Statistics and Probability Commons^™

Hierarchical Bivariate Time Series Models: A Combined Analysis Of The Effects Of Particulate Matter On Morbidity And Mortality, Francesca Dominici, Antonella Zanobetti, Scott L. Zeger, Joel Schwartz, Jonathan M. Samet

Johns Hopkins University, Dept. of Biostatistics Working Papers

In this paper we develop a hierarchical bivariate time series model to characterize the relationship between particulate matter less than 10 microns in aerodynamic diameter (PM10) and both mortality and hospital admissions for cardiovascular diseases. The model is applied to time series data on mortality and morbidity for 10 metropolitan areas in the United States from 1986 to 1993. We postulate that these time series should be related through a shared relationship with PM10.

At the first stage of the hierarchy, we fit two seemingly unrelated Poisson regression models to produce city-specific estimates of the log relative rates of mortality …

Statistical Inferences Based On Non-Smooth Estimating Functions, Lu Tian, Jun S. Liu, Mary Zhao, L. J. Wei

Harvard University Biostatistics Working Paper Series

No abstract provided.

On The Cox Model With Time-Varying Regression Coefficients, Lu Tian, David Zucker, L. J. Wei

Harvard University Biostatistics Working Paper Series

No abstract provided.

Maximum Likelihood Estimation Of Ordered Multinomial Parameters , Nicholas P. Jewell, Jack Kalbfleisch

The University of Michigan Department of Biostatistics Working Paper Series

The pool-adjacent violator-algorithm (Ayer et al., 1955) has long been known to give the maximum likelihood estimator of a series of ordered binomial parameters, based on an independent observation from each distribution (see, Barlow et al., 1972). This result has immediate application to estimation of a survival distribution based on current survival status at a set of monitoring times. This paper considers an extended problem of maximum likelihood estimation of a series of ‘ordered’ multinomial parameters pi = (p1i, p2i, . . . , pmi) for 1 < = I < = k, where ordered means that pj1 < = pj2 < = .. . < = pjk for each j with 1 < = j < = m-1. The data consist of k independent observations X1, . . . ,Xk where Xi has a multinomial distribution with probability parameter pi and known index ni > = 1. By making use of variants of the pool adjacent violator algorithm, …

Nonparametric Estimation Of The Bivariate Recurrence Time Distribution, Chiung-Yu Huang, Mei-Cheng Wang

Johns Hopkins University, Dept. of Biostatistics Working Papers

This paper considers statistical models in which two different types of events, such as the diagnosis of a disease and the remission of the disease, occur alternately over time and are observed subject to right censoring. We propose nonparametric estimators for the joint distribution of bivariate recurrence times and the marginal distribution of the first recurrence time. In general, the marginal distribution of the second recurrence time cannot be estimated due to an identifiability problem, but a conditional distribution of the second recurrence time can be estimated non-parametrically. In literature, statistical methods have been developed to estimate the joint distribution …

A Nested Unsupervised Approach To Identifying Novel Molecular Subtypes, Elizabeth Garrett, Giovanni Parmigiani

Johns Hopkins University, Dept. of Biostatistics Working Papers

In classification problems arising in genomics research it is common to study populations for which a broad class assignment is known (say, normal versus diseased) and one seeks to find undiscovered subclasses within one or both of the known classes. Formally, this problem can be thought of as an unsupervised analysis nested within a supervised one. Here we take the view that the nested unsupervised analysis can successfully utilize information from the entire data set for constructing and/or selecting useful predictors. Specifically, we propose a mixture model approach to the nested unsupervised problem, where the supervised information is used to …

A Population Pharmacokinetic Model With Time-Dependent Covariates Measured With Errors, Lang Lil, Xihong Lin, Mort B. Brown, Suneel Gupta, Kyung-Hoon Lee

The University of Michigan Department of Biostatistics Working Paper Series

We propose a population pharmacokinetic (PK) model with time-dependent covariates measured with errors. This model is used to model S-oxybutynin's kinetics following an oral administration of Ditropan, and allows the distribution rate to depend on time-dependent covariates blood pressure and heart rate, which are measured with errors. We propose two two-step estimation methods: the second order two-step method with numerical solutions of differential equations (2orderND), and the second order two-step method with closed form approximate solutions of differential equations (2orderAD). The proposed methods are computationally easy and require fitting a linear mixed model at the first step and a nonlinear …

Stochastic Models Based On Molecular Hybridization Theory For Short Oligonucleotide Microarrays, Zhijin Wu, Richard Leblanc, Rafael A. Irizarry

Johns Hopkins University, Dept. of Biostatistics Working Papers

High density oligonucleotide expression arrays are a widely used tool for the measurement of gene expression on a large scale. Affymetrix GeneChip arrays appear to dominate this market. These arrays use short oligonucleotides to probe for genes in an RNA sample. Due to optical noise, non-specific hybridization, probe-specific effects, and measurement error, ad-hoc measures of expression, that summarize probe intensities, can lead to imprecise and inaccurate results. Various researchers have demonstrated that expression measures based on simple statistical models can provide great improvements over the ad-hoc procedure offered by Affymetrix. Recently, physical models based on molecular hybridization theory, have been …

Efficient Semiparametric Marginal Estimation For Longitudinal/Clustered Data, Naisyin Wang, Raymond J. Carroll, Xihong Lin

The University of Michigan Department of Biostatistics Working Paper Series

We consider marginal generalized semiparametric partially linear models for clustered data. Lin and Carroll (2001a) derived the semiparametric efficinet score funtion for this problem in the mulitvariate Gaussian case, but they were unable to contruct a semiparametric efficient estimator that actually achieved the semiparametric information bound. We propose such an estimator here and generalize the work to marginal generalized partially liner models. Asymptotic relative efficincies of the estimation or throughout are investigated. The finite sample performance of these estimators is evaluated through simulations and illustrated using a longtiudinal CD4 count data set. Both theoretical and numerical results indicate that properly …

Equivalent Kernels Of Smoothing Splines In Nonparametric Regression For Clustered/Longitudinal Data, Xihong Lin, Naisyin Wang, Alan H. Welsh, Raymond J. Carroll

The University of Michigan Department of Biostatistics Working Paper Series

We compare spline and kernel methods for clustered/longitudinal data. For independent data, it is well known that kernel methods and spline methods are essentially asymptotically equivalent (Silverman, 1984). However, the recent work of Welsh, et al. (2002) shows that the same is not true for clustered/longitudinal data. First, conventional kernel methods fail to account for the within- cluster correlation, while spline methods are able to account for this correlation. Second, kernel methods and spline methods were found to have different local behavior, with conventional kernels being local and splines being non-local. To resolve these differences, we show that a smoothing …

Histospline Method In Nonparametric Regression Models With Application To Clustered/Longitudinal Data, Raymond J. Carroll, Peter Hall, Tatiyana V. Apanasovich, Xihong Lin

The University of Michigan Department of Biostatistics Working Paper Series

Kernel and smoothing methods for nonparametric function and curve estimation have been particularly successful in "standard" settings, where function values are observed subject to independent errors. However, when aspects of the function are known parametrically, or where the sampling scheme has significant structure, it can be quite difficult to adapt standard methods in such a way that they retain good statistical performance and continue to enjoy easy computability and good numerical properties. In particular, when using local linear modeling it is often awkward to both respect the sampling scheme and produce an estimator with good variance properties, without resorting to …

Measuring Treatment Effects Using Semiparametric Models, Zhuo Yu, Mark J. Van Der Laan

U.C. Berkeley Division of Biostatistics Working Paper Series

In order to estimate the causal effect of treatments on an outcome of interest, one has to account for the effect of confounding factors which covary with the treatments and also contribute to the outcome of interest. In this paper, we use the semiparametric regression model to estimate the causal parameters. We assume the causal effect of the treatments can be described by the parametric component of the semiparametric regression model. Following the general methodology which was developed in van der Laan and Robins (2002) we give the orthogonal complement of the nuisance tangent space which identifies all the estimating …

A Varying-Coefficient Cox Model For The Effect Of Age At A Marker Event On Age At Menopause, Bin Nan, Xihong Lin, Lynda D. Lisabeth, Sioban D. Harlow

The University of Michigan Department of Biostatistics Working Paper Series

. It is of recent interest in reproductive health research to investigate the validity of a marker event for the onset of menopausal transition and to estimate age at menopause using age at the marker event. We propose a varying coefficient Cox model to investigate the association between age at a marker event, denned as a specific bleeding pattern change, and age at menopause, where both events are subject to censoring and their association varies with age at the marker event. Estimation proceeds using the regression spline method. The proposed method is applied to the Tremin Trust Data to evaluate …

Asymptotically Optimal Model Selection Method With Right Censored Outcomes, Sunduz Keles, Mark J. Van Der Laan, Sandrine Dudoit

U.C. Berkeley Division of Biostatistics Working Paper Series

Over the last two decades, non-parametric and semi-parametric approaches that adapt well known techniques such as regression methods to the analysis of right censored data, e.g. right censored survival data, became popular in the statistics literature. However, the problem of choosing the best model (predictor) among a set of proposed models (predictors) in the right censored data setting have not gained much attention. In this paper, we develop a new cross-validation based model selection method to select among predictors of right censored outcomes such as survival times. The proposed method considers the risk of a given predictor based on the …

Tree-Based Multivariate Regression And Density Estimation With Right-Censored Data , Annette M. Molinaro, Sandrine Dudoit, Mark J. Van Der Laan

U.C. Berkeley Division of Biostatistics Working Paper Series

We propose a unified strategy for estimator construction, selection, and performance assessment in the presence of censoring. This approach is entirely driven by the choice of a loss function for the full (uncensored) data structure and can be stated in terms of the following three main steps. (1) Define the parameter of interest as the minimizer of the expected loss, or risk, for a full data loss function chosen to represent the desired measure of performance. Map the full data loss function into an observed (censored) data loss function having the same expected value and leading to an efficient estimator …

Cross-Calibration Of Stroke Disability Measures: Bayesian Analysis Of Longitudinal Ordinal Categorical Data Using Negative Dependence, Giovanni Parmigiani, Heidi W. Ashih, Gregory P. Samsa, Pamela W. Duncan, Sue Min Lai, David B. Matchar

Johns Hopkins University, Dept. of Biostatistics Working Papers

It is common to assess disability of stroke patients using standardized scales, such as the Rankin Stroke Outcome Scale (RS) and the Barthel Index (BI). The Rankin Scale, which was designed for applications to stroke, is based on assessing directly the global conditions of a patient. The Barthel Index, which was designed for general applications, is based on a series of questions about the patient’s ability to carry out 10 basis activities of daily living. As both scales are commonly used, but few studies use both, translating between scales is important in gaining an overall understanding of the efficacy of …

An Extended General Location Model For Causal Inference From Data Subject To Noncompliance And Missing Values, Yahong Peng, Rod Little, Trivellore E. Raghuanthan

The University of Michigan Department of Biostatistics Working Paper Series

Noncompliance is a common problem in experiments involving randomized assignment of treatments, and standard analyses based on intention-to treat or treatment received have limitations. An attractive alternative is to estimate the Complier-Average Causal Effect (CACE), which is the average treatment effect for the subpopulation of subjects who would comply under either treatment (Angrist, Imbens and Rubin, 1996, henceforth AIR). We propose an Extended General Location Model to estimate the CACE from data with non-compliance and missing data in the outcome and in baseline covariates. Models for both continuous and categorical outcomes and ignorable and latent ignorable (Frangakis and Rubin, 1999) …

Inference For The Population Total From Probability-Proportional-To-Size Samples Based On Predictions From A Penalized Spline Nonparametric Model, Hui Zheng, Rod Little

The University of Michigan Department of Biostatistics Working Paper Series

Inference about the finite population total from probability-proportional-to-size (PPS) samples is considered. In previous work (Zheng and Little, 2003), penalized spline (p-spline) nonparametric model-based estimators were shown to generally outperform the Horvitz-Thompson (HT) and generalized regression (GR) estimators in terms of the root mean squared error. In this article we develop model-based, jackknife and balanced repeated replicate variance estimation methods for the p-spline based estimators. Asymptotic properties of the jackknife method are discussed. Simulations show that p-spline point estimators and their jackknife standard errors lead to inferences that are superior to HT or GR based inferences. This suggests that nonparametric …

On The Formation Of Weighting Adjustment Cells For Unit Nonresponse, Sonya Vartivarian, Rod Little

The University of Michigan Department of Biostatistics Working Paper Series

A method is proposed for weighting adjustments for unit nonresponse based on a crossclassification by the estimated propensity to respond and by the predicted mean of a survey outcome. Simulations to assess the performance of the method are described.

Locally Efficient Estimation Of Nonparametric Causal Effects On Mean Outcomes In Longitudinal Studies, Romain Neugebauer, Mark J. Van Der Laan

U.C. Berkeley Division of Biostatistics Working Paper Series

Marginal Structural Models (MSM) have been introduced by Robins (1998a) as a powerful tool for causal inference as they directly model causal curves of interest, i.e. mean treatment-specific outcomes possibly adjusted for baseline covariates. Two estimators of the corresponding MSM parameters of interest have been proposed, see van der Laan and Robins (2002): the Inverse Probability of Treatment Weighted (IPTW) and the Double Robust (DR) estimators. A parametric MSM approach to causal inference has been favored since the introduction of MSM. It relies on correct specification of a parametric MSM to consistently estimate the parameter of interest using the IPTW …

Adjusting For Non-Ignorable Verification Bias In Clinical Studies For Alzheimer’S Disease, Xiao-Hua Zhou, Pete Castelluccio

UW Biostatistics Working Paper Series

A common problem for comparing the relative accuracy of two screening tests for Alzheimer’s disease (D) in a two-stage design study is verification bias. If the verification bias can be assumed to be ignorable, Zhou and Higgs (2000) have proposed a maximum likelihood approach to compare the relative accuracy of screening tests in a two-stage design study. However, if the verification mechanism also depends on the unobserved disease status, the ignorable assumption does not hold. In this paper, we discuss how to use a profile likelihood approach to compare the relative accuracy of two screening tests for AD without assuming …

Resampling-Based Multiple Testing: Asymptotic Control Of Type I Error And Applications To Gene Expression Data, Katherine S. Pollard, Mark J. Van Der Laan

U.C. Berkeley Division of Biostatistics Working Paper Series

We define a general statistical framework for multiple hypothesis testing and show that the correct null distribution for the test statistics is obtained by projecting the true distribution of the test statistics onto the space of mean zero distributions. For common choices of test statistics (based on an asymptotically linear parameter estimator), this distribution is asymptotically multivariate normal with mean zero and the covariance of the vector influence curve for the parameter estimator. This test statistic null distribution can be estimated by applying the non-parametric or parametric bootstrap to correctly centered test statistics. We prove that this bootstrap estimated null …

Maximization By Parts In Likelihood Inference, Peter Xuekun Song, Yanqin Fan, Jack Kalbfleisch

The University of Michigan Department of Biostatistics Working Paper Series

This paper presents and examines a new algorithm for solving a score equation for the maximum likelyhood estimate in certain problems of practical interest. The method circumvents the need to compute second order derivaties of the full likelihood function. It exploits the structure of certain models that yield a natural decomposition of a very complicated likelihood function. In this decomposition, the first part is a log likelihood from a simply analyzed model and the second part is used to update estimates from the first. Convergence properties of this fixed point algorithm are examined and asymptotics are derived for estimators obtained …

Design Considerations For Efficient And Effective Microarray Studies, M. Kathleen Kerr

UW Biostatistics Working Paper Series

This paper describes the theoretical and practical issues in experimental design for gene expression microarrays. Specifically, this paper (1) discusses the basic principles of design (randomization, replication, and blocking) as they pertain to microarrays, and (2) provides some general guidelines for statisticians designing microarray studies.

Cluster Stability Scores For Microarray Data In Cancer Studies, Mark Smolkin, Debashis Ghosh

The University of Michigan Department of Biostatistics Working Paper Series

A potential benefit of profiling of tissue samples using microarrays is the generation of molecular fingerprints that will define subtypes of disease. Hierarchical clustering has been the primary analytical tool used to define disease subtypes from microarray experiments in cancer settings. Assessing cluster reliability poses a major complication in analyzing output from these procedures. While much work has been done on assessing the global question of number of clusters in a dataset, relatively little research exists on assessing stability of individual clusters. A potential benefit of profiling of tissue samples using microarrays is the generation of molecular fingerprints that will …

Double Robust Estimation In Longitudinal Marginal Structural Models, Zhuo Yu, Mark J. Van Der Laan

U.C. Berkeley Division of Biostatistics Working Paper Series

Consider estimation of causal parameters in a marginal structural model for the discrete intensity of the treatment specific counting process (e.g. hazard of a treatment specific survival time) based on longitudinal observational data on treatment, covariates and survival. We assume the sequential randomization assumption (SRA) on the treatment assignment mechanism and the so called experimental treatment assignment assumption which is needed to identify the causal parameters from the observed data distribution. Under SRA, the likelihood of the observed data structure factorizes in the auxiliary treatment mechanism and the partial likelihood consisting of the product over time of conditional distributions of …

A New Confidence Interval For The Difference Between Two Binomial Proportions Of Paired Data, Xiao-Hua Zhou, Gengsheng Qin

UW Biostatistics Working Paper Series

Motivated by a study on comparing sensitivities and specificities of two diagnostic tests in a paired design when the sample size is small, we first derived an Edgeworth expansion for the studentized difference between two binomial proportions of paired data. The Edgeworth expansion can help us understand why the usual Wald interval for the difference has poor coverage performance in the small sample size. Based on the Edgeworth expansion, we then derived a transformation based confidence interval for the difference. The new interval removes the skewness in the Edgeworth expansion; the new interval is easy to compute, and its coverage …

Supervised Detection Of Regulatory Motifs In Dna Sequences, Sunduz Keles, Mark J. Van Der Laan, Sandrine Dudoit, Biao Xing, Michael B. Eisen

U.C. Berkeley Division of Biostatistics Working Paper Series

Identification of transcription factor binding sites (regulatory motifs) is a major interest in contemporary biology. We propose a new likelihood based method, COMODE, for identifying structural motifs in DNA sequences. Commonly used methods (e.g. MEME, Gibbs sampler) model binding sites as families of sequences described by a position weight matrix (PWM) and identify PWMs that maximize the likelihood of observed sequence data under a simple multinomial mixture model. This model assumes that the positions of the PWM correspond to independent multinomial distributions with four cell probabilities. We address supervising the search for DNA binding sites using the information derived from …

Improved Confidence Intervals For The Sensitivity At A Fixed Level Of Specificity Of A Continuous-Scale Diagnostic Test, Xiao-Hua Zhou, Gengsheng Qin

UW Biostatistics Working Paper Series

For a continuous-scale test, it is an interest to construct a confidence interval for the sensitivity of the diagnostic test at the cut-off that yields a predetermined level of its specificity (eg. 80%, 90%, or 95%). IN this paper we proposed two new intervals for the sensitivity of a continuous-scale diagnostic test at a fixed level of specificity. We then conducted simulation studies to compare the relative performance of these two intervals with the best existing BCa bootstrap interval, proposed by Platt et al. (2000). Our simulation results showed that the newly proposed intervals are better than the BCa bootstrap …

Bootstrap Confidence Intervals For Medical Costs With Censored Observations, Hongyu Jiang, Xiao-Hua Zhou

UW Biostatistics Working Paper Series

Medical costs data with administratively censored observations often arise in cost-effectiveness studies of treatments for life threatening diseases. Mean of medical costs incurred from the start of a treatment till death or certain timepoint after the implementation of treatment is frequently of interest. In many situations, due to the skewed nature of the cost distribution and non-uniform rate of cost accumulation over time, the currently available normal approximation confidence interval has poor coverage accuracy. In this paper, we proposed a bootstrap confidence interval for the mean of medical costs with censored observations. In simulation studies, we showed that the proposed …