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Background  Batch effects were not accounted for in most of the studies of computational drug repositioning based on gene expression signatures. It is unknown how batch effect removal methods impact the results of signature-based drug repositioning. Herein, we conducted differential analyses on the Connectivity Map (CMAP) database using several batch effect correction methods to evaluate the influence of batch effect correction methods on computational drug repositioning using microarray data and compare several batch effect correction methods.    Results  Differences in average signature size were observed with different methods applied. The gene signatures identified by the Latent Effect Adjustment after Primary Projection (LEAPP) method and the methods fitted with Linear Models for Microarray Data ( limma ) software demonstrated little agreement. The external validity of the gene signatures was evaluated by connectivity mapping between the CMAP database and the Library of Integrated Network-based Cellular Signatures (LINCS) database. The results of connectivity mapping indicate that the genes identified were not reliable for drugs with total sample size (drug + control samples) smaller than 40, irrespective of the batch effect correction method applied. With total sample size larger than 40, the methods correcting for batch effects produced significantly better results than the method with no batch effect correction. In a simulation study, the power was generally low for simulated data with sample size smaller than 40. We observed best performance when using the  limma  method correcting for two principal components.    Conclusion  Batch effect correction methods strongly impact differential gene expression analysis when the sample size is large enough to contain sufficient information and thus the downstream drug repositioning. We recommend including two or three principal components as covariates in fitting models with  limma  when sample size is sufficient (larger than 40 drug and controls combined).    Electronic supplementary material  The online version of this article (10.1186/s12859-019-3028-6) contains supplementary material, which is available to authorized users.

Influence of batch effect correction methods on drug induced differential gene expression profiles