To be more informative, the thresholds are therefore mapped to the original ones using Euclidean distance. Thresholds are then sorted by GSI-IX mw frequency and the Q first thresholds of each biomarker are selected for an exhaustive search. At the programming level, the ICBT search was optimized to run faster. First, it was implemented in the compiled programming language Java, which typically runs much faster than interpreted languages such as R, Perl or Python. Efficient implementation was achieved by minimizing the creation of objects, using explicit programmatic loops instead of recursion, and multithreading. Biomarkers

with missing values are ignored. Missing value imputations must be performed before submitting the data to PanelomiX (see [23] for an in-depth review of this topic). Cross-validation is a simple and widely used computational method to assess a classification model’s performance and robustness [1] and [10]. PanelomiX features a CV procedure for panel verification [10]. Its primary goal is to test panel performance in an unbiased manner and to produce graphical diagnostic plots for evaluating consistency and robustness. After CV, ROC analyses are performed on the individual

biomarkers and Gefitinib mouse the panel, and several plots are generated to assess the quality of the data. A standard, k-fold cross-validation (CV) scheme is used to compare the different models generated. To avoid model-to-model scoring differences and make predictions comparable between the CV steps, which may produce panels of different lengths with different Ts, the

prediction is centred as follows: Yp=Sp−TsYp=Sp−Ts equation(5) Zp(Yp)=Yp/Ts,Yp<0Yp/(n−Ts),Yp>0As a result, the centred vector Z of patient scores is in the [−1;+1] interval and Ts = 0. We perform ROC analysis of the curves of both the individual biomarkers and the panels using the pROC tool [22] in R [24]. Three tables are generated showing AUC, sensitivity, and specificity, all with confidence intervals. The first table reports the ROC performance of single biomarkers and their best univariate thresholds; the second table shows the oxyclozanide comparison of the panel with the best individual biomarker (analysed as a panel composed of 1 biomarker, to be comparable with the other panels); and the third table compares the ICBT panel with other classic combination methods. Comparisons between two AUCs are performed using DeLong’s test [25] and between two pAUCs using the bootstrap test [22] with 10 000 stratified replicates. The ROC curves of the CV are built as the mean of centred predictions over the k CV folds. For the CV of the individual biomarkers, the ICBT algorithm is applied with n = 1 and no other modification. Users can access a password-protected server implementing the algorithms described in this article from the following website: http://www.panelomix.net.