the prior variance is often done via simulation over a grid search of possible values until suitable operating characteristics are found. However, it is under-appreciated that the operating characteristics for a given value of the prior variance vary by the “skeleton,” which is the vector of a priori probabilities of DLT for each dose. The skeleton implicitly leads to a set of indifference intervals, with one …

Proxy Pattern-Mixture Analysis For A Binary Variable Subject To Nonresponse., Rebecca H. Andridge, Roderick J. Little

The University of Michigan Department of Biostatistics Working Paper Series

We consider assessment of the impact of nonresponse for a binary survey

variable Y subject to nonresponse, when there is a set of covariates

observed for nonrespondents and respondents. To reduce dimensionality and

for simplicity we reduce the covariates to a continuous proxy variable X

that has the highest correlation with Y, estimated from a probit

regression analysis of respondent data. We extend our previously proposed

proxy-pattern mixture analysis (PPMA) for continuous outcomes to the binary

outcome using a latent variable approach. The method does not assume data

are missing at random, and creates a framework for sensitivity analyses.

Maximum …

Subsample Ignorable Likelihood For Accelerated Failure Time Models With Missing Predictors, Nanhua Zhang, Roderick J. Little

The University of Michigan Department of Biostatistics Working Paper Series

No abstract provided.

Predicting Treatment Efficacy Via Quantitative Mri: A Bayesian Joint Model, Jincao Wu, Tim Johnson

The University of Michigan Department of Biostatistics Working Paper Series

The prognosis for patients with high-grade gliomas is poor, with a median survival of one year. Treatment efficacy assessment is typically unavailable until 5{6 months post diagnosis. Investigators hypothesize that quantitative MRI (qMRI) can assess treatment efficacy three weeks after therapy starts, thereby allowing salvage treatments to begin earlier. The purpose of this work is to build a predictive model of treatment efficacy using qMRI data and to assess its performance. The outcome is one-year survival status. We propose a joint, two-stage Bayesian model. In stage I, we smooth the image data with a multivariate spatio-temporal pairwise dierence prior. We …

Modeling Menstrual Cycle Length And Variability At The Approach Of Menopause Using Bayesian Changepoint Models, Xiaobi Huang, Michael R. Elliott, Sioban D. Harlow

The University of Michigan Department of Biostatistics Working Paper Series

As women approach menopause, the patterns of their menstruation cycle lengths change. To study these changes, we need to jointly model both the mean and variability of the cycle length. The model incorporates separate mean and variance change points for each woman and a hierarchical model to link them together, along with regression components to include predictors of menopausal onset such as age at menarche and parity. Data are from TREMIN, an ongoing 70-year old longitudinal study that has obtained menstrual calendar data of women throughout their reproductive life course. An additional complexity arises from the fact that these calendars …

An Analysis Of Nonignorable Nonresponse In A Survey With A Rotating Panel Design, Caterina Giusti, Roderick J. Little

The University of Michigan Department of Biostatistics Working Paper Series

Missing values to income questions are common in survey data. When the probabilities of nonresponse are assumed to depend on the observed information and not on the underlining unobserved amounts, the missing income values are missing at random (MAR), and methods such as sequential multiple imputation can be applied. However, the MAR assumption is often considered questionable in this context, since missingness of income is thought to be related to the value of income itself, after conditioning on available covariates. In this article we describe a sensitivity analysis based on a pattern-mixture model for deviations from MAR, in the context …

Doubly Regularized Reml For Estimation And Selection Of Fixed And Random Effects In Linear Mixed-Effects Models, Sijian Wang, Peter Xuewin Song, Ji Zhu

The University of Michigan Department of Biostatistics Working Paper Series

The linear mixed effects model (LMM) is widely used in the analysis of clustered or longitudinal data. In the practice of LMM, the inference on the structure of the random effects component is of great importance, not only to yield proper interpretation of subject-specific effects but also to draw valid statistical conclusions. This task of inference becomes significantly challenging when a large number of fixed effects and random effects are involved in the analysis. The difficulty of variable selection arises from the need of simultaneously regularizing both mean model and covariance structures, with possible parameter constraints between the two. In …

Composite Likelihood Bayesian Information Criteria For Model Selection In High Dimensional Data, X Gao, Peter Xuekun Song

The University of Michigan Department of Biostatistics Working Paper Series

For high-dimensional data set with complicated dependency structures, the full likelihood approach often renders to intractable computational complexity. This imposes di±culty on model selection as most of the traditionally used information criteria require the evaluation of the full likelihood. We propose a composite likelihood version of the Bayesian information criterion (BIC) and establish its consistency property for the selection of the true underlying model. Under some mild regularity conditions, the proposed BIC is shown to be selection consistent, where the number of potential model parameters is allowed to increase to in¯nity at a certain rate of the sample size. Simulation …

Longitudinal Image Analysis Of Tumor/Brain Change In Contrast Uptake Induced By Radiation, Xiaoxi Zhang, Tim Johnson, Rod Little, Yue Cao

The University of Michigan Department of Biostatistics Working Paper Series

This work is motivated by a quantitative Magnetic Resonance Imaging study of the differential tumor/healthy tissue change in contrast uptake induced by radiation. The goal is to determine the time in which there is maximal contrast uptake, a surrogate for permeability, in the tumor relative to healthy tissue. A notable feature of the data is its spatial heterogeneity. Zhang, Johnson, Little, and Cao (2008a and 2008b) discuss two parallel approaches to “denoise” a single image of change in contrast uptake from baseline to a single follow-up visit of interest. In this work we explore the longitudinal profile of the tumor/healthy …

Weighting And Prediction In Sample Surveys, Rod Little

The University of Michigan Department of Biostatistics Working Paper Series

A fundamental technique in survey sampling is to weight included units by the inverse of their probability of inclusion, which may be known (as in the case of sampling weights) or estimated (as in the case of nonresponse weights). The technique is closely associated with the design-based approach to survey inference, with the idea that units in the sample are representing a certain number of units in the population. I discuss weighting from a modeling perspective. Some common misconceptions of weighting will be addressed, including the idea that modelers can ignore the sampling weights, or that weighting necessarily reduces bias …

A Bayesian Approach To Modeling Associations Between Pulsatile Hormones, Nichole E. Carlson, Timothy D. Johnson, Morton B. Brown

The University of Michigan Department of Biostatistics Working Paper Series

Many hormones are secreted in pulses. The pulsatile relationship between hormones regulates many biological processes. To understand endocrine system regulation, time series of hormone concentrations are collected. The goal is to characterize pulsatile patterns and associations between hormones. Currently each hormone on each subject is fitted univariately. This leads to estimates of the number of pulses and estimates of the amount of hormone secreted; however, when the signal-to-noise ratio is small, pulse detection and parameter estimation remains di±cult with existing approaches. In this paper, we present a bivariate deconvolution model of pulsatile hormone data focusing on incorporating pulsatile associations. Through …

Parametric Non-Mixture Cure Models For Schedule-Finding Of Therapeutic Agents, Thomas M. Braun, Changying A. Liu

The University of Michigan Department of Biostatistics Working Paper Series

We propose a Phase I clinical trial design that seeks to determine the cumulative safety of a series of administrations of a fixed dose of an investigational agent. In contrast to traditional Phase I trials that are designed to solely find the maximum tolerated dose (MTD) of the agent, our design instead identifies a maximum tolerated schedule (MTS) that includes an MTD as well as a vector of recommended administration times. Our model is based upon a non-mixture cure model that constrains the probability of toxicity for all subjects to monotonically increase with both dose and the number of administrations …

Cluster Mass Inference Method Via Random Field Theory, Hui Zhang, Thomas E. Nichols, Timothy D. Johnson

The University of Michigan Department of Biostatistics Working Paper Series

Cluster extent and voxel intensity are two widely used statistics in neuroimaging inference. Cluster extent is sensitive to spatially extended signals while voxel intensity is better for intense but focal signals. In order to leverage strength from both statistics, several nonparametric permutation methods have been proposed to combine the two methods. Simulation studies have shown that of the different cluster permutation methods, the cluster mass statistic is generally the best. However, to date, there is no parametric cluster mass inference available. In this paper, we propose a cluster mass inference method based on random field theory (RFT). We develop this …

A Bayesian Image Analysis Of The Change In Tumor/Brain Contrast Uptake Induced By Radiation Via Reversible Jump Markov Chain Monte Carlo, Xiaoxi Zhang, Tim Johnson, Roderick J.A. Little

The University of Michigan Department of Biostatistics Working Paper Series

This work is motivated by a pilot study on the change in tumor/brain contrast uptake induced by radiation via quantitative Magnetic Resonance Imaging. The results inform the optimal timing of administering chemotherapy in the context of radiotherapy. A noticeable feature of the data is spatial heterogeneity. The tumor is physiologically and pathologically distinct from surrounding healthy tissue. Also, the tumor itself is usually highly heterogeneous. We employ a Gaussian Hidden Markov Random Field model that respects the above features. The model introduces a latent layer of discrete labels from an Markov Random Field (MRF) governed by a spatial regularization parameter. …

Bayesian Bivariate Image Analysis With Application To Dual Autoradiography, Timothy D. Johnson, Morand Piert

The University of Michigan Department of Biostatistics Working Paper Series

We present a Bayesian bivariate image model and apply it to a study that was designed to investigate the relationship between hypoxia and angiogenesis in an animal tumor model. Two radiolabeled tracers (one measuring angio- genesis, the other measuring hypoxia) were simultaneously injected into the animals, the tumors removed and autoradiographic images of the tracer concentrations were obtained. We model correlation between tracers with a mixture of bivariate normal distributions and the spatial correlation inherent in the images by means of the celebrated Potts model. Although the Potts model is typically used for image segmentation, we use it solely as …

Quantitative Magnetic Resonance Image Analysis Via The Em Algorithm With Stochastic Variation, Xiaoxi Zhang, Timothy D. Johnson, Roderick J.A. Little

The University of Michigan Department of Biostatistics Working Paper Series

Quantitative Magnetic Resonance Imaging (qMRI) provides researchers insight into pathological and physiological alterations of living tissue, with the help of which, researchers hope to predict (local) therapeutic efficacy early and determine optimal treatment schedule. However, the analysis of qMRI has been limited to ad-hoc heuristic methods. Our research provides a powerful statistical framework for image analysis and sheds light on future localized adaptive treatment regimes tailored to the individual’s response. We assume in an imperfect world we only observe a blurred and noisy version of the underlying “true” scene via qMRI, due to measurement errors or unpredictable influences. We use …

Bayesian Spatial Modeling Of Fmri Data: A Multiple-Subject Analysis, Lei Xu, Timothy Johnson, Thomas Nichols

The University of Michigan Department of Biostatistics Working Paper Series

The aim of this work is to develop a spatial model for multi-subject fMRI data. While there has been much work on univariate modeling of each voxel for single- and multi-subject data, and some work on spatial modeling for single-subject data, there has been no work on spatial models that explicitly account for intersubject variability in activation location. We use a Bayesian hierarchical spatial model to fit the data. At the first level we model "population centers" that mark the centers of regions of activation. For a given population center each subject may have zero or more associated "individual components". …

Semiparametric Regression Of Multi-Dimensional Genetic Pathway Data: Least Squares Kernel Machines And Linear Mixed Models, Dawei Liu, Xihong Lin, Debashis Ghosh

The University of Michigan Department of Biostatistics Working Paper Series

SUMMARY. We consider a semiparametric regression model that relates a normal outcome to covariates and a genetic pathway, where the covariate effects are modeled parametrically and the pathway effect of multiple gene expressions is modeled parametrically or nonparametrically using least squares kernel machines (LSKMs). This unified framework allows a flexible function for the joint effect of multiple genes within a pathway by specifying a kernel function and allows for the possibility that each gene expression effect might be nonlinear and the genes within the same pathway are likely to interact with each other in a complicated way. This semiparametric model …

Analysis Of Case-Control Age-At-Onset Data Using A Modified Case-Cohort Method, Bin Nan, Xihong Lin

The University of Michigan Department of Biostatistics Working Paper Series

Case-control designs are widely used in rare disease studies. In a typical case-control study, data are collected from a sample of all available subjects who have experienced a disease (cases) and a sub-sample of subjects who have not experienced the disease (controls) in a study cohort. Cases are often oversampled in case-control studies. Logistic regression is a common tool to estimate the relative risks of the disease and a set of covariates. Very often in such a study, information of ages-at-onset of the disease for all cases and ages at survey of controls are known. Standard logistic regression analysis using …

Doubly Penalized Buckley-James Method For Survival Data With High-Dimensional Covariates, Sijian Wang, Bin Nan, Ji Zhu, David G. Beer

The University of Michigan Department of Biostatistics Working Paper Series

Recent interest in cancer research focuses on predicting patients' survival by investigating gene expression profiles based on microarray analysis. We propose a doubly penalized Buckley-James method for the semiparametric accelerated failure time model to relate high-dimensional genomic data to censored survival outcomes, which uses a mixture of L₁-norm and L₂-norm penalties. Similar to the elastic-net method for linear regression model with uncensored data, the proposed method performs automatic gene selection and parameter estimation, where highly correlated genes are able to be selected (or removed) together. The two-dimensional tuning parameter is determined by cross-validation and uniform design. …

Exploiting Gene-Environment Independence For Analysis Of Case-Control Studies: An Empirical Bayes Approach To Trade Off Between Bias And Efficiency, Bhramar Mukherjee, Nilanjan Chatterjee

The University of Michigan Department of Biostatistics Working Paper Series

Standard prospective logistic regression analysis of case-control data often leads to very imprecise estimates of gene-environment interactions due to small numbers of cases or controls in cells of crossing genotype and exposure. In contrast, under the assumption of gene-environment independence, modern “retrospective” methods, including the “case-only” approach, can estimate the interaction parameters much more precisely, but they can be seriously biased when the underlying assumption of gene-environment independence is violated. In this article, we propose a novel approach to analyze case-control data that can relax the gene-environment independence assumption using an empirical Bayes framework. In the special case, involving a …

A Note On Bias Due To Fitting Prospective Multivariate Generalized Linear Models To Categorical Outcomes Ignoring Retrospective Sampling Schemes, Bhramar Mukherjee, Ivy Liu

The University of Michigan Department of Biostatistics Working Paper Series

Outcome dependent sampling designs are commonly used in economics, market research and epidemiological studies. Case-control sampling design is a classic example of outcome dependent sampling, where exposure information is collected on subjects conditional on their disease status. In many situations, the outcome under consideration may have multiple categories instead of a simple dichotomization. For example, in a case-control study, there may be disease sub-classification among the “cases” based on progression of the disease, or in terms of other histological and morphological characteristics of the disease. In this note, we investigate the issue of fitting prospective multivariate generalized linear models to …

Simultaneously Optimizing Dose And Schedule Of A New Cytotoxic Agent, Thomas M. Braun, Peter F. Thall, Hoang Nguyen, Marcos De Lima

The University of Michigan Department of Biostatistics Working Paper Series

Traditionally, phase I clinical trial designs determine a maximum tolerated dose of an experimental cytotoxic agent based on a fixed schedule, usually one course consisting of multiple administrations, while varying the dose per administration between patients. However, in actual medical practice patients often receive several courses of treatment, and some patients may receive one or more dose reductions due to low-grade (non-dose limiting) toxicity in previous courses. As a result, the overall risk of toxicity for each patient is a function of both the schedule and the dose used at each adminstration. We propose a new paradigm for Phase I …

Generalized Monotonic Functional Mixed Models With Application To Modeling Normal Tissue Complications , Matthew Schipper, Jeremy Taylor, Xihong Lin

The University of Michigan Department of Biostatistics Working Paper Series

Normal tissue complications are a common side effect of radiation therapy. They are the consequence of the dose of radiation received by the normal tissue surrounding the tumor site. It is not known what function of the dose distribution to the normal tissue drives the presence and severity of the complications. Regarding the density of the dose distribution as a curve, a summary measure is obtained by integrating a weighting function of dose (w(d)) over the dose density. For biological reasons the weight function should be monotonic. We propose to study the dose effect on a clinical outcome using a …

Permutation Methods In Relative Risk Regression Models, Wenyu Jiang, Jack Kalbfleisch

The University of Michigan Department of Biostatistics Working Paper Series

In this paper, we develop a weighted permutation (WP) method to construct confidence intervals for regression parameters in relative risk regression models. The WP method is a generalized permutation approach. It constructs a resampled history which mimics the observed history for individuals under study. Inference procedures are based on studentized score statistics that are insensitive to the forms of the relative risk function. This makes the WP method appealing in the general framework of the relative risk regression model. First order accuracy of the WP method is established using the counting process approach with a partial likelihood filtration. A simulation …

Multiple Imputation In The Presence Of Outliers, Michael Elliott

The University of Michigan Department of Biostatistics Working Paper Series

We consider the problem of obtaining population-based inference in the presence of missing data and outliers in the context of estimating obesity prevalence and body-mass index (BMI) measures from the Healthy For Life Study. Identifying multiple outliers in a multivariate setting is problematic because of problems such as masking, in which groups of outliers inflate the covariance matrix in a fashion that prevents their identification when included, and swamping, in which outliers skew covariances in a fashion that make non-outling observations appear to be outliers. We develop a latent class model that assumes each observation belongs to one of $K$ …

Combining Information From Two Surveys To Estimate County-Level Prevalence Rates Of Cancer Risk Factors And Screening, Trivellore E. Raghuanthan, Dawei Xie, Nathaniel Schenker, Van Parsons, William W. Davis, Kevin W. Dodd, Eric J. Feuer

The University of Michigan Department of Biostatistics Working Paper Series

Cancer surveillance requires estimates of the prevalence of cancer risk factors and screening for small areas such as counties. Two popular data sources are the Behavioral Risk Factor Surveillance System (BRFSS), a telephone survey conducted by state agencies, and the National Health Interview Survey (NHIS), an area probability sample survey conducted through face-to-face interviews. Both data sources have advantages and disadvantages. The BRFSS is a larger survey, and almost every county is included in the survey; but it has lower response rates as is typical with telephone surveys, and it does not include subjects who live in households with no …