Statistics and Probability Commons^™

Hierarchical Rank Aggregation With Applications To Nanotoxicology, Trina Patel, Donatello Telesca, Robert Rallo, Saji George, Xia Tian, Nel Andre

COBRA Preprint Series

The development of high throughput screening (HTS) assays in the field of nanotoxicology provide new opportunities for the hazard assessment and ranking of engineered nanomaterials (ENM). It is often necessary to rank lists of materials based on multiple risk assessment parameters, often aggregated across several measures of toxicity and possibly spanning an array of experimental platforms. Bayesian models coupled with the optimization of loss functions have been shown to provide an effective framework for conducting inference on ranks. In this article we present various loss function based ranking approaches for comparing ENM within experiments and toxicity parameters. Additionally, we propose …

Robustness Of Measures Of Interaction To Unmeasured Confounding, Eric J. Tchetgen Tchetgen, Tyler J. Vanderweele

COBRA Preprint Series

In this paper, we study the impact of unmeasured confounding on inference about a two-way interaction in a mean regression model with identity, log or logit link function. Necessary and sufficient conditions are established for a two-way interaction to be nonparametrically identified from the observed data, despite unmeasured confounding for the factors defining the interaction. A lung cancer data application illustrates the results.

Modeling Criminal Careers As Departures From A Unimodal Population Age-Crime Curve: The Case Of Marijuana Use, Donatello Telesca, Elena Erosheva, Derek Kreager, Ross Matsueda

COBRA Preprint Series

A major aim of longitudinal analyses of life course data is to describe the within- and between-individual variability in a behavioral outcome, such as crime. Statistical analyses of such data typically draw on mixture and mixed-effects growth models. In this work, we present a functional analytic point of view and develop an alternative method that models individual crime trajectories as departures from a population age-crime curve. Drawing on empirical and theoretical claims in criminology, we assume a unimodal population age-crime curve and allow individual expected crime trajectories to differ by their levels of offending and patterns of temporal misalignment. We …

Toxicity Profiling Of Engineered Nanomaterials Via Multivariate Dose Response Surface Modeling, Trina Patel, Donatello Telesca, Saji George, Andre Nel

COBRA Preprint Series

New generation in-vitro high throughput screening (HTS) assays for the assessment of engineered nanomaterials provide an opportunity to learn how these particles interact at the cellular level, particularly in relation to injury pathways. These types of assays are often characterized by small sample sizes, high measurement error and high dimensionality as multiple cytotoxicity outcomes are measured across an array of doses and durations of exposure. In this article we propose a probability model for toxicity profiling of engineered nanomaterials. A hierarchical framework is used to account for the multivariate nature of the data by modeling dependence between outcomes and thereby …

A Proof Of Bell's Inequality In Quantum Mechanics Using Causal Interactions, James M. Robins, Tyler J. Vanderweele, Richard D. Gill

COBRA Preprint Series

We give a simple proof of Bell's inequality in quantum mechanics which, in conjunction with experiments, demonstrates that the local hidden variables assumption is false. The proof sheds light on relationships between the notion of causal interaction and interference between particles.

A Unified Approach To Non-Negative Matrix Factorization And Probabilistic Latent Semantic Indexing, Karthik Devarajan, Guoli Wang, Nader Ebrahimi

COBRA Preprint Series

Non-negative matrix factorization (NMF) by the multiplicative updates algorithm is a powerful machine learning method for decomposing a high-dimensional nonnegative matrix V into two matrices, W and H, each with nonnegative entries, V ~ WH. NMF has been shown to have a unique parts-based, sparse representation of the data. The nonnegativity constraints in NMF allow only additive combinations of the data which enables it to learn parts that have distinct physical representations in reality. In the last few years, NMF has been successfully applied in a variety of areas such as natural language processing, information retrieval, image processing, speech recognition …

A Bayesian Model Averaging Approach For Observational Gene Expression Studies, Xi Kathy Zhou, Fei Liu, Andrew J. Dannenberg

COBRA Preprint Series

Identifying differentially expressed (DE) genes associated with a sample characteristic is the primary objective of many microarray studies. As more and more studies are carried out with observational rather than well controlled experimental samples, it becomes important to evaluate and properly control the impact of sample heterogeneity on DE gene finding. Typical methods for identifying DE genes require ranking all the genes according to a pre-selected statistic based on a single model for two or more group comparisons, with or without adjustment for other covariates. Such single model approaches unavoidably result in model misspecification, which can lead to increased error …

Propensity Score Analysis With Matching Weights, Liang Li

COBRA Preprint Series

The propensity score analysis is one of the most widely used methods for studying the causal treatment effect in observational studies. This paper studies treatment effect estimation with the method of matching weights. This method resembles propensity score matching but offers a number of new features including efficient estimation, rigorous variance calculation, simple asymptotics, statistical tests of balance, clearly identified target population with optimal sampling property, and no need for choosing matching algorithm and caliper size. In addition, we propose the mirror histogram as a useful tool for graphically displaying balance. The method also shares some features of the inverse …

Evaluation Of Flexible Regression For Non-Unimodal Hazard Functions, Marco Fornili, Patrizia Boracchi, Federico Ambrogi, Elia Biganzoli

COBRA Preprint Series

Longer follow-up for various kinds of cancer, particularly breast cancer, has made it possible the observation of complex forms of the hazard function of occurrence of metastasis and death. In several studies a bimodal hazard function was obtained, with a possible interpretation in the context of tumor dormancy. The shape of the hazard function is usually estimated by spline regression functions. In the case of breast cancer, no general agreement is obtained on the presence of a complex behavior. This may depend on the properties of the smoothing function adopted. We evaluate through simulations of a bimodal hazard function the …

Causal Inference Under Multiple Versions Of Treatment, Tyler J. Vanderweele, Miguel A. Hernan

COBRA Preprint Series

In this article we discuss the no-multiple-versions-of-treatment assumption and extend the potential outcomes framework to accommodate causal inference under violations of this assumption. A variety of examples are discussed in which the assumption may be violated. Identification results are provided for the overall treatment effect and the effect of treatment on the treated when multiple versions of treatment are present and also for the causal effect comparing a version of one treatment to some other version of the same or a different treatment. Further identification and interpretative results are given for cases in which a treatment variable is dichotomized to …

Minimum Description Length Measures Of Evidence For Enrichment, Zhenyu Yang, David R. Bickel

COBRA Preprint Series

In order to functionally interpret differentially expressed genes or other discovered features, researchers seek to detect enrichment in the form of overrepresentation of discovered features associated with a biological process. Most enrichment methods treat the p-value as the measure of evidence using a statistical test such as the binomial test, Fisher's exact test or the hypergeometric test. However, the p-value is not interpretable as a measure of evidence apart from adjustments in light of the sample size. As a measure of evidence supporting one hypothesis over the other, the Bayes factor (BF) overcomes this drawback of the p-value but lacks …

A Bayesian Shared Component Model For Genetic Association Studies, Juan J. Abellan, Carlos Abellan, Juan R. Gonzalez

COBRA Preprint Series

We present a novel approach to address genome association studies between single nucleotide polymorphisms (SNPs) and disease. We propose a Bayesian shared component model to tease out the genotype information that is common to cases and controls from the one that is specific to cases only. This allows to detect the SNPs that show the strongest association with the disease. The model can be applied to case-control studies with more than one disease. In fact, we illustrate the use of this model with a dataset of 23,418 SNPs from a case-control study by The Welcome Trust Case Control Consortium (2007) …

Minimum Description Length And Empirical Bayes Methods Of Identifying Snps Associated With Disease, Ye Yang, David R. Bickel

COBRA Preprint Series

The goal of determining which of hundreds of thousands of SNPs are associated with disease poses one of the most challenging multiple testing problems. Using the empirical Bayes approach, the local false discovery rate (LFDR) estimated using popular semiparametric models has enjoyed success in simultaneous inference. However, the estimated LFDR can be biased because the semiparametric approach tends to overestimate the proportion of the non-associated single nucleotide polymorphisms (SNPs). One of the negative consequences is that, like conventional p-values, such LFDR estimates cannot quantify the amount of information in the data that favors the null hypothesis of no disease-association.

We …

Improving Statistical Analysis Of Prospective Clinical Trials In Stem Cell Transplantation. An Inventory Of New Approaches In Survival Analysis, Aurelien Latouche

COBRA Preprint Series

The CLINT project is an European Union funded project, run as a specific support action, under the sixth framework programme. It is a 2 year project aimed at supporting the European Group for Blood and Marrow Transplantation (EBMT) to develop its infrastructure for the conduct of trans-European clinical trials in accordance with the EU Clinical Trials Directive, and to facilitate International prospective clinical trials in stem cell transplantation. The initial task is to create an inventory of the existing biostatistical literature on new approaches to survival analyses that are not currently widely utilised. The estimation of survival endpoints is introduced, …

The Strength Of Statistical Evidence For Composite Hypotheses: Inference To The Best Explanation, David R. Bickel

COBRA Preprint Series

A general function to quantify the weight of evidence in a sample of data for one hypothesis over another is derived from the law of likelihood and from a statistical formalization of inference to the best explanation. For a fixed parameter of interest, the resulting weight of evidence that favors one composite hypothesis over another is the likelihood ratio using the parameter value consistent with each hypothesis that maximizes the likelihood function over the parameter of interest. Since the weight of evidence is generally only known up to a nuisance parameter, it is approximated by replacing the likelihood function with …

The Linkset Model For 2^N Contingency Tables, Mikel Aickin

COBRA Preprint Series

Abstract The linkset model is defined for parametrizing the general 2^n contingency table. The linkset parameters are designed to represent latent influences that promote the co-occurrences of binary events beyond that explained by chance. Linkages involving 2 through n binary variables are included in this parametrization. The intent of this process is to elucidate the patterns of linkage, no matter how complex they might be, rather than to fit simplifying models. The relationship between linkset parameters and the natural parameters for a 2n table are derived, and large sample inference methods are provided. Examples are given from medical diagnostics, survival …

Recovery Of The Baseline Incidence Density In Censored Time-To-Event Analysis, Mikel Aickin

COBRA Preprint Series

Abstract Time-to-event analyses are often concerned with the effects of explanatory factors on the underlying incidence density, but since there is no intrinsic interest in the form of the incidence density itself, a proportional hazards model is used. When part of the purpose of the analysis is to use actual cumulative incidence for simulation, or for providing informative visual displays of the results, an estimate of the baseline incidence density is required. The usual method for estimating the baseline hazards in Cox’s proportional hazards analysis yields values that are of little use, and furthermore no standard deviations of the estimates …

Efficient Design And Inference For Multi-Stage Randomized Trials Of Individualized Treatment Policies, Ree Dawson, Philip W. Lavori

COBRA Preprint Series

Increased clinical interest in individualized ‘adaptive’ treatment policies has shifted the methodological focus for their development from the analysis of naturalistically observed strategies to experimental evaluation of a pre-selected set of strategies via multi-stage designs. Because multi-stage studies often avoid the ‘curse of dimensionality’ inherent in uncontrolled studies, and hence the need to parametrically smooth trial data, it is not surprising in this context to find direct connections among different methodological approaches. We show by asymptotic and algebraic proof that the maximum likelihood (ML) and optimal semi-parametric estimators of the mean of a treatment policy and its standard error are …

Mean Survival Time From Right Censored Data, Ming Zhong, Kenneth R. Hess

COBRA Preprint Series

A nonparametric estimate of the mean survival time can be obtained as the area under the Kaplan-Meier estimate of the survival curve. A common modification is to change the largest observation to a death time if it is censored. We conducted a simulation study to assess the behavior of this estimator of the mean survival time in the presence of right censoring.

We simulated data from seven distributions: exponential, normal, uniform, lognormal, gamma, log-logistic, and Weibull. This allowed us to compare the results of the estimates to the known true values and to quantify the bias and the variance. Our …

Two-Stage Decompositions For The Analysis Of Functional Connectivity For Fmri With Application To Alzheimer's Disease Risk, Brian S. Caffo, Ciprian M. Crainiceanu, Guillermo Verduzco, Stewart H. Mostofsky, Susan Spear-Bassett, James J. Pekar

COBRA Preprint Series

Functional connectivity is the study of correlations in measured neurophysiological signals. Altered functional connectivity has been shown to be associated with numerous diseases including Alzheimer's disease and mild cognitive impairment. In this manuscript we use a two-stage application of the singular value decomposition to obtain data driven population-level measures of functional connectivity in functional magnetic resonance imaging (fMRI). The method is computationally simple and amenable to high dimensional fMRI data with large numbers of subjects. Simulation studies suggest the ability of the decomposition methods to recover population brain networks and their associated loadings. We further demonstrate the utility of these …

Modeling Multilevel Sleep Transitional Data Via Poisson Log-Linear Multilevel Models, Bruce J. Swihart

COBRA Preprint Series

This paper proposes Poisson log-linear multilevel models to investigate population variability in sleep state transition rates. We specifically propose a Bayesian Poisson regression model that is more flexible, scalable to larger studies, and easily fit than other attempts in the literature. We further use hierarchical random effects to account for pairings of individuals and repeated measures within those individuals, as comparing diseased to non-diseased subjects while minimizing bias is of epidemiologic importance. We estimate essentially non-parametric piecewise constant hazards and smooth them, and allow for time varying covariates and segment of the night comparisons. The Bayesian Poisson regression is justified …

Composite Likelihood Em Algorithm With Applications To Multivariate Hidden Markov Model , Xin Gao, Peter Xuekun Song

COBRA Preprint Series

The method of composite likelihood is useful to deal with estimation and inference in parametric models with high-dimensional data, where the full likelihood approach renders to intractable computational complexity. We develop an extension of the EM algorithm in the framework of composite likelihood estimation in the presence of missing data or latent variables. We establish three key theoretical properties of the composite likelihood EM (CLEM) algorithm, including the ascent property, the algorithmic convergence and the convergence rate. The proposed method is applied to estimate the transition probabilities in multivariate hidden Markov model. Simulation studies are presented to demonstrate the empirical …

Shrinkage Estimation Of Expression Fold Change As An Alternative To Testing Hypotheses Of Equivalent Expression, Zahra Montazeri, Corey M. Yanofsky, David R. Bickel

COBRA Preprint Series

Research on analyzing microarray data has focused on the problem of identifying differentially expressed genes to the neglect of the problem of how to integrate evidence that a gene is differentially expressed with information on the extent of its differential expression. Consequently, researchers currently prioritize genes for further study either on the basis of volcano plots or, more commonly, according to simple estimates of the fold change after filtering the genes with an arbitrary statistical significance threshold. While the subjective and informal nature of the former practice precludes quantification of its reliability, the latter practice is equivalent to using a …

Reliability Of The Model For Clustering Of Longitudinal Datasets Of Infant Mortality Rate In India, Ajay Kumar Bansal, S D. Sharma

COBRA Preprint Series

Because of the natural tendency of human beings and heavenly bodies to form groups, the technique of cluster analysis or segmentation analysis find its importance and applications in many fields of study. A model for clustering of time trends was proposed by authors whose beauty is that 2-way dimensions that is the horizontal flow of the trend and vertical distance of the trend from a common base are considered to obtain the natural clusters. In the present paper, the reliability of this model is studied in two steps namely (i) by repeating the analysis but using different interval distance measures …

Simple, Defensible Sample Sizes Based On Cost Efficiency -- With Discussion And Rejoinder, Peter Bacchetti, Charles E. Mcculloch, Mark R. Segal, Richard Simon, Peter Muller, Gary L. Rosner, James A. Hanley, Stan Shapiro

COBRA Preprint Series

The conventional approach of choosing sample size to provide 80% or greater power ignores the cost implications of different sample size choices. Costs, however, are often impossible for investigators and funders to ignore in actual practice. Here, we propose and justify a new approach for choosing sample size based on cost efficiency, the ratio of a study’s projected scientific and/or practical value to its total cost. By showing that a study’s projected value exhibits diminishing marginal returns as a function of increasing sample size for a wide variety of definitions of study value, we are able to develop two simple …

Correlated Binary Regression Using Orthogonalized Residuals, Richard C. Zink, Bahjat F. Qaqish

COBRA Preprint Series

This paper focuses on marginal regression models for correlated binary responses when estimation of the association structure is of primary interest. A new estimating function approach based on orthogonalized residuals is proposed. This procedure allows a new representation and addresses some of the difficulties of the conditional-residual formulation of alternating logistic regressions of Carey, Zeger & Diggle (1993). The new method is illustrated with an analysis of data on impaired pulmonary function.

Validation Of Differential Gene Expression Algorithms: Application Comparing Fold Change Estimation To Hypothesis Testing, David R. Bickel, Corey M. Yanofsky

COBRA Preprint Series

Sustained research on the problem of determining which genes are differentially expressed on the basis of microarray data has yielded a plethora of statistical algorithms, each justified by theory, simulation, or ad hoc validation and yet differing in practical results from equally justified algorithms. The widespread confusion on which method to use in practice has been exacerbated by the finding that simply ranking genes by their fold changes sometimes outperforms popular statistical tests.

Algorithms may be compared by quantifying each method's error in predicting expression ratios, whether such ratios are defined across microarray channels or between two independent groups. For …

Space-Time Regression Modeling Of Tree Growth Using The Skew-T Distribution, Farouk S. Nathoo

COBRA Preprint Series

In this article we present new statistical methodology for the analysis of repeated measures of spatially correlated growth data. Our motivating application, a ten year study of height growth in a plantation of even-aged white spruce, presents several challenges for statistical analysis. Here, the growth measurements arise from an asymmetric distribution, with heavy tails, and thus standard longitudinal regression models based on a Gaussian error structure are not appropriate. We seek more flexibility for modeling both skewness and fat tails, and achieve this within the class of skew-elliptical distributions. Within this framework, robust space-time regression models are formulated using random …

Reversal In Declining Trend Of Adult Mortality In Many States Of India, 1970-2001: Is It Due To Aids?, Abhaya Indrayan, Ajay Kumar Bansal

COBRA Preprint Series

Objectives: To investigate the reversal in adult mortality trend from declining to rising in some segments of population in India, and to use an indirect demographic method to examine if this increase could be due to AIDS mortality. Also, to estimate the total excess deaths.

Design: Cross-sectional data on age-specific death rate in 5-year age-intervals from 25 to 44 years for the years 1970 to 1998 for rural/urban and male/female segments for each of 16 major states of India obtained from the government reports, and their projections till the year 2001.

Methods: In view of reversal of trend in some …

Change-Point Problem And Regression: An Annotated Bibliography, Ahmad Khodadadi, Masoud Asgharian

COBRA Preprint Series

The problems of identifying changes at unknown times and of estimating the location of changes in stochastic processes are referred to as "the change-point problem" or, in the Eastern literature, as "disorder".

The change-point problem, first introduced in the quality control context, has since developed into a fundamental problem in the areas of statistical control theory, stationarity of a stochastic process, estimation of the current position of a time series, testing and estimation of change in the patterns of a regression model, and most recently in the comparison and matching of DNA sequences in microarray data analysis.

Numerous methodological approaches …