The Illusion of Distribution-Free Small-Sample Classification in Genomics

Classification has emerged as a major area of investigation in bioinformatics owing to the desire to discriminate phenotypes, in particular, disease conditions, using high-throughput genomic data. While many classification rules have been posed, there is a paucity of error estimation rules and an even greater paucity of theory concerning error estimation accuracy. This is problematic because the worth of a classifier depends mainly on its error rate. It is common place in bio-informatics papers to have a classification rule applied to a small labeled data set and the error of the resulting classifier be estimated on the same data set, most often via cross-validation, without any assumptions being made on the underlying feature-label distribution. Concomitant with a lack of distributional assumptions is the absence of any statement regarding the accuracy of the error estimate. Without such a measure of accuracy, the most common one being the root-mean-square (RMS), the error estimate is essentially meaningless and the worth of the entire paper is questionable. The concomitance of an absence of distributional assumptions and of a measure of error estimation accuracy is assured in small-sample settings because even when distribution-free bounds exist (and that is rare), the sample sizes required under the bounds are so large as to make them useless for small samples. Thus, distributional bounds are necessary and the distributional assumptions need to be stated. Owing to the epistemological dependence of classifiers on the accuracy of their estimated errors, scientifically meaningful distribution-free classification in high-throughput, small-sample biology is an illusion

Classification and Error Estimation for Discrete Data

Discrete classification is common in Genomic Signal Processing applications, in particular in classification of discretized gene expression data, and in discrete gene expression prediction and the inference of boolean genomic regulatory networks. Once a discrete classifier is obtained from sample data, its performance must be evaluated through its classification error. In practice, error estimation methods must then be employed to obtain reliable estimates of the classification error based on the available data. Both classifier design and error estimation are complicated, in the case of Genomics, by the prevalence of small-sample data sets in such applications. This paper presents a broad review of the methodology of classification and error estimation for discrete data, in the context of Genomics, focusing on the study of performance in small sample scenarios, as well as asymptotic behavior

Which Is Better: Holdout or Full-Sample Classifier Design?

Is it better to design a classifier and estimate its error on the full sample or to design a classifier on a training subset and estimate its error on the holdout test subset? Full-sample design provides the better classifier; nevertheless, one might choose holdout with the hope of better error estimation. A conservative criterion to decide the best course is to aim at a classifier whose error is less than a given bound. Then the choice between full-sample and holdout designs depends on which possesses the smaller expected bound. Using this criterion, we examine the choice between holdout and several full-sample error estimators using covariance models and a patient-data model. Full-sample design consistently outperforms holdout design. The relation between the two designs is revealed via a decomposition of the expected bound into the sum of the expected true error and the expected conditional standard deviation of the true error

Nonparametric Estimation of the Bayes Error

This thesis is concerned with the performance of nonparametric classifiers and their application to the estimation of the Rayes error. Although the behavior of these classifiers as the number of preclassified design samples becomes infinite is well understood, very little is known regarding their finite sample error performance. Here, we examine the performance of Parzen and k-nearest neighbor (k-NN) classifiers, relating the expected error rates to the size of the design set and the various, design parameters (kernel size and shape, value of k, distance metric for nearest neighbor calculation, etc.). These results lead to several significant improvements in the design procedures for nonparametric classifiers, as well as improved estimates of the Bayes error rate. , Our results show that increasing the sample size is in many cases not an effective practical means of improving the classifier performance. Rather, careful attention must be paid to the decision threshold, selection of the kernel size and shape (for Parzen classifiers), and selection of k and the distance metric (for k-NN classifiers). Guidelines are developed toward propper selection of each of these parameters. The use of nonparametric error rates for Bayes error estimation is also considered, and techniques are given which reduce or compensate for the biases of the nonparametric error rates. A bootstrap technique is also developed which allows the designer to estimate the standard deviation of a nonparametric estimate of the Bayes error

Small Sample Issues for Microarray-Based Classification

In order to study the molecular biological differences between normal and diseased tissues, it is desirable to perform classification among diseases and stages of disease using microarray-based gene-expression values. Owing to the limited number of microarrays typically used in these studies, serious issues arise with respect to the design, performance and analysis of classifiers based on microarray data. This paper reviews some fundamental issues facing small-sample classification: classification rules, constrained classifiers, error estimation and feature selection. It discusses both unconstrained and constrained classifier design from sample data, and the contributions to classifier error from constrained optimization and lack of optimality owing to design from sample data. The difficulty with estimating classifier error when confined to small samples is addressed, particularly estimating the error from training data. The impact of small samples on the ability to include more than a few variables as classifier features is explained

Asymptotics of Cross-Validated Risk Estimation in Estimator Selection and Performance Assessment

Risk estimation is an important statistical question for the purposes of selecting a good estimator (i.e., model selection) and assessing its performance (i.e., estimating generalization error). This article introduces a general framework for cross-validation and derives distributional properties of cross-validated risk estimators in the context of estimator selection and performance assessment. Arbitrary classes of estimators are considered, including density estimators and predictors for both continuous and polychotomous outcomes. Results are provided for general full data loss functions (e.g., absolute and squared error, indicator, negative log density). A broad definition of cross-validation is used in order to cover leave-one-out cross-validation, V-fold cross-validation, Monte Carlo cross-validation, and bootstrap procedures. For estimator selection, finite sample risk bounds are derived and applied to establish the asymptotic optimality of cross-validation, in the sense that a selector based on a cross-validated risk estimator performs asymptotically as well as an optimal oracle selector based on the risk under the true, unknown data generating distribution. The asymptotic results are derived under the assumption that the size of the validation sets converges to infinity and hence do not cover leave-one-out cross-validation. For performance assessment, cross-validated risk estimators are shown to be consistent and asymptotically linear for the risk under the true data generating distribution and confidence intervals are derived for this unknown risk. Unlike previously published results, the theorems derived in this and our related articles apply to general data generating distributions, loss functions (i.e., parameters), estimators, and cross-validation procedures