Biostatistics Commons^™

Decline In Health For Older Adults: 5-Year Change In 13 Key Measures Of Standardized Health, Paula H. Diehr, Stephen M. Thielke, Anne B. Newman, Calvin H. Hirsch, Russell Tracy

UW Biostatistics Working Paper Series

Introduction

The health of older adults declines over time, but there are many ways of measuring health. We examined whether all measures declined at the same rate, or whether some aspects of health were less sensitive to aging than others.

Methods

We compared the decline in 13 measures of physical, mental, and functional health from the Cardiovascular Health Study: hospitalization, bed days, cognition, extremity strength, feelings about life as a whole, satisfaction with the purpose of life, self-rated health, depression, digit symbol substitution test, grip strength, ADLs, IADLs, and gait speed. Each measure was standardized against self-rated health. We compared …

Methods For Evaluating Prediction Performance Of Biomarkers And Tests, Margaret Pepe, Holly Janes

UW Biostatistics Working Paper Series

This chapter describes and critiques methods for evaluating the performance of markers to predict risk of a current or future clinical outcome. We consider three criteria that are important for evaluating a risk model: calibration, benefit for decision making and accurate classification. We also describe and discuss a variety of summary measures in common use for quantifying predictive information such as the area under the ROC curve and R-squared. The roles and problems with recently proposed risk reclassification approaches are discussed in detail.

Borrowing Information Across Populations In Estimating Positive And Negative Predictive Values, Ying Huang, Youyi Fong, John Wei, Ziding Feng

UW Biostatistics Working Paper Series

A marker's capacity to predict risk of a disease depends on disease prevalence in the target population and its classification accuracy, i.e. its ability to discriminate diseased subjects from non-diseased subjects. The latter is often considered an intrinsic property of the marker; it is independent of disease prevalence and hence more likely to be similar across populations than risk prediction measures. In this paper, we are interested in evaluating the population-specific performance of a risk prediction marker in terms of positive predictive value (PPV) and negative predictive value (NPV) at given thresholds, when samples are available from the target population …

Fitting And Interpreting Continuous-Time Latent Markov Models For Panel Data, Jane M. Lange, Vladimir N. Minin

UW Biostatistics Working Paper Series

Multistate models are used to characterize disease processes within an individual. Clinical studies often observe the disease status of individuals at discrete time points, making exact times of transitions between disease states unknown. Such panel data pose considerable modeling challenges. Assuming the disease process progresses according a standard continuous-time Markov chain (CTMC) yields tractable likelihoods, but the assumption of exponential sojourn time distributions is typically unrealistic. More flexible semi-Markov models permit generic sojourn distributions yet yield intractable likelihoods for panel data in the presence of reversible transitions. One attractive alternative is to assume that the disease process is characterized by …

Transitions Among Health States Using 12 Measures Of Successful Aging: Results From The Cardiovascular Health Study, Stephen Thielke, Paula Diehr

UW Biostatistics Working Paper Series

Introduction

Successful aging has many dimensions, which may manifest differently in men and women and at different ages. We sought to characterize one-year transitions in 12 measures of successful aging among a large cohort of older adults.

Methods

We analyzed twelve different measures of health in the Cardiovascular Health Study: self-rated health, ADLs, IADLs, depression, cognition, timed walk, number of days spent in bed, number of blocks walked, extremity strength, recent hospitalizations, feelings about life as a whole, and life satisfaction. We dichotomized responses for each variable into “healthy” or “sick”, and estimated the prevalence of the healthy state and …

Testing For Improvement In Prediction Model Performance, Margaret S. Pepe Phd, Kathleen F. Kerr, Gary M. Longton, Zheyu Wang

UW Biostatistics Working Paper Series

New methodology has been proposed in recent years for evaluating the improvement in prediction performance gained by adding a new predictor, Y, to a risk model containing a set of baseline predictors, X, for a binary outcome D. We prove theoretically that null hypotheses concerning no improvement in performance are equivalent to the simple null hypothesis that the coefficient for Y is zero in the risk model, P(D = 1|X, Y ). Therefore, testing for improvement in prediction performance is redundant if Y has already been shown to be a risk factor. We investigate properties of tests through simulation studies, …

Some Observations On The Wilcoxon Rank Sum Test, Scott S. Emerson

UW Biostatistics Working Paper Series

This manuscript presents some general comments about the Wilcoxon rank sum test. Even the most casual reader will gather that I am not too impressed with the scientific usefulness of the Wilcoxon test. However, the actual motivation is more to illustrate differences between parametric, semiparametric, and nonparametric (distribution-free) inference, and to use this example to illustrate how many misconceptions have been propagated through a focus on (semi)parametric probability models as the basis for evaluating commonly used statistical analysis models. The document itself arose as a teaching tool for courses aimed at graduate students in biostatistics and statistics, with parts of …

The Importance Of Statistical Theory In Outlier Detection, Sarah C. Emerson, Scott S. Emerson

UW Biostatistics Working Paper Series

We explore the performance of the outlier-sum statistic (Tibshirani and Hastie, Biostatistics 2007 8:2--8), a proposed method for identifying genes for which only a subset of a group of samples or patients exhibits differential expression levels. Our discussion focuses on this method as an example of how inattention to standard statistical theory can lead to approaches that exhibit some serious drawbacks. In contrast to the results presented by those authors, when comparing this method to several variations of the $t$-test, we find that the proposed method offers little benefit even in the most idealized scenarios, and suffers from a number …

When Does Combining Markers Improve Classification Performance And What Are Implications For Practice?, Aasthaa Bansal, Margaret Sullivan Pepe

UW Biostatistics Working Paper Series

When an existing standard marker does not have sufficient classification accuracy on its own, new markers are sought with the goal of yielding a combination with better performance. The primary criterion for selecting new markers is that they have good performance on their own and preferably be uncorrelated with the standard. Most often linear combinations are considered. In this paper we investigate the increment in performance that is possible by combining a novel continuous marker with a moderately performing standard continuous marker under a variety of biologically motivated models for their joint distribution. We find that an uncorrelated continuous marker …

Bate Curve In Assessment Of Clinical Utility Of Predictive Biomarkers, Xiao-Hua Zhou, Yunbei Ma

UW Biostatistics Working Paper Series

In this paper, for time-to-event data, we propose a new statistical framework for casual inference in evaluating clinical utility of predictive biomarkers and in selecting an optimal treatment for a particular patient. This new casual framework is based on a new concept, called Biomarker Adjusted Treatment Effect (BATE) curve, which can be used to represent the clinical utility of a predictive biomarker and select an optimal treatment for one particular patient. We then propose semi-parametric methods for estimating the BATE curves of biomarkers and establish asymptotic results of the proposed estimators for the BATE curves. We also conduct extensive simulation …

Non-Homogeneous Markov Process Models With Incomplete Observations: Application To A Dementia Disease Study, Xiao-Hua Zhou, Baojiang Chen

UW Biostatistics Working Paper Series

Identifying risk factors for transition rates among normal cognition, mildly cognitive impairment, dementia and death in an Alzheimer's disease study is very important. It is known that transition rates among these states are strongly time dependent. While Markov process models are often used to describe these disease progressions, the literature mainly focuses on time homogeneous processes, and limited tools are available for dealing with non-homogeneity. Further, patients may choose when they want to visit the clinics, which creates informative observations. In this paper, we develop methods to deal with non-homogeneous Markov processes through time scale transformation when observation times are …

Doubly Robust Estimates For Binary Longitudinal Data Analysis With Missing Response And Missing Covariates, Baojiang Chen, Xiao-Hua Zhou

UW Biostatistics Working Paper Series

Longitudinal studies often feature incomplete response and covariate data. Likelihood-based methods such as the EM algorithm give consistent estimators for model parameters when data are missing at random provided that the response model and the missing covariate model are correctly specified; but we do not need to specify the missing data mechanism. An alternative method is the weighted estimating equation which gives consistent estimators if the missing data and response models are correctly specified; but we do not need to specify the distribution of the covariates that have missing values. In this paper we develop a doubly robust estimation method …

Semiparametric Estimation Of The Covariate-Specific Roc Curve In Presence Of Ignorable Verification Bias, Danping Liu, Xiao-Hua Zhou

UW Biostatistics Working Paper Series

Covariate-specific ROC curves are often used to evaluate the classification accuracy of a medical diagnostic test or a biomarker, when the accuracy of the test is associated with certain covariates. In many large-scale screening tests, the gold standard is subject to missingness due to high cost or harmfulness to the patient. In this paper, we propose a semiparametric estimation method for the covariate-specific ROC curves with a partial missing gold standard. A location-scale model is constructed for the test result to model the covariates' effect, but the residual distributions are left unspecified. Thus the baseline and link functions of the …

Evaluating Markers For Treatment Selection Based On Survival Time, Xiao Song, Xiao-Hua Zhou

UW Biostatistics Working Paper Series

For many medical conditions there are several treatment options available to patients. We consider evaluating markers based on a simple treatment selection policy that incorporates information on the patient's marker value exceeding a threshold. Although traditional regression methods may assess the effect of the marker and treatment on outcomes, it is appealing to quantify more directly the potential impact on the population of using the marker to select treatment. A useful tool is the selection impact (SI) curve proposed by Song and Pepe (2004, \textit{Biometrics} \textbf{60}, 874--883) for binary outcomes. However, this approach does not deal with continuous outcomes, nor …

Multi-State Life Tables, Equilibrium Prevalence, And Baseline Selection Bias, Paula Diehr, David Yanez

UW Biostatistics Working Paper Series

Consider a 3-state system with one absorbing state, such as Healthy, Sick, and Dead. If the system satisfies the 1-step Markov conditions, the prevalence of the Healthy state will converge to a value that is independent of the initial distribution. This equilibrium prevalence and its variance are known under the assumption of time homogeneity, and provided reasonable estimates in the time non-homogeneous systems studied. Here, we derived the equilibrium prevalence for a system with more than three states. Under time homogeneity, the equilibrium prevalence distribution was shown to be an eigenvector of a partition of the matrix of transition probabilities. …

Bio-Creep In Non-Inferiority Clinical Trials, Siobhan P. Everson-Stewart, Scott S. Emerson

UW Biostatistics Working Paper Series

After a non-inferiority clinical trial, a new therapy may be accepted as effective, even if its treatment effect is slightly smaller than the current standard. It is therefore possible that, after a series of trials where the new therapy is slightly worse than the preceding drugs, an ineffective or harmful therapy might be incorrectly declared efficacious; this is known as “bio-creep.” Several factors may influence the rate at which bio-creep occurs, including the distribution of the effects of the new agents being tested and how that changes over time, the choice of active comparator, the method used to model the …

Estimates Of Information Growth In Longitudinal Clinical Trials, Abigail Shoben, Kyle Rudser, Scott S. Emerson

UW Biostatistics Working Paper Series

In group sequential clinical trials, it is necessary to estimate the amount of information present at interim analysis times relative to the amount of information that would be present at the final analysis. If only one measurement is made per individual, this is often the ratio of sample sizes available at the interim and final analyses. However, as discussed by Wu and Lan (1992), when the statistic of interest is a change over time, as with longitudinal data, such an approach overstates the information. In this paper, we discuss other problems that can result in overestimating the information, such as …

Is Survival The Only Or Even The Right Outcome For Evaluating Treatments For Out-Of-Hospital Cardiac Arrest? A Proposed Test Based On Both An Intermediate And Ultimate Outcome., Al Hallstrom

UW Biostatistics Working Paper Series

It is generally agreed that the goal of resuscitation is survival with neurological and physiological status similar to that preceding the cardiac arrest. Previously I have argued that the lack of improvement in outcome from resuscitation over the past 3 to 4 decades, as compared to the substantial progress made in treatment of ischemic heart disease, is a consequence of the absence of randomized clinical trials of new interventions and the use of intermediate endpoints such as return of spontaneous circulation or admittance to hospital. Proponents of these intermediate endpoints have argued that those involved in the resuscitation have no …

Robustness Of Semiparametric Efficiency In Nearly-Correct Models For Two-Phase Samples, Thomas Lumley

UW Biostatistics Working Paper Series

Augmented inverse-probability weighted (AIPW) estimators for incomplete-data models typically do not have full semiparametric efficiency, but do have model-robustness properties not shared by the efficient estimator. We examine the performance of efficient and AIPW estimators when the complete-data model is nearly correctly specified, in the sense that the misspecification is not reliably detectable from the data by any possible diagnostic or test. Asymptotic results for these nearly true models are obtained by representing them as sequences of misspecified models that are mutually contiguous with a correctly specified model. For some least favorable direction of model misspecification the bias in the …

Nonparametric And Semiparametric Estimation Of The Three Way Receiver Operating Characteristic Surface, Jialiang Li, Xiao-Hua Zhou

UW Biostatistics Working Paper Series

In many situations the diagnostic decision is not limited to a binary choice. Binary statistical tools such as receiver operating characteristic (ROC) curve and area under the ROC curve (AUC) need to be expanded to address three-category classification problem. Previous authors have suggest various ways to model the extension of AUC but not the ROC surface. Only simple parametric approaches are proposed for modeling the ROC measure under the assumption that test results all follow normal distributions. We study the estimation methods of three dimensional ROC surfaces with nonparametric and semiparametric estimators. Asymptotical results are provided as a basis for …

Evaluating Markers For Treatment Selection Based On Survival Time, Xiao Song, Xiao-Hua Zhou

UW Biostatistics Working Paper Series

For many medical conditions several treatment options may be available for treating patients. We consider evaluating markers based on a simple treatment selection policy that incorporates information on the patient's marker value exceeding a threshold. For example, colon cancer patients may be treated by surgery alone or surgery plus chemotherapy. The c-myc gene expression level may be used as a biomarker for treatment selection. Although traditional regression methods may assess the effect of the marker and treatment on outcomes, it is appealing to quantify more directly the potential impact on the population of using the marker to select treatment. A …

Interval Estimation For The Difference In Paired Areas Under The Roc Curves In The Absence Of A Gold Standard Test, Hsin-Neng Hsieh, Hsiu-Yuan Su, Xiao-Hua Zhou

UW Biostatistics Working Paper Series

Receiver operating characteristic (ROC) curves can be used to assess the accuracy of tests measured on ordinal or continuous scales. The most commonly used measure for the overall diagnostic accuracy of diagnostic tests is the area under the ROC curve (AUC). A gold standard test on the true disease status is required to estimate the AUC. However, a gold standard test may sometimes be too expensive or infeasible. Therefore, in many medical research studies, the true disease status of the subjects may remain unknown. Under the normality assumption on test results from each disease group of subjects, using the expectation-maximization …

A Semi-Parametric Two-Part Mixed-Effects Heteroscedastic Transformation Model For Correlated Right-Skewed Semi-Continuous Data, Huazhen Lin, Xiao-Hua Zhou

UW Biostatistics Working Paper Series

In longitudinal or hierarchical structure studies, we often encounter a semi-continuous variable that has a certain proportion of a single value and a continuous and skewed distribution among the rest of values. In the paper, we propose a new semi-parametric two-part mixed-effects transformation model to fit correlated skewed semi-continuous data. In our model, we allow the transformation to be non-parametric. Fitting the proposed model faces computational challenges due to intractable numerical integrations. We derive the estimates for the parameter and the transformation function based on an approximate likelihood, which has high order accuracy but less computational burden. We also propose …

Semiparametric Two-Part Models With Proportionality Constraints: Analysis Of The Multi-Ethnic Study Of Atherosclerosis (Mesa), Anna Liu, Richard Kronmal, Xiao-Hua Zhou, Shuangge Ma

UW Biostatistics Working Paper Series

SUMMARY. In this article, we analyze the coronary artery calcium (CAC) score in the Multi-Ethnic Study of Atherosclerosis (MESA), where about half of the CAC scores are zero and the rest are continuously distributed. When the observed data has a mixture distribution, two-part models can be the natural choice. With a two-part model, there are two covariate effects, with one in each part of the model. Determination of whether the two covariate effects are proportional can provide more insights into the process underlying development and progression of CAC. In this study, we model the CAC score using a semiparametric two-part …

Pooled Nucleic Acid Testing To Identify Antiretroviral Treatment Failure During Hiv Infection, Susanne May, Anthony Gamst, Richard Haubrich, Constance Benson, Davey Smith

UW Biostatistics Working Paper Series

Abstract Background: Pooling strategies have been used to reduce the costs of polymerase chain reaction based screening for acute HIV infection in populations where the prevalence of acute infection is low (<1%). Only limited research has been done for conditions where the prevalence of screening positivity is higher (>1%). Methods and Results: We present data on a variety of pooling strategies that incorporate the use of PCR-based quantitative measures to monitor for virologic failure among HIV-infected patients receiving antiretroviral therapy. For a prevalence of virologic failure between 1% and 25%, we demonstrate relative efficiency and accuracy of various strategies. These results could be used to choose the best strategy based on the requirements of individual laboratory …

Synthesis Analysis Of Regression Models With A Continuous Outcome, Andrew Zhou, Nan Hu, Guizhou Hu, Martin Root

UW Biostatistics Working Paper Series

Synthesis Analysis of Regression Models with a Continuous Outcome Xiao-Hua Zhou 1,2, Nan Hu 2, Guizhou Hu3, and Martin Root3 1 HSR&D Center of Excellence, VA Puget Sound Health Care System, Seattle, WA 98101. 2 Department of Biostatistics, University of Washington, Seattle, WA 98195. 3 BioSignia, Inc., 1822 East NC Highway 54, Suite 350, Durham, NC 27713 To estimate the multivariate regression model from multiple individual studies, it would be challenging to obtain results if the input from individual studies only provide univariate or incomplete multivariate regression information. Samsa et al [1] proposed a simple method to combine coefficients from …

Using Longitudinal Data To Estimate The Effect Of Starting To Exercise On The Health Of Sedentary Older Adults, Paula Diehr, Calvin Hirsch

UW Biostatistics Working Paper Series

Background It is difficult to estimate the effect of exercise on future health from observational data because exercising may be both a cause and an effect of health status. Unadjusted analyses suffer from selection bias (healthier persons more likely to exercise), while adjusted analyses may adjust away some of the benefits of exercise.

Objective To obtain a "low-bias" interpretable estimate of the effect of exercise on future health.

Methods We used data from the Cardiovascular Health Study, a longitudinal study of 5,888 older adults. The number of blocks walked in the previous week, collected annually, were classified as Sedentary (less …

Semiparametric And Nonparametric Methods For Evaluating Risk Prediction Markers In Case-Control Studies, Ying Huang, Margaret Pepe

UW Biostatistics Working Paper Series

The performance of a well calibrated risk model, Risk(Y)=P(D=1|Y), can be characterized by the population distribution of Risk(Y) and displayed with the predictiveness curve. Better performance is characterized by a wider distribution of Risk(Y), since this corresponds to better risk stratification in the sense that more subjects are identified at low and high risk for the outcome D=1. Although methods have been developed to estimate predictiveness curves from cohort studies, most studies to evaluate novel risk prediction markers employ case-control designs. Here we develop semiparametric and nonparametric methods that accommodate case-control data and assume apriori knowledge of P(D=1). Large and …

Semiparametric Methods For Evaluating The Covariate-Specific Predictiveness Of Continuous Markers In Matched Case-Control Studies, Ying Huang, Margaret S. Pepe

UW Biostatistics Working Paper Series

To assess the value of a continuous marker in predicting the risk of a disease, a graphical tool called the predictiveness curve has been proposed. It characterizes the marker's predictiveness, or capacity to risk stratify the population by displaying the population distribution of risk endowed by the marker. Methods for making inference about the curve and for comparing curves in a general population have been developed. However, knowledge about a marker's performance in the general population only is not enough. Since a marker's effect on the risk model and its distribution can both differ across subpopulations, its predictiveness may vary …

Nonparametric Heteroscedastic Transformation Regression Models For Skewed Data With An Application To Health Care Costs, Xiao-Hua Zhou, Huazhen Lin, Eric Johnson

UW Biostatistics Working Paper Series

No abstract provided.