Statistics and Probability Commons^™

Prognosis Of Stage Ii Colon Cancer By Non-Neoplastic Mucosa Gene Expresssion Profiling, Alain Barrier, Sandrine Dudoit, Et Al.

U.C. Berkeley Division of Biostatistics Working Paper Series

Aims. This study assessed the possibility to build a prognosis predictor, based on non-neoplastic mucosa microarray gene expression measures, in stage II colon cancer patients. Materials and Methods. Non-neoplastic colonic mucosa mRNA samples from 24 patients (10 with a metachronous metastasis, 14 with no recurrence) were profiled using the Affymetrix HGU133A GeneChip. The k-nearest neighbor method was used for prognosis prediction using microarray gene expression measures. Leave-one-out cross-validation was used to select the number of neighbors and number of informative genes to include in the predictor. Based on this information, a prognosis predictor was proposed and its accuracy estimated by …

Colon Cancer Prognosis Prediction By Gene Expression Profiling, Alain Barrier, Sandrine Dudoit, Et Al.

U.C. Berkeley Division of Biostatistics Working Paper Series

Aims. This study assessed the possibility to build a prognosis predictor, based on microarray gene expression measures, in stage II and III colon cancer patients. Materials and Methods. Tumour (T) and non-neoplastic mucosa (NM) mRNA samples from 18 patients (9 with a recurrence, 9 with no recurrence) were profiled using the Affymetrix HGU133A GeneChip. The k-nearest neighbour method was used for prognosis prediction using T and NM gene expression measures. Six-fold cross-validation was applied to select the number of neighbours and the number of informative genes to include in the predictors. Based on this information, one T-based and one NM-based …

Multiple Imputation For Correcting Verification Bias, Ofer Harel, Xiao-Hua Zhou

UW Biostatistics Working Paper Series

In the case in which all subjects are screened using a common test, and only a subset of these subjects are tested using a golden standard test, it is well documented that there is a risk for bias, called verification bias. When the test has only two levels (e.g. positive and negative) and we are trying to estimate the sensitivity and specificity of the test, one is actually constructing a confidence interval for a binomial proportion. Since it is well documented that this estimation is not trivial even with complete data, we adopt Multiple imputation (MI) framework for verification bias …

A Comparison Of Parametric And Coarsened Bayesian Interval Estimation In The Presence Of A Known Mean-Variance Relationship, Kent Koprowicz, Scott S. Emerson, Peter Hoff

UW Biostatistics Working Paper Series

While the use of Bayesian methods of analysis have become increasingly common, classical frequentist hypothesis testing still holds sway in medical research - especially clinical trials. One major difference between a standard frequentist approach and the most common Bayesian approaches is that even when a frequentist hypothesis test is derived from parametric models, the interpretation and operating characteristics of the test may be considered in a distribution-free manner. Bayesian inference, on the other hand, is often conducted in a parametric setting where the interpretation of the results is dependent on the parametric model. Here we consider a Bayesian counterpart to …

Causal Inference In Longitudinal Studies With History-Restricted Marginal Structural Models, Romain Neugebauer, Mark J. Van Der Laan, Ira B. Tager

U.C. Berkeley Division of Biostatistics Working Paper Series

Causal Inference based on Marginal Structural Models (MSMs) is particularly attractive to subject-matter investigators because MSM parameters provide explicit representations of causal effects. We introduce History-Restricted Marginal Structural Models (HRMSMs) for longitudinal data for the purpose of defining causal parameters which may often be better suited for Public Health research. This new class of MSMs allows investigators to analyze the causal effect of a treatment on an outcome based on a fixed, shorter and user-specified history of exposure compared to MSMs. By default, the latter represents the treatment causal effect of interest based on a treatment history defined by the …

Application Of The Time-Dependent Roc Curves For Prognostic Accuracy With Multiple Biomarkers, Yingye Zheng, Tianxi Cai, Ziding Feng

UW Biostatistics Working Paper Series

The rapid advancement in molecule technology has lead to the discovery of many markers that have potential applications in disease diagnosis and prognosis. In a prospective cohort study, information on a panel of biomarkers as well as the disease status for a patient are routinely collected over time. Such information is useful to predict patients' prognosis and select patients for targeted therapy. In this paper, we develop procedures for constructing a composite test with optimal discrimination power when there are multiple markers available to assist in prediction and characterize the accuracy of the resulting test by extending the time-dependent receiver …

The Sensitivity And Specificity Of Markers For Event Times, Tianxi Cai, Margaret S. Pepe, Thomas Lumley, Yingye Zheng, Nancy Swords Jenny

Harvard University Biostatistics Working Paper Series

No abstract provided.

Survival Ensembles, Torsten Hothorn, Peter Buhlmann, Sandrine Dudoit, Annette M. Molinaro, Mark J. Van Der Laan

U.C. Berkeley Division of Biostatistics Working Paper Series

We propose a unified and flexible framework for ensemble learning in the presence of censoring. For right-censored data, we introduce a random forest algorithm and a generic gradient boosting algorithm for the construction of prognostic models. The methodology is utilized for predicting the survival time of patients suffering from acute myeloid leukemia based on clinical and genetic covariates. Furthermore, we compare the diagnostic capabilities of the proposed censored data random forest and boosting methods applied to the recurrence free survival time of node positive breast cancer patients with previously published findings.

The Bayesian Two-Sample T-Test, Mithat Gonen, Wesley O. Johnson, Yonggang Lu, Peter H. Westfall

Memorial Sloan-Kettering Cancer Center, Dept. of Epidemiology & Biostatistics Working Paper Series

In this article we show how the pooled-variance two-sample t-statistic arises from a Bayesian formulation of the two-sided point null testing problem, with emphasis on teaching. We identify a reasonable and useful prior giving a closed-form Bayes factor that can be written in terms of the distribution of the two-sample t-statistic under the null and alternative hypotheses respectively. This provides a Bayesian motivation for the two-sample t-statistic, which has heretofore been buried as a special case of more complex linear models, or given only roughly via analytic or Monte Carlo approximations. The resulting formulation of the Bayesian test is easy …

Nonparametric Estimation Of The Case Fatality Ratio With Competing Risks Data: An Application To Severe Acute Respiratory Syndome (Sars) , Nicholas P. Jewell, Xiudong Lei, A. C. Ghani, C. A. Donnelly, G. M. Leung, L. M. Ho, B. Cowling, A. J. Hedley

U.C. Berkeley Division of Biostatistics Working Paper Series

For diseases with some level of associated mortality, the case fatality ratio measures the proportion of diseased individuals who die from the disease. In principle, it is straightforward to estimate this quantity from individual follow-up data that provides times from onset to death or recovery. In particular, in a competing risks context, the case fatality ratio is defined by the limiting value of the sub-distribution function, associated with death, at infinity. When censoring is present, however, estimation of this quantity is complicated by the possibility of little information in the right tail of of the sub-distribution function, requiring use of …

Resampling Based Multiple Testing Procedure Controlling Tail Probability Of The Proportion Of False Positives, Mark J. Van Der Laan, Merrill D. Birkner, Alan E. Hubbard

U.C. Berkeley Division of Biostatistics Working Paper Series

Simultaneously testing a collection of null hypotheses about a data generating distribution based on a sample of independent and identically distributed observations is a fundamental and important statistical problem involving many applications. In this article we propose a new resampling based multiple testing procedure asymptotically controlling the probability that the proportion of false positives among the set of rejections exceeds q at level alpha, where q and alpha are user supplied numbers. The procedure involves 1) specifying a conditional distribution for a guessed set of true null hypotheses, given the data, which asymptotically is degenerate at the true set of …

New Confidence Intervals For The Difference Between Two Sensitivities At A Fixed Level Of Specificity, Gengsheng Qin, Yu-Sheng Hsu, Xiao-Hua Zhou

UW Biostatistics Working Paper Series

For two continuous-scale diagnostic tests, it is of interest to compare their sensitivities at a predetermined level of specificity. In this paper we propose three new intervals for the difference between two sensitivities at a fixed level of specificity. These intervals are easy to compute. We also conduct simulation studies to compare the relative performance of the new intervals with the existing normal approximation based interval proposed by Wieand et al (1989). Our simulation results show that the newly proposed intervals perform better than the existing normal approximation based interval in terms of coverage accuracy and interval length.

Frequentist Evaluation Of Group Sequential Clinical Trial Designs, Scott S. Emerson, John M. Kittelson, Daniel L. Gillen

UW Biostatistics Working Paper Series

Group sequential stopping rules are often used as guidelines in the monitoring of clinical trials in order to address the ethical and efficiency issues inherent in human testing of a new treatment or preventive agent for disease. Such stopping rules have been proposed based on a variety of different criteria, both scientific (e.g., estimates of treatment effect) and statistical (e.g., frequentist type I error, Bayesian posterior probabilities, stochastic curtailment). It is easily shown, however, that a stopping rule based on one of those criteria induces a stopping rule on all other criteria. Thus the basis used to initially define a …

Bayesian Evaluation Of Group Sequential Clinical Trial Designs, Scott S. Emerson, John M. Kittelson, Daniel L. Gillen

UW Biostatistics Working Paper Series

Clincal trial designs often incorporate a sequential stopping rule to serve as a guide in the early termination of a study. When choosing a particular stopping rule, it is most common to examine frequentist operating characteristics such as type I error, statistical power, and precision of confi- dence intervals (Emerson, et al. [1]). Increasingly, however, clinical trials are designed and analyzed in the Bayesian paradigm. In this paper we describe how the Bayesian operating characteristics of a particular stopping rule might be evaluated and communicated to the scientific community. In particular, we consider a choice of probability models and a …

On The Use Of Stochastic Curtailment In Group Sequential Clinical Trials, Scott S. Emerson, John M. Kittelson, Daniel L. Gillen

UW Biostatistics Working Paper Series

Many different criteria have been proposed for the selection of a stopping rule for group sequen- tial trials. These include both scientific (e.g., estimates of treatment effect) and statistical (e.g., frequentist type I error, Bayesian posterior probabilities, stochastic curtailment) measures of the evidence for or against beneficial treatment effects. Because a stopping rule based on one of those criteria induces a stopping rule on all other criteria, the utility of any particular scale relates to the ease with which it allows a clinical trialist to search for sequential sampling plans having de- sirable operating characteristics. In this paper we examine …

A Causal Inference Approach For Constructing Transcriptional Regulatory Networks, Biao Xing, Mark J. Van Der Laan

U.C. Berkeley Division of Biostatistics Working Paper Series

Transcriptional regulatory networks specify the interactions among regulatory genes and between regulatory genes and their target genes. Discovering transcriptional regulatory networks helps us to understand the underlying mechanism of complex cellular processes and responses. In this paper, we describe a causal inference approach for constructing transcriptional regulatory networks using gene expression data, promoter sequences and information on transcription factor binding sites. The method rst identies active transcription factors under each individual experiment using a feature selection approach similar to Bussemaker et al. (2001), Keles et al. (2002) and Conlon et al. (2003). Transcription factors are viewed as `treatments' and gene …

A Statistical Framework For The Analysis Of Microarray Probe-Level Data, Zhijin Wu, Rafael A. Irizarry

Johns Hopkins University, Dept. of Biostatistics Working Papers

Microarrays are an example of the powerful high through-put genomics tools that are revolutionizing the measurement of biological systems. In this and other technologies, a number of critical steps are required to convert the raw measures into the data relied upon by biologists and clinicians. These data manipulations, referred to as preprocessing, have enormous influence on the quality of the ultimate measurements and studies that rely upon them. Many researchers have previously demonstrated that the use of modern statistical methodology can substantially improve accuracy and precision of gene expression measurements, relative to ad-hoc procedures introduced by designers and manufacturers of …

Implementation Of Estimating-Function Based Inference Procedures With Mcmc Sampler, Lu Tian, Jun S. Liu, L. J. Wei

Harvard University Biostatistics Working Paper Series

No abstract provided.

Fixed-Width Output Analysis For Markov Chain Monte Carlo, Galin L. Jones, Murali Haran, Brian S. Caffo, Ronald Neath

Johns Hopkins University, Dept. of Biostatistics Working Papers

Markov chain Monte Carlo is a method of producing a correlated sample in order to estimate features of a complicated target distribution via simple ergodic averages. A fundamental question in MCMC applications is when should the sampling stop? That is, when are the ergodic averages good estimates of the desired quantities? We consider a method that stops the MCMC sampling the first time the width of a confidence interval based on the ergodic averages is less than a user-specified value. Hence calculating Monte Carlo standard errors is a critical step in assessing the output of the simulation. In particular, we …

Designs In Partially Controlled Studies: Messages From A Review, Fan Li, Constantine E. Frangakis

Johns Hopkins University, Dept. of Biostatistics Working Papers

The ability to evaluate effects of factors on outcomes is increasingly important for a class of studies that control some but not all of the factors. Although important advances have been made in methods of analysis for such partially controlled studies,work on designs for such studies has been relatively limited. To help understand why, we review main designs that have been used for such partially controlled studies. Based on the review, we give two complementary reasons that explain the limited work on such designs, and suggest a new direction in this area.

The Clustering Of Regression Models Method With Applications In Gene Expression Data, Li-Xuan Qin, Steven G. Self

UW Biostatistics Working Paper Series

Identification of differentially expressed genes and clustering of genes are two important and complementary objectives addressed with gene expression data. For the differential expression question, many "per-gene" analytic methods have been proposed. These methods can generally be characterized as using a regression function to independently model the observations for each gene; various adjustments for multiplicity are then used to interpret the statistical significance of these per-gene regression models over the collection of genes analyzed. Motivated by this common structure of per-gene models, we propose a new model-based clustering method -- the clustering of regression models method, which groups genes that …

Insights Into Latent Class Analysis, Margaret S. Pepe, Holly Janes

UW Biostatistics Working Paper Series

Latent class analysis is a popular statistical technique for estimating disease prevalence and test sensitivity and specificity. It is used when a gold standard assessment of disease is not available but results of multiple imperfect tests are. We derive analytic expressions for the parameter estimates in terms of the raw data, under the conditional independence assumption. These expressions indicate explicitly how observed two- and three-way associations between test results are used to infer disease prevalence and test operating characteristics. Although reasonable if the conditional independence model holds, the estimators have no basis when it fails. We therefore caution against using …

Standardizing Markers To Evaluate And Compare Their Performances, Margaret S. Pepe, Gary M. Longton

UW Biostatistics Working Paper Series

Introduction: Markers that purport to distinguish subjects with a condition from those without a condition must be evaluated rigorously for their classification accuracy. A single approach to statistically evaluating and comparing markers is not yet established.

Methods: We suggest a standardization that uses the marker distribution in unaffected subjects as a reference. For an affected subject with marker value Y, the standardized placement value is the proportion of unaffected subjects with marker values that exceed Y.

Results: We apply the standardization to two illustrative datasets. In patients with pancreatic cancer placement values calculated for the CA 19-9 marker are smaller …

Combining Predictors For Classification Using The Area Under The Roc Curve, Margaret S. Pepe, Tianxi Cai, Zheng Zhang, Gary M. Longton

UW Biostatistics Working Paper Series

No single biomarker for cancer is considered adequately sensitive and specific for cancer screening. It is expected that the results of multiple markers will need to be combined in order to yield adequately accurate classification. Typically the objective function that is optimized for combining markers is the likelihood function. In this paper we consider an alternative objective function -- the area under the empirical receiver operating characteristic curve (AUC). We note that it yields consistent estimates of parameters in a generalized linear model for the risk score but does not require specifying the link function. Like logistic regression it yields …

Cluster Analysis Of Genomic Data With Applications In R, Katherine S. Pollard, Mark J. Van Der Laan

U.C. Berkeley Division of Biostatistics Working Paper Series

In this paper, we provide an overview of existing partitioning and hierarchical clustering algorithms in R. We discuss statistical issues and methods in choosing the number of clusters, the choice of clustering algorithm, and the choice of dissimilarity matrix. In particular, we illustrate how the bootstrap can be employed as a statistical method in cluster analysis to establish the reproducibility of the clusters and the overall variability of the followed procedure. We also show how to visualize a clustering result by plotting ordered dissimilarity matrices in R. We present a new R package, hopach, which implements the hybrid clustering method, …

Multiple Testing Procedures And Applications To Genomics, Merrill D. Birkner, Katherine S. Pollard, Mark J. Van Der Laan, Sandrine Dudoit

U.C. Berkeley Division of Biostatistics Working Paper Series

This chapter proposes widely applicable resampling-based single-step and stepwise multiple testing procedures (MTP) for controlling a broad class of Type I error rates, in testing problems involving general data generating distributions (with arbitrary dependence structures among variables), null hypotheses, and test statistics (Dudoit and van der Laan, 2005; Dudoit et al., 2004a,b; van der Laan et al., 2004a,b; Pollard and van der Laan, 2004; Pollard et al., 2005). Procedures are provided to control Type I error rates defined as tail probabilities for arbitrary functions of the numbers of Type I errors, V_n, and rejected hypotheses, R_n. These error rates include: …

Robust Inferences For Covariate Effects On Survival Time With Censored Linear Regression Models, Larry Leon, Tianxi Cai, L. J. Wei

Harvard University Biostatistics Working Paper Series

Various inference procedures for linear regression models with censored failure times have been studied extensively. Recent developments on efficient algorithms to implement these procedures enhance the practical usage of such models in survival analysis. In this article, we present robust inferences for certain covariate effects on the failure time in the presence of "nuisance" confounders under a semiparametric, partial linear regression setting. Specifically, the estimation procedures for the regression coefficients of interest are derived from a working linear model and are valid even when the function of the confounders in the model is not correctly specified. The new proposals are …

Estimating Percentile-Specific Causal Effects: A Case Study Of Micronutrient Supplementation, Birth Weight, And Infant Mortality, Francesca Dominici, Scott L. Zeger, Giovanni Parmigiani, Joanne Katz, Parul Christian

Johns Hopkins University, Dept. of Biostatistics Working Papers

In developing countries, higher infant mortality is partially caused by poor maternal and fetal nutrition. Clinical trials of micronutrient supplementation are aimed at reducing the risk of infant mortality by increasing birth weight. Because infant mortality is greatest among the low birth weight infants (LBW) (• 2500 grams), an effective intervention may need to increase the birth weight among the smallest babies. Although it has been demonstrated that supplementation increases the birth weight in a trial conducted in Nepal, there is inconclusive evidence that the supplementation improves their survival. It has been hypothesized that a potential benefit of the treatment …

A Hybrid Newton-Type Method For The Linear Regression In Case-Cohort Studies, Menggang Yu, Bin Nan

The University of Michigan Department of Biostatistics Working Paper Series

Case-cohort designs are increasingly commonly used in large epidemiological cohort studies. Nan, Yu, and Kalbeisch (2004) provided the asymptotic results for censored linear regression models in case-cohort studies. In this article, we consider computational aspects of their proposed rank based estimating methods. We show that the rank based discontinuous estimating functions for case-cohort studies are monotone, a property established for cohort data in the literature, when generalized Gehan type of weights are used. Though the estimating problem can be formulated to a linear programming problem as that for cohort data, due to its easily uncontrollable large scale even for a …

Multiple Testing Procedures For Controlling Tail Probability Error Rates, Sandrine Dudoit, Mark J. Van Der Laan, Merrill D. Birkner

U.C. Berkeley Division of Biostatistics Working Paper Series

The present article discusses and compares multiple testing procedures (MTP) for controlling Type I error rates defined as tail probabilities for the number (gFWER) and proportion (TPPFP) of false positives among the rejected hypotheses. Specifically, we consider the gFWER- and TPPFP-controlling MTPs proposed recently by Lehmann & Romano (2004) and in a series of four articles by Dudoit et al. (2004), van der Laan et al. (2004b,a), and Pollard & van der Laan (2004). The former Lehmann & Romano (2004) procedures are marginal, in the sense that they are based solely on the marginal distributions of the test statistics, i.e., …