Transcriptome signature reversion (TSR) has been extensively proposed and used to discover new indications for existing drugs (i.e. drug repositioning, drug repurposing) for various cancer types. TSR relies on the assumption that a drug that can revert gene expression changes induced by a disease back to original, i.e. healthy, levels is likely to be therapeutically active in treating the disease. Here, we aimed to validate the concept of TSR using the PRISM repurposing data set, which is-as of writing-the largest pharmacogenomic data set. The predictive utility of the TSR approach as it has currently been used appears to be much lower than previously reported and is completely nullified after the drug gene expression signatures are adjusted for the general anti-proliferative downstream effects of drug-induced decreased cell viability. Therefore, TSR mainly relies on generic anti-proliferative drug effects rather than on targeting cancer pathways specifically upregulated in tumor types.

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).

In this paper, we present a novel approach to automatic 3D facial landmarking using 2D Gabor wavelets. Our algorithm considers the face to be a surface and uses map projections to derive 2D features from raw data. Extracted features include texture, relief map, and transformations thereof. We extend an established 2D landmarking method for simultaneous evaluation of these data. The method is validated by performing landmarking experiments on two data sets using 21 landmarks and compared with an active shape model implementation. On average, landmarking error for our method was 1.9 mm, whereas the active shape model resulted in an average landmarking error of 2.3 mm. A second study investigating facial shape heritability in related individuals concludes that automatic landmarking is on par with manual landmarking for some landmarks. Our algorithm can be trained in 30 min to automatically landmark 3D facial data sets of any size, and allows for fast and robust landmarking of 3D faces.