Biostatistics Commons^™

Functional Car Models For Spatially Correlated Functional Datasets, Lin Zhang, Veerabhadran Baladandayuthapani, Hongxiao Zhu, Keith A. Baggerly, Tadeusz Majewski, Bogdan Czerniak, Jeffrey S. Morris

Jeffrey S. Morris

We develop a functional conditional autoregressive (CAR) model for spatially correlated data for which functions are collected on areal units of a lattice. Our model performs functional response regression while accounting for spatial correlations with potentially nonseparable and nonstationary covariance structure, in both the space and functional domains. We show theoretically that our construction leads to a CAR model at each functional location, with spatial covariance parameters varying and borrowing strength across the functional domain. Using basis transformation strategies, the nonseparable spatial-functional model is computationally scalable to enormous functional datasets, generalizable to different basis functions, and can be used on …

Bayesian Function-On-Function Regression For Multi-Level Functional Data, Mark J. Meyer, Brent A. Coull, Francesco Versace, Paul Cinciripini, Jeffrey S. Morris

Jeffrey S. Morris

Medical and public health research increasingly involves the collection of more and more complex and high dimensional data. In particular, functional data|where the unit of observation is a curve or set of curves that are finely sampled over a grid -- is frequently obtained. Moreover, researchers often sample multiple curves per person resulting in repeated functional measures. A common question is how to analyze the relationship between two functional variables. We propose a general function-on-function regression model for repeatedly sampled functional data, presenting a simple model as well as a more extensive mixed model framework, along with multiple functional posterior …

Functional Regression, Jeffrey S. Morris

Jeffrey S. Morris

Functional data analysis (FDA) involves the analysis of data whose ideal units of observation are functions defined on some continuous domain, and the observed data consist of a sample of functions taken from some population, sampled on a discrete grid. Ramsay and Silverman's 1997 textbook sparked the development of this field, which has accelerated in the past 10 years to become one of the fastest growing areas of statistics, fueled by the growing number of applications yielding this type of data. One unique characteristic of FDA is the need to combine information both across and within functions, which Ramsay and …

Ordinal Probit Wavelet-Based Functional Models For Eqtl Analysis, Mark J. Meyer, Jeffrey S. Morris, Craig P. Hersh, Jarret D. Morrow, Christoph Lange, Brent A. Coull

Jeffrey S. Morris

Current methods for conducting expression Quantitative Trait Loci (eQTL) analysis are limited in scope to a pairwise association testing between a single nucleotide polymorphism (SNPs) and expression probe set in a region around a gene of interest, thus ignoring the inherent between-SNP correlation. To determine association, p-values are then typically adjusted using Plug-in False Discovery Rate. As many SNPs are interrogated in the region and multiple probe-sets taken, the current approach requires the fitting of a large number of models. We propose to remedy this by introducing a flexible function-on-scalar regression that models the genome as a functional outcome. The …

Moving Towards Best Practice When Using Inverse Probability Of Treatment Weighting (Iptw) Using The Propensity Score To Estimate Causal Treatment Effects In Observational Studies, Peter Austin, Elizabeth Stuart

Peter Austin

The propensity score is defined as a subject’s probability of treatment selection, conditional on observed baseline covariates.Weighting subjects by the inverse probability of treatment received creates a synthetic sample in which treatment assignment is independent of measured baseline covariates. Inverse probability of treatment weighting (IPTW) using the propensity score allows one to obtain unbiased estimates of average treatment effects. However, these estimates are only valid if there are no residual systematic differences in observed baseline characteristics between treated and control subjects in the sample weighted by the estimated inverse probability of treatment. We report on a systematic literature review, in …

Bayesian Joint Selection Of Genes And Pathways: Applications In Multiple Myeloma Genomics, Lin Zhang, Jeffrey S. Morris, Jiexin Zhang, Robert Orlowski, Veerabhadran Baladandayuthapani

Jeffrey S. Morris

It is well-established that the development of a disease, especially cancer, is a complex process that results from the joint effects of multiple genes involved in various molecular signaling pathways. In this article, we propose methods to discover genes and molecular pathways significantly associ- ated with clinical outcomes in cancer samples. We exploit the natural hierarchal structure of genes related to a given pathway as a group of interacting genes to conduct selection of both pathways and genes. We posit the problem in a hierarchical structured variable selection (HSVS) framework to analyze the corresponding gene expression data. HSVS methods conduct …

Sas Macro: Weighted Kappa Statistic For Clustered Matched-Pair Ordinal Data, Zhao Yang

Zhao (Tony) Yang, Ph.D.

This SAS macro calculate the weighted kappa statistic and its corresponding non-parametric variance estimator for the clustered matched-pair ordinal data.

Sas Macro: Kappa Statistic For Clustered Physician-Patients Polytomous Data, Zhao Yang

Zhao (Tony) Yang, Ph.D.

This SAS macro calculate the kappa statistic and its semi-parametric variance estimator for the clustered physician-patients polytomous data. The proposed method depends on the assumption of conditional independence for the clustered physician-patients data structure.

A Comparison Of 12 Algorithms For Matching On The Propensity Score, Peter C. Austin

Peter Austin

Propensity-score matching is increasingly being used to reduce the confounding that can occur in observational studies examining the effects of treatments or interventions on outcomes. We used Monte Carlo simulations to examine the following algorithms for forming matched pairs of treated and untreated subjects: optimal matching, greedy nearest neighbor matching without replacement, and greedy nearest neighbor matching without replacement within specified caliper widths. For each of the latter two algorithms, we examined four different sub-algorithms defined by the order in which treated subjects were selected for matching to an untreated subject: lowest to highest propensity score, highest to lowest propensity …

The Use Of Propensity Score Methods With Survival Or Time-To-Event Outcomes: Reporting Measures Of Effect Similar To Those Used In Randomized Experiments, Peter C. Austin

Peter Austin

Propensity score methods are increasingly being used to estimate causal treatment effects in observational studies. In medical and epidemiological studies, outcomes are frequently time-to-event in nature. Propensity-score methods are often applied incorrectly when estimating the effect of treatment on time-to-event outcomes. This article describes how two different propensity score methods (matching and inverse probability of treatment weighting) can be used to estimate the measures of effect that are frequently reported in randomized controlled trials: (i) marginal survival curves, which describe survival in the population if all subjects were treated or if all subjects were untreated; and (ii) marginal hazard ratios. …

The Performance Of Different Propensity Score Methods For Estimating Absolute Effects Of Treatments On Survival Outcomes: A Simulation Study, Peter C. Austin

Peter Austin

Observational studies are increasingly being used to estimate the effect of treatments, interventions and exposures on outcomes that can occur over time. Historically, the hazard ratio, which is a relative measure of effect, has been reported. However, medical decision making is best informed when both relative and absolute measures of effect are reported. When outcomes are time-to-event in nature, the effect of treatment can also be quantified as the change in mean or median survival time due to treatment and the absolute reduction in the probability of the occurrence of an event within a specified duration of follow-up. We describe …

Global Quantitative Assessment Of The Colorectal Polyp Burden In Familial Adenomatous Polyposis Using A Web-Based Tool, Patrick M. Lynch, Jeffrey S. Morris, William A. Ross, Miguel A. Rodriguez-Bigas, Juan Posadas, Rossa Khalaf, Diane M. Weber, Valerie O. Sepeda, Bernard Levin, Imad Shureiqi

Jeffrey S. Morris

Background: Accurate measures of the total polyp burden in familial adenomatous polyposis (FAP) are lacking. Current assessment tools include polyp quantitation in limited-field photographs and qualitative total colorectal polyp burden by video.

Objective: To develop global quantitative tools of the FAP colorectal adenoma burden.

Design: A single-arm, phase II trial.

Patients: Twenty-seven patients with FAP.

Intervention: Treatment with celecoxib for 6 months, with before-treatment and after-treatment videos posted to an intranet with an interactive site for scoring.

Main Outcome Measurements: Global adenoma counts and sizes (grouped into categories: less than 2 mm, 2-4 mm, and greater than 4 mm) were …

Sas Macro: Kappa Statistic For Clustered Matched-Pair Data, Zhao Yang

Zhao (Tony) Yang, Ph.D.

The SAS macro was developed to calculate the kappa statistic for the clustered matched-pair data.

Bayesian Inferences For Beta Semiparametric Mixed Models To Analyze Longitudinal Neuroimaging Data, Xiaofeng Wang, Yingxing Li

Xiaofeng Wang

Diffusion tensor imaging (DTI) is a quantitative magnetic resonance imaging technique that measures the three-dimensional diffusion of water molecules within tissue through the application of multiple diffusion gradients. This technique is rapidly increasing in popularity for studying white matter properties and structural connectivity in the living human brain. The major measure derived from the DTI process is known as fractional anisotropy, a continuous measure restricted on the interval (0,1). Motivated from a DTI study of multiple sclerosis, we use a beta semiparametric mixed-effect regression model for the longitudinal neuroimaging data. This work extends the generalized additive model methodology with beta …

Bayesian Nonparametric Regression And Density Estimation Using Integrated Nested Laplace Approximations, Xiaofeng Wang

Xiaofeng Wang

Integrated nested Laplace approximations (INLA) are a recently proposed approximate Bayesian approach to fit structured additive regression models with latent Gaussian field. INLA method, as an alternative to Markov chain Monte Carlo techniques, provides accurate approximations to estimate posterior marginals and avoid time-consuming sampling. We show here that two classical nonparametric smoothing problems, nonparametric regression and density estimation, can be achieved using INLA. Simulated examples and \texttt{R} functions are demonstrated to illustrate the use of the methods. Some discussions on potential applications of INLA are made in the paper.

Using Methods From The Data-Mining And Machine-Learning Literature For Disease Classification And Prediction: A Case Study Examining Classification Of Heart Failure Subtypes, Peter C. Austin

Peter Austin

OBJECTIVE: Physicians classify patients into those with or without a specific disease. Furthermore, there is often interest in classifying patients according to disease etiology or subtype. Classification trees are frequently used to classify patients according to the presence or absence of a disease. However, classification trees can suffer from limited accuracy. In the data-mining and machine-learning literature, alternate classification schemes have been developed. These include bootstrap aggregation (bagging), boosting, random forests, and support vector machines.

STUDY DESIGN AND SETTING: We compared the performance of these classification methods with that of conventional classification trees to classify patients with heart failure (HF) …

Predictive Accuracy Of Risk Factors And Markers: A Simulation Study Of The Effect Of Novel Markers On Different Performance Measures For Logistic Regression Models, Peter C. Austin

Peter Austin

The change in c-statistic is frequently used to summarize the change in predictive accuracy when a novel risk factor is added to an existing logistic regression model. We explored the relationship between the absolute change in the c-statistic, Brier score, generalized R(2) , and the discrimination slope when a risk factor was added to an existing model in an extensive set of Monte Carlo simulations. The increase in model accuracy due to the inclusion of a novel marker was proportional to both the prevalence of the marker and to the odds ratio relating the marker to the outcome but inversely …

Generalized Estimating Equations, Second Edition.Pdf, James W. Hardin, Joseph M.. Hilbe

Joseph M Hilbe

Generalized Estimating Equations, Second edition, updates the best-selling previous edition, which has been the standard text on the subject since it was published a decade ago. Combining theory and application, the text provides readers with a comprehensive discussion of GEE and related models. Numerous examples are employed throughout the text, along with the software code used to create, run, and evaluate the models being examined. Stata is used as the primary software for running and displaying modeling output; associated R code is also given to allow R users to replicate Stata examples. Specific examples of SAS usage are provided in …

Targeted Maximum Likelihood Estimation For Dynamic Treatment Regimes In Sequential Randomized Controlled Trials, Paul Chaffee, Mark J. Van Der Laan

Paul H. Chaffee

Sequential Randomized Controlled Trials (SRCTs) are rapidly becoming essential tools in the search for optimized treatment regimes in ongoing treatment settings. Analyzing data for multiple time-point treatments with a view toward optimal treatment regimes is of interest in many types of afflictions: HIV infection, Attention Deficit Hyperactivity Disorder in children, leukemia, prostate cancer, renal failure, and many others. Methods for analyzing data from SRCTs exist but they are either inefficient or suffer from the drawbacks of estimating equation methodology. We describe an estimation procedure, targeted maximum likelihood estimation (TMLE), which has been fully developed and implemented in point treatment settings, …

Statistical Methods For Proteomic Biomarker Discovery Based On Feature Extraction Or Functional Modeling Approaches, Jeffrey S. Morris

Jeffrey S. Morris

In recent years, developments in molecular biotechnology have led to the increased promise of detecting and validating biomarkers, or molecular markers that relate to various biological or medical outcomes. Proteomics, the direct study of proteins in biological samples, plays an important role in the biomarker discovery process. These technologies produce complex, high dimensional functional and image data that present many analytical challenges that must be addressed properly for effective comparative proteomics studies that can yield potential biomarkers. Specific challenges include experimental design, preprocessing, feature extraction, and statistical analysis accounting for the inherent multiple testing issues. This paper reviews various computational …

Integrative Bayesian Analysis Of High-Dimensional Multi-Platform Genomics Data, Wenting Wang, Veerabhadran Baladandayuthapani, Jeffrey S. Morris, Bradley M. Broom, Ganiraju C. Manyam, Kim-Anh Do

Jeffrey S. Morris

Motivation: Analyzing data from multi-platform genomics experiments combined with patients’ clinical outcomes helps us understand the complex biological processes that characterize a disease, as well as how these processes relate to the development of the disease. Current integration approaches that treat the data are limited in that they do not consider the fundamental biological relationships that exist among the data from platforms.

Statistical Model: We propose an integrative Bayesian analysis of genomics data (iBAG) framework for identifying important genes/biomarkers that are associated with clinical outcome. This framework uses a hierarchical modeling technique to combine the data obtained from multiple platforms …

R Code: A Non-Iterative Implementation Of Tango's Score Confidence Interval For A Paired Difference Of Proportions, Zhao Yang

Zhao (Tony) Yang, Ph.D.

For matched-pair binary data, a variety of approaches have been proposed for the construction of a confidence interval (CI) for the difference of marginal probabilities between two procedures. The score-based approximate CI has been shown to outperform other asymptotic CIs. Tango’s method provides a score CI by inverting a score test statistic using an iterative procedure. In the developed R code, we propose an efficient non-iterative method with closed-form expression to calculate Tango’s CIs. Examples illustrate the practical application of the new approach.

Comparing The Cohort Design And The Nested Case-Control Design In The Presence Of Both Time-Invariant And Time-Dependent Treatment And Competing Risks: Bias And Precision, Peter C. Austin

Peter Austin

Purpose: Observational studies using electronic administrative health care databases are often used to estimate the effects of treatments and exposures. Traditionally, a cohort design has been used to estimate these effects, but increasingly studies are using a nested case-control (NCC) design. The relative statistical efficiency of these two designs has not been examined in detail.

Methods: We used Monte Carlo simulations to compare these two designs in terms of the bias and precision of effect estimates. We examined three different settings: (A): treatment occurred at baseline and there was a single outcome of interest; (B): treatment was time-varying and there …

Using Ensemble-Based Methods For Directly Estimating Causal Effects: An Investigation Of Tree-Based G-Computation, Peter C. Austin

Peter Austin

Researchers are increasingly using observational or nonrandomized data to estimate causal treatment effects. Essential to the production of high-quality evidence is the ability to reduce or minimize the confounding that frequently occurs in observational studies. When using the potential outcome framework to define causal treatment effects, one requires the potential outcome under each possible treatment. However, only the outcome under the actual treatment received is observed, whereas the potential outcomes under the other treatments are considered missing data. Some authors have proposed that parametric regression models be used to estimate potential outcomes. In this study, we examined the use of …

Regression Trees For Predicting Mortality In Patients With Cardiovascular Disease: What Improvement Is Achieved By Using Ensemble-Based Methods?, Peter C. Austin

Peter Austin

In biomedical research, the logistic regression model is the most commonly used method for predicting the probability of a binary outcome. While many clinical researchers have expressed an enthusiasm for regression trees, this method may have limited accuracy for predicting health outcomes. We aimed to evaluate the improvement that is achieved by using ensemble-based methods, including bootstrap aggregation (bagging) of regression trees, random forests, and boosted regression trees. We analyzed 30-day mortality in two large cohorts of patients hospitalized with either acute myocardial infarction (N = 16,230) or congestive heart failure (N = 15,848) in two distinct eras (1991-2001 and …

Generating Survival Times To Simulate Cox Proportional Hazards Models With Time-Varying Covariates., Peter C. Austin

Peter Austin

Simulations and Monte Carlo methods serve an important role in modern statistical research. They allow for an examination of the performance of statistical procedures in settings in which analytic and mathematical derivations may not be feasible. A key element in any statistical simulation is the existence of an appropriate data-generating process: one must be able to simulate data from a specified statistical model. We describe data-generating processes for the Cox proportional hazards model with time-varying covariates when event times follow an exponential, Weibull, or Gompertz distribution. We consider three types of time-varying covariates: first, a dichotomous time-varying covariate that can …

Flexible Distributed Lag Models Using Random Functions With Application To Estimating Mortality Displacement From Heat-Related Deaths, Roger D. Peng, Matthew J. Heaton

Roger D. Peng

No abstract provided.

Comparing Paired Vs. Non-Paired Statistical Methods Of Analyses When Making Inferences About Absolute Risk Reductions In Propensity-Score Matched Samples., Peter C. Austin

Peter Austin

Propensity-score matching allows one to reduce the effects of treatment-selection bias or confounding when estimating the effects of treatments when using observational data. Some authors have suggested that methods of inference appropriate for independent samples can be used for assessing the statistical significance of treatment effects when using propensity-score matching. Indeed, many authors in the applied medical literature use methods for independent samples when making inferences about treatment effects using propensity-score matched samples. Dichotomous outcomes are common in healthcare research. In this study, we used Monte Carlo simulations to examine the effect on inferences about risk differences (or absolute risk …

Optimal Caliper Widths For Propensity-Score Matching When Estimating Differences In Means And Differences In Proportions In Observational Studies., Peter C. Austin

Peter Austin

In a study comparing the effects of two treatments, the propensity score is the probability of assignment to one treatment conditional on a subject's measured baseline covariates. Propensity-score matching is increasingly being used to estimate the effects of exposures using observational data. In the most common implementation of propensity-score matching, pairs of treated and untreated subjects are formed whose propensity scores differ by at most a pre-specified amount (the caliper width). There has been a little research into the optimal caliper width. We conducted an extensive series of Monte Carlo simulations to determine the optimal caliper width for estimating differences …

A Tutorial And Case Study In Propensity Score Analysis: An Application To Estimating The Effect Of In-Hospital Smoking Cessation Counseling On Mortality, Peter C. Austin

Peter Austin

Propensity score methods allow investigators to estimate causal treatment effects using observational or nonrandomized data. In this article we provide a practical illustration of the appropriate steps in conducting propensity score analyses. For illustrative purposes, we use a sample of current smokers who were discharged alive after being hospitalized with a diagnosis of acute myocardial infarction. The exposure of interest was receipt of smoking cessation counseling prior to hospital discharge and the outcome was mortality with 3 years of hospital discharge. We illustrate the following concepts: first, how to specify the propensity score model; second, how to match treated and …