Use of structure-activity landscape index curves and curve integrals to evaluate the performance of multiple machine learning prediction models

<p>Abstract</p> <p>Background</p> <p>Standard approaches to address the performance of predictive models that used common statistical measurements for the entire data set provide an overview of the average performance of the models across the entire predictive space, but give little insight into applicability of the model across the prediction space. Guha and Van Drie recently proposed the use of structure-activity landscape index (SALI) curves via the SALI curve integral (SCI) as a means to map the predictive power of computational models within the predictive space. This approach evaluates model performance by assessing the accuracy of pairwise predictions, comparing compound pairs in a manner similar to that done by medicinal chemists.</p> <p>Results</p> <p>The SALI approach was used to evaluate the performance of continuous prediction models for MDR1-MDCK <it>in vitro </it>efflux potential. Efflux models were built with ADMET Predictor neural net, support vector machine, kernel partial least squares, and multiple linear regression engines, as well as SIMCA-P+ partial least squares, and random forest from Pipeline Pilot as implemented by AstraZeneca, using molecular descriptors from <it>SimulationsPlus </it>and AstraZeneca.</p> <p>Conclusion</p> <p>The results indicate that the choice of training sets used to build the prediction models is of great importance in the resulting model quality and that the SCI values calculated for these models were very similar to their Kendall τ values, leading to our suggestion of an approach to use this SALI/SCI paradigm to evaluate predictive model performance that will allow more informed decisions regarding model utility. The use of SALI graphs and curves provides an additional level of quality assessment for predictive models.</p

Sequence and characterisation of the RET proto-oncogene 5′ flanking region: analysis of retinoic acid responsiveness at the transcriptional level

AbstractThe RET proto-oncogene encodes a receptor tyrosine kinase expressed during neural crest development. RET expression is enhanced in vitro by several differentiating agents, including retinoic acid (RA), which up-regulates RET expression in neuroblastoma cell lines. In the present work we sequenced and analysed a 5 kbp genomic fragment 5′ to RET. Three deletion fragments of this region were tested for their RA inducibility in transient transfection assays and failed to support the hypothesis of a direct transcriptional activation. Finally, our functional analysis of a candidate RA response element present in the RET promoter provides new hints for the understanding of the interaction between nuclear receptors and their specific recognition sites