MedWorm.com provides a medical RSS filtering service. Over 6000 RSS medical sources are combined and output via different filters. This feed contains the latest items from the 'Biostatistics' source. Thu, 18 Mar 2010 16:39:20 +0100 http://www.medworm.com/index.php?rid=3321942&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F11%2F2%2F373%3Frss%3D1 When analyzing a 2 x 2 table, the two-sided Fisher's exact test and the usual exact confidence interval (CI) for the odds ratio may give conflicting inferences; for example, the test rejects but the associated CI contains an odds ratio of 1. The problem is that the usual exact CI is the inversion of the test that rejects if either of the one-sided Fisher's exact tests rejects at half the nominal significance level. Further, the confidence set that is the inversion of the usual two-sided Fisher's exact test may not be an interval, so following Blaker (2000, Confidence curves and improved exact confidence intervals for discrete distributions. Canadian Journal of Statistics 28, 783–798), we define the "matching" interval as the smallest interval that contains the confidence set. We expl... Biostatistics journals http://www.medworm.com/rss/comments.php?id=3321942 Tue, 02 Mar 2010 08:05:32 +0100 3321942 http://www.medworm.com/index.php?rid=3321941&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F11%2F2%2F353%3Frss%3D1 Most investigations in the social and health sciences aim to understand the directional or causal relationship between a treatment or risk factor and outcome. Given the multitude of pathways through which the treatment or risk factor may affect the outcome, there is also an interest in decomposing the effect of a treatment of risk factor into "direct" and "mediated" effects. For example, child's socioeconomic status (risk factor) may have a direct effect on the risk of death (outcome) and an effect that may be mediated through the adulthood socioeconomic status (mediator). Building on the potential outcome framework for causal inference, we develop a Bayesian approach for estimating direct and mediated effects in the context of a dichotomous mediator and dichotomous outcome, which is chall... Biostatistics journals http://www.medworm.com/rss/comments.php?id=3321941 Tue, 02 Mar 2010 08:05:32 +0100 3321941 http://www.medworm.com/index.php?rid=3321940&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F11%2F2%2F337%3Frss%3D1 Quantile regression has emerged as a useful supplement to ordinary mean regression. Traditional frequentist quantile regression makes very minimal assumptions on the form of the error distribution and thus is able to accommodate nonnormal errors, which are common in many applications. However, inference for these models is challenging, particularly for clustered or censored data. A Bayesian approach enables exact inference and is well suited to incorporate clustered, missing, or censored data. In this paper, we propose a flexible Bayesian quantile regression model. We assume that the error distribution is an infinite mixture of Gaussian densities subject to a stochastic constraint that enables inference on the quantile of interest. This method outperforms the traditional frequentist method... Biostatistics journals http://www.medworm.com/rss/comments.php?id=3321940 Tue, 02 Mar 2010 08:05:32 +0100 3321940 http://www.medworm.com/index.php?rid=3321939&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F11%2F2%2F317%3Frss%3D1 Skew-normal and skew-t distributions have proved to be useful for capturing skewness and kurtosis in data directly without transformation. Recently, finite mixtures of such distributions have been considered as a more general tool for handling heterogeneous data involving asymmetric behaviors across subpopulations. We consider such mixture models for both univariate as well as multivariate data. This allows robust modeling of high-dimensional multimodal and asymmetric data generated by popular biotechnological platforms such as flow cytometry. We develop Bayesian inference based on data augmentation and Markov chain Monte Carlo (MCMC) sampling. In addition to the latent allocations, data augmentation is based on a stochastic representation of the skew-normal distribution in terms of a rand... Biostatistics journals http://www.medworm.com/rss/comments.php?id=3321939 Tue, 02 Mar 2010 08:05:32 +0100 3321939 http://www.medworm.com/index.php?rid=3321938&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F11%2F2%2F304%3Frss%3D1 Continuous-time Markov processes are frequently used to describe the evolution of a disease over different phases. Such modeling can provide estimates for important parameters that are defined on the paths of the process. A simple example is the mean first hitting time to a set of states. However, more interesting events are defined by several time points such as the first time the process stays in state j for at least time units. These kinds of events are very important in relapsing–remitting diseases such as in multiple sclerosis (MS) where the focus is on a sustained worsening that lasts 6 months or longer. The current paper considers data on independent continuous Markov processes that are only observed intermittently. It reviews modeling and estimation, presents a new general co... Biostatistics journals http://www.medworm.com/rss/comments.php?id=3321938 Tue, 02 Mar 2010 08:05:32 +0100 3321938 http://www.medworm.com/index.php?rid=3321937&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F11%2F2%2F290%3Frss%3D1 The competing risks illness–death model describes the dynamics of healthy subjects who may move to an "illness" state before entering into one of several competing terminal states. A motivating example concerns patients in a hospital who may acquire infections during their stay, where the competing terminal states are discharged alive and death in the hospital. We consider a cross-sectional sampling of independent competing risks illness–death processes in which data are subject to length bias and censoring and develop estimators for functionals of the underlying distribution such as the joint probability of the terminal state and illness (infection) and cumulative incidence functions. We apply the methodology to infection data obtained in a cross-sectional study of patients ho... Biostatistics journals http://www.medworm.com/rss/comments.php?id=3321937 Tue, 02 Mar 2010 08:05:32 +0100 3321937 http://www.medworm.com/index.php?rid=3321936&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F11%2F2%2F281%3Frss%3D1 The main purpose of microarray studies is screening to identify differentially expressed genes as candidates for further investigation. Because of limited resources in this stage, prioritizing or ranking genes is a relevant statistical task in microarray studies. In this article, we develop 3 empirical Bayes methods for gene ranking on the basis of differential expression, using hierarchical mixture models. These methods are based on (i) minimizing mean squared errors of estimation for parameters, (ii) minimizing mean squared errors of estimation for ranks of parameters, and (iii) maximizing sensitivity in selecting prespecified numbers of differential genes, with the largest effect. Our methods incorporate the mixture structures of differential and nondifferential components in empirical ... Biostatistics journals http://www.medworm.com/rss/comments.php?id=3321936 Tue, 02 Mar 2010 08:05:32 +0100 3321936 http://www.medworm.com/index.php?rid=3321935&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F11%2F2%2F265%3Frss%3D1 Array comparative genomic hybridization (aCGH) is a microarray technology that allows one to detect and map genomic alterations. The goal of aCGH analysis is to identify the boundaries of the regions where the number of DNA copies changes (breakpoint identification) and then to label each region as loss, neutral, or gain (calling). In this paper, we introduce a new algorithm, based on the shifting level model (SLM), with the aim of locating regions with different means of the log2 ratio in genomic profiles obtained from aCGH data. We combine the SLM algorithm with the CGHcall calling procedure and compare their performances with 5 state-of-the-art methods. When dealing with synthetic data, our method outperforms the other 5 algorithms in detecting the change in the number of DNA copies in ... Biostatistics journals http://www.medworm.com/rss/comments.php?id=3321935 Tue, 02 Mar 2010 08:05:32 +0100 3321935 http://www.medworm.com/index.php?rid=3321934&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F11%2F2%2F254%3Frss%3D1 Microarray experiments provide data on the expression levels of thousands of genes and, therefore, statistical methods applicable to the analysis of such high-dimensional data are needed. In this paper, we propose robust nonparametric tools for the description and analysis of microarray data based on the concept of functional depth, which measures the centrality of an observation within a sample. We show that this concept can be easily adapted to high-dimensional observations and, in particular, to gene expression data. This allows the development of the following depth-based inference tools: (1) a scale curve for measuring and visualizing the dispersion of a set of points, (2) a rank test for deciding if 2 groups of multidimensional observations come from the same population, and (3) supe... Biostatistics journals http://www.medworm.com/rss/comments.php?id=3321934 Tue, 02 Mar 2010 08:05:32 +0100 3321934 http://www.medworm.com/index.php?rid=3321933&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F11%2F2%2F242%3Frss%3D1 Robust multiarray analysis (RMA) is the most widely used preprocessing algorithm for Affymetrix and Nimblegen gene expression microarrays. RMA performs background correction, normalization, and summarization in a modular way. The last 2 steps require multiple arrays to be analyzed simultaneously. The ability to borrow information across samples provides RMA various advantages. For example, the summarization step fits a parametric model that accounts for probe effects, assumed to be fixed across arrays, and improves outlier detection. Residuals, obtained from the fitted model, permit the creation of useful quality metrics. However, the dependence on multiple arrays has 2 drawbacks: (1) RMA cannot be used in clinical settings where samples must be processed individually or in small batches a... Biostatistics journals http://www.medworm.com/rss/comments.php?id=3321933 Tue, 02 Mar 2010 08:05:32 +0100 3321933 http://www.medworm.com/index.php?rid=3321932&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F11%2F2%2F226%3Frss%3D1 Accurate knowledge of the null distribution of hypothesis tests is important for valid application of the tests. In previous papers and software, the asymptotic null distribution of likelihood ratio tests for detecting genetic linkage in multivariate variance components models has been stated to be a mixture of chi-square distributions with binomial mixing probabilities. For variance components models under the complete pleiotropy assumption, we show by simulation and by theoretical arguments based on the geometry of the parameter space that all aspects of the previously stated asymptotic null distribution are incorrect—both the binomial mixing probabilities and the chi-square components. Correcting the null distribution gives more conservative critical values than previously stated,... Biostatistics journals http://www.medworm.com/rss/comments.php?id=3321932 Tue, 02 Mar 2010 08:05:32 +0100 3321932 http://www.medworm.com/index.php?rid=3321931&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F11%2F2%2F213%3Frss%3D1 We develop a locally efficient test for (multiplicative) gene–environment interaction in family studies that collect genotypic information and environmental exposures for affected offspring along with genotypic information for their parents or relatives. The proposed test does not require modeling the effects of environmental exposures and is doubly robust in the sense of being valid if either a model for the main genetic effect holds or a model for the expected environmental exposure (given the offspring affection status and parental mating types) but not necessarily both. It extends the FBAT-I to allow for missing parental mating types and families of arbitrary size. Simulation studies and the analysis of an Alzheimer's disease study confirm the adequate performance of the proposed... Biostatistics journals http://www.medworm.com/rss/comments.php?id=3321931 Tue, 02 Mar 2010 08:05:32 +0100 3321931 http://www.medworm.com/index.php?rid=3321930&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F11%2F2%2F195%3Frss%3D1 Boosting is an important tool in classification methodology. It combines the performance of many weak classifiers to produce a powerful committee, and its validity can be explained by additive modeling and maximum likelihood. The method has very general applications, especially for high-dimensional predictors. For example, it can be applied to distinguish cancer samples from healthy control samples by using antibody microarray data. Microarray data are often high-dimensional and many of them are incomplete. One natural idea is to impute a missing variable based on the observed predictors. However, the calculation of imputation for high-dimensional predictors with missing data may be rather tedious. In this paper, we propose 2 conditional mean imputation methods. They can be applied to the ... Biostatistics journals http://www.medworm.com/rss/comments.php?id=3321930 Tue, 02 Mar 2010 08:05:32 +0100 3321930 http://www.medworm.com/index.php?rid=3321929&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F11%2F2%2F177%3Frss%3D1 We propose a new methodological framework for the analysis of hierarchical functional data when the functions at the lowest level of the hierarchy are correlated. For small data sets, our methodology leads to a computational algorithm that is orders of magnitude more efficient than its closest competitor (seconds versus hours). For large data sets, our algorithm remains fast and has no current competitors. Thus, in contrast to published methods, we can now conduct routine simulations, leave-one-out analyses, and nonparametric bootstrap sampling. Our methods are inspired by and applied to data obtained from a state-of-the-art colon carcinogenesis scientific experiment. However, our models are general and will be relevant to many new data sets where the object of inference are functions or i... Biostatistics journals http://www.medworm.com/rss/comments.php?id=3321929 Tue, 02 Mar 2010 08:05:32 +0100 3321929 http://www.medworm.com/index.php?rid=3100236&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F11%2F1%2F176%3Frss%3D1 (Source: Biostatistics) Biostatistics journals http://www.medworm.com/rss/comments.php?id=3100236 Thu, 17 Dec 2009 17:19:24 +0100 3100236 http://www.medworm.com/index.php?rid=3100235&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F11%2F1%2F164%3Frss%3D1 High-throughput oligonucleotide microarrays are commonly employed to investigate genetic disease, including cancer. The algorithms employed to extract genotypes and copy number variation function optimally for diploid genomes usually associated with inherited disease. However, cancer genomes are aneuploid in nature leading to systematic errors when using these techniques. We introduce a preprocessing transformation and hidden Markov model algorithm bespoke to cancer. This produces genotype classification, specification of regions of loss of heterozygosity, and absolute allelic copy number segmentation. Accurate prediction is demonstrated with a combination of independent experimental techniques. These methods are exemplified with affymetrix genome-wide SNP6.0 data from 755 cancer cell line... Biostatistics journals http://www.medworm.com/rss/comments.php?id=3100235 Thu, 17 Dec 2009 17:19:24 +0100 3100235 http://www.medworm.com/index.php?rid=3100234&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F11%2F1%2F151%3Frss%3D1 Before a comparative diagnostic trial is carried out, maximum sample sizes for the diseased group and the nondiseased group need to be obtained to achieve a nominal power to detect a meaningful difference in diagnostic accuracy. Sample size calculation depends on the variance of the statistic of interest, which is the difference between receiver operating characteristic summary measures of 2 medical diagnostic tests. To obtain an appropriate value for the variance, one often has to assume an arbitrary parametric model and the associated parameter values for the 2 groups of subjects under 2 tests to be compared. It becomes more tedious to do so when the same subject undergoes 2 different tests because the correlation is then involved in modeling the test outcomes. The calculated variance ba... Biostatistics journals http://www.medworm.com/rss/comments.php?id=3100234 Thu, 17 Dec 2009 17:19:24 +0100 3100234 http://www.medworm.com/index.php?rid=3100233&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F11%2F1%2F139%3Frss%3D1 Genome-wide association studies (GWAS) are increasingly utilized for identifying novel susceptible genetic variants for complex traits, but there is little consensus on analysis methods for such data. Most commonly used methods include single single nucleotide polymorphism (SNP) analysis or haplotype analysis with Bonferroni correction for multiple comparisons. Since the SNPs in typical GWAS are often in linkage disequilibrium (LD), at least locally, Bonferroni correction of multiple comparisons often leads to conservative error control and therefore lower statistical power. In this paper, we propose a hidden Markov random field model (HMRF) for GWAS analysis based on a weighted LD graph built from the prior LD information among the SNPs and an efficient iterative conditional mode algorith... Biostatistics journals http://www.medworm.com/rss/comments.php?id=3100233 Thu, 17 Dec 2009 17:19:24 +0100 3100233 http://www.medworm.com/index.php?rid=3100232&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F11%2F1%2F127%3Frss%3D1 Longitudinal data with binary and ordinal outcomes routinely appear in medical applications. Existing methods are typically designed to deal with short measurement series. In contrast, modern longitudinal data can result in large numbers of subject-specific serial observations. In this framework, we consider multivariate probit models with random effects to capture heterogeneity and autoregressive terms for describing the serial dependence. Since likelihood inference for the proposed class of models is computationally burdensome because of high-dimensional intractable integrals, a pseudolikelihood approach is followed. The methodology is motivated by the analysis of a large longitudinal study on the determinants of migraine severity. (Source: Biostatistics) Biostatistics journals http://www.medworm.com/rss/comments.php?id=3100232 Thu, 17 Dec 2009 17:19:24 +0100 3100232 http://www.medworm.com/index.php?rid=3100231&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F11%2F1%2F111%3Frss%3D1 In epidemiological and clinical studies, time-to-event data often violate the assumptions of Cox regression due to the presence of time-dependent covariate effects and unmeasured risk factors. An alternative approach, which does not require proportional hazards, is to use a first hitting time model which treats a subject's health status as a latent stochastic process that fails when it reaches a threshold value. Although more flexible than Cox regression, existing methods do not account for unmeasured covariates in both the initial state and the rate of the process. To address this issue, we propose a Bayesian methodology that models an individual's health status as a Wiener process with subject-specific initial state and drift. Posterior inference proceeds via a Markov chain Monte Carlo m... Biostatistics journals http://www.medworm.com/rss/comments.php?id=3100231 Thu, 17 Dec 2009 17:19:23 +0100 3100231 http://www.medworm.com/index.php?rid=3100230&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F11%2F1%2F93%3Frss%3D1 Dropout is a common occurrence in longitudinal studies. Building upon the pattern-mixture modeling approach within the Bayesian paradigm, we propose a general framework of varying-coefficient models for longitudinal data with informative dropout, where measurement times can be irregular and dropout can occur at any point in continuous time (not just at observation times) together with administrative censoring. Specifically, we assume that the longitudinal outcome process depends on the dropout process through its model parameters. The unconditional distribution of the repeated measures is a mixture over the dropout (administrative censoring) time distribution, and the continuous dropout time distribution with administrative censoring is left completely unspecified. We use Markov chain Mont... Biostatistics journals http://www.medworm.com/rss/comments.php?id=3100230 Thu, 17 Dec 2009 17:19:23 +0100 3100230 http://www.medworm.com/index.php?rid=3100229&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F11%2F1%2F82%3Frss%3D1 Bandeen-Roche and Liang (2002, Modelling multivariate failure time associations in the presence of a competing risk. Biometrika 89, 299–314.) tailored Oakes (1989, Bivariate survival models induced by frailties. Journal of the American Statistical Association 84, 487–493.)'s conditional hazard ratio to evaluate cause-specific associations in bivariate competing risks data. In many population-based family studies, one observes complex multivariate competing risks data, where the family sizes may be > 2, certain marginals may be exchangeable, and there may be multiple correlated relative pairs having a given pairwise association. Methods for bivariate competing risks data are inadequate in these settings. We show that the rank correlation estimator of Bandeen-Roche and Liang (... Biostatistics journals http://www.medworm.com/rss/comments.php?id=3100229 Thu, 17 Dec 2009 17:19:23 +0100 3100229 http://www.medworm.com/index.php?rid=3100228&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F11%2F1%2F70%3Frss%3D1 Genome-wide association studies (GWAS) have become the method of choice for investigating the genetic basis of common diseases and complex traits. The immense scale of these experiments is unprecedented, involving thousands of samples and up to a million variables. The careful execution of exploratory data analysis (EDA) prior to the actual genotype–phenotype association analysis is crucial as this identifies problematic samples and poorly assayed genetic polymorphisms that, if undetected, can compromise the outcome of the experiment. EDA of such large-scale genetic data sets thus requires specialized numerical and graphical strategies, and this article provides a review of the current exploratory tools commonly used in GWAS. (Source: Biostatistics) Biostatistics journals http://www.medworm.com/rss/comments.php?id=3100228 Thu, 17 Dec 2009 17:19:23 +0100 3100228 http://www.medworm.com/index.php?rid=3100227&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F11%2F1%2F57%3Frss%3D1 Age–period–cohort (APC) models are frequently used to analyze mortality or morbidity rates stratified by age group and period. For the case in which rates are given in different strata, multivariate APC models have been considered only recently. Such models share a set of parameters, for example, the age effects, while the other parameters may vary across strata. We show that differences of strata-specific effects are identifiable. We then propose a Bayesian approach based on smoothing priors to estimate multivariate APC models. This provides an alternative to maximum likelihood (ML) estimates of relative risk in the case of equal intervals and gives useful results even in the case of unequal intervals, where ML estimates have severe artifacts. This is illustrated with data on ... Biostatistics journals http://www.medworm.com/rss/comments.php?id=3100227 Thu, 17 Dec 2009 17:19:23 +0100 3100227 http://www.medworm.com/index.php?rid=3100226&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F11%2F1%2F48%3Frss%3D1 Genetic data collected from surveys such as the Third National Health and Nutrition Examination Survey (NHANES III) enable researchers to investigate the association between wide varieties of health factors and genetic variation for the US population. Tests for trend in disease with increasing number of alleles have been developed for simple random samples. However, surveys such as the NHANES III have complex sample designs involving multistage cluster sampling and sample weighting. These types of sample designs can affect Type I error and power properties of statistical tests based on simple random samples. In order to address these issues, we have derived tests of trend based on Wald and quasi-score statistics, with and without assuming a genetic model, that account for the complex sampl... Biostatistics journals http://www.medworm.com/rss/comments.php?id=3100226 Thu, 17 Dec 2009 17:19:23 +0100 3100226 http://www.medworm.com/index.php?rid=3100225&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F11%2F1%2F34%3Frss%3D1 In the past decade, several principal stratification–based statistical methods have been developed for testing and estimation of a treatment effect on an outcome measured after a postrandomization event. Two examples are the evaluation of the effect of a cancer treatment on quality of life in subjects who remain alive and the evaluation of the effect of an HIV vaccine on viral load in subjects who acquire HIV infection. However, in general the developed methods have not addressed the issue of missing outcome data, and hence their validity relies on a missing completely at random (MCAR) assumption. Because in many applications the MCAR assumption is untenable, while a missing at random (MAR) assumption is defensible, we extend the semiparametric likelihood sensitivity analysis approac... Biostatistics journals http://www.medworm.com/rss/comments.php?id=3100225 Thu, 17 Dec 2009 17:19:23 +0100 3100225 http://www.medworm.com/index.php?rid=3100224&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F11%2F1%2F18%3Frss%3D1 This article is focused on discovering the functional diversification within a protein family. A Bayesian mixture approach is proposed to model a protein family as a mixture of profile hidden Markov models. For a given mixture size, a hybrid Markov chain Monte Carlo sampler comprising both Gibbs sampling steps and hierarchical clustering–based split/merge proposals is used to obtain posterior inference. Inference for mixture size concentrates on comparing the integrated likelihoods. The choice of priors is critical with respect to the performance of the procedure. Through simulation studies, we show that 2 priors that are based on independent data sets allow correct identification of the mixture size, both when the data are homogeneous and when the data are generated from a mixture. ... Biostatistics journals http://www.medworm.com/rss/comments.php?id=3100224 Thu, 17 Dec 2009 17:19:23 +0100 3100224 http://www.medworm.com/index.php?rid=3100223&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F11%2F1%2F1%3Frss%3D1 It is our experience that in many settings, crossover trials that have within-period baseline measurements are analyzed wrongly. A "conventional" analysis of covariance in this setting uses each baseline as a covariate for the following outcome variable in the same period but not for any other outcome. If used with random subject effects such an analysis leads to biased treatment comparisons; this is an example of cross-level bias. Using a postulated covariance structure that reflects the symmetry of the crossover setting, we quantify such bias and, at the same time, investigate potential gains and losses in efficiency through the use of the baselines. We then describe alternative methods of analysis that avoid the cross-level bias. The development is illustrated throughout with 2 example ... Biostatistics journals http://www.medworm.com/rss/comments.php?id=3100223 Thu, 17 Dec 2009 17:19:23 +0100 3100223 http://www.medworm.com/index.php?rid=2788379&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F4%2F808%3Frss%3D1 (Source: Biostatistics) Biostatistics journals http://www.medworm.com/rss/comments.php?id=2788379 Thu, 10 Sep 2009 23:00:00 +0100 2788379 http://www.medworm.com/index.php?rid=2788378&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F4%2F806%3Frss%3D1 (Source: Biostatistics) Biostatistics journals http://www.medworm.com/rss/comments.php?id=2788378 Thu, 10 Sep 2009 23:00:00 +0100 2788378 http://www.medworm.com/index.php?rid=2788377&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F4%2F792%3Frss%3D1 In mixed treatment comparison (MTC) meta-analysis, modeling the heterogeneity in between-trial variances across studies is a difficult problem because of the constraints on the variances inherited from the MTC structure. Starting from a consistent Bayesian hierarchical model for the mean treatment effects, we represent the variance configuration by a set of triangle inequalities on the standard deviations. We take the separation strategy (Barnard and others, 2000) to specify prior distributions for standard deviations and correlations separately. The covariance matrix of the latent treatment arm effects can be employed as a vehicle to load the triangular constraints, which in addition allows incorporation of prior beliefs about the correlations between treatment effects. The spherical para... Biostatistics journals http://www.medworm.com/rss/comments.php?id=2788377 Thu, 10 Sep 2009 23:00:00 +0100 2788377 http://www.medworm.com/index.php?rid=2788376&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F4%2F779%3Frss%3D1 The objective is to make inference for the infection rate parameters in the underlying model of disease transmission. The principal challenge is that the required likelihood of the data is intractable in all but the simplest cases. Demiris and O'Neill (2005b) used data augmentation methods involving a certain random graph in a Markov chain Monte Carlo setting to address this situation in the special case where the sample is the same as the entire population. Here, we take an approach relying on broadly similar principles, but for which the implementation details are markedly different. Specifically, to cover the general case of sample data, we use an alternative data augmentation scheme and employ noncentering methods. The methods are illustrated using data from an influenza outbreak. (Sou... Biostatistics journals http://www.medworm.com/rss/comments.php?id=2788376 Thu, 10 Sep 2009 23:00:00 +0100 2788376 http://www.medworm.com/index.php?rid=2788375&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F4%2F773%3Frss%3D1 The number of copies of DNA in human cells can be measured using array comparative genomic hybridization (aCGH), which provides intensity ratios of sample to reference DNA at genomic locations corresponding to probes on a microarray. In the present paper, we devise a statistical model, based on a latent continuous-index Markov jump process, that is aimed to capture certain features of aCGH data, including probes that are unevenly long, unevenly spaced, and overlapping. The model has a continuous state space, with 1 state representing a normal copy number of 2, and the rest of the states being either amplifications or deletions. We adopt a Bayesian approach and apply Markov chain Monte Carlo (MCMC) methods for estimating the parameters and the Markov process. The model can be applied to dat... Biostatistics journals http://www.medworm.com/rss/comments.php?id=2788375 Thu, 10 Sep 2009 23:00:00 +0100 2788375 http://www.medworm.com/index.php?rid=2788374&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F4%2F756%3Frss%3D1 We present methods of estimating the baseline marginal distributions, covariate effects, and association parameters for clustered current status data based on second-order generalized estimating equations. We examine the efficiency gains realized from using second-order estimating equations compared with first-order equations, issues of copula misspecification, and apply the methods to motivating studies including one on the incidence of joint damage in patients with psoriatic arthritis. (Source: Biostatistics) Biostatistics journals http://www.medworm.com/rss/comments.php?id=2788374 Thu, 10 Sep 2009 23:00:00 +0100 2788374 http://www.medworm.com/index.php?rid=2788373&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F4%2F744%3Frss%3D1 A mixed model framework is presented to model the characteristic multivariate binary anomaly data as provided in some teratology studies. The key features of the model are the incorporation of covariate effects, a flexible random effects distribution by means of a finite mixture, and the application of copula functions to better account for the relation structure of the anomalies. The framework is motivated by data of the Boston Anticonvulsant Teratogenesis study and offers an integrated approach to investigate substantive questions, concerning general and anomaly-specific exposure effects of covariates, interrelations between anomalies, and objective diagnostic measurement. (Source: Biostatistics) Biostatistics journals http://www.medworm.com/rss/comments.php?id=2788373 Thu, 10 Sep 2009 23:00:00 +0100 2788373 http://www.medworm.com/index.php?rid=2788372&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F4%2F729%3Frss%3D1 Interval-censored longitudinal data taken from a Norwegian study of individuals with Parkinson's disease are investigated with respect to the onset of dementia. Of interest are risk factors for dementia and the subdivision of total life expectancy (LE) into LE with and without dementia. To estimate LEs using extrapolation, a parametric continuous-time 3-state illness–death Markov model is presented in a Bayesian framework. The framework is well suited to allow for heterogeneity via random effects and to investigate additional computation using model parameters. In the estimation of LEs, microsimulation is used to take into account random effects. Intensities of moving between the states are allowed to change in a piecewise-constant fashion by linking them to age as a time-dependent c... Biostatistics journals http://www.medworm.com/rss/comments.php?id=2788372 Thu, 10 Sep 2009 23:00:00 +0100 2788372 http://www.medworm.com/index.php?rid=2788371&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F4%2F719%3Frss%3D1 Leptospirosis is the most widespread zoonosis throughout the world and human mortality from severe disease forms is high even when optimal treatment is provided. Leptospirosis is also one of the most common causes of reproductive losses in cattle worldwide and is associated with significant economic costs to the dairy farming industry. Herds are tested for exposure to the causal organism either through serum testing of individual animals or through testing bulk milk samples. Using serum results from a commonly used enzyme-linked immunosorbent assay (ELISA) test for Leptospira interrogans serovar Hardjo (L. hardjo) on samples from 979 animals across 12 Scottish dairy herds and the corresponding bulk milk results, we develop a model that predicts the mean proportion of exposed animals in a h... Biostatistics journals http://www.medworm.com/rss/comments.php?id=2788371 Thu, 10 Sep 2009 23:00:00 +0100 2788371 http://www.medworm.com/index.php?rid=2788370&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F4%2F706%3Frss%3D1 Network reconstruction is a main goal of many biological endeavors. Graphical Gaussian models (GGMs) are often used since the underlying assumptions are well understood, the graph is readily estimated by calculating the partial correlation (paCor) matrix, and its interpretation is straightforward. In spite of these advantages, GGMs are limited in that interactions are not accommodated as the underlying multivariate normality assumption allows for linear dependencies only. As we show, when applied in the presence of interactions, the GGM framework can lead to incorrect inference regarding dependence. Identifying the exact dependence structure in this context is a difficult problem, largely because an analogue of the paCor matrix is not available and dependencies can involve many nodes. We h... Biostatistics journals http://www.medworm.com/rss/comments.php?id=2788370 Thu, 10 Sep 2009 23:00:00 +0100 2788370 http://www.medworm.com/index.php?rid=2788369&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F4%2F694%3Frss%3D1 The false discovery proportion (FDP), the proportion of false rejections among all rejections, provides useful criteria for controlling false positives in multiple testing to detect differential genes in microarray experiments. Owing to a substantial variability in FDP for correlated genes, some authors considered controlling actual FDP, instead of its expectation, that is false discovery rate, in multiple testing. However, there has been no attempt to do this in the design of microarray experiments. In this article, we develop a procedure for sample size calculation to control the distributions of FDP and true positives simultaneously under blockwise correlation structures among genes. The sizes of gene blocks, correlation coefficients, and effect sizes within gene blocks can vary across ... Biostatistics journals http://www.medworm.com/rss/comments.php?id=2788369 Thu, 10 Sep 2009 23:00:00 +0100 2788369 http://www.medworm.com/index.php?rid=2788368&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F4%2F680%3Frss%3D1 Association studies have been widely used to identify genetic liability variants for complex diseases. While scanning the chromosomal region 1 single nucleotide polymorphism (SNP) at a time may not fully explore linkage disequilibrium, haplotype analyses tend to require a fairly large number of parameters, thus potentially losing power. Clustering algorithms, such as the cladistic approach, have been proposed to reduce the dimensionality, yet they have important limitations. We propose a SNP-Haplotype Adaptive REgression (SHARE) algorithm that seeks the most informative set of SNPs for genetic association in a targeted candidate region by growing and shrinking haplotypes with 1 more or less SNP in a stepwise fashion, and comparing prediction errors of different models via cross-validation.... Biostatistics journals http://www.medworm.com/rss/comments.php?id=2788368 Thu, 10 Sep 2009 23:00:00 +0100 2788368 http://www.medworm.com/index.php?rid=2788367&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F4%2F667%3Frss%3D1 Time course gene microarray is an important tool to identify genes with differential expressions over time. Traditional analysis of variance (ANOVA) type of longitudinal investigation may not be applicable because of irregular time intervals and possible missingness due to contamination in microarray experiments. Functional principal components analysis is proposed to test hypotheses in the change of the mean curves. A permutation test under a mild assumption is used to make the method more robust. The proposed method outperforms the recently developed extraction of differential gene expression and a 2-way mixed effects ANOVA under reasonable gene expression models in simulation. Real data on transcriptional profiles of blood cells microarray from treated and untreated individuals were use... Biostatistics journals http://www.medworm.com/rss/comments.php?id=2788367 Thu, 10 Sep 2009 23:00:00 +0100 2788367 http://www.medworm.com/index.php?rid=2788366&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F4%2F659%3Frss%3D1 We consider estimation and variable selection in the partial linear model for censored data. The partial linear model for censored data is a direct extension of the accelerated failure time model, the latter of which is a very important alternative model to the proportional hazards model. We extend rank-based lasso-type estimators to a model that may contain nonlinear effects. Variable selection in such partial linear model has direct application to high-dimensional survival analyses that attempt to adjust for clinical predictors. In the microarray setting, previous methods can adjust for other clinical predictors by assuming that clinical and gene expression data enter the model linearly in the same fashion. Here, we select important variables after adjusting for prognostic clinical varia... Biostatistics journals http://www.medworm.com/rss/comments.php?id=2788366 Thu, 10 Sep 2009 23:00:00 +0100 2788366 http://www.medworm.com/index.php?rid=2788365&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F4%2F640%3Frss%3D1 In longitudinal or hierarchical structure studies, we often encounter a semicontinuous variable that has a certain proportion of a single value and a continuous and skewed distribution among the rest of values. In this paper, we propose a new semiparametric 2-part mixed-effects transformation model to fit correlated skewed semicontinuous data. In our model, we allow the transformation to be nonparametric. 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 an estimator for the expected value of the semicontinuous outcome on the original scale. Finally, we ap... Biostatistics journals http://www.medworm.com/rss/comments.php?id=2788365 Thu, 10 Sep 2009 23:00:00 +0100 2788365 http://www.medworm.com/index.php?rid=2788364&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F4%2F621%3Frss%3D1 We describe a new stochastic search algorithm for linear regression models called the bounded mode stochastic search (BMSS). We make use of BMSS to perform variable selection and classification as well as to construct sparse dependency networks. Furthermore, we show how to determine genetic networks from genomewide data that involve any combination of continuous and discrete variables. We illustrate our methodology with several real-world data sets. (Source: Biostatistics) Biostatistics journals http://www.medworm.com/rss/comments.php?id=2788364 Thu, 10 Sep 2009 23:00:00 +0100 2788364 http://www.medworm.com/index.php?rid=2788363&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F4%2F603%3Frss%3D1 A novel 3-step random forests methodology involving survival data (survival forests), ordinal data (multiclass forests), and continuous data (regression forests) is introduced for cancer staging. The methodology is illustrated for esophageal cancer using worldwide esophageal cancer collaboration data involving 4627 patients. (Source: Biostatistics) Biostatistics journals http://www.medworm.com/rss/comments.php?id=2788363 Thu, 10 Sep 2009 23:00:00 +0100 2788363 http://www.medworm.com/index.php?rid=2788362&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F4%2F591%3Frss%3D1 In occupational case–control studies, work-related exposure assessments are often fallible measures of the true underlying exposure. In lieu of a gold standard, often more than 2 imperfect measurements (e.g. triads) are used to assess exposure. While methods exist to assess the diagnostic accuracy in the absence of a gold standard, these methods are infrequently used to correct for measurement error in exposure–disease associations in occupational case–control studies. Here, we present a likelihood-based approach that (a) provides evidence regarding whether the misclassification of tests is differential or nondifferential; (b) provides evidence whether the misclassification of tests is independent or dependent conditional on latent exposure status, and (c) estimates the m... Biostatistics journals http://www.medworm.com/rss/comments.php?id=2788362 Thu, 10 Sep 2009 23:00:00 +0100 2788362 http://www.medworm.com/index.php?rid=2506267&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F3%2F588%3Frss%3D1 (Source: Biostatistics) Biostatistics journals http://www.medworm.com/rss/comments.php?id=2506267 Mon, 15 Jun 2009 23:00:00 +0100 2506267 http://www.medworm.com/index.php?rid=2506266&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F3%2F575%3Frss%3D1 Disease prevalence is the combined result of duration, disease incidence, case fatality, and other mortality. If information is available on all these factors, and on fixed covariates such as genotypes, prevalence information can be utilized in the estimation of the effects of the covariates on disease incidence. Study cohorts that are recruited as cross-sectional samples and subsequently followed up for disease events of interest produce both prevalence and incidence information. In this paper, we make use of both types of information using a likelihood, which is conditioned on survival until the cross section. In a simulation study making use of real cohort data, we compare the proposed conditional likelihood method to a standard analysis where prevalent cases are omitted and the likelih... Biostatistics journals http://www.medworm.com/rss/comments.php?id=2506266 Mon, 15 Jun 2009 23:00:00 +0100 2506266 http://www.medworm.com/index.php?rid=2506265&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F3%2F561%3Frss%3D1 Statisticians can play a crucial role in the design of gene expression studies to ensure the most effective allocation of available resources. This paper considers Pareto optimal designs for gene expression studies involving 2-color microarrays. Pareto optimality enables the recommendation of designs that are particularly efficient for the effects of most interest to biologists. This is relevant in the microarray context where analysis is typically carried out separately for those effects. Our approach will allow for effects of interest that correspond to contrasts rather than solely considering parameters of the linear model. We further develop the approach to cater for additional experimental considerations such as contrasts that are of equal scientific interest. This amounts to partitio... Biostatistics journals http://www.medworm.com/rss/comments.php?id=2506265 Mon, 15 Jun 2009 23:00:00 +0100 2506265 http://www.medworm.com/index.php?rid=2506264&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F3%2F550%3Frss%3D1 We develop an inference framework for the difference in errors between 2 prediction procedures. The 2 procedures may differ in any aspect and possibly utilize different sets of covariates. We apply training and testing on the same data set, which is accommodated by sample splitting. For each split, both procedures predict the response of the same samples, which results in paired residuals to which a signed-rank test is applied. Multiple splits result in multiple p-values. The median p-value and the mean inverse normal transformed p-value are proposed as summary (test) statistics, for which bounds on the overall type I error rate under a variety of assumptions are proven. A simulation study is performed to check type I error control of the least conservative bound. Moreover, it confirms sup... Biostatistics journals http://www.medworm.com/rss/comments.php?id=2506264 Mon, 15 Jun 2009 23:00:00 +0100 2506264 http://www.medworm.com/index.php?rid=2506263&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F3%2F535%3Frss%3D1 Prostate-specific antigen (PSA) is a biomarker routinely and repeatedly measured on prostate cancer patients treated by radiation therapy (RT). It was shown recently that its whole pattern over time rather than just its current level was strongly associated with prostate cancer recurrence. To more accurately guide clinical decision making, monitoring of PSA after RT would be aided by dynamic powerful prognostic tools that incorporate the complete posttreatment PSA evolution. In this work, we propose a dynamic prognostic tool derived from a joint latent class model and provide a measure of variability obtained from the parameters asymptotic distribution. To validate this prognostic tool, we consider predictive accuracy measures and provide an empirical estimate of their variability. We also... Biostatistics journals http://www.medworm.com/rss/comments.php?id=2506263 Mon, 15 Jun 2009 23:00:00 +0100 2506263 http://www.medworm.com/index.php?rid=2506262&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F3%2F515%3Frss%3D1 We present a penalized matrix decomposition (PMD), a new framework for computing a rank-K approximation for a matrix. We approximate the matrix X as , where dk, uk, and vk minimize the squared Frobenius norm of X , subject to penalties on uk and vk. This results in a regularized version of the singular value decomposition. Of particular interest is the use of L1-penalties on uk and vk, which yields a decomposition of X using sparse vectors. We show that when the PMD is applied using an L1-penalty on vk but not on uk, a method for sparse principal components results. In fact, this yields an efficient algorithm for the "SCoTLASS" proposal (Jolliffe and others 2003) for obtaining sparse principal components. This method is demonstrated on a publicly available gene expression data set. We als... Biostatistics journals http://www.medworm.com/rss/comments.php?id=2506262 Mon, 15 Jun 2009 23:00:00 +0100 2506262 http://www.medworm.com/index.php?rid=2506261&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F3%2F501%3Frss%3D1 The incidence of nasopharyngeal carcinoma (NPC) varies widely according to age at diagnosis, geographic location, and ethnic background. On a global scale, NPC incidence is common among specific populations primarily living in southern and eastern Asia and northern Africa, but in most areas, including almost all western countries, it remains a relatively uncommon malignancy. Specific to these low-risk populations is a general observation of possible bimodality in the observed age-incidence curves. We have developed a multiplicative frailty model that allows for the demonstrated points of inflection at ages 15–24 and 65–74. The bimodal frailty model has 2 independent compound Poisson-distributed frailties and gives a significant improvement in fit over a unimodal frailty model. ... Biostatistics journals http://www.medworm.com/rss/comments.php?id=2506261 Mon, 15 Jun 2009 23:00:00 +0100 2506261 http://www.medworm.com/index.php?rid=2506260&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F3%2F481%3Frss%3D1 Mass spectrometry is a powerful tool with much promise in global proteomic studies. The discipline of statistics offers robust methodologies to extract and interpret high-dimensional mass-spectrometry data and will be a valuable contributor to the field. Here, we describe the process by which data are produced, characteristics of the data, and the analytical preprocessing steps that are taken in order to interpret the data and use it in downstream statistical analyses. Because of the complexity of data acquisition, statistical methods developed for gene expression microarray data are not directly applicable to proteomic data. Areas in need of statistical research for proteomic data include alignment, experimental design, abundance normalization, and statistical analysis. (Source: Biostatis... Biostatistics journals http://www.medworm.com/rss/comments.php?id=2506260 Mon, 15 Jun 2009 23:00:00 +0100 2506260 http://www.medworm.com/index.php?rid=2506259&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F3%2F468%3Frss%3D1 Microarray time-course data can be used to explore interactions among genes and infer gene network. The crucial step in constructing gene network is to develop an appropriate causality test. In this regard, the expression profile of each gene can be treated as a time series. A typical existing method establishes the Granger causality based on Wald type of test, which relies on the homoscedastic normality assumption of the data distribution. However, this assumption can be seriously violated in real microarray experiments and thus may lead to inconsistent test results and false scientific conclusions. To overcome the drawback, we propose an estimating equation–based method which is robust to both heteroscedasticity and nonnormality of the gene expression data. In fact, it only require... Biostatistics journals http://www.medworm.com/rss/comments.php?id=2506259 Mon, 15 Jun 2009 23:00:00 +0100 2506259 http://www.medworm.com/index.php?rid=2506258&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F3%2F451%3Frss%3D1 This paper deals with the analysis of recurrent event data subject to censored observation. Using a suitable adaptation of generalized estimating equations for longitudinal data, we propose a straightforward methodology for estimating the parameters indexing the conditional means and variances of the process interevent (i.e. gap) times. The proposed methodology permits the use of both time-fixed and time-varying covariates, as well as transformations of the gap times, creating a flexible and useful class of methods for analyzing gap-time data. Censoring is dealt with by imposing a parametric assumption on the censored gap times, and extensive simulation results demonstrate the relative robustness of parameter estimates even when this parametric assumption is incorrect. A suitable large-sam... Biostatistics journals http://www.medworm.com/rss/comments.php?id=2506258 Mon, 15 Jun 2009 23:00:00 +0100 2506258 http://www.medworm.com/index.php?rid=2506257&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F3%2F446%3Frss%3D1 Novel techniques for analyzing microarray data are constantly being developed. Though many of the methods contribute to biological discoveries, inability to properly evaluate the novel techniques limits their ability to advance science. Because the underlying distribution of microarray data is unknown, novel methods are typically tested against the assumed normal distribution. However, microarray data are not, in fact, normally distributed, and assuming so can have misleading consequences. Using an Affymetrix technical replicate spike-in data set, we show that oligonucleotide expression values are not normally distributed for any of the standard methods for calculating expression values. The resulting data tend to have a large proportion of skew and heavy tailed genes. Additionally, we sho... Biostatistics journals http://www.medworm.com/rss/comments.php?id=2506257 Mon, 15 Jun 2009 23:00:00 +0100 2506257 http://www.medworm.com/index.php?rid=2506256&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F3%2F436%3Frss%3D1 This study addresses this problem by proposing a hybrid method that combines multiple GEEs based on different working correlation models, using the empirical likelihood method (Qin and Lawless, 1994). Analyses show that this hybrid method is more efficient than a GEE using a misspecified working correlation model. Furthermore, if one of the working correlation structures correctly models the within-subject correlations, then this hybrid method provides the most efficient parameter estimates. In simulations, the hybrid method's finite-sample performance is superior to a GEE under any of the commonly used working correlation models and is almost fully efficient in all scenarios studied. The hybrid method is illustrated using data from a longitudinal study of the respiratory infection rates i... Biostatistics journals http://www.medworm.com/rss/comments.php?id=2506256 Mon, 15 Jun 2009 23:00:00 +0100 2506256 http://www.medworm.com/index.php?rid=2506255&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F3%2F424%3Frss%3D1 Classification studies with high-dimensional measurements and relatively small sample sizes are increasingly common. Prospective analysis of the role of sample sizes in the performance of such studies is important for study design and interpretation of results, but the complexity of typical pattern discovery methods makes this problem challenging. The approach developed here combines Monte Carlo methods and new approximations for linear discriminant analysis, assuming multivariate normal distributions. Monte Carlo methods are used to sample the distribution of which features are selected for a classifier and the mean and variance of features given that they are selected. Given selected features, the linear discriminant problem involves different distributions of training data and generaliz... Biostatistics journals http://www.medworm.com/rss/comments.php?id=2506255 Mon, 15 Jun 2009 23:00:00 +0100 2506255 http://www.medworm.com/index.php?rid=2506254&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F3%2F409%3Frss%3D1 This paper presents an epidemiological study investigating the effects of long-term air pollution exposure on public health in Scotland, focusing on the 4 major urban areas, Aberdeen, Dundee, Edinburgh, and Glasgow. In particular, the associations between respiratory hospital admissions in 2005 and exposure to both PM10 and NO2 between 2002 and 2004 are estimated using a small-area ecological design. The implementation of such studies requires careful consideration of a number of statistical issues, including how to model spatial correlation, identifiability of the model parameters, and the possible effects of ecological bias. The results show that long-term exposures (over 3 years) to PM10 and NO2 are significantly associated with respiratory hospital admissions in Edinburgh and Glasgow, ... Biostatistics journals http://www.medworm.com/rss/comments.php?id=2506254 Mon, 15 Jun 2009 23:00:00 +0100 2506254 http://www.medworm.com/index.php?rid=2506253&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F3%2F405%3Frss%3D1 (Source: Biostatistics) Biostatistics journals http://www.medworm.com/rss/comments.php?id=2506253 Mon, 15 Jun 2009 23:00:00 +0100 2506253 http://www.medworm.com/index.php?rid=2221067&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F2%2F390%3Frss%3D1 Antiviral agents are an important component in mitigation/containment strategies for pandemic influenza. However, most research for mitigation/containment strategies relies on the antiviral efficacies evaluated from limited data of clinical trials. Which efficacy measures can be reliably estimated from these studies depends on the trial design, the size of the epidemics, and the statistical methods. We propose a Bayesian framework for modeling the influenza transmission dynamics within households. This Bayesian framework takes into account asymptomatic infections and is able to estimate efficacies with respect to protecting against viral infection, infection with clinical disease, and pathogenicity (the probability of disease given infection). We use the method to reanalyze 2 clinical stud... Biostatistics journals http://www.medworm.com/rss/comments.php?id=2221067 Fri, 27 Feb 2009 05:00:00 +0100 2221067 http://www.medworm.com/index.php?rid=2221066&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F2%2F374%3Frss%3D1 Semicontinuous data in the form of a mixture of zeros and continuously distributed positive values frequently arise in biomedical research. Two-part mixed models with correlated random effects are an attractive approach to characterize the complex structure of longitudinal semicontinuous data. In practice, however, an independence assumption about random effects in these models may often be made for convenience and computational feasibility. In this article, we show that bias can be induced for regression coefficients when random effects are truly correlated but misspecified as independent in a 2-part mixed model. Paralleling work on bias under nonignorable missingness within a shared parameter model, we derive and investigate the asymptotic bias in selected settings for misspecified 2-par... Biostatistics journals http://www.medworm.com/rss/comments.php?id=2221066 Fri, 27 Feb 2009 05:00:00 +0100 2221066 http://www.medworm.com/index.php?rid=2221065&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F2%2F364%3Frss%3D1 This paper presents a robust method to conduct inference in finely stratified familial studies under proband-based sampling. We assume that the interest is in both the marginal effects of subject-specific covariates on a binary response and the familial aggregation of the response, as quantified by intrafamilial pairwise odds ratios. We adopt an estimating function for proband-based family studies originally developed by Zhao and others (1998) in the context of an unstratified design and treat the stratification effects as fixed nuisance parameters. Our method requires modeling only the first 2 joint moments of the observations and reduces by 2 orders of magnitude the bias induced by fitting the stratum-specific nuisance parameters. An analytical standard error estimator for the proposed e... Biostatistics journals http://www.medworm.com/rss/comments.php?id=2221065 Fri, 27 Feb 2009 05:00:00 +0100 2221065 http://www.medworm.com/index.php?rid=2221064&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F2%2F352%3Frss%3D1 This article develops the normexp method further by improving the estimation of the parameters. A complete mathematical development is given of the normexp model and the associated saddle-point approximation. Some subtle numerical programming issues are solved which caused the original normexp method to fail occasionally when applied to unusual data sets. A practical and reliable algorithm is developed for exact maximum likelihood estimation (MLE) using high-quality optimization software and using the saddle-point estimates as starting values. "MLE" is shown to outperform heuristic estimators proposed by other authors, both in terms of estimation accuracy and in terms of performance on real data. The saddle-point approximation is an adequate replacement in most practical situations. The pe... Biostatistics journals http://www.medworm.com/rss/comments.php?id=2221064 Fri, 27 Feb 2009 05:00:00 +0100 2221064 http://www.medworm.com/index.php?rid=2221063&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F2%2F335%3Frss%3D1 Routinely collected administrative data sets, such as national registers, aim to collect information on a limited number of variables for the whole population. In contrast, survey and cohort studies contain more detailed data from a sample of the population. This paper describes Bayesian graphical models for fitting a common regression model to a combination of data sets with different sets of covariates. The methods are applied to a study of low birth weight and air pollution in England and Wales using a combination of register, survey, and small-area aggregate data. We discuss issues such as multiple imputation of confounding variables missing in one data set, survey selection bias, and appropriate propagation of information between model components. From the register data, there appears... Biostatistics journals http://www.medworm.com/rss/comments.php?id=2221063 Fri, 27 Feb 2009 05:00:00 +0100 2221063 http://www.medworm.com/index.php?rid=2221062&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F2%2F327%3Frss%3D1 Following the recent success of genome-wide association studies in uncovering disease-associated genetic variants, the next challenge is to understand how these variants affect downstream pathways. The most proximal trait to a disease-associated variant, most commonly a single nucleotide polymorphism (SNP), is differential gene expression due to the cis effect of SNP alleles on transcription, translation, and/or splicing gene expression quantitative trait loci (eQTL). Several genome-wide SNP–gene expression association studies have already provided convincing evidence of widespread association of eQTLs. As a consequence, some eQTL associations are found in the same genomic region as a disease variant, either as a coincidence or a causal relationship. Cis-regulation of RPS26 gene expr... Biostatistics journals http://www.medworm.com/rss/comments.php?id=2221062 Fri, 27 Feb 2009 05:00:00 +0100 2221062 http://www.medworm.com/index.php?rid=2221061&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F2%2F324%3Frss%3D1 (Source: Biostatistics) Biostatistics journals http://www.medworm.com/rss/comments.php?id=2221061 Fri, 27 Feb 2009 05:00:00 +0100 2221061 http://www.medworm.com/index.php?rid=2221060&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F2%2F310%3Frss%3D1 Randomized clinical trials with a multivariate response and/or multiple treatment arms are increasingly common, in part because of their efficiency and a greater concern about balancing risks with benefits. In some trials, the specific types and magnitudes of treatment group differences that would warrant early termination cannot easily be specified prior to the onset of the trial and/or could change as the trial progresses. This underscores the need for more flexible monitoring methods than traditional approaches. This paper extends the repeated confidence bands approach for interim monitoring to more general settings where there can be a multivariate response and/or multiple treatment arms and where the metrics for comparing treatment groups can change during the conduct of the trial. We... Biostatistics journals http://www.medworm.com/rss/comments.php?id=2221060 Fri, 27 Feb 2009 05:00:00 +0100 2221060 http://www.medworm.com/index.php?rid=2221059&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F2%2F297%3Frss%3D1 Genome-wide association studies (GWAS) have become increasingly affordable but they are still costly. Therefore, cost saving 2-stage designs were proposed in the literature. The restriction to 2 stages, however, seems artificial and does not exploit the full potential of the underlying methods. We extend the 2-stage approach to the general framework of any number of stages. Based on the theory of group sequential methods, we derive optimal multistage designs. With current genotyping cost structures, our results suggest that up to 4 stages are sufficient in order to get feasible and efficient designs. Furthermore, we consider the problem of choosing the optimal number of stages depending on the costs of the statistical interim analysis at each stage and provide guidelines for planning the n... Biostatistics journals http://www.medworm.com/rss/comments.php?id=2221059 Fri, 27 Feb 2009 05:00:00 +0100 2221059 http://www.medworm.com/index.php?rid=2221058&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F2%2F282%3Frss%3D1 Constructing a confidence interval for the actual, conditional error rate of a prediction rule from multivariate data is problematic because this error rate is not a population parameter in the traditional sense—it is a functional of the training set. When the training set changes, so does this "parameter." A valid method for constructing confidence intervals for the actual error rate had been previously developed by McLachlan. However, McLachlan's method cannot be applied in many cancer research settings because it requires the number of samples to be much larger than the number of dimensions (n >> p), and it assumes that no dimension-reducing feature selection step is performed. Here, an alternative to McLachlan's method is presented that can be applied when p >> n, wit... Biostatistics journals http://www.medworm.com/rss/comments.php?id=2221058 Fri, 27 Feb 2009 05:00:00 +0100 2221058 http://www.medworm.com/index.php?rid=2221057&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F2%2F275%3Frss%3D1 Recently, meta-analysis has been widely utilized to combine information across comparative clinical studies for evaluating drug efficacy or safety profile. When dealing with rather rare events, a substantial proportion of studies may not have any events of interest. Conventional methods either exclude such studies or add an arbitrary positive value to each cell of the corresponding 2x2 tables in the analysis. In this article, we present a simple, effective procedure to make valid inferences about the parameter of interest with all available data without artificial continuity corrections. We then use the procedure to analyze the data from 48 comparative trials involving rosiglitazone with respect to its possible cardiovascular toxicity. (Source: Biostatistics) Biostatistics journals http://www.medworm.com/rss/comments.php?id=2221057 Fri, 27 Feb 2009 05:00:00 +0100 2221057 http://www.medworm.com/index.php?rid=2221056&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F2%2F258%3Frss%3D1 In many environmental epidemiology studies, the locations and/or times of exposure measurements and health assessments do not match. In such settings, health effects analyses often use the predictions from an exposure model as a covariate in a regression model. Such exposure predictions contain some measurement error as the predicted values do not equal the true exposures. We provide a framework for spatial measurement error modeling, showing that smoothing induces a Berkson-type measurement error with nondiagonal error structure. From this viewpoint, we review the existing approaches to estimation in a linear regression health model, including direct use of the spatial predictions and exposure simulation, and explore some modified approaches, including Bayesian models and out-of-sample re... Biostatistics journals http://www.medworm.com/rss/comments.php?id=2221056 Fri, 27 Feb 2009 05:00:00 +0100 2221056 http://www.medworm.com/index.php?rid=2221055&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F2%2F245%3Frss%3D1 We describe a new multivariate gamma distribution and discuss its implication in a Poisson-correlated gamma-frailty model. This model is introduced to account for between-subjects correlation occurring in longitudinal count data. For likelihood-based inference involving distributions in which high-dimensional dependencies are present, it may be useful to approximate likelihoods based on the univariate or bivariate marginal distributions. The merit of composite likelihood is to reduce the computational complexity of the full likelihood. A 2-stage composite-likelihood procedure is developed for estimating the model parameters. The suggested method is applied to a meta-analysis study for survival curves. (Source: Biostatistics) Biostatistics journals http://www.medworm.com/rss/comments.php?id=2221055 Fri, 27 Feb 2009 05:00:00 +0100 2221055 http://www.medworm.com/index.php?rid=2221054&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F2%2F228%3Frss%3D1 The classification accuracy of a continuous marker is typically evaluated with the receiver operating characteristic (ROC) curve. In this paper, we study an alternative conceptual framework, the "percentile value." In this framework, the controls only provide a reference distribution to standardize the marker. The analysis proceeds by analyzing the standardized marker in cases. The approach is shown to be equivalent to ROC analysis. Advantages are that it provides a framework familiar to a broad spectrum of biostatisticians and it opens up avenues for new statistical techniques in biomarker evaluation. We develop several new procedures based on this framework for comparing biomarkers and biomarker performance in different populations. We develop methods that adjust such comparisons for cov... Biostatistics journals http://www.medworm.com/rss/comments.php?id=2221054 Fri, 27 Feb 2009 05:00:00 +0100 2221054 http://www.medworm.com/index.php?rid=2221053&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F2%2F219%3Frss%3D1 Functional magnetic resonance imaging (f MRI) is a noninvasive technique which is commonly used to quantify changes in blood oxygenation and flow coupled to neuronal activation. One of the primary goals of f MRI 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 is desirable in order to improve efficiency. Here, we construct a hierarchical model and apply an empirical Bayesian framework for the analysis of group f MRI data, employing techniques used in ... Biostatistics journals http://www.medworm.com/rss/comments.php?id=2221053 Fri, 27 Feb 2009 05:00:00 +0100 2221053 http://www.medworm.com/index.php?rid=2221052&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F2%2F205%3Frss%3D1 We propose a new class of semiparametric generalized linear models. As with existing models, these models are specified via a linear predictor and a link function for the mean of response Y as a function of predictors X. Here, however, the "baseline" distribution of Y at a given reference mean µ0 is left unspecified and is estimated from the data. The response distribution when the mean differs from µ0 is then generated via exponential tilting of the baseline distribution, yielding a response model that is a natural exponential family, with corresponding canonical link and variance functions. The resulting model has a level of flexibility similar to the popular proportional odds model. Maximum likelihood estimation is developed for response distributions with finite support, an... Biostatistics journals http://www.medworm.com/rss/comments.php?id=2221052 Fri, 27 Feb 2009 05:00:00 +0100 2221052 http://www.medworm.com/index.php?rid=2032020&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F1%2F201%3Frss%3D1 (Source: Biostatistics) Biostatistics journals http://www.medworm.com/rss/comments.php?id=2032020 Fri, 12 Dec 2008 05:00:00 +0100 2032020 http://www.medworm.com/index.php?rid=2032019&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F1%2F187%3Frss%3D1 For many diseases, it seems that the age at onset is genetically influenced. Therefore, the age-at-onset data are often collected in order to map the disease gene(s). The ages are often (right) censored or truncated, and therefore, many standard techniques for linkage analysis cannot be used. In this paper, we present a correlated frailty model for censored survival data of siblings. The model is used for testing heritability for the age at onset and linkage between the loci and the gene(s) that influence(s) the survival time. The model is applied to interval-censored migraine twin data. Heritability (obtained from the frailties rather than actual onset times) was estimated as 0.42; this value was highly significant. The highest lod score, a score of 1.9, was found at the end of chromosome... Biostatistics journals http://www.medworm.com/rss/comments.php?id=2032019 Fri, 12 Dec 2008 05:00:00 +0100 2032019 http://www.medworm.com/index.php?rid=2032018&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F1%2F172%3Frss%3D1 Consider a set of baseline predictors X to predict a binary outcome D and let Y be a novel marker or predictor. This paper is concerned with evaluating the performance of the augmented risk model P(D = 1|Y,X) compared with the baseline model P(D = 1|X). The diagnostic likelihood ratio, DLRX(y), quantifies the change in risk obtained with knowledge of Y = y for a subject with baseline risk factors X. The notion is commonly used in clinical medicine to quantify the increment in risk prediction due to Y. It is contrasted here with the notion of covariate-adjusted effect of Y in the augmented risk model. We also propose methods for making inference about DLRX(y). Case–control study designs are accommodated. The methods provide a mechanism to investigate if the predictive information in Y... Biostatistics journals http://www.medworm.com/rss/comments.php?id=2032018 Fri, 12 Dec 2008 05:00:00 +0100 2032018 http://www.medworm.com/index.php?rid=2032017&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F1%2F155%3Frss%3D1 Finite mixtures of Gaussian distributions are known to provide an accurate approximation to any unknown density. Motivated by DNA repair studies in which data are collected for samples of cells from different individuals, we propose a class of hierarchically weighted finite mixture models. The modeling framework incorporates a collection of k Gaussian basis distributions, with the individual-specific response densities expressed as mixtures of these bases. To allow heterogeneity among individuals and predictor effects, we model the mixture weights, while treating the basis distributions as unknown but common to all distributions. This results in a flexible hierarchical model for samples of distributions. We consider analysis of variance–type structures and a parsimonious latent facto... Biostatistics journals http://www.medworm.com/rss/comments.php?id=2032017 Fri, 12 Dec 2008 05:00:00 +0100 2032017 http://www.medworm.com/index.php?rid=2032016&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F1%2F147%3Frss%3D1 Cross-sectional covariate-related reference ranges are widely used in clinical medicine to put individual observations in the context of population values. Usually, such reference ranges are created from data sets of independent observations. If multiple measurements per individual are available, then ignoring the within-person correlation between repeats will lead to overestimation of centile precision. Furthermore, if abnormal measurements have triggered more frequent assessment, the data set will be biased thus producing biased centiles. Where multiple measures per individual exist, the methods commonly used are either randomly or systematically to select one observation per individual or to model individual trajectories and combine these. The first of these approaches may result in dis... Biostatistics journals http://www.medworm.com/rss/comments.php?id=2032016 Fri, 12 Dec 2008 05:00:00 +0100 2032016 http://www.medworm.com/index.php?rid=2032015&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F1%2F136%3Frss%3D1 The goal of relative survival methodology is to compare the survival experience of a cohort with that of the background population. Most often an additive excess hazard model is employed, which assumes that each person's hazard is a sum of 2 components—the population hazard obtained from life tables and an excess hazard attributable to the specific condition. Usually covariate effects on the excess hazard are assumed to have a proportional hazards structure with parametrically modelled baseline. In this paper, we introduce a new fitting procedure using the expectation–maximization algorithm, treating the cause of death as missing data. The method requires no assumptions about the baseline excess hazard thus reducing the risk of bias through misspecification. It accommodates the... Biostatistics journals http://www.medworm.com/rss/comments.php?id=2032015 Fri, 12 Dec 2008 05:00:00 +0100 2032015 http://www.medworm.com/index.php?rid=2032014&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F1%2F121%3Frss%3D1 This article focuses on parameter estimation of multilevel nonlinear mixed-effects models (MNLMEMs). These models are used to analyze data presenting multiple hierarchical levels of grouping (cluster data, clinical trials with several observation periods, ...). The variability of the individual parameters of the regression function is thus decomposed as a between-subject variability and higher levels of variability (e.g. within-subject variability). We propose maximum likelihood estimates of parameters of those MNLMEMs with 2 levels of random effects, using an extension of the stochastic approximation version of expectation–maximization (SAEM)–Monte Carlo Markov chain algorithm. The extended SAEM algorithm is split into an explicit direct expectation–maximization (EM) alg... Biostatistics journals http://www.medworm.com/rss/comments.php?id=2032014 Fri, 12 Dec 2008 05:00:00 +0100 2032014 http://www.medworm.com/index.php?rid=2032013&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F1%2F106%3Frss%3D1 Phylogeneticists have developed several statistical methods to infer recombination among molecular sequences that are evolutionarily related. Of these methods, Markov change-point models currently provide the most coherent framework. Yet, the Markov assumption is faulty in that the inferred relatedness of homologous sequences across regions divided by recombinant events is not independent, particularly for nonrecombinant sequences as they share the same history. To correct this limitation, we introduce a novel random tips (RT) model. The model springs from the idea that a recombinant sequence inherits its characters from an unknown number of ancestral full-length sequences, of which one only observes the incomplete portions. The RT model decomposes recombinant sequences into their ancestra... Biostatistics journals http://www.medworm.com/rss/comments.php?id=2032013 Fri, 12 Dec 2008 05:00:00 +0100 2032013 http://www.medworm.com/index.php?rid=2032012&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F1%2F94%3Frss%3D1 Important properties of diagnostic methods are their sensitivity, specificity, and positive and negative predictive values (PPV and NPV). These methods are typically assessed via case–control samples, which include one cohort of cases known to have the disease and a second control cohort of disease-free subjects. Such studies give direct estimates of sensitivity and specificity but only indirect estimates of PPV and NPV, which also depend on the disease prevalence in the tested population. The motivating example arises in assay testing, where usage is contemplated in populations with known prevalences. Further instances include biomarker development, where subjects are selected from a population with known prevalence and assessment of PPV and NPV is crucial, and the assessment of dia... Biostatistics journals http://www.medworm.com/rss/comments.php?id=2032012 Fri, 12 Dec 2008 05:00:00 +0100 2032012 http://www.medworm.com/index.php?rid=2032011&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F1%2F80%3Frss%3D1 In microarray experiments, it is often of interest to identify genes which have a prespecified gene expression profile with respect to time. Methods available in the literature are, however, typically not stringent enough in identifying such genes, particularly when the profile requires equivalence of gene expression levels at certain time points. In this paper, the authors introduce a new methodology, called gene profiling, that uses simultaneous differential and equivalent gene expression level testing to rank genes according to a prespecified gene expression profile. Gene profiling treats the vector of true gene expression levels as a linear combination of appropriate vectors, for example, vectors that give the required criteria for the profile. This gene profile model is fitted to the ... Biostatistics journals http://www.medworm.com/rss/comments.php?id=2032011 Fri, 12 Dec 2008 05:00:00 +0100 2032011 http://www.medworm.com/index.php?rid=2032010&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F1%2F70%3Frss%3D1 Researchers subject to time and budget constraints may conduct small nested case–control studies with individually matched controls to help optimize statistical power. In this paper, we show how precision can be improved considerably by combining data from a small nested case–control study with data from a larger nested case–control study of a different outcome in the same or overlapping cohort. Our approach is based on the inverse probability weighting concept, in which the log-likelihood contribution of each individual observation is weighted by the inverse of its probability of inclusion in either study. We illustrate our approach using simulated data and an application where we combine data sets from 2 nested case–control studies to investigate risk factors for ... Biostatistics journals http://www.medworm.com/rss/comments.php?id=2032010 Fri, 12 Dec 2008 05:00:00 +0100 2032010 http://www.medworm.com/index.php?rid=2032009&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F1%2F60%3Frss%3D1 In most analyses of large-scale genomic data sets, differential expression analysis is typically assessed by testing for differences in the mean of the distributions between 2 groups. A recent finding by Tomlins and others (2005) is of a different type of pattern of differential expression in which a fraction of samples in one group have overexpression relative to samples in the other group. In this work, we describe a general mixture model framework for the assessment of this type of expression, called outlier profile analysis. We start by considering the single-gene situation and establishing results on identifiability. We propose 2 nonparametric estimation procedures that have natural links to familiar multiple testing procedures. We then develop multivariate extensions of this methodol... Biostatistics journals http://www.medworm.com/rss/comments.php?id=2032009 Fri, 12 Dec 2008 05:00:00 +0100 2032009 http://www.medworm.com/index.php?rid=2032008&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F1%2F46%3Frss%3D1 Intensive care unit (ICU) patients are highly susceptible to hospital-acquired infections due to their poor health and many invasive therapeutic treatments. The effect on mortality of acquiring such infections is, however, poorly understood. Our goal is to quantify this using data from the National Surveillance Study of Nosocomial Infections in ICUs (Belgium). This is challenging because of the presence of time-dependent confounders, such as mechanical ventilation, which lie on the causal path from infection to mortality. Standard statistical analyses may be severely misleading in such settings and have shown contradictory results. Inverse probability weighting for marginal structural models may instead be used but is not directly applicable because these models parameterize the effect of ... Biostatistics journals http://www.medworm.com/rss/comments.php?id=2032008 Fri, 12 Dec 2008 05:00:00 +0100 2032008 http://www.medworm.com/index.php?rid=2032007&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F1%2F32%3Frss%3D1 Current clustering methods are routinely applied to gene expression time course data to find genes with similar activation patterns and ultimately to understand the dynamics of biological processes. As the dynamic unfolding of a biological process often involves the activation of genes at different rates, successful clustering in this context requires dealing with varying time and shape patterns simultaneously. This motivates the combination of a novel pairwise warping with a suitable clustering method to discover expression shape clusters. We develop a novel clustering method that combines an initial pairwise curve alignment to adjust for time variation within likely clusters. The cluster-specific time synchronization method shows excellent performance over standard clustering methods in ... Biostatistics journals http://www.medworm.com/rss/comments.php?id=2032007 Fri, 12 Dec 2008 05:00:00 +0100 2032007 http://www.medworm.com/index.php?rid=2032006&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F1%2F17%3Frss%3D1 Retrospective case–control studies are more susceptible to selection bias than other epidemiologic studies as by design they require that both cases and controls are representative of the same population. However, as cases and control recruitment processes are often different, it is not always obvious that the necessary exchangeability conditions hold. Selection bias typically arises when the selection criteria are associated with the risk factor under investigation. We develop a method which produces bias-adjusted estimates for the odds ratio. Our method hinges on 2 conditions. The first is that a variable that separates the risk factor from the selection criteria can be identified. This is termed the "bias breaking" variable. The second condition is that data can be found such that... Biostatistics journals http://www.medworm.com/rss/comments.php?id=2032006 Fri, 12 Dec 2008 05:00:00 +0100 2032006 http://www.medworm.com/index.php?rid=2032005&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F1%2F3%3Frss%3D1 A new method is developed for analyzing case series data in situations where occurrence of the event censors, curtails, or otherwise affects post-event exposures. Unbiased estimating equations derived from the self-controlled case series model are adapted to allow for exposures whose occurrence or observation is influenced by the event. The method applies to transient point exposures and rare nonrecurrent events. Asymptotic efficiency is studied in some special cases. A computational scheme based on a pseudo-likelihood is proposed to make the computations feasible in complex models. Simulations, a validation study, and 2 applications are described. (Source: Biostatistics) Biostatistics journals http://www.medworm.com/rss/comments.php?id=2032005 Fri, 12 Dec 2008 05:00:00 +0100 2032005 http://www.medworm.com/index.php?rid=2032004&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F10%2F1%2F1%3Frss%3D1 (Source: Biostatistics) Biostatistics journals http://www.medworm.com/rss/comments.php?id=2032004 Fri, 12 Dec 2008 05:00:00 +0100 2032004 http://www.medworm.com/index.php?rid=1797286&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F9%2F4%2F780%3Frss%3D1 (Source: Biostatistics) Biostatistics journals http://www.medworm.com/rss/comments.php?id=1797286 Tue, 16 Sep 2008 04:00:00 +0100 1797286 http://www.medworm.com/index.php?rid=1797285&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F9%2F4%2F779%3Frss%3D1 (Source: Biostatistics) Biostatistics journals http://www.medworm.com/rss/comments.php?id=1797285 Tue, 16 Sep 2008 04:00:00 +0100 1797285 http://www.medworm.com/index.php?rid=1797284&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F9%2F4%2F777%3Frss%3D1 (Source: Biostatistics) Biostatistics journals http://www.medworm.com/rss/comments.php?id=1797284 Tue, 16 Sep 2008 04:00:00 +0100 1797284 http://www.medworm.com/index.php?rid=1797283&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F9%2F4%2F765%3Frss%3D1 Separate Cox analyses of all cause-specific hazards are the standard technique of choice to study the effect of a covariate in competing risks, but a synopsis of these results in terms of cumulative event probabilities is challenging. This difficulty has led to the development of the proportional subdistribution hazards model. If the covariate is known at baseline, the model allows for a summarizing assessment in terms of the cumulative incidence function. black Mathematically, the model also allows for including random time-dependent covariates, but practical implementation has remained unclear due to a certain risk set peculiarity. We use the intimate relationship of discrete covariates and multistate models to naturally treat time-dependent covariates within the subdistribution hazards ... Biostatistics journals http://www.medworm.com/rss/comments.php?id=1797283 Tue, 16 Sep 2008 04:00:00 +0100 1797283 http://www.medworm.com/index.php?rid=1797282&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F9%2F4%2F750%3Frss%3D1 Longitudinal ordinal data are common in many scientific studies, including those of multiple sclerosis (MS), and are frequently modeled using Markov dependency. Several authors have proposed random-effects Markov models to account for heterogeneity in the population. In this paper, we go one step further and study prediction based on random-effects Markov models. In particular, we show how to calculate the probabilities of future events and confidence intervals for those probabilities, given observed data on the ordinal outcome and a set of covariates, and how to update them over time. We discuss the usefulness of depicting these probabilities for visualization and interpretation of model results and illustrate our method using data from a phase III clinical trial that evaluated the utilit... Biostatistics journals http://www.medworm.com/rss/comments.php?id=1797282 Tue, 16 Sep 2008 04:00:00 +0100 1797282 http://www.medworm.com/index.php?rid=1797281&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F9%2F4%2F735%3Frss%3D1 A typical longitudinal study prospectively collects both repeated measures of a health status outcome as well as covariates that are used either as the primary predictor of interest or as important adjustment factors. In many situations, all covariates are measured on the entire study cohort. However, in some scenarios the primary covariates are time dependent yet may be ascertained retrospectively after completion of the study. One common example would be covariate measurements based on stored biological specimens such as blood plasma. While authors have previously proposed generalizations of the standard case–control design in which the clustered outcome measurements are used to selectively ascertain covariates (Neuhaus and Jewell, 1990) and therefore provide resource efficient col... Biostatistics journals http://www.medworm.com/rss/comments.php?id=1797281 Tue, 16 Sep 2008 04:00:00 +0100 1797281 http://www.medworm.com/index.php?rid=1797280&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F9%2F4%2F715%3Frss%3D1 Multiparameter evidence synthesis is becoming widely used as a way of combining evidence from multiple and often disparate sources of information concerning a number of parameters. Synthesizing data in one encompassing model allows propagation of evidence and learning. We demonstrate the use of such an approach in estimating the number of people infected with the hepatitis C virus (HCV) in England and Wales. Data are obtained from seroprevalence studies conducted in different subpopulations. Each subpopulation is modeled as a composition of 3 main HCV risk groups (current injecting drug users (IDUs), ex-IDUs, and non-IDUs). Further, data obtained on the prevalence (size) of each risk group provide an estimate of the prevalence of HCV in the whole population. We simultaneously estimate all ... Biostatistics journals http://www.medworm.com/rss/comments.php?id=1797280 Tue, 16 Sep 2008 04:00:00 +0100 1797280 http://www.medworm.com/index.php?rid=1797279&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F9%2F4%2F700%3Frss%3D1 Detecting genetic markers with biologically relevant effects remains a challenge due to multiple testing. Standard analysis methods focus on evidence against the null and protect primarily the type I error. On the other hand, the worthwhile alternative is specified for power calculations at the design stage. The balanced test as proposed by Moerkerke and others (2006) and Moerkerke and Goetghebeur (2006) incorporates this alternative directly in the decision criterion to achieve better power. Genetic markers are selected and ranked in order of the balance of evidence they contain against the null and the target alternative. In this paper, we build on this guiding principle to develop 2-stage designs for screening genetic markers when the cost of measurements is high. For a given marker, a ... Biostatistics journals http://www.medworm.com/rss/comments.php?id=1797279 Tue, 16 Sep 2008 04:00:00 +0100 1797279 http://www.medworm.com/index.php?rid=1797278&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F9%2F4%2F686%3Frss%3D1 Flexible multilevel models are proposed to allow for cluster-specific smooth estimation of growth curves in a mixed-effects modeling format that includes subject-specific random effects on the growth parameters. Attention is then focused on models that examine between-cluster comparisons of the effects of an ecologic covariate of interest (e.g. air pollution) on nonlinear functionals of growth curves (e.g. maximum rate of growth). A Gibbs sampling approach is used to get posterior mean estimates of nonlinear functionals along with their uncertainty estimates. A second-stage ecologic random-effects model is used to examine the association between a covariate of interest (e.g. air pollution) and the nonlinear functionals. A unified estimation procedure is presented along with its computation... Biostatistics journals http://www.medworm.com/rss/comments.php?id=1797278 Tue, 16 Sep 2008 04:00:00 +0100 1797278 http://www.medworm.com/index.php?rid=1797277&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F9%2F4%2F668%3Frss%3D1 This article is focused on the recognition of overpresented short patterns, called "motifs", that may correspond to regulatory binding sites in the DNA sequences upstream of genes. An integrated Bayesian model is proposed to incorporate all unknown characteristics in motif discovery, including the number of motifs, motif widths, motif compositions, the number of motif sites, and locations of motif sites. Reversible jump Markov chain Monte Carlo is used to obtain posterior inference in the transdimensional parameter space. We present a number of suggestions for graphical summarization of the posterior distribution over the complex parameter space. The basic model is extended using a third-order Markov structure for nonmotif bases and allowing positions within a motif to be switched between ... Biostatistics journals http://www.medworm.com/rss/comments.php?id=1797277 Tue, 16 Sep 2008 04:00:00 +0100 1797277 http://www.medworm.com/index.php?rid=1797276&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F9%2F4%2F658%3Frss%3D1 We propose a general class of nonlinear transformation models for analyzing censored survival data, of which the nonlinear proportional hazards and proportional odds models are special cases. A cubic smoothing spline–based component-wise boosting algorithm is derived to estimate covariate effects nonparametrically using the gradient of the marginal likelihood, that is computed using importance sampling. The proposed method can be applied to survival data with high-dimensional covariates, including the case when the sample size is smaller than the number of predictors. Empirical performance of the proposed method is evaluated via simulations and analysis of a microarray survival data. (Source: Biostatistics) Biostatistics journals http://www.medworm.com/rss/comments.php?id=1797276 Tue, 16 Sep 2008 04:00:00 +0100 1797276 http://www.medworm.com/index.php?rid=1797275&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F9%2F4%2F635%3Frss%3D1 This manuscript describes a novel, linear mixed-effects model–fitting technique for the setting in which correlated data indicators are not completely observed. Mixed modeling is a useful analytical tool for characterizing genotype–phenotype associations among multiple potentially informative genetic loci. This approach involves grouping individuals into genetic clusters, where individuals in the same cluster have similar or identical multilocus genotypes. In haplotype-based investigations of unrelated individuals, corresponding cluster assignments are unobservable since the alignment of alleles within chromosomal copies is not generally observed. We derive an expectation conditional maximization approach to estimation in the mixed modeling setting, where cluster assignments ar... Biostatistics journals http://www.medworm.com/rss/comments.php?id=1797275 Tue, 16 Sep 2008 04:00:00 +0100 1797275 http://www.medworm.com/index.php?rid=1797274&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F9%2F4%2F621%3Frss%3D1 Genome-wide association studies (GWAS) provide an important approach to identifying common genetic variants that predispose to human disease. A typical GWAS may genotype hundreds of thousands of single nucleotide polymorphisms (SNPs) located throughout the human genome in a set of cases and controls. Logistic regression is often used to test for association between a SNP genotype and case versus control status, with corresponding odds ratios (ORs) typically reported only for those SNPs meeting selection criteria. However, when these estimates are based on the original data used to detect the variant, the results are affected by a selection bias sometimes referred to the "winner's curse" (Capen and others, 1971). The actual genetic association is typically overestimated. We show that such s... Biostatistics journals http://www.medworm.com/rss/comments.php?id=1797274 Tue, 16 Sep 2008 04:00:00 +0100 1797274 http://www.medworm.com/index.php?rid=1797273&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F9%2F4%2F613%3Frss%3D1 We present a model for estimation of temperature effects on mortality that is able to capture jointly the typical features of every temperature–death relationship, that is, nonlinearity and delayed effect of cold and heat over a few days. Using a segmented approximation along with a doubly penalized spline-based distributed lag parameterization, estimates and relevant standard errors of the cold- and heat-related risks and the heat tolerance are provided. The model is applied to data from Milano, Italy. (Source: Biostatistics) Biostatistics journals http://www.medworm.com/rss/comments.php?id=1797273 Tue, 16 Sep 2008 04:00:00 +0100 1797273 http://www.medworm.com/index.php?rid=1797272&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F9%2F4%2F601%3Frss%3D1 We present a new method to efficiently estimate very large numbers of p-values using empirically constructed null distributions of a test statistic. The need to evaluate a very large number of p-values is increasingly common with modern genomic data, and when interaction effects are of interest, the number of tests can easily run into billions. When the asymptotic distribution is not easily available, permutations are typically used to obtain p-values but these can be computationally infeasible in large problems. Our method constructs a prediction model to obtain a first approximation to the p-values and uses Bayesian methods to choose a fraction of these to be refined by permutations. We apply and evaluate our method on the study of association between 2-way interactions of genetic marker... Biostatistics journals http://www.medworm.com/rss/comments.php?id=1797272 Tue, 16 Sep 2008 04:00:00 +0100 1797272 http://www.medworm.com/index.php?rid=1797271&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F9%2F4%2F593%3Frss%3D1 The problem of testing for genotype–phenotype association with loci on the X chromosome in mixed-sex samples has received surprisingly little attention. A simple test can be constructed by counting alleles, with males contributing a single allele and females 2. This approach does assume not only Hardy–Weinberg equilibrium in the population from which the study subjects are sampled but also, perhaps, an unrealistic alternative hypothesis. This paper proposes 1 and 2 degree-of-freedom tests for association which do not assume Hardy–Weinberg equilibrium and which treat males as homozygous females. The proposed method remains valid when phenotype varies between sexes, provided the allele frequency does not, and avoids the loss of power resulting from stratification by sex in ... Biostatistics journals http://www.medworm.com/rss/comments.php?id=1797271 Tue, 16 Sep 2008 04:00:00 +0100 1797271 http://www.medworm.com/index.php?rid=1524744&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F9%2F3%2F577%3Frss%3D1 The power variance function distributions, which include the gamma and compound Poisson (CP) distributions among others, are commonly used in frailty models for family data. In a previous paper, we presented a frailty model constructed by randomizing the scale parameter in a CP distribution. When combined with a parametric baseline hazard, this yields a model with heterogeneity on both the individual and the family level and a subgroup with zero frailty, corresponding to people not experiencing the event. In this paper, we discuss covariates in the model. Depending on where the covariates are inserted in the model, one may have proportional hazards at the individual level, the family level, and a larger group level (for covariates shared by many families, e.g. ethnic groups) or get acceler... Biostatistics journals http://www.medworm.com/rss/comments.php?id=1524744 Wed, 18 Jun 2008 04:00:00 +0100 1524744 http://www.medworm.com/index.php?rid=1524743&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F9%2F3%2F566%3Frss%3D1 The accuracy of a single diagnostic test for binary outcome can be summarized by the area under the receiver operating characteristic (ROC) curve. Volume under the surface and hypervolume under the manifold have been proposed as extensions for multiple class diagnosis (Scurfield, 1996, 1998). However, the lack of simple inferential procedures for such measures has limited their practical utility. Part of the difficulty is that calculating such quantities may not be straightforward, even with a single test. The decision rule used to generate the ROC surface requires class probability assessments, which are not provided by the tests. We develop a method based on estimating the probabilities via some procedure, for example, multinomial logistic regression. Bootstrap inferences are proposed to... Biostatistics journals http://www.medworm.com/rss/comments.php?id=1524743 Wed, 18 Jun 2008 04:00:00 +0100 1524743 http://www.medworm.com/index.php?rid=1524742&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F9%2F3%2F555%3Frss%3D1 We describe one example using landmarks and another using facial curves from the cleft lip study, the latter using B-splines to provide an efficient parameterization. The results are presented in 2 dimensions, both in the profile and in the frontal views, with bivariate confidence intervals for the mean position of each landmark or curve, allowing objective assessment of significant differences in particular areas of the face between the 2 groups. Model comparison is performed using Wald and pseudolikelihood ratio tests. (Source: Biostatistics) Biostatistics journals http://www.medworm.com/rss/comments.php?id=1524742 Wed, 18 Jun 2008 04:00:00 +0100 1524742 http://www.medworm.com/index.php?rid=1524741&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F9%2F3%2F540%3Frss%3D1 Model-based clustering is a popular tool for summarizing high-dimensional data. With the number of high-throughput large-scale gene expression studies still on the rise, the need for effective data- summarizing tools has never been greater. By grouping genes according to a common experimental expression profile, we may gain new insight into the biological pathways that steer biological processes of interest. Clustering of gene profiles can also assist in assigning functions to genes that have not yet been functionally annotated. In this paper, we propose 2 model selection procedures for model-based clustering. Model selection in model-based clustering has to date focused on the identification of data dimensions that are relevant for clustering. However, in more complex data structures, wit... Biostatistics journals http://www.medworm.com/rss/comments.php?id=1524741 Wed, 18 Jun 2008 04:00:00 +0100 1524741 http://www.medworm.com/index.php?rid=1524740&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F9%2F3%2F523%3Frss%3D1 The deviance information criterion (DIC) is widely used for Bayesian model comparison, despite the lack of a clear theoretical foundation. DIC is shown to be an approximation to a penalized loss function based on the deviance, with a penalty derived from a cross-validation argument. This approximation is valid only when the effective number of parameters in the model is much smaller than the number of independent observations. In disease mapping, a typical application of DIC, this assumption does not hold and DIC under-penalizes more complex models. Another deviance-based loss function, derived from the same decision-theoretic framework, is applied to mixture models, which have previously been considered an unsuitable application for DIC (Source: Biostatistics) Biostatistics journals http://www.medworm.com/rss/comments.php?id=1524740 Wed, 18 Jun 2008 04:00:00 +0100 1524740 http://www.medworm.com/index.php?rid=1524739&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F9%2F3%2F513%3Frss%3D1 We propose random-effects models to summarize and quantify the accuracy of the diagnosis of multiple lesions on a single image without assuming independence between lesions. The number of false-positive lesions was assumed to be distributed as a Poisson mixture, and the proportion of true-positive lesions was assumed to be distributed as a binomial mixture. We considered univariate and bivariate, both parametric and nonparametric mixture models. We applied our tools to simulated data and data of a study assessing diagnostic accuracy of virtual colonography with computed tomography in 200 patients suspected of having one or more polyps. (Source: Biostatistics) Biostatistics journals http://www.medworm.com/rss/comments.php?id=1524739 Wed, 18 Jun 2008 04:00:00 +0100 1524739 http://www.medworm.com/index.php?rid=1524738&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F9%2F3%2F501%3Frss%3D1 Longitudinal data often contain missing observations and error-prone covariates. Extensive attention has been directed to analysis methods to adjust for the bias induced by missing observations. There is relatively little work on investigating the effects of covariate measurement error on estimation of the response parameters, especially on simultaneously accounting for the biases induced by both missing values and mismeasured covariates. It is not clear what the impact of ignoring measurement error is when analyzing longitudinal data with both missing observations and error-prone covariates. In this article, we study the effects of covariate measurement error on estimation of the response parameters for longitudinal studies. We develop an inference method that adjusts for the biases induc... Biostatistics journals http://www.medworm.com/rss/comments.php?id=1524738 Wed, 18 Jun 2008 04:00:00 +0100 1524738 http://www.medworm.com/index.php?rid=1524737&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F9%2F3%2F484%3Frss%3D1 Array comparative genomic hybridization (aCGH) is a laboratory technique to measure chromosomal copy number changes. A clear biological interpretation of the measurements is obtained by mapping these onto an ordinal scale with categories loss/normal/gain of a copy. The pattern of gains and losses harbors a level of tumor specificity. Here, we present WECCA (weighted clustering of called aCGH data), a method for weighted clustering of samples on the basis of the ordinal aCGH data. Two similarities to be used in the clustering and particularly suited for ordinal data are proposed, which are generalized to deal with weighted observations. In addition, a new form of linkage, especially suited for ordinal data, is introduced. In a simulation study, we show that the proposed cluster method is co... Biostatistics journals http://www.medworm.com/rss/comments.php?id=1524737 Wed, 18 Jun 2008 04:00:00 +0100 1524737 http://www.medworm.com/index.php?rid=1524736&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F9%2F3%2F467%3Frss%3D1 When applying hierarchical clustering algorithms to cluster patient samples from microarray data, the clustering patterns generated by most algorithms tend to be dominated by groups of highly differentially expressed genes that have closely related expression patterns. Sometimes, these genes may not be relevant to the biological process under study or their functions may already be known. The problem is that these genes can potentially drown out the effects of other genes that are relevant or have novel functions. We propose a procedure called complementary hierarchical clustering that is designed to uncover the structures arising from these novel genes that are not as highly expressed. Simulation studies show that the procedure is effective when applied to a variety of examples. We also d... Biostatistics journals http://www.medworm.com/rss/comments.php?id=1524736 Wed, 18 Jun 2008 04:00:00 +0100 1524736 http://www.medworm.com/index.php?rid=1524735&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F9%2F3%2F458%3Frss%3D1 When testing large numbers of null hypotheses, one needs to assess the evidence against the global null hypothesis that none of the hypotheses is false. Such evidence typically is based on the test statistic of the largest magnitude, whose statistical significance is evaluated by permuting the sample units to simulate its null distribution. Efron (2007) has noted that correlation among the test statistics can induce substantial interstudy variation in the shapes of their histograms, which may cause misleading tail counts. Here, we show that permutation-based estimates of the overall significance level also can be misleading when the test statistics are correlated. We propose that such estimates be conditioned on a simple measure of the spread of the observed histogram, and we provide a met... Biostatistics journals http://www.medworm.com/rss/comments.php?id=1524735 Wed, 18 Jun 2008 04:00:00 +0100 1524735 http://www.medworm.com/index.php?rid=1524734&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F9%2F3%2F442%3Frss%3D1 Late-onset (LO) toxicities are a serious concern in many phase I trials. Since most dose-limiting toxicities occur soon after therapy begins, most dose-finding methods use a binary indicator of toxicity occurring within a short initial time period. If an agent causes LO toxicities, however, an undesirably large number of patients may be treated at toxic doses before any toxicities are observed. A method addressing this problem is the time-to-event continual reassessment method (TITE-CRM, Cheung and Chappell, 2000). We propose a Bayesian dose-finding method similar to the TITE-CRM in which doses are chosen using time-to-toxicity data. The new aspect of our method is a set of rules, based on predictive probabilities, that temporarily suspend accrual if the risk of toxicity at prospective dos... Biostatistics journals http://www.medworm.com/rss/comments.php?id=1524734 Wed, 18 Jun 2008 04:00:00 +0100 1524734 http://www.medworm.com/index.php?rid=1524733&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F9%2F3%2F432%3Frss%3D1 We consider the problem of estimating sparse graphs by a lasso penalty applied to the inverse covariance matrix. Using a coordinate descent procedure for the lasso, we develop a simple algorithm—the graphical lasso—that is remarkably fast: It solves a 1000-node problem (~500000 parameters) in at most a minute and is 30–4000 times faster than competing methods. It also provides a conceptual link between the exact problem and the approximation suggested by Meinshausen and Bühlmann (2006). We illustrate the method on some cell-signaling data from proteomics. (Source: Biostatistics) Biostatistics journals http://www.medworm.com/rss/comments.php?id=1524733 Wed, 18 Jun 2008 04:00:00 +0100 1524733 http://www.medworm.com/index.php?rid=1524732&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F9%2F3%2F419%3Frss%3D1 Patients who have undergone renal transplantation are monitored longitudinally at irregular time intervals over 10 years or more. This yields a set of biochemical and physiological markers containing valuable information to anticipate a failure of the graft. A general linear, generalized linear, or nonlinear mixed model is used to describe the longitudinal profile of each marker. To account for the correlation between markers, the univariate mixed models are combined into a multivariate mixed model (MMM) by specifying a joint distribution for the random effects. Due to the high number of markers, a pairwise modeling strategy, where all possible pairs of bivariate mixed models are fitted, is used to obtain parameter estimates for the MMM. These estimates are used in a Bayes rule to obtain, ... Biostatistics journals http://www.medworm.com/rss/comments.php?id=1524732 Wed, 18 Jun 2008 04:00:00 +0100 1524732 http://www.medworm.com/index.php?rid=1524731&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F9%2F3%2F411%3Frss%3D1 We propose a new statistics for the detection of differentially expressed genes when the genes are activated only in a subset of the samples. Statistics designed for this unconventional circumstance has proved to be valuable for most cancer studies, where oncogenes are activated for a small number of disease samples. Previous efforts made in this direction include cancer outlier profile analysis (Tomlins and others, 2005), outlier sum (Tibshirani and Hastie, 2007), and outlier robust t-statistics (Wu, 2007). We propose a new statistics called maximum ordered subset t-statistics (MOST) which seems to be natural when the number of activated samples is unknown. We compare MOST to other statistics and find that the proposed method often has more power then its competitors. (Source: Biostatisti... Biostatistics journals http://www.medworm.com/rss/comments.php?id=1524731 Wed, 18 Jun 2008 04:00:00 +0100 1524731 http://www.medworm.com/index.php?rid=1524730&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F9%2F3%2F400%3Frss%3D1 In this paper, we apply flexible Bayesian survival analysis methods to investigate the risk of lymphoma associated with kidney transplantation among patients with end-stage renal disease. Of key interest is the potentially time-varying effect of a time-dependent exposure: transplant status. Bayesian modeling of the baseline hazard and the effect of transplant requires consideration of 2 timescales: time since study start and time since transplantation, respectively. Previous related work has not dealt with the separation of multiple timescales. Using a hierarchical model for the hazard function, both timescales are incorporated via conditionally independent stochastic processes; smoothing of each process is specified via intrinsic conditional Gaussian autoregressions. Features of the corre... Biostatistics journals http://www.medworm.com/rss/comments.php?id=1524730 Wed, 18 Jun 2008 04:00:00 +0100 1524730 http://www.medworm.com/index.php?rid=1524729&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F9%2F3%2F391%3Frss%3D1 The Cochran–Armitage trend test (CATT) is well suited for testing association between a marker and a disease in case–control studies. When the underlying genetic model for the disease is known, the CATT optimal for the genetic model is used. For complex diseases, however, the genetic models of the true disease loci are unknown. In this situation, robust tests are preferable. We propose a two-phase analysis with model selection for the case–control design. In the first phase, we use the difference of Hardy–Weinberg disequilibrium coefficients between the cases and the controls for model selection. Then, an optimal CATT corresponding to the selected model is used for testing association. The correlation of the statistics used for selection and the test for association... Biostatistics journals http://www.medworm.com/rss/comments.php?id=1524729 Wed, 18 Jun 2008 04:00:00 +0100 1524729 http://www.medworm.com/index.php?rid=1307339&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F9%2F2%2F373%3Frss%3D1 In a growth model, individuals move progressively through a series of states in which each state is indicative of developmental status. Interest lies in estimating the rate of progression through each state while incorporating covariates that might affect the transition rates. We develop a Bayesian discrete-time multistate growth model for inference from cross-sectional data with unknown initiation times. For each subject, data are collected at only one time point at which we observe the state as well as covariates that measure developmental progress. We link the developmental progress variables to an underlying latent growth variable that can also affect the state transition rates. A subject with slow latent growth will then have relatively small developmental progress covariates and move... Biostatistics journals http://www.medworm.com/rss/comments.php?id=1307339 Mon, 17 Mar 2008 04:00:00 +0100 1307339 http://www.medworm.com/index.php?rid=1307338&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F9%2F2%2F364%3Frss%3D1 We develop a permutation test for assessing a difference in the areas under the curve (AUCs) in a paired setting where both modalities are given to each diseased and nondiseased subject. We propose that permutations be made between subjects specifically by shuffling the diseased/nondiseased labels of the subjects within each modality. As these permutations are made within modality, the permutation test is valid even if both modalities are measured on different scales. We show that our permutation test is a sign test for the symmetry of an underlying discrete distribution whose size remains valid under the assumption of equal AUCs. We demonstrate the operating characteristics of our test via simulation and show that our test is equal in power to a permutation test recently proposed by Bando... Biostatistics journals http://www.medworm.com/rss/comments.php?id=1307338 Mon, 17 Mar 2008 04:00:00 +0100 1307338 http://www.medworm.com/index.php?rid=1307337&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F9%2F2%2F355%3Frss%3D1 We propose a simple and general resampling strategy to estimate variances for parameter estimators derived from nonsmooth estimating functions. This approach applies to a wide variety of semiparametric and nonparametric problems in biostatistics. It does not require solving estimating equations and is thus much faster than the existing resampling procedures. Its usefulness is illustrated with heteroscedastic quantile regression and censored data rank regression. Numerical results based on simulated and real data are provided. (Source: Biostatistics) Biostatistics journals http://www.medworm.com/rss/comments.php?id=1307337 Mon, 17 Mar 2008 04:00:00 +0100 1307337 http://www.medworm.com/index.php?rid=1307336&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F9%2F2%2F333%3Frss%3D1 We describe these approaches in the context of studies of breast cancer and illustrate that it is possible to identify a substantial biologically relevant subset of the human genome within which hybridization results are reliable. The subset generally varies with the platforms used, the tissues studied, and the populations being sampled. Despite important differences, it is also possible to develop simple expression measures that allow comparison across platforms, studies, laboratories and populations. Important biological signals are often preserved or enhanced. Cross-study validation and combination of microarray results requires careful, but not overly complex, statistical thinking and can become a routine component of genomic analysis. (Source: Biostatistics) Biostatistics journals http://www.medworm.com/rss/comments.php?id=1307336 Mon, 17 Mar 2008 04:00:00 +0100 1307336 http://www.medworm.com/index.php?rid=1307335&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F9%2F2%2F321%3Frss%3D1 We derive a quantile-adjusted conditional maximum likelihood estimator for the dispersion parameter of the negative binomial distribution and compare its performance, in terms of bias, to various other methods. Our estimation scheme outperforms all other methods in very small samples, typical of those from serial analysis of gene expression studies, the motivating data for this study. The impact of dispersion estimation on hypothesis testing is studied. We derive an "exact" test that outperforms the standard approximate asymptotic tests. (Source: Biostatistics) Biostatistics journals http://www.medworm.com/rss/comments.php?id=1307335 Mon, 17 Mar 2008 04:00:00 +0100 1307335 http://www.medworm.com/index.php?rid=1307334&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F9%2F2%2F308%3Frss%3D1 This article considers a nonlinear mixed-effects model for the longitudinal process and the Cox proportional hazards model for the time-to-event process. We provide a method for simultaneous likelihood inference on the 2 models and allow for nonignorable data missing. The approach is illustrated with a recent AIDS study by jointly modeling HIV viral dynamics and time to viral rebound. (Source: Biostatistics) Biostatistics journals http://www.medworm.com/rss/comments.php?id=1307334 Mon, 17 Mar 2008 04:00:00 +0100 1307334 http://www.medworm.com/index.php?rid=1307333&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F9%2F2%2F290%3Frss%3D1 Array-based comparative genomic hybridization (array-CGH) is a high throughput, high resolution technique for studying the genetics of cancer. Analysis of array-CGH data typically involves estimation of the underlying chromosome copy numbers from the log fluorescence ratios and segmenting the chromosome into regions with the same copy number at each location. We propose for the analysis of array-CGH data, a new stochastic segmentation model and an associated estimation procedure that has attractive statistical and computational properties. An important benefit of this Bayesian segmentation model is that it yields explicit formulas for posterior means, which can be used to estimate the signal directly without performing segmentation. Other quantities relating to the posterior distribution t... Biostatistics journals http://www.medworm.com/rss/comments.php?id=1307333 Mon, 17 Mar 2008 04:00:00 +0100 1307333 http://www.medworm.com/index.php?rid=1307332&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F9%2F2%2F277%3Frss%3D1 In behavioral medicine trials, such as smoking cessation trials, 2 or more active treatments are often compared. Noncompliance by some subjects with their assigned treatment poses a challenge to the data analyst. The principal stratification framework permits inference about causal effects among subpopulations characterized by potential compliance. However, in the absence of prior information, there are 2 significant limitations: (1) the causal effects cannot be point identified for some strata and (2) individuals in the subpopulations (strata) cannot be identified. We propose to use additional information—compliance-predictive covariates—to help identify the causal effects and to help describe characteristics of the subpopulations. The probability of membership in each princip... Biostatistics journals http://www.medworm.com/rss/comments.php?id=1307332 Mon, 17 Mar 2008 04:00:00 +0100 1307332 http://www.medworm.com/index.php?rid=1307331&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F9%2F2%2F263%3Frss%3D1 The efficacy of an HIV vaccine to prevent infection is likely to depend on the genetic variation of the exposing virus. This paper addresses the problem of using data on the HIV sequences that infect vaccine efficacy trial participants to (1) test for vaccine efficacy more powerfully than procedures that ignore the sequence data and (2) evaluate the dependence of vaccine efficacy on the divergence of infecting HIV strains from the HIV strain that is contained in the vaccine. Because hundreds of amino acid sites in each HIV genome are sequenced, it is natural to treat the genetic divergence as a continuous mark variable that accompanies each failure (infection) time. Problems (1) and (2) can then be approached by testing whether the ratio of the mark-specific hazard functions for the vaccin... Biostatistics journals http://www.medworm.com/rss/comments.php?id=1307331 Mon, 17 Mar 2008 04:00:00 +0100 1307331 http://www.medworm.com/index.php?rid=1307330&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F9%2F2%2F249%3Frss%3D1 Latent class models provide a useful framework for clustering observations based on several features. Application of latent class methodology to correlated, high-dimensional ordinal data poses many challenges. Unconstrained analyses may not result in an estimable model. Thus, information contained in ordinal variables may not be fully exploited by researchers. We develop a penalized latent class model to facilitate analysis of high-dimensional ordinal data. By stabilizing maximum likelihood estimation, we are able to fit an ordinal latent class model that would otherwise not be identifiable without application of strict constraints. We illustrate our methodology in a study of schwannoma, a peripheral nerve sheath tumor, that included 3 clinical subtypes and 23 ordinal histological measures... Biostatistics journals http://www.medworm.com/rss/comments.php?id=1307330 Mon, 17 Mar 2008 04:00:00 +0100 1307330 http://www.medworm.com/index.php?rid=1307329&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F9%2F2%2F234%3Frss%3D1 This article is concerned with regression analysis of multivariate panel count data which arise if more than one type of recurrent event is of interest and individuals are only observed intermittently. We present a class of marginal mean models which leave the dependence structures for related types of recurrent events completely unspecified. Estimating equations are developed for regression parameters, and the resulting estimates are shown to be consistent and asymptotically normal. Simulation studies show that the proposed estimation procedures work well for practical situations. The methodology is applied to a motivating study of patients with psoriatic arthritis in which the events of interest are the onset of joint damage according to 2 different criteria. (Source: Biostatistics) Biostatistics journals http://www.medworm.com/rss/comments.php?id=1307329 Mon, 17 Mar 2008 04:00:00 +0100 1307329 http://www.medworm.com/index.php?rid=1307328&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F9%2F2%2F216%3Frss%3D1 Recent advancement in technology promises to yield a multitude of tests for disease diagnosis and prognosis. When there are multiple sources of information available, it is often of interest to construct a composite score that can provide better classification accuracy than any individual measurement. In this paper, we consider robust procedures for optimally combining tests when test results are measured prior to disease onset and disease status evolves over time. To account for censoring of disease onset time, the most commonly used approach to combining tests to detect subsequent disease status is to fit a proportional hazards model (Cox, 1972) and use the estimated risk score. However, simulation studies suggested that such a risk score may have poor accuracy when the proportional haza... Biostatistics journals http://www.medworm.com/rss/comments.php?id=1307328 Mon, 17 Mar 2008 04:00:00 +0100 1307328 http://www.medworm.com/index.php?rid=1307327&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F9%2F2%2F201%3Frss%3D1 Some case–control genome-wide association studies (CCGWASs) select promising single nucleotide polymorphisms (SNPs) by ranking corresponding p-values, rather than by applying the same p-value threshold to each SNP. For such a study, we define the detection probability (DP) for a specific disease-associated SNP as the probability that the SNP will be "T-selected," namely have one of the top T largest chi-square values (or smallest p-values) for trend tests of association. The corresponding proportion positive (PP) is the fraction of selected SNPs that are true disease-associated SNPs. We study DP and PP analytically and via simulations, both for fixed and for random effects models of genetic risk, that allow for heterogeneity in genetic risk. DP increases with genetic effect size and ... Biostatistics journals http://www.medworm.com/rss/comments.php?id=1307327 Mon, 17 Mar 2008 04:00:00 +0100 1307327 http://www.medworm.com/index.php?rid=1095431&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F9%2F1%2F199%3Frss%3D1 (Source: Biostatistics) Biostatistics journals http://www.medworm.com/rss/comments.php?id=1095431 Fri, 14 Dec 2007 05:00:00 +0100 1095431 http://www.medworm.com/index.php?rid=1095430&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F9%2F1%2F187%3Frss%3D1 Interactions of single nucleotide polymorphisms (SNPs) are assumed to be responsible for complex diseases such as sporadic breast cancer. Important goals of studies concerned with such genetic data are thus to identify combinations of SNPs that lead to a higher risk of developing a disease and to measure the importance of these interactions. There are many approaches based on classification methods such as CART and random forests that allow measuring the importance of single variables. But none of these methods enable the importance of combinations of variables to be quantified directly. In this paper, we show how logic regression can be employed to identify SNP interactions explanatory for the disease status in a case–control study and propose 2 measures for quantifying the importan... Biostatistics journals http://www.medworm.com/rss/comments.php?id=1095430 Fri, 14 Dec 2007 05:00:00 +0100 1095430 http://www.medworm.com/index.php?rid=1095429&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F9%2F1%2F172%3Frss%3D1 Multivariate meta-analysis models can be used to synthesize multiple, correlated endpoints such as overall and disease-free survival. A hierarchical framework for multivariate random-effects meta-analysis includes both within-study and between-study correlation. The within-study correlations are assumed known, but they are usually unavailable, which limits the multivariate approach in practice. In this paper, we consider synthesis of 2 correlated endpoints and propose an alternative model for bivariate random-effects meta-analysis (BRMA). This model maintains the individual weighting of each study in the analysis but includes only one overall correlation parameter, , which removes the need to know the within-study correlations. Further, the only data needed to fit the model are those requi... Biostatistics journals http://www.medworm.com/rss/comments.php?id=1095429 Fri, 14 Dec 2007 05:00:00 +0100 1095429 http://www.medworm.com/index.php?rid=1095428&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F9%2F1%2F159%3Frss%3D1 Higher moments of the frequency distribution of child height and weight change with age, particularly during puberty, though why is not known. Our aims were to confirm that height skewness and kurtosis change with age during puberty, to devise a model to explain why, and to test the model by analyzing the data longitudinally. Heights of 3245 Christ's Hospital School boys born during 1927–1956 were measured twice termly from 9 to 20 years ($$n=129508$$). Treating the data as independent, the mean, standard deviation (SD), skewness, and kurtosis were calculated in 40 age groups and plotted as functions of age t. The data were also analyzed longitudinally using the nonlinear random-effects growth model $$H\left(t\right)=h(t-\epsilon )+\alpha $$, with $$H\left(t\right)$$ the cross-sectio... Biostatistics journals http://www.medworm.com/rss/comments.php?id=1095428 Fri, 14 Dec 2007 05:00:00 +0100 1095428 http://www.medworm.com/index.php?rid=1095427&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F9%2F1%2F152%3Frss%3D1 A method of inverse sampling of controls in a matched case–control study is described in which, for each case, controls are sampled until a discordant set is achieved. For a binary exposure, inverse sampling is used to determine the number of controls for each case. When most individuals in a population have the same exposure, standard case–control sampling may result in many case–control sets being concordant with respect to exposure and thus uninformative in the conditional logistic analysis. The method using inverse control sampling is proposed as a solution to this problem in situations when it is practically feasible. In many circumstances, inverse control sampling is found to offer improved statistical efficiency relative to a comparable study with a fixed number of... Biostatistics journals http://www.medworm.com/rss/comments.php?id=1095427 Fri, 14 Dec 2007 05:00:00 +0100 1095427 http://www.medworm.com/index.php?rid=1095426&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F9%2F1%2F137%3Frss%3D1 For many diseases, it is difficult or impossible to establish a definitive diagnosis because a perfect "gold standard" may not exist or may be too costly to obtain. In this paper, we propose a method to use continuous test results to estimate prevalence of disease in a given population and to estimate the effects of factors that may influence prevalence. Motivated by a study of human herpesvirus 8 among children with sickle-cell anemia in Uganda, where 2 enzyme immunoassays were used to assess infection status, we fit 2-component multivariate mixture models. We model the component densities using parametric densities that include data transformation as well as flexible transformed models. In addition, we model the mixing proportion, the probability of a latent variable corresponding to the... Biostatistics journals http://www.medworm.com/rss/comments.php?id=1095426 Fri, 14 Dec 2007 05:00:00 +0100 1095426 http://www.medworm.com/index.php?rid=1095425&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F9%2F1%2F128%3Frss%3D1 Standard clustering algorithms when applied to DNA microarray data often tend to produce erroneous clusters. A major contributor to this divergence is the feature characteristic of microarray data sets that the number of predictors (genes) in such data far exceeds the number of samples by many orders of magnitude, with only a small percentage of predictors being truly informative with regards to the clustering while the rest merely add noise. An additional complication is that the predictors exhibit an unknown complex correlational configuration embedded in a small subspace of the entire predictor space. Under these conditions, standard clustering algorithms fail to find the true clusters even when applied in tandem with some sort of gene filtering or dimension reduction to reduce the numb... Biostatistics journals http://www.medworm.com/rss/comments.php?id=1095425 Fri, 14 Dec 2007 05:00:00 +0100 1095425 http://www.medworm.com/index.php?rid=1095424&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F9%2F1%2F114%3Frss%3D1 Statistical methods for linkage analysis are well established for both binary and quantitative traits. However, numerous diseases including cancer and psychiatric disorders are rated on discrete ordinal scales. To analyze pedigree data with ordinal traits, we recently proposed a latent variable model which has higher power to detect linkage using ordinal traits than methods using the dichotomized traits. The challenge with the latent variable model is that the likelihood is usually very complicated, and as a result, the computation of the likelihood ratio statistic is too intensive for large pedigrees. In this paper, we derive a computationally efficient score statistic based on the identity-by-decent sharing information between relatives. Using simulation studies, we examined the asymptot... Biostatistics journals http://www.medworm.com/rss/comments.php?id=1095424 Fri, 14 Dec 2007 05:00:00 +0100 1095424 http://www.medworm.com/index.php?rid=1095423&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F9%2F1%2F100%3Frss%3D1 One important problem in genomic research is to identify genomic features such as gene expression data or DNA single nucleotide polymorphisms (SNPs) that are related to clinical phenotypes. Often these genomic data can be naturally divided into biologically meaningful groups such as genes belonging to the same pathways or SNPs within genes. In this paper, we propose group additive regression models and a group gradient descent boosting procedure for identifying groups of genomic features that are related to clinical phenotypes. Our simulation results show that by dividing the variables into appropriate groups, we can obtain better identification of the group features that are related to the phenotypes. In addition, the prediction mean square errors are also smaller than the component-wise ... Biostatistics journals http://www.medworm.com/rss/comments.php?id=1095423 Fri, 14 Dec 2007 05:00:00 +0100 1095423 http://www.medworm.com/index.php?rid=1095422&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F9%2F1%2F81%3Frss%3D1 Genetic epidemiologic studies often involve investigation of the association of a disease with a genomic region in terms of the underlying haplotypes, that is the combination of alleles at multiple loci along homologous chromosomes. In this article, we consider the problem of estimating haplotype–environment interactions from case–control studies when some of the environmental exposures themselves may be influenced by genetic susceptibility. We specify the distribution of the diplotypes (haplotype pair) given environmental exposures for the underlying population based on a novel semiparametric model that allows haplotypes to be potentially related with environmental exposures, while allowing the marginal distribution of the diplotypes to maintain certain population genetics con... Biostatistics journals http://www.medworm.com/rss/comments.php?id=1095422 Fri, 14 Dec 2007 05:00:00 +0100 1095422 http://www.medworm.com/index.php?rid=1095421&cid=s_31987_79_f&fid=31987&url=http%3A%2F%2Fbiostatistics.oxfordjournals.org%2Fcgi%2Fcontent%2Fshort%2F9%2F1%2F66%3Frss%3D1 We consider model-based clustering of data that lie on a unit sphere. Such data arise in the analysis of microarray experiments when the gene expressions are standardized so that they have mean 0 and variance 1 across the arrays. We propose to model the clusters on the sphere with inverse stereographic projections of multivariate normal distributions. The corresponding model-based clustering algorithm is described. This algorithm is applied first to simulated data sets to assess the performance of several criteria for determining the number of clusters and to compare its performance with existing methods and second to a real reference data set of standardized gene expression profiles. (Source: Biostatistics) Biostatistics journals http://www.medworm.com/rss/comments.php?id=1095421 Fri, 14 Dec 2007 05:00:00 +0100 1095421