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Cluster analysis is an unsupervised learning strategy that can be employed to identify subgroups of observations in data sets of unknown structure. This strategy is particularly useful for analyzing high-dimensional data such as microarray gene expression data. Many clustering methods are available, but it is challenging to determine if the identified clusters represent distinct subgroups. We propose a novel strategy to investigate the significance of identified clusters by comparing the within- cluster sum of squares from the original data to that produced by clustering an appropriate unimodal null distribution. The null distribution we present for this problem uses kernel density estimation and thus does not require that the data follow any particular distribution. We find that our method can accurately test for the presence of clustering even when the number of features is high.

In many situations it is desirable to identify clusters that differ with respect to only a subset of features. Such clusters may represent homogeneous subgroups of patients with a disease, such as cancer or chronic pain. We define a bicluster to be a submatrix U of a larger data matrix X such that the features and observations in U differ from those not contained in U. For example, the observations in U could have different means or variances with respect to the features in U. We propose a general framework for biclustering based on the sparse clustering method of Witten and Tibshirani (2010). We develop a method for identifying features that belong to biclusters. This framework can be used to identify biclusters that differ with respect to the means of the features, the variance of the features, or more general differences. We apply these methods to several simulated and real-world data sets and compare the results of our method with several previously published methods. The results of our method compare favorably with existing methods with respect to both predictive accuracy and computing time., Comment: 40 pages, 8 figures, 10 tables

Cluster analysis methods seek to partition a data set into homogeneous subgroups. It is useful in a wide variety of applications, including document processing and modern genetics. Conventional clustering methods are unsupervised, meaning that there is no outcome variable nor is anything known about the relationship between the observations in the data set. In many situations, however, information about the clusters is available in addition to the values of the features. For example, the cluster labels of some observations may be known, or certain observations may be known to belong to the same cluster. In other cases, one may wish to identify clusters that are associated with a particular outcome variable. This review describes several clustering algorithms (known as "semi-supervised clustering" methods) that can be applied in these situations. The majority of these methods are modifications of the popular k-means clustering method, and several of them will be described in detail. A brief description of some other semi-supervised clustering algorithms is also provided., Comment: 28 pages, 5 figures

In a prospective cohort study, examining all participants for incidence of the condition of interest may be prohibitively expensive. For example, the "gold standard" for diagnosing temporomandibular disorder (TMD) is a physical examination by a trained clinician. In large studies, examining all participants in this manner is infeasible. Instead, it is common to use questionnaires to screen for incidence of TMD and perform the "gold standard" examination only on participants who screen positively. Unfortunately, some participants may leave the study before receiving the "gold standard" examination. Within the framework of survival analysis, this results in missing failure indicators. Motivated by the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study, a large cohort study of TMD, we propose a method for parameter estimation in survival models with missing failure indicators. We estimate the probability of being an incident case for those lacking a "gold standard" examination using logistic regression. These estimated probabilities are used to generate multiple imputations of case status for each missing examination that are combined with observed data in appropriate regression models. The variance introduced by the procedure is estimated using multiple imputation. The method can be used to estimate both regression coefficients in Cox proportional hazard models as well as incidence rates using Poisson regression. We simulate data with missing failure indicators and show that our method performs as well as or better than competing methods. Finally, we apply the proposed method to data from the OPPERA study., Comment: Version 4: 23 pages, 0 figures

DNA microarrays are a relatively new technology that can simultaneously measure the expression level of thousands of genes. They have become an important tool for a wide variety of biological experiments. One of the most common goals of DNA microarray experiments is to identify genes associated with biological processes of interest. Conventional statistical tests often produce poor results when applied to microarray data due to small sample sizes, noisy data, and correlation among the expression levels of the genes. Thus, novel statistical methods are needed to identify significant genes in DNA microarray experiments. This article discusses the challenges inherent in DNA microarray analysis and describes a series of statistical techniques that can be used to overcome these challenges. The problem of multiple hypothesis testing and its relation to microarray studies is also considered, along with several possible solutions., Comment: 35 pages, 6 figures. To be published in WIREs Computational Statistics

Cluster analysis methods are used to identify homogeneous subgroups in a data set. In biomedical applications, one frequently applies cluster analysis in order to identify biologically interesting subgroups. In particular, one may wish to identify subgroups that are associated with a particular outcome of interest. Conventional clustering methods generally do not identify such subgroups, particularly when there are a large number of high-variance features in the data set. Conventional methods may identify clusters associated with these high-variance features when one wishes to obtain secondary clusters that are more interesting biologically or more strongly associated with a particular outcome of interest. A modification of sparse clustering can be used to identify such secondary clusters or clusters associated with an outcome of interest. This method correctly identifies such clusters of interest in several simulation scenarios. The method is also applied to a large prospective cohort study of temporomandibular disorders and a leukemia microarray data set., Comment: Version 4: 49 pages, 5 figures

Cross-validation is frequently used for model selection in a variety of applications. However, it is difficult to apply cross-validation to mixed effects models (including nonlinear mixed effects models or NLME models) due to the fact that cross-validation requires "out-of-sample" predictions of the outcome variable, which cannot be easily calculated when random effects are present. We describe two novel variants of cross-validation that can be applied to nonlinear mixed effects models. One variant, where out-of-sample predictions are based on post hoc estimates of the random effects, can be used to select the overall structural model. Another variant, where cross-validation seeks to minimize the estimated random effects rather than the estimated residuals, can be used to select covariates to include in the model. We show that these methods produce accurate results in a variety of simulated data sets and apply them to two publicly available population pharmacokinetic data sets., Comment: 38 pages, 15 figures To be published in the Journal of Pharmacokinetics and Pharmacodynamics

We consider regression problems where the number of predictors greatly exceeds the number of observations. We propose a method for variable selection that first estimates the regression function, yielding a "pre-conditioned" response variable. The primary method used for this initial regression is supervised principal components. Then we apply a standard procedure such as forward stepwise selection or the LASSO to the pre-conditioned response variable. In a number of simulated and real data examples, this two-step procedure outperforms forward stepwise selection or the usual LASSO (applied directly to the raw outcome). We also show that under a certain Gaussian latent variable model, application of the LASSO to the pre-conditioned response variable is consistent as the number of predictors and observations increases. Moreover, when the observational noise is rather large, the suggested procedure can give a more accurate estimate than LASSO. We illustrate our method on some real problems, including survival analysis with microarray data.