Statistics and Probability Commons^™

Generalized Multilevel Functional Regression, Ciprian M. Crainiceanu, Ana-Maria Staicu, Chongzhi Di

Johns Hopkins University, Dept. of Biostatistics Working Papers

We introduce Generalized Multilevel Functional Linear Models (GMFLM), a novel statistical framework motivated by and applied to the Sleep Heart Health Study (SHHS), the largest community cohort study of sleep. The primary goal of SHHS is to study the association between sleep disrupted breathing (SDB) and adverse health effects. An exposure of primary interest is the sleep electroencephalogram (EEG), which was observed for thousands of individuals at two visits, roughly 5 years apart. This unique study design led to the development of models where the outcome, e.g. hypertension, is in an exponential family and the exposure, e.g. sleep EEG, is …

A Novel And Simple Rule Of Thumb For Multiplicity Control In Equivalence Testing Using Two One-Sided Tests, Carolyn Lauzon, Brian S. Caffo

Johns Hopkins University, Dept. of Biostatistics Working Papers

Equivalence testing is growing in use in scientific research outside of its traditional role in the drug approval process. Largely due to its ease of use and recommendation from the United States Food and Drug Administration guidance, the most common statistical method for testing (bio)equivalence is the two one-sided tests procedure (TOST). Like classical point-null hypothesis testing, TOST is subject to multiplicity concerns as more comparisons are made. In this manuscript, a condition that bounds the family-wise error rate (FWER) using TOST is given. This condition then leads to a simple solution for controlling the FWER. Specifically, we demonstrate that …

Estimating The Causal Effect Of Lower Tidal Volume Ventilation On Survival In Patients With Acute Lung Injury, Weiwei Wang, Daniel Scharfstein, Roy Brower, Dale Needham

Johns Hopkins University, Dept. of Biostatistics Working Papers

Acute lung injury (ALI) is a condition characterized by acute onset of severe hypoxemia and bliateral pulmonary infiltrates. ALI patients typically require mechanical ventilation in an intensive care unit. Low tidal volume ventilation (LTVV), a time-varying dynamic treatment regime, has been recommended as an effective ventilation strategy. This recommendation was based on the results of the ARMA study, a randomized clinical trial designed to compare low vs. high tidal volume strategies (ARDSNetwork, 2000) . After publication of the trial, some critics focused on the high non-adherence rates in the LTVV arm suggesting that non-adherence occurred because treating physicians felt that …

Bayesian Inference For Smoking Cessation With A Latent Cure State, Sheng Luo, Ciprian M. Crainiceanu, Thomas A. Louis, Nilanjan Chatterjee

Johns Hopkins University, Dept. of Biostatistics Working Papers

We present a Bayesian approach to modeling dynamic smoking addiction behavior processes when cure is not directly observed due to censoring. Subject-specic probabilities model the stochastic transitions among three behavioral states: smoking, transient quitting, and permanent quitting (absorbent state). A multivariate normal distribution for random e ects is used to account for the potential correlation among the subject-specic transition probabilities. Inference is conducted using a Bayesian framework via Markov Chain Monte Carlo simulation. This framework provides various measures of subject-specic predictions, which are useful for policy making, intervention development, and evaluation. Simulations are used to validate our Bayesian methodology, and …

Analysis Of Subgroup Effects In Randomized Trials When Subgroup Membership Is Informatively Missing: Application To The Madit Ii Study, Daniel O. Scharfstein, Georgiana Onicescu, Steven Goodman

Johns Hopkins University, Dept. of Biostatistics Working Papers

In this paper, we develop and implement a general sensitivity analysis methodology for drawing inference about subgroup effects in a two-arm randomized trial when subgroup status is only known for a non-random sample in one of the trial arms. The methodology is developed in the context of the MADIT II study, a randomized trial designed to evaluate the effectiveness of implantable defibrillators on survival.

Causal Inference In Observational Studies With Outcome-Dependent Sampling, Weiwei Wang, Daniel Scharfstein, Zhiqiang Tan, Ellen J. Mackenzie

Johns Hopkins University, Dept. of Biostatistics Working Papers

In this paper, we consider estimation of the causal effect of a treatment on an outcome from observational data collected in two phases. In the first phase, a simple random sample of individuals are drawn from a population. On these individuals, information is obtained on treatment, outcome, and a few low-dimensional confounders. These individuals are then stratified according to these factors. In the second phase, a random sub-sample of individuals are drawn from each stratum, with known, stratum-specific selection probabilities. On these individuals, a rich set of confounding factors are collected. In this setting, we introduce four estimators: (1) simple …

A Method For Visualizing Multivariate Time Series Data, Roger D. Peng

Johns Hopkins University, Dept. of Biostatistics Working Papers

Visualization and exploratory analysis is an important part of any data analysis and is made more challenging when the data are voluminous and high-dimensional. One such example is environmental monitoring data, which are often collected over time and at multiple locations, resulting in a geographically indexed multivariate time series. Financial data, although not necessarily containing a geographic component, present another source of high-volume multivariate time series data. We present the mvtsplot function which provides a method for visualizing multivariate time series data. We outline the basic design concepts and provide some examples of its usage by applying it to a …

Jointly Modeling Continuous And Binary Outcomes For Boolean Outcomes: An Application To Modeling Hypertension, Xianbin Li, Brian S. Caffo, Elizabeth Stuart

Johns Hopkins University, Dept. of Biostatistics Working Papers

Binary outcomes defined by logical (Boolean) "and" or "or" operations on original continuous and discrete outcomes arise commonly in medical diagnoses and epidemiological research. In this manuscript,we consider applying the “or” operator to two continuous variables above a threshold and a binary variable, a setting that occurs frequently in the modeling of hypertension. Rather than modeling the resulting composite outcome defined by the logical operator, we present a method that models the original outcomes thus utilizing all information in the data, yet continues to yield conclusions on the composite scale. A stratified propensity score adjustment is proposed to account for …

A Bayesian Approach To Effect Estimation Accounting For Adjustment Uncertainty, Chi Wang, Giovanni Parmigiani, Ciprian Crainiceanu, Francesca Dominici

Johns Hopkins University, Dept. of Biostatistics Working Papers

Adjustment for confounding factors is a common goal in the analysis of both observational and controlled studies. The choice of which confounding factors should be included in the model used to estimate an effect of interest is both critical and uncertain. For this reason it is important to develop methods that estimate an effect, while accounting not only for confounders, but also for the uncertainty about which confounders should be included. In a recent article, Crainiceanu et al. (2008) have identified limitations and potential biases of Bayesian Model Averaging (BMA) (Raftery et al., 1997; Hoeting et al., 1999)when applied to …

On The Merits Of Voxel-Based Morphometric Path-Analysis For Investigating Volumetric Mediation Of A Toxicant's Influence On Cognitive Function, Shu-Chih Su, Brian S. Caffo, Lynn E. Eberly, Elizabeth Garrett-Mayer, Walter F. Stewart, Sining Chen, David Yousem, Christos Davatzikos, Brian Schwartz

Johns Hopkins University, Dept. of Biostatistics Working Papers

We previously showed that lifetime cumulative lead dose, measured as lead concentration in the tibia bone by X-ray fluorescence, was associated with persistent and progressive declines in cognitive function and with decreases in MRI-based brain volumes in former lead workers. Moreover, larger region-specific brain volumes were associated with better cognitive function. These findings motivated us to explore a novel application of path analysis to evaluate effect mediation. Voxel-wise path analysis, at face value, represents the natural evolution of voxel-based morphometry methods to answer questions of mediation. Application of these methods to the former lead worker data demonstrated potential limitations in …

Geostatistical Inference Under Preferential Sampling, Peter J. Diggle, Raquel Menezes, Ting-Li Su

Johns Hopkins University, Dept. of Biostatistics Working Papers

Geostatistics involves the fitting of spatially continuous models to spatially discrete data (Chil`es and Delfiner, 1999). Preferential sampling arises when the process that determines the data-locations and the process being modelled are stochastically dependent. Conventional geostatistical methods assume, if only implicitly, that sampling is non-preferential. However, these methods are often used in situations where sampling is likely to be preferential. For example, in mineral exploration samples may be concentrated in areas thought likely to yield high-grade ore. We give a general expression for the likelihood function of preferentially sampled geostatistical data and describe how this can be evaluated approximately using …

Bayesian Analysis For Penalized Spline Regression Using Win Bugs, Ciprian M. Crainiceanu, David Ruppert, M.P. Wand

Johns Hopkins University, Dept. of Biostatistics Working Papers

Penalized splines can be viewed as BLUPs in a mixed model framework, which allows the use of mixed model software for smoothing. Thus, software originally developed for Bayesian analysis of mixed models can be used for penalized spline regression. Bayesian inference for nonparametric models enjoys the flexibility of nonparametric models and the exact inference provided by the Bayesian inferential machinery. This paper provides a simple, yet comprehensive, set of programs for the implementation of nonparametric Bayesian analysis in WinBUGS. MCMC mixing is substantially improved from the previous versions by using low{rank thin{plate splines instead of truncated polynomial basis. Simulation time …

Decomposition Of Regression Estimators To Explore The Influence Of "Unmeasured" Time-Varying Confounders, Yun Lu, Scott L. Zeger

Johns Hopkins University, Dept. of Biostatistics Working Papers

In environmental epidemiology, exposure X and health outcome Y vary in space and time. We present a method to diagnose the possible influence of unmeasured confounders U on the estimated effect of X on Y and to propose several approaches to robust estimation. The idea is to use space and time as proxy measures for the unmeasured factors U. We start with the time series case where X and Y are continuous variables at equally-spaced times and assume a linear model. We define matching estimator b(u)s that correspond to pairs of observations with specific lag u. Controlling for a smooth …

A Smoothing Approach To Data Masking, Yijie Zhous, Francesca Dominici, Thomas A. Louis

Johns Hopkins University, Dept. of Biostatistics Working Papers

Individual-level data are often not publicly available due to confidentiality. Instead, masked data are released for public use. However, analyses performed using masked data may produce invalid statistical results such as biased parameter estimates or incorrect standard errors. In this paper, we propose a data masking method using spatial smoothing, and we investigate the bias of parameter estimates resulting from analyses using the masked data for Generalized Linear Models (GLM). The method allows for varying both the form and the degree of masking by utilizing a smoothing weight function and a smoothness parameter. We show that data masking by using …

Optimal Propensity Score Stratification, Jessica A. Myers, Thomas A. Louis

Johns Hopkins University, Dept. of Biostatistics Working Papers

Stratifying on propensity score in observational studies of treatment is a common technique used to control for bias in treatment assignment; however, there have been few studies of the relative efficiency of the various ways of forming those strata. The standard method is to use the quintiles of propensity score to create subclasses, but this choice is not based on any measure of performance either observed or theoretical. In this paper, we investigate the optimal subclassification of propensity scores for estimating treatment effect with respect to mean squared error of the estimate. We consider the optimal formation of subclasses within …

Multiple Model Evaluation Absent The Gold Standard Via Model Combination, Edwin J. Iversen, Jr., Giovanni Parmigiani, Sining Chen

Johns Hopkins University, Dept. of Biostatistics Working Papers

We describe a method for evaluating an ensemble of predictive models given a sample of observations comprising the model predictions and the outcome event measured with error. Our formulation allows us to simultaneously estimate measurement error parameters, true outcome — aka the gold standard — and a relative weighting of the predictive scores. We describe conditions necessary to estimate the gold standard and for these estimates to be calibrated and detail how our approach is related to, but distinct from, standard model combination techniques. We apply our approach to data from a study to evaluate a collection of BRCA1/BRCA2 gene …

Effective Communication Of Standard Errors And Confidence Intervals, Thomas A. Louis, Scott L. Zeger

Johns Hopkins University, Dept. of Biostatistics Working Papers

We recommend a format for communicating an estimate with its standard error or confidence interval. The format reinforces that the associated variability is an inseparable component of the estimate and it substantially improves clarity in tabular displays.

Inference For Survival Curves With Informatively Coarsened Discrete Event-Time Data: Application To Alive, Michelle Shardell, Daniel O. Scharfstein, David Vlahov, Noya Galai

Johns Hopkins University, Dept. of Biostatistics Working Papers

In many prospective studies, including AIDS Link to the Intravenous Experience (ALIVE), researchers are interested in comparing event-time distributions (e.g.,for human immunodeficiency virus seroconversion) between a small number of groups (e.g., risk behavior categories). However, these comparisons are complicated by participants missing visits or attending visits off schedule and seroconverting during this absence. Such data are interval-censored, or more generally,coarsened. Most analysis procedures rely on the assumption of non-informative censoring, a special case of coarsening at random that may produce biased results if not valid. Our goal is to perform inference for estimated survival functions across a small number of …

Random Effects Models In A Meta-Analysis Of The Accuracy Of Diagnostic Tests Within A Gold Standard In The Presence Of Missing Data, Haitao Chu, Sining Chen, Thomas A. Louis

Johns Hopkins University, Dept. of Biostatistics Working Papers

In evaluating the accuracy of diagnosis tests, it is common to apply two imperfect tests jointly or sequentially to a study population. In a recent meta-analysis of the accuracy of microsatellite instability testing (MSI) and traditional mutation analysis (MUT) in predicting germline mutations of the mismatch repair (MMR) genes, a Bayesian approach (Chen, Watson, and Parmigiani 2005) was proposed to handle missing data resulting from partial testing and the lack of a gold standard. In this paper, we demonstrate an improved estimation of the sensitivities and specificities of MSI and MUT by using a nonlinear mixed model and a Bayesian …

Identifying Effect Modifiers In Air Pollution Time-Series Studies Using A Two-Stage Analysis, Sandrah P. Eckel, Thomas A. Louis

Johns Hopkins University, Dept. of Biostatistics Working Papers

Studies of the health effects of air pollution such as the National Morbidity and Mortality Air Pollution Study (NMMAPS) relate changes in daily pollution to daily deaths in a sample of cities and calendar years. Generally, city-specific estimates are combined into regional and national estimates using two-stage models. Our two-stage analysis identifies effect modifiers of the relation between single-day lagged PM10 and daily mortality in people age 65 and older from the 50 largest NMMAPS cities. We build on the standard approach by "fractionating" city-specific analyses to produce month-year-city specific estimated air pollution effects (slopes) in Stage I. In Stage …

Racial Disparities In Mortality Risks In A Sample Of The U.S. Medicare Population, Yijie Zhou, Francesca Dominici, Thomas A. Louis

Johns Hopkins University, Dept. of Biostatistics Working Papers

Racial disparities in mortality risks adjusted by socioeconomic status (SES) are not well understood. To add to the understanding of racial disparities, we construct and analyze a data set that links, at individual and zip code levels, three government databases: Medicare, Medicare Current Beneficiary Survey and U.S. Census. Our study population includes more than 4 million Medicare enrollees residing in 2095 zip codes in the Northeast region of U.S. We develop hierarchical models to estimate Black-White disparity in risk of death, adjusted by both individual-level and zip codelevel income. We define population-level attributable risk (AR), relative attributable risk (RAR) and …

A Case Study In Pharmacologic Imaging Using Principal Curves In Single Photon Emission Computed Tomography, Brian S. Caffo, Ciprian M. Crainiceanu, Lijuan Deng, Craig W. Hendrix

Johns Hopkins University, Dept. of Biostatistics Working Papers

In this manuscript we are concerned with functional imaging of the colon to assess the kinetics of a microbicide lubricant. The overarching goal is to understand the distribution of the lubricant in the colon. Such information is crucial for understanding the potential impact of the microbicide on HIV viral transmission. The experiment was conducted by imaging a radiolabeled lubricant distributed in the subject’s colon. The tracer imaging was conducted via single photon emission computed tomography (SPECT), a non-invasive, in-vivo functional imaging technique. We develop a novel principal curve algorithm to construct a three dimensional curve through the colon images. The …

A Bayesian Hierarchical Framework For Spatial Modeling Of Fmri Data, F. Dubois Bowman, Brian S. Caffo, Susan Spear Bassett, Clinton Kilts

Johns Hopkins University, Dept. of Biostatistics Working Papers

Functional neuroimaging techniques enable investigations into the neural basis of human cognition, emotions, and behaviors. In practice, applications of functional magnetic resonance imaging (fMRI) have provided novel insights into the neuropathophysiology of major psychiatric,neurological, and substance abuse disorders, as well as into the neural responses to their treatments. Modern activation studies often compare localized task-induced changes in brain activity between experimental groups. One may also extend voxel-level analyses by simultaneously considering the ensemble of voxels constituting an anatomically defined region of interest (ROI) or by considering means or quantiles of the ROI. In this work we present a Bayesian extension …

Fast Adaptive Penalized Splines, Tatyana Krivobokova, Ciprian M. Crainiceanu, Goran Kauermann

Johns Hopkins University, Dept. of Biostatistics Working Papers

This paper proposes a numerically simple routine for locally adaptive smoothing. The locally heterogeneous regression function is modelled as a penalized spline with a smoothly varying smoothing parameter modelled as another penalized spline. This is being formulated as hierarchical mixed model, with spline coe±cients following a normal distribution, which by itself has a smooth structure over the variances. The modelling exercise is in line with Baladandayuthapani, Mallick & Carroll (2005) or Crainiceanu, Ruppert & Carroll (2006). But in contrast to these papers Laplace's method is used for estimation based on the marginal likelihood. This is numerically simple and fast and …

Modified Test Statistics By Inter-Voxel Variance Shrinkage With An Application To Fmri, Shu-Chih Su, Brian Caffo, Elizabeth Garrett-Mayer, Susan Bassett

Johns Hopkins University, Dept. of Biostatistics Working Papers

Functional Magnetic Resonance Imaging (fMRI) is a non-invasive technique which is commonly used to quantify changes in blood oxygenation and flow coupled to neuronal activation. One of the primary goals of fMRI studies is to identify localized brain regions where neuronal activation levels vary between groups. Single voxel t-tests have been commonly used to determine whether activation related to the protocol differs across groups. Due to the generally limited number of subjects within each study, accurate estimation of variance at each voxel is difficult. Thus, combining information across voxels in the statistical analysis of fMRI data is desirable in order …

Semiparametric Bivariate Quantile-Quantile Regression For Analyzing Semi-Competing Risks Data, Daniel O. Scharfstein, James M. Robins, Mark Van Der Laan

Johns Hopkins University, Dept. of Biostatistics Working Papers

In this paper, we consider estimation of the effect of a randomized treatment on time to disease progression and death, possibly adjusting for high-dimensional baseline prognostic factors. We assume that patients may or may not have a specific type of disease progression prior to death and those who have this endpoint are followed for their survival information. Progression and survival may also be censored due to loss to follow-up or study termination. We posit a semi-parametric bivariate quantile-quantile regression failure time model and show how to construct estimators of the regression parameters. The causal interpretation of the parameters depends on …

A Survey Of The Likelihood Approach To Bioequivalence Trials, Leena Choi, Brian S. Caffo, Charles Rohde

Johns Hopkins University, Dept. of Biostatistics Working Papers

Bioequivalence trials are abbreviated clinical trials whereby a generic drug or new formulation is evaluated to determine if it is "equivalent" to a corresponding previously approved brand-name drug or formulation. In this manuscript, we survey the process of testing bioequivalence and advocate the likelihood paradigm for representing the resulting data as evidence. We emphasize the unique conflicts between hypothesis testing and confidence intervals in this area - which we believe are indicative of the existence of the systemic defects in the frequentist approach - that the likelihood paradigm avoids. We suggest the direct use of profile likelihoods for evaluating bioequivalence …

Mortality In The Medicare Population And Chronic Exposure To Fine Particulate Air Pollution , Scott L. Zeger, Francesca Dominici, Aidan Mcdermott, Jonathan M. Samet

Johns Hopkins University, Dept. of Biostatistics Working Papers

Prospective cohort studies have provided evidence on longer-term mortality risks of fine particulate matter (PM2.5), but due to their complexity and costs, only a few have been conducted.

By linking monitoring data to the U.S. Medicare system by county of residence, we developed a retrospective cohort study, the Medicare Air Pollution Cohort Study (MCAPS), comprising over 20 million enrollees in the 250 largest counties during 2000-2002. We estimated log-linear regression models having as outcome the age-specific mortality rate for each county and as the main predictor, the average level for the study period 2000. Area-level covariates were used to adjust …

A Bayesian Hierarchical Model For Constrained Distributed Lag Functions: Estimating The Time Course Of Hospitalization Associated With Air Pollution Exposure, Roger Peng, Francesca Dominici, Leah J. Welty

Johns Hopkins University, Dept. of Biostatistics Working Papers

Numerous time series studies have provided strong evidence of an association between increased levels of ambient air pollution and increased levels of hospital admissions, typically at 0, 1, or 2 days after an air pollution episode. An important research aim is to extend existing statistical models so that a more detailed understanding of the time course of hospitalization after exposure to air pollution can be obtained. Information about this time course, combined with prior knowledge about biological mechanisms, could provide the basis for hypotheses concerning the mechanism by which air pollution causes disease. Previous studies have identified two important methodological …

Gamma Shape Mixtures For Heavy-Tailed Distributions, Sergio Venturini, Francesca Dominici, Giovanni Parmigiani

Johns Hopkins University, Dept. of Biostatistics Working Papers

An important question in health services research is the estimation of the proportion of medical expenditures that exceed a given threshold. Typically, medical expenditures present highly skewed, heavy tailed distributions, for which a) simple variable transformations are insufficient to achieve a tractable low- dimensional parametric form and b) nonparametric methods are not efficient in estimating exceedance probabilities for large thresholds. Motivated by this context, in this paper we propose a general Bayesian approach for the estimation of tail probabilities of heavy-tailed distributions,based on a mixture of gamma distributions in which the mixing occurs over the shape parameter. This family provides …