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1.  Bias in error estimation when using cross-validation for model selection 
BMC Bioinformatics  2006;7:91.
Background
Cross-validation (CV) is an effective method for estimating the prediction error of a classifier. Some recent articles have proposed methods for optimizing classifiers by choosing classifier parameter values that minimize the CV error estimate. We have evaluated the validity of using the CV error estimate of the optimized classifier as an estimate of the true error expected on independent data.
Results
We used CV to optimize the classification parameters for two kinds of classifiers; Shrunken Centroids and Support Vector Machines (SVM). Random training datasets were created, with no difference in the distribution of the features between the two classes. Using these "null" datasets, we selected classifier parameter values that minimized the CV error estimate. 10-fold CV was used for Shrunken Centroids while Leave-One-Out-CV (LOOCV) was used for the SVM. Independent test data was created to estimate the true error. With "null" and "non null" (with differential expression between the classes) data, we also tested a nested CV procedure, where an inner CV loop is used to perform the tuning of the parameters while an outer CV is used to compute an estimate of the error.
The CV error estimate for the classifier with the optimal parameters was found to be a substantially biased estimate of the true error that the classifier would incur on independent data. Even though there is no real difference between the two classes for the "null" datasets, the CV error estimate for the Shrunken Centroid with the optimal parameters was less than 30% on 18.5% of simulated training data-sets. For SVM with optimal parameters the estimated error rate was less than 30% on 38% of "null" data-sets. Performance of the optimized classifiers on the independent test set was no better than chance.
The nested CV procedure reduces the bias considerably and gives an estimate of the error that is very close to that obtained on the independent testing set for both Shrunken Centroids and SVM classifiers for "null" and "non-null" data distributions.
Conclusion
We show that using CV to compute an error estimate for a classifier that has itself been tuned using CV gives a significantly biased estimate of the true error. Proper use of CV for estimating true error of a classifier developed using a well defined algorithm requires that all steps of the algorithm, including classifier parameter tuning, be repeated in each CV loop. A nested CV procedure provides an almost unbiased estimate of the true error.
doi:10.1186/1471-2105-7-91
PMCID: PMC1397873  PMID: 16504092
2.  Stratification bias in low signal microarray studies 
BMC Bioinformatics  2007;8:326.
Background
When analysing microarray and other small sample size biological datasets, care is needed to avoid various biases. We analyse a form of bias, stratification bias, that can substantially affect analyses using sample-reuse validation techniques and lead to inaccurate results. This bias is due to imperfect stratification of samples in the training and test sets and the dependency between these stratification errors, i.e. the variations in class proportions in the training and test sets are negatively correlated.
Results
We show that when estimating the performance of classifiers on low signal datasets (i.e. those which are difficult to classify), which are typical of many prognostic microarray studies, commonly used performance measures can suffer from a substantial negative bias. For error rate this bias is only severe in quite restricted situations, but can be much larger and more frequent when using ranking measures such as the receiver operating characteristic (ROC) curve and area under the ROC (AUC). Substantial biases are shown in simulations and on the van 't Veer breast cancer dataset. The classification error rate can have large negative biases for balanced datasets, whereas the AUC shows substantial pessimistic biases even for imbalanced datasets. In simulation studies using 10-fold cross-validation, AUC values of less than 0.3 can be observed on random datasets rather than the expected 0.5. Further experiments on the van 't Veer breast cancer dataset show these biases exist in practice.
Conclusion
Stratification bias can substantially affect several performance measures. In computing the AUC, the strategy of pooling the test samples from the various folds of cross-validation can lead to large biases; computing it as the average of per-fold estimates avoids this bias and is thus the recommended approach. As a more general solution applicable to other performance measures, we show that stratified repeated holdout and a modified version of k-fold cross-validation, balanced, stratified cross-validation and balanced leave-one-out cross-validation, avoids the bias. Therefore for model selection and evaluation of microarray and other small biological datasets, these methods should be used and unstratified versions avoided. In particular, the commonly used (unbalanced) leave-one-out cross-validation should not be used to estimate AUC for small datasets.
doi:10.1186/1471-2105-8-326
PMCID: PMC2211509  PMID: 17764577
3.  Improved shrunken centroid classifiers for high-dimensional class-imbalanced data 
BMC Bioinformatics  2013;14:64.
Background
PAM, a nearest shrunken centroid method (NSC), is a popular classification method for high-dimensional data. ALP and AHP are NSC algorithms that were proposed to improve upon PAM. The NSC methods base their classification rules on shrunken centroids; in practice the amount of shrinkage is estimated minimizing the overall cross-validated (CV) error rate.
Results
We show that when data are class-imbalanced the three NSC classifiers are biased towards the majority class. The bias is larger when the number of variables or class-imbalance is larger and/or the differences between classes are smaller. To diminish the class-imbalance problem of the NSC classifiers we propose to estimate the amount of shrinkage by maximizing the CV geometric mean of the class-specific predictive accuracies (g-means).
Conclusions
The results obtained on simulated and real high-dimensional class-imbalanced data show that our approach outperforms the currently used strategy based on the minimization of the overall error rate when NSC classifiers are biased towards the majority class. The number of variables included in the NSC classifiers when using our approach is much smaller than with the original approach. This result is supported by experiments on simulated and real high-dimensional class-imbalanced data.
doi:10.1186/1471-2105-14-64
PMCID: PMC3687811  PMID: 23433084
4.  Evaluation of normalization methods for cDNA microarray data by k-NN classification 
BMC Bioinformatics  2005;6:191.
Background
Non-biological factors give rise to unwanted variations in cDNA microarray data. There are many normalization methods designed to remove such variations. However, to date there have been few published systematic evaluations of these techniques for removing variations arising from dye biases in the context of downstream, higher-order analytical tasks such as classification.
Results
Ten location normalization methods that adjust spatial- and/or intensity-dependent dye biases, and three scale methods that adjust scale differences were applied, individually and in combination, to five distinct, published, cancer biology-related cDNA microarray data sets. Leave-one-out cross-validation (LOOCV) classification error was employed as the quantitative end-point for assessing the effectiveness of a normalization method. In particular, a known classifier, k-nearest neighbor (k-NN), was estimated from data normalized using a given technique, and the LOOCV error rate of the ensuing model was computed. We found that k-NN classifiers are sensitive to dye biases in the data. Using NONRM and GMEDIAN as baseline methods, our results show that single-bias-removal techniques which remove either spatial-dependent dye bias (referred later as spatial effect) or intensity-dependent dye bias (referred later as intensity effect) moderately reduce LOOCV classification errors; whereas double-bias-removal techniques which remove both spatial- and intensity effect reduce LOOCV classification errors even further. Of the 41 different strategies examined, three two-step processes, IGLOESS-SLFILTERW7, ISTSPLINE-SLLOESS and IGLOESS-SLLOESS, all of which removed intensity effect globally and spatial effect locally, appear to reduce LOOCV classification errors most consistently and effectively across all data sets. We also found that the investigated scale normalization methods do not reduce LOOCV classification error.
Conclusion
Using LOOCV error of k-NNs as the evaluation criterion, three double-bias-removal normalization strategies, IGLOESS-SLFILTERW7, ISTSPLINE-SLLOESS and IGLOESS-SLLOESS, outperform other strategies for removing spatial effect, intensity effect and scale differences from cDNA microarray data. The apparent sensitivity of k-NN LOOCV classification error to dye biases suggests that this criterion provides an informative measure for evaluating normalization methods. All the computational tools used in this study were implemented using the R language for statistical computing and graphics.
doi:10.1186/1471-2105-6-191
PMCID: PMC1201132  PMID: 16045803
5.  Stable feature selection and classification algorithms for multiclass microarray data 
Biology Direct  2012;7:33.
Background
Recent studies suggest that gene expression profiles are a promising alternative for clinical cancer classification. One major problem in applying DNA microarrays for classification is the dimension of obtained data sets. In this paper we propose a multiclass gene selection method based on Partial Least Squares (PLS) for selecting genes for classification. The new idea is to solve multiclass selection problem with the PLS method and decomposition to a set of two-class sub-problems: one versus rest (OvR) and one versus one (OvO). We use OvR and OvO two-class decomposition for other recently published gene selection method. Ranked gene lists are highly unstable in the sense that a small change of the data set often leads to big changes in the obtained ordered lists. In this paper, we take a look at the assessment of stability of the proposed methods. We use the linear support vector machines (SVM) technique in different variants: one versus one, one versus rest, multiclass SVM (MSVM) and the linear discriminant analysis (LDA) as a classifier. We use balanced bootstrap to estimate the prediction error and to test the variability of the obtained ordered lists.
Results
This paper focuses on effective identification of informative genes. As a result, a new strategy to find a small subset of significant genes is designed. Our results on real multiclass cancer data show that our method has a very high accuracy rate for different combinations of classification methods, giving concurrently very stable feature rankings.
Conclusions
This paper shows that the proposed strategies can improve the performance of selected gene sets substantially. OvR and OvO techniques applied to existing gene selection methods improve results as well. The presented method allows to obtain a more reliable classifier with less classifier error. In the same time the method generates more stable ordered feature lists in comparison with existing methods.
Reviewers
This article was reviewed by Prof Marek Kimmel, Dr Hans Binder (nominated by Dr Tomasz Lipniacki) and Dr Yuriy Gusev
doi:10.1186/1745-6150-7-33
PMCID: PMC3599581  PMID: 23031190
6.  Class prediction for high-dimensional class-imbalanced data 
BMC Bioinformatics  2010;11:523.
Background
The goal of class prediction studies is to develop rules to accurately predict the class membership of new samples. The rules are derived using the values of the variables available for each subject: the main characteristic of high-dimensional data is that the number of variables greatly exceeds the number of samples. Frequently the classifiers are developed using class-imbalanced data, i.e., data sets where the number of samples in each class is not equal. Standard classification methods used on class-imbalanced data often produce classifiers that do not accurately predict the minority class; the prediction is biased towards the majority class. In this paper we investigate if the high-dimensionality poses additional challenges when dealing with class-imbalanced prediction. We evaluate the performance of six types of classifiers on class-imbalanced data, using simulated data and a publicly available data set from a breast cancer gene-expression microarray study. We also investigate the effectiveness of some strategies that are available to overcome the effect of class imbalance.
Results
Our results show that the evaluated classifiers are highly sensitive to class imbalance and that variable selection introduces an additional bias towards classification into the majority class. Most new samples are assigned to the majority class from the training set, unless the difference between the classes is very large. As a consequence, the class-specific predictive accuracies differ considerably. When the class imbalance is not too severe, down-sizing and asymmetric bagging embedding variable selection work well, while over-sampling does not. Variable normalization can further worsen the performance of the classifiers.
Conclusions
Our results show that matching the prevalence of the classes in training and test set does not guarantee good performance of classifiers and that the problems related to classification with class-imbalanced data are exacerbated when dealing with high-dimensional data. Researchers using class-imbalanced data should be careful in assessing the predictive accuracy of the classifiers and, unless the class imbalance is mild, they should always use an appropriate method for dealing with the class imbalance problem.
doi:10.1186/1471-2105-11-523
PMCID: PMC3098087  PMID: 20961420
7.  New bandwidth selection criterion for Kernel PCA: Approach to dimensionality reduction and classification problems 
BMC Bioinformatics  2014;15:137.
Background
DNA microarrays are potentially powerful technology for improving diagnostic classification, treatment selection, and prognostic assessment. The use of this technology to predict cancer outcome has a history of almost a decade. Disease class predictors can be designed for known disease cases and provide diagnostic confirmation or clarify abnormal cases. The main input to this class predictors are high dimensional data with many variables and few observations. Dimensionality reduction of these features set significantly speeds up the prediction task. Feature selection and feature transformation methods are well known preprocessing steps in the field of bioinformatics. Several prediction tools are available based on these techniques.
Results
Studies show that a well tuned Kernel PCA (KPCA) is an efficient preprocessing step for dimensionality reduction, but the available bandwidth selection method for KPCA was computationally expensive. In this paper, we propose a new data-driven bandwidth selection criterion for KPCA, which is related to least squares cross-validation for kernel density estimation. We propose a new prediction model with a well tuned KPCA and Least Squares Support Vector Machine (LS-SVM). We estimate the accuracy of the newly proposed model based on 9 case studies. Then, we compare its performances (in terms of test set Area Under the ROC Curve (AUC) and computational time) with other well known techniques such as whole data set + LS-SVM, PCA + LS-SVM, t-test + LS-SVM, Prediction Analysis of Microarrays (PAM) and Least Absolute Shrinkage and Selection Operator (Lasso). Finally, we assess the performance of the proposed strategy with an existing KPCA parameter tuning algorithm by means of two additional case studies.
Conclusion
We propose, evaluate, and compare several mathematical/statistical techniques, which apply feature transformation/selection for subsequent classification, and consider its application in medical diagnostics. Both feature selection and feature transformation perform well on classification tasks. Due to the dynamic selection property of feature selection, it is hard to define significant features for the classifier, which predicts classes of future samples. Moreover, the proposed strategy enjoys a distinctive advantage with its relatively lesser time complexity.
doi:10.1186/1471-2105-15-137
PMCID: PMC4025604  PMID: 24886083
8.  Estimating misclassification error: a closer look at cross-validation based methods 
BMC Research Notes  2012;5:656.
Background
To estimate a classifier’s error in predicting future observations, bootstrap methods have been proposed as reduced-variation alternatives to traditional cross-validation (CV) methods based on sampling without replacement. Monte Carlo (MC) simulation studies aimed at estimating the true misclassification error conditional on the training set are commonly used to compare CV methods. We conducted an MC simulation study to compare a new method of bootstrap CV (BCV) to k-fold CV for estimating clasification error.
Findings
For the low-dimensional conditions simulated, the modest positive bias of k-fold CV contrasted sharply with the substantial negative bias of the new BCV method. This behavior was corroborated using a real-world dataset of prognostic gene-expression profiles in breast cancer patients. Our simulation results demonstrate some extreme characteristics of variance and bias that can occur due to a fault in the design of CV exercises aimed at estimating the true conditional error of a classifier, and that appear not to have been fully appreciated in previous studies. Although CV is a sound practice for estimating a classifier’s generalization error, using CV to estimate the fixed misclassification error of a trained classifier conditional on the training set is problematic. While MC simulation of this estimation exercise can correctly represent the average bias of a classifier, it will overstate the between-run variance of the bias.
Conclusions
We recommend k-fold CV over the new BCV method for estimating a classifier’s generalization error. The extreme negative bias of BCV is too high a price to pay for its reduced variance.
doi:10.1186/1756-0500-5-656
PMCID: PMC3556102  PMID: 23190936
Cross-validation; Bootstrap Cross-validation; Classification Error Estimation; Mean Squared Error
9.  On the statistical assessment of classifiers using DNA microarray data 
BMC Bioinformatics  2006;7:387.
Background
In this paper we present a method for the statistical assessment of cancer predictors which make use of gene expression profiles. The methodology is applied to a new data set of microarray gene expression data collected in Casa Sollievo della Sofferenza Hospital, Foggia – Italy. The data set is made up of normal (22) and tumor (25) specimens extracted from 25 patients affected by colon cancer. We propose to give answers to some questions which are relevant for the automatic diagnosis of cancer such as: Is the size of the available data set sufficient to build accurate classifiers? What is the statistical significance of the associated error rates? In what ways can accuracy be considered dependant on the adopted classification scheme? How many genes are correlated with the pathology and how many are sufficient for an accurate colon cancer classification? The method we propose answers these questions whilst avoiding the potential pitfalls hidden in the analysis and interpretation of microarray data.
Results
We estimate the generalization error, evaluated through the Leave-K-Out Cross Validation error, for three different classification schemes by varying the number of training examples and the number of the genes used. The statistical significance of the error rate is measured by using a permutation test. We provide a statistical analysis in terms of the frequencies of the genes involved in the classification. Using the whole set of genes, we found that the Weighted Voting Algorithm (WVA) classifier learns the distinction between normal and tumor specimens with 25 training examples, providing e = 21% (p = 0.045) as an error rate. This remains constant even when the number of examples increases. Moreover, Regularized Least Squares (RLS) and Support Vector Machines (SVM) classifiers can learn with only 15 training examples, with an error rate of e = 19% (p = 0.035) and e = 18% (p = 0.037) respectively. Moreover, the error rate decreases as the training set size increases, reaching its best performances with 35 training examples. In this case, RLS and SVM have error rates of e = 14% (p = 0.027) and e = 11% (p = 0.019). Concerning the number of genes, we found about 6000 genes (p < 0.05) correlated with the pathology, resulting from the signal-to-noise statistic. Moreover the performances of RLS and SVM classifiers do not change when 74% of genes is used. They progressively reduce up to e = 16% (p < 0.05) when only 2 genes are employed. The biological relevance of a set of genes determined by our statistical analysis and the major roles they play in colorectal tumorigenesis is discussed.
Conclusions
The method proposed provides statistically significant answers to precise questions relevant for the diagnosis and prognosis of cancer. We found that, with as few as 15 examples, it is possible to train statistically significant classifiers for colon cancer diagnosis. As for the definition of the number of genes sufficient for a reliable classification of colon cancer, our results suggest that it depends on the accuracy required.
doi:10.1186/1471-2105-7-387
PMCID: PMC1564153  PMID: 16919171
10.  An Empirical Study of Univariate and Genetic Algorithm-Based Feature Selection in Binary Classification with Microarray Data 
Cancer Informatics  2007;2:313-327.
Background
We consider both univariate- and multivariate-based feature selection for the problem of binary classification with microarray data. The idea is to determine whether the more sophisticated multivariate approach leads to better misclassification error rates because of the potential to consider jointly significant subsets of genes (but without overfitting the data).
Methods
We present an empirical study in which 10-fold cross-validation is applied externally to both a univariate-based and two multivariate- (genetic algorithm (GA)-) based feature selection processes. These procedures are applied with respect to three supervised learning algorithms and six published two-class microarray datasets.
Results
Considering all datasets, and learning algorithms, the average 10-fold external cross-validation error rates for the univariate-, single-stage GA-, and two-stage GA-based processes are 14.2%, 14.6%, and 14.2%, respectively. We also find that the optimism bias estimates from the GA analyses were half that of the univariate approach, but the selection bias estimates from the GA analyses were 2.5 times that of the univariate results.
Conclusions
We find that the 10-fold external cross-validation misclassification error rates were very comparable. Further, we find that a two-stage GA approach did not demonstrate a significant advantage over a 1-stage approach. We also find that the univariate approach had higher optimism bias and lower selection bias compared to both GA approaches.
PMCID: PMC2675488  PMID: 19458774
cross-validation; feature selection; supervised-learning; genetic algorithm
11.  Evaluating bias due to data linkage error in electronic healthcare records 
Background
Linkage of electronic healthcare records is becoming increasingly important for research purposes. However, linkage error due to mis-recorded or missing identifiers can lead to biased results. We evaluated the impact of linkage error on estimated infection rates using two different methods for classifying links: highest-weight (HW) classification using probabilistic match weights and prior-informed imputation (PII) using match probabilities.
Methods
A gold-standard dataset was created through deterministic linkage of unique identifiers in admission data from two hospitals and infection data recorded at the hospital laboratories (original data). Unique identifiers were then removed and data were re-linked by date of birth, sex and Soundex using two classification methods: i) HW classification - accepting the candidate record with the highest weight exceeding a threshold and ii) PII–imputing values from a match probability distribution. To evaluate methods for linking data with different error rates, non-random error and different match rates, we generated simulation data. Each set of simulated files was linked using both classification methods. Infection rates in the linked data were compared with those in the gold-standard data.
Results
In the original gold-standard data, 1496/20924 admissions linked to an infection. In the linked original data, PII provided least biased results: 1481 and 1457 infections (upper/lower thresholds) compared with 1316 and 1287 (HW upper/lower thresholds). In the simulated data, substantial bias (up to 112%) was introduced when linkage error varied by hospital. Bias was also greater when the match rate was low or the identifier error rate was high and in these cases, PII performed better than HW classification at reducing bias due to false-matches.
Conclusions
This study highlights the importance of evaluating the potential impact of linkage error on results. PII can help incorporate linkage uncertainty into analysis and reduce bias due to linkage error, without requiring identifiers.
doi:10.1186/1471-2288-14-36
PMCID: PMC4015706  PMID: 24597489
Data linkage; Routine data; Bias; Electronic health records; Evaluation; Linkage quality
12.  Optimally splitting cases for training and testing high dimensional classifiers 
BMC Medical Genomics  2011;4:31.
Background
We consider the problem of designing a study to develop a predictive classifier from high dimensional data. A common study design is to split the sample into a training set and an independent test set, where the former is used to develop the classifier and the latter to evaluate its performance. In this paper we address the question of what proportion of the samples should be devoted to the training set. How does this proportion impact the mean squared error (MSE) of the prediction accuracy estimate?
Results
We develop a non-parametric algorithm for determining an optimal splitting proportion that can be applied with a specific dataset and classifier algorithm. We also perform a broad simulation study for the purpose of better understanding the factors that determine the best split proportions and to evaluate commonly used splitting strategies (1/2 training or 2/3 training) under a wide variety of conditions. These methods are based on a decomposition of the MSE into three intuitive component parts.
Conclusions
By applying these approaches to a number of synthetic and real microarray datasets we show that for linear classifiers the optimal proportion depends on the overall number of samples available and the degree of differential expression between the classes. The optimal proportion was found to depend on the full dataset size (n) and classification accuracy - with higher accuracy and smaller n resulting in more assigned to the training set. The commonly used strategy of allocating 2/3rd of cases for training was close to optimal for reasonable sized datasets (n ≥ 100) with strong signals (i.e. 85% or greater full dataset accuracy). In general, we recommend use of our nonparametric resampling approach for determing the optimal split. This approach can be applied to any dataset, using any predictor development method, to determine the best split.
doi:10.1186/1755-8794-4-31
PMCID: PMC3090739  PMID: 21477282
13.  Entropy-based gene ranking without selection bias for the predictive classification of microarray data 
BMC Bioinformatics  2003;4:54.
Background
We describe the E-RFE method for gene ranking, which is useful for the identification of markers in the predictive classification of array data. The method supports a practical modeling scheme designed to avoid the construction of classification rules based on the selection of too small gene subsets (an effect known as the selection bias, in which the estimated predictive errors are too optimistic due to testing on samples already considered in the feature selection process).
Results
With E-RFE, we speed up the recursive feature elimination (RFE) with SVM classifiers by eliminating chunks of uninteresting genes using an entropy measure of the SVM weights distribution. An optimal subset of genes is selected according to a two-strata model evaluation procedure: modeling is replicated by an external stratified-partition resampling scheme, and, within each run, an internal K-fold cross-validation is used for E-RFE ranking. Also, the optimal number of genes can be estimated according to the saturation of Zipf's law profiles.
Conclusions
Without a decrease of classification accuracy, E-RFE allows a speed-up factor of 100 with respect to standard RFE, while improving on alternative parametric RFE reduction strategies. Thus, a process for gene selection and error estimation is made practical, ensuring control of the selection bias, and providing additional diagnostic indicators of gene importance.
doi:10.1186/1471-2105-4-54
PMCID: PMC293475  PMID: 14604446
14.  SMOTE for high-dimensional class-imbalanced data 
BMC Bioinformatics  2013;14:106.
Background
Classification using class-imbalanced data is biased in favor of the majority class. The bias is even larger for high-dimensional data, where the number of variables greatly exceeds the number of samples. The problem can be attenuated by undersampling or oversampling, which produce class-balanced data. Generally undersampling is helpful, while random oversampling is not. Synthetic Minority Oversampling TEchnique (SMOTE) is a very popular oversampling method that was proposed to improve random oversampling but its behavior on high-dimensional data has not been thoroughly investigated. In this paper we investigate the properties of SMOTE from a theoretical and empirical point of view, using simulated and real high-dimensional data.
Results
While in most cases SMOTE seems beneficial with low-dimensional data, it does not attenuate the bias towards the classification in the majority class for most classifiers when data are high-dimensional, and it is less effective than random undersampling. SMOTE is beneficial for k-NN classifiers for high-dimensional data if the number of variables is reduced performing some type of variable selection; we explain why, otherwise, the k-NN classification is biased towards the minority class. Furthermore, we show that on high-dimensional data SMOTE does not change the class-specific mean values while it decreases the data variability and it introduces correlation between samples. We explain how our findings impact the class-prediction for high-dimensional data.
Conclusions
In practice, in the high-dimensional setting only k-NN classifiers based on the Euclidean distance seem to benefit substantially from the use of SMOTE, provided that variable selection is performed before using SMOTE; the benefit is larger if more neighbors are used. SMOTE for k-NN without variable selection should not be used, because it strongly biases the classification towards the minority class.
doi:10.1186/1471-2105-14-106
PMCID: PMC3648438  PMID: 23522326
15.  Elastic SCAD as a novel penalization method for SVM classification tasks in high-dimensional data 
BMC Bioinformatics  2011;12:138.
Background
Classification and variable selection play an important role in knowledge discovery in high-dimensional data. Although Support Vector Machine (SVM) algorithms are among the most powerful classification and prediction methods with a wide range of scientific applications, the SVM does not include automatic feature selection and therefore a number of feature selection procedures have been developed. Regularisation approaches extend SVM to a feature selection method in a flexible way using penalty functions like LASSO, SCAD and Elastic Net.
We propose a novel penalty function for SVM classification tasks, Elastic SCAD, a combination of SCAD and ridge penalties which overcomes the limitations of each penalty alone.
Since SVM models are extremely sensitive to the choice of tuning parameters, we adopted an interval search algorithm, which in comparison to a fixed grid search finds rapidly and more precisely a global optimal solution.
Results
Feature selection methods with combined penalties (Elastic Net and Elastic SCAD SVMs) are more robust to a change of the model complexity than methods using single penalties. Our simulation study showed that Elastic SCAD SVM outperformed LASSO (L1) and SCAD SVMs. Moreover, Elastic SCAD SVM provided sparser classifiers in terms of median number of features selected than Elastic Net SVM and often better predicted than Elastic Net in terms of misclassification error.
Finally, we applied the penalization methods described above on four publicly available breast cancer data sets. Elastic SCAD SVM was the only method providing robust classifiers in sparse and non-sparse situations.
Conclusions
The proposed Elastic SCAD SVM algorithm provides the advantages of the SCAD penalty and at the same time avoids sparsity limitations for non-sparse data. We were first to demonstrate that the integration of the interval search algorithm and penalized SVM classification techniques provides fast solutions on the optimization of tuning parameters.
The penalized SVM classification algorithms as well as fixed grid and interval search for finding appropriate tuning parameters were implemented in our freely available R package 'penalizedSVM'.
We conclude that the Elastic SCAD SVM is a flexible and robust tool for classification and feature selection tasks for high-dimensional data such as microarray data sets.
doi:10.1186/1471-2105-12-138
PMCID: PMC3113938  PMID: 21554689
16.  A comparison of univariate, vector, bilinear autoregressive, and band power features for brain–computer interfaces 
Selecting suitable feature types is crucial to obtain good overall brain–computer interface performance. Popular feature types include logarithmic band power (logBP), autoregressive (AR) parameters, time-domain parameters, and wavelet-based methods. In this study, we focused on different variants of AR models and compare performance with logBP features. In particular, we analyzed univariate, vector, and bilinear AR models. We used four-class motor imagery data from nine healthy users over two sessions. We used the first session to optimize parameters such as model order and frequency bands. We then evaluated optimized feature extraction methods on the unseen second session. We found that band power yields significantly higher classification accuracies than AR methods. However, we did not update the bias of the classifiers for the second session in our analysis procedure. When updating the bias at the beginning of a new session, we found no significant differences between all methods anymore. Furthermore, our results indicate that subject-specific optimization is not better than globally optimized parameters. The comparison within the AR methods showed that the vector model is significantly better than both univariate and bilinear variants. Finally, adding the prediction error variance to the feature space significantly improved classification results.
doi:10.1007/s11517-011-0828-x
PMCID: PMC3208819  PMID: 21947797
Brain–computer interface; Autoregressive model; Logarithmic band power; Feature extraction; Motor imagery
17.  Systematic Bias in Genomic Classification Due to Contaminating Non-neoplastic Tissue in Breast Tumor Samples 
BMC Medical Genomics  2011;4:54.
Background
Genomic tests are available to predict breast cancer recurrence and to guide clinical decision making. These predictors provide recurrence risk scores along with a measure of uncertainty, usually a confidence interval. The confidence interval conveys random error and not systematic bias. Standard tumor sampling methods make this problematic, as it is common to have a substantial proportion (typically 30-50%) of a tumor sample comprised of histologically benign tissue. This "normal" tissue could represent a source of non-random error or systematic bias in genomic classification.
Methods
To assess the performance characteristics of genomic classification to systematic error from normal contamination, we collected 55 tumor samples and paired tumor-adjacent normal tissue. Using genomic signatures from the tumor and paired normal, we evaluated how increasing normal contamination altered recurrence risk scores for various genomic predictors.
Results
Simulations of normal tissue contamination caused misclassification of tumors in all predictors evaluated, but different breast cancer predictors showed different types of vulnerability to normal tissue bias. While two predictors had unpredictable direction of bias (either higher or lower risk of relapse resulted from normal contamination), one signature showed predictable direction of normal tissue effects. Due to this predictable direction of effect, this signature (the PAM50) was adjusted for normal tissue contamination and these corrections improved sensitivity and negative predictive value. For all three assays quality control standards and/or appropriate bias adjustment strategies can be used to improve assay reliability.
Conclusions
Normal tissue sampled concurrently with tumor is an important source of bias in breast genomic predictors. All genomic predictors show some sensitivity to normal tissue contamination and ideal strategies for mitigating this bias vary depending upon the particular genes and computational methods used in the predictor.
doi:10.1186/1755-8794-4-54
PMCID: PMC3151208  PMID: 21718502
biomarker validation; genomic assays; breast cancer; normal tissue; bias
18.  A comparative study of different machine learning methods on microarray gene expression data 
BMC Genomics  2008;9(Suppl 1):S13.
Background
Several classification and feature selection methods have been studied for the identification of differentially expressed genes in microarray data. Classification methods such as SVM, RBF Neural Nets, MLP Neural Nets, Bayesian, Decision Tree and Random Forrest methods have been used in recent studies. The accuracy of these methods has been calculated with validation methods such as v-fold validation. However there is lack of comparison between these methods to find a better framework for classification, clustering and analysis of microarray gene expression results.
Results
In this study, we compared the efficiency of the classification methods including; SVM, RBF Neural Nets, MLP Neural Nets, Bayesian, Decision Tree and Random Forrest methods. The v-fold cross validation was used to calculate the accuracy of the classifiers. Some of the common clustering methods including K-means, DBC, and EM clustering were applied to the datasets and the efficiency of these methods have been analysed. Further the efficiency of the feature selection methods including support vector machine recursive feature elimination (SVM-RFE), Chi Squared, and CSF were compared. In each case these methods were applied to eight different binary (two class) microarray datasets. We evaluated the class prediction efficiency of each gene list in training and test cross-validation using supervised classifiers.
Conclusions
We presented a study in which we compared some of the common used classification, clustering, and feature selection methods. We applied these methods to eight publicly available datasets, and compared how these methods performed in class prediction of test datasets. We reported that the choice of feature selection methods, the number of genes in the gene list, the number of cases (samples) substantially influence classification success. Based on features chosen by these methods, error rates and accuracy of several classification algorithms were obtained. Results revealed the importance of feature selection in accurately classifying new samples and how an integrated feature selection and classification algorithm is performing and is capable of identifying significant genes.
doi:10.1186/1471-2164-9-S1-S13
PMCID: PMC2386055  PMID: 18366602
19.  A new method for class prediction based on signed-rank algorithms applied to Affymetrix® microarray experiments 
BMC Bioinformatics  2008;9:16.
Background
The huge amount of data generated by DNA chips is a powerful basis to classify various pathologies. However, constant evolution of microarray technology makes it difficult to mix data from different chip types for class prediction of limited sample populations. Affymetrix® technology provides both a quantitative fluorescence signal and a decision (detection call: absent or present) based on signed-rank algorithms applied to several hybridization repeats of each gene, with a per-chip normalization. We developed a new prediction method for class belonging based on the detection call only from recent Affymetrix chip type. Biological data were obtained by hybridization on U133A, U133B and U133Plus 2.0 microarrays of purified normal B cells and cells from three independent groups of multiple myeloma (MM) patients.
Results
After a call-based data reduction step to filter out non class-discriminative probe sets, the gene list obtained was reduced to a predictor with correction for multiple testing by iterative deletion of probe sets that sequentially improve inter-class comparisons and their significance. The error rate of the method was determined using leave-one-out and 5-fold cross-validation. It was successfully applied to (i) determine a sex predictor with the normal donor group classifying gender with no error in all patient groups except for male MM samples with a Y chromosome deletion, (ii) predict the immunoglobulin light and heavy chains expressed by the malignant myeloma clones of the validation group and (iii) predict sex, light and heavy chain nature for every new patient. Finally, this method was shown powerful when compared to the popular classification method Prediction Analysis of Microarray (PAM).
Conclusion
This normalization-free method is routinely used for quality control and correction of collection errors in patient reports to clinicians. It can be easily extended to multiple class prediction suitable with clinical groups, and looks particularly promising through international cooperative projects like the "Microarray Quality Control project of US FDA" MAQC as a predictive classifier for diagnostic, prognostic and response to treatment. Finally, it can be used as a powerful tool to mine published data generated on Affymetrix systems and more generally classify samples with binary feature values.
doi:10.1186/1471-2105-9-16
PMCID: PMC2248160  PMID: 18190711
20.  Loss Function Based Ranking in Two-Stage, Hierarchical Models 
Bayesian analysis (Online)  2006;1(4):915-946.
Performance evaluations of health services providers burgeons. Similarly, analyzing spatially related health information, ranking teachers and schools, and identification of differentially expressed genes are increasing in prevalence and importance. Goals include valid and efficient ranking of units for profiling and league tables, identification of excellent and poor performers, the most differentially expressed genes, and determining “exceedances” (how many and which unit-specific true parameters exceed a threshold). These data and inferential goals require a hierarchical, Bayesian model that accounts for nesting relations and identifies both population values and random effects for unit-specific parameters. Furthermore, the Bayesian approach coupled with optimizing a loss function provides a framework for computing non-standard inferences such as ranks and histograms.
Estimated ranks that minimize Squared Error Loss (SEL) between the true and estimated ranks have been investigated. The posterior mean ranks minimize SEL and are “general purpose,” relevant to a broad spectrum of ranking goals. However, other loss functions and optimizing ranks that are tuned to application-specific goals require identification and evaluation. For example, when the goal is to identify the relatively good (e.g., in the upper 10%) or relatively poor performers, a loss function that penalizes classification errors produces estimates that minimize the error rate. We construct loss functions that address this and other goals, developing a unified framework that facilitates generating candidate estimates, comparing approaches and producing data analytic performance summaries. We compare performance for a fully parametric, hierarchical model with Gaussian sampling distribution under Gaussian and a mixture of Gaussians prior distributions. We illustrate approaches via analysis of standardized mortality ratio data from the United States Renal Data System.
Results show that SEL-optimal ranks perform well over a broad class of loss functions but can be improved upon when classifying units above or below a percentile cut-point. Importantly, even optimal rank estimates can perform poorly in many real-world settings; therefore, data-analytic performance summaries should always be reported.
doi:10.1214/06-BA130
PMCID: PMC2896056  PMID: 20607112
percentiling; Bayesian models; decision theory; operating characteristic
21.  Class-Specific Weighting for Markov Random Field Estimation: Application to Medical Image Segmentation 
Medical image analysis  2012;16(8):1477-1489.
Many estimation tasks require Bayesian classifiers capable of adjusting their performance (e.g. sensitivity/Specificity). In situations where the optimal classification decision can be identified by an exhaustive search over all possible classes, means for adjusting classifier performance, such as probability thresholding or weighting the a posteriori probabilities, are well established. Unfortunately, analogous methods compatible with Markov random fields (i.e. large collections of dependent random variables) are noticeably absent from the literature. Consequently, most Markov random field (MRF) based classification systems typically restrict their performance to a single, static operating point (i.e. a paired sensitivity/Specificity). To address this deficiency, we previously introduced an extension of maximum posterior marginals (MPM) estimation that allows certain classes to be weighted more heavily than others, thus providing a means for varying classifier performance. However, this extension is not appropriate for the more popular maximum a posteriori (MAP) estimation. Thus, a strategy for varying the performance of MAP estimators is still needed. Such a strategy is essential for several reasons: 1) the MAP cost function may be more appropriate in certain classification tasks than the MPM cost function, 2) the literature provides a surfeit of MAP estimation implementations, several of which are considerably faster than the typical Markov Chain Monte Carlo methods used for MPM, and 3) MAP estimation is used far more often than MPM. Consequently, in this paper we introduce multiplicative weighted MAP (MWMAP) estimation — achieved via the incorporation of multiplicative weights into the MAP cost function — which allows certain classes to be preferred over others. This creates a natural bias for Specific classes, and consequently a means for adjusting classifier performance. Similarly, we show how this multiplicative weighting strategy can be applied to the MPM cost function (in place of the strategy we presented previously), yielding multiplicative weighted MPM (MWMPM) estimation. Furthermore, we describe how MWMAP and MWMPM can be implemented using adaptations of current estimation strategies such as iterated conditional modes and MPM Monte Carlo. To illustrate these implementations, we first integrate them into two separate MRF-based classification systems for detecting carcinoma of the prostate (CaP) on 1) digitized histological sections from radical prostatectomies and 2) T2-weighted 4 Tesla ex vivo prostate MRI. To highlight the extensibility of MWMAP and MWMPM to estimation tasks involving more than two classes, we also incorporate these estimation criteria into a MRF-based classifier used to segment synthetic brain MR images. In the context of these tasks, we show how our novel estimation criteria can be used to arbitrarily adjust the sensitivities of these systems, yielding receiver operator characteristic curves (and surfaces).
doi:10.1016/j.media.2012.06.007
PMCID: PMC3508385  PMID: 22986078
Markov Random Fields; Prostate Cancer Detection; Histology; Digital Pathology; Magnetic Resonance Imaging; Maximum Posterior Marginals; Maximum a Posteriori
22.  Improved variance estimation of classification performance via reduction of bias caused by small sample size 
BMC Bioinformatics  2006;7:127.
Background
Supervised learning for classification of cancer employs a set of design examples to learn how to discriminate between tumors. In practice it is crucial to confirm that the classifier is robust with good generalization performance to new examples, or at least that it performs better than random guessing. A suggested alternative is to obtain a confidence interval of the error rate using repeated design and test sets selected from available examples. However, it is known that even in the ideal situation of repeated designs and tests with completely novel samples in each cycle, a small test set size leads to a large bias in the estimate of the true variance between design sets. Therefore different methods for small sample performance estimation such as a recently proposed procedure called Repeated Random Sampling (RSS) is also expected to result in heavily biased estimates, which in turn translates into biased confidence intervals. Here we explore such biases and develop a refined algorithm called Repeated Independent Design and Test (RIDT).
Results
Our simulations reveal that repeated designs and tests based on resampling in a fixed bag of samples yield a biased variance estimate. We also demonstrate that it is possible to obtain an improved variance estimate by means of a procedure that explicitly models how this bias depends on the number of samples used for testing. For the special case of repeated designs and tests using new samples for each design and test, we present an exact analytical expression for how the expected value of the bias decreases with the size of the test set.
Conclusion
We show that via modeling and subsequent reduction of the small sample bias, it is possible to obtain an improved estimate of the variance of classifier performance between design sets. However, the uncertainty of the variance estimate is large in the simulations performed indicating that the method in its present form cannot be directly applied to small data sets.
doi:10.1186/1471-2105-7-127
PMCID: PMC1435937  PMID: 16533392
23.  Rough sets for in silico identification of differentially expressed miRNAs 
International Journal of Nanomedicine  2013;8(Suppl 1):63-74.
The microRNAs, also known as miRNAs, are the class of small noncoding RNAs. They repress the expression of a gene posttranscriptionally. In effect, they regulate expression of a gene or protein. It has been observed that they play an important role in various cellular processes and thus help in carrying out normal functioning of a cell. However, dysregulation of miRNAs is found to be a major cause of a disease. Various studies have also shown the role of miRNAs in cancer and the utility of miRNAs for the diagnosis of cancer and other diseases. Unlike with mRNAs, a modest number of miRNAs might be sufficient to classify human cancers. However, the absence of a robust method to identify differentially expressed miRNAs makes this an open problem. In this regard, this paper presents a novel approach for in silico identification of differentially expressed miRNAs from microarray expression data sets. It integrates judiciously the theory of rough sets and merit of the so-called B.632+ bootstrap error estimate. While rough sets select relevant and significant miRNAs from expression data, the B.632+ error rate minimizes the variability and bias of the derived results. The effectiveness of the proposed approach, along with a comparison with other related approaches, is demonstrated on several miRNA microarray expression data sets, using the support vector machine.
doi:10.2147/IJN.S40739
PMCID: PMC3790281  PMID: 24098080
microRNA; feature selection; bootstrap error; support vector machine
24.  Development of a microarray platform for FFPET profiling: application to the classification of human tumors 
Background
mRNA profiling has become an important tool for developing and validating prognostic assays predictive of disease treatment response and outcome. Archives of annotated formalin-fixed paraffin-embedded tissues (FFPET) are available as a potential source for retrospective studies. Methods are needed to profile these FFPET samples that are linked to clinical outcomes to generate hypotheses that could lead to classifiers for clinical applications.
Methods
We developed a two-color microarray-based profiling platform by optimizing target amplification, experimental design, quality control, and microarray content and applied it to the profiling of FFPET samples. We profiled a set of 50 fresh frozen (FF) breast cancer samples and assigned class labels according to the signature and method by van 't Veer et al [1] and then profiled 50 matched FFPET samples to test how well the FFPET data predicted the class labels. We also compared the sorting power of classifiers derived from FFPET sample data with classifiers derived from data from matched FF samples.
Results
When a classifier developed with matched FF samples was applied to FFPET data to assign samples to either "good" or "poor" outcome class labels, the classifier was able to assign the FFPET samples to the correct class label with an average error rate = 12% to 16%, respectively, with an Odds Ratio = 36.4 to 60.4, respectively. A classifier derived from FFPET data was able to predict the class label in FFPET samples (leave-one-out cross validation) with an error rate of ~14% (p-value = 3.7 × 10-7). When applied to the matched FF samples, the FFPET-derived classifier was able to assign FF samples to the correct class labels with 96% accuracy. The single misclassification was attributed to poor sample quality, as measured by qPCR on total RNA, which emphasizes the need for sample quality control before profiling.
Conclusion
We have optimized a platform for expression analyses and have shown that our profiling platform is able to accurately sort FFPET samples into class labels derived from FF classifiers. Furthermore, using this platform, a classifier derived from FFPET samples can reliably provide the same sorting power as a classifier derived from matched FF samples. We anticipate that these techniques could be used to generate hypotheses from archives of FFPET samples, and thus may lead to prognostic and predictive classifiers that could be used, for example, to segregate patients for clinical trial enrollment or to guide patient treatment.
doi:10.1186/1479-5876-7-65
PMCID: PMC2732596  PMID: 19638234
25.  Classification across gene expression microarray studies 
BMC Bioinformatics  2009;10:453.
Background
The increasing number of gene expression microarray studies represents an important resource in biomedical research. As a result, gene expression based diagnosis has entered clinical practice for patient stratification in breast cancer. However, the integration and combined analysis of microarray studies remains still a challenge. We assessed the potential benefit of data integration on the classification accuracy and systematically evaluated the generalization performance of selected methods on four breast cancer studies comprising almost 1000 independent samples. To this end, we introduced an evaluation framework which aims to establish good statistical practice and a graphical way to monitor differences. The classification goal was to correctly predict estrogen receptor status (negative/positive) and histological grade (low/high) of each tumor sample in an independent study which was not used for the training. For the classification we chose support vector machines (SVM), predictive analysis of microarrays (PAM), random forest (RF) and k-top scoring pairs (kTSP). Guided by considerations relevant for classification across studies we developed a generalization of kTSP which we evaluated in addition. Our derived version (DV) aims to improve the robustness of the intrinsic invariance of kTSP with respect to technologies and preprocessing.
Results
For each individual study the generalization error was benchmarked via complete cross-validation and was found to be similar for all classification methods. The misclassification rates were substantially higher in classification across studies, when each single study was used as an independent test set while all remaining studies were combined for the training of the classifier. However, with increasing number of independent microarray studies used in the training, the overall classification performance improved. DV performed better than the average and showed slightly less variance. In particular, the better predictive results of DV in across platform classification indicate higher robustness of the classifier when trained on single channel data and applied to gene expression ratios.
Conclusions
We present a systematic evaluation of strategies for the integration of independent microarray studies in a classification task. Our findings in across studies classification may guide further research aiming on the construction of more robust and reliable methods for stratification and diagnosis in clinical practice.
doi:10.1186/1471-2105-10-453
PMCID: PMC2811711  PMID: 20042109

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