Dataset Information

Enhanced ranking of PknB Inhibitors using data fusion methods.

ABSTRACT: BACKGROUND:Mycobacterium tuberculosis encodes 11 putative serine-threonine proteins Kinases (STPK) which regulates transcription, cell development and interaction with the host cells. From the 11 STPKs three kinases namely PknA, PknB and PknG have been related to the mycobacterial growth. From previous studies it has been observed that PknB is essential for mycobacterial growth and expressed during log phase of the growth and phosphorylates substrates involved in peptidoglycan biosynthesis. In recent years many high affinity inhibitors are reported for PknB. Previously implementation of data fusion has shown effective enrichment of active compounds in both structure and ligand based approaches .In this study we have used three types of data fusion ranking algorithms on the PknB dataset namely, sum rank, sum score and reciprocal rank. We have identified reciprocal rank algorithm is capable enough to select compounds earlier in a virtual screening process. We have also screened the Asinex database with reciprocal rank algorithm to identify possible inhibitors for PknB. RESULTS:In our work we have used both structure-based and ligand-based approaches for virtual screening, and have combined their results using a variety of data fusion methods. We found that data fusion increases the chance of actives being ranked highly. Specifically, we found that the ranking of Pharmacophore search, ROCS and Glide XP fused with a reciprocal ranking algorithm not only outperforms structure and ligand based approaches but also capable of ranking actives better than the other two data fusion methods using the BEDROC, robust initial enhancement (RIE) and AUC metrics. These fused results were used to identify 45 candidate compounds for further experimental validation. CONCLUSION:We show that very different structure and ligand based methods for predicting drug-target interactions can be combined effectively using data fusion, outperforming any single method in ranking of actives. Such fused results show promise for a coherent selection of candidates for biological screening.

SUBMITTER: Seal A

PROVIDER: S-EPMC3600029 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Enhanced ranking of PknB Inhibitors using data fusion methods.

Seal Abhik A Yogeeswari Perumal P Sriram Dharmaranjan D Wild David J DJ

Journal of cheminformatics 20130114 1

<h4>Background</h4>Mycobacterium tuberculosis encodes 11 putative serine-threonine proteins Kinases (STPK) which regulates transcription, cell development and interaction with the host cells. From the 11 STPKs three kinases namely PknA, PknB and PknG have been related to the mycobacterial growth. From previous studies it has been observed that PknB is essential for mycobacterial growth and expressed during log phase of the growth and phosphorylates substrates involved in peptidoglycan biosynthes ...[more]

PMID: 23317154

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Project description:Study designRetrospective analysis of administrative billing data.ObjectiveTo evaluate the extent to which a metric of serious complications determined from administrative data can reliably profile hospital performance in spine fusion surgery.Summary of background dataWhile payers are increasingly focused on implementing pay-for-performance measures, quality metrics must reliably reflect true differences in performance among the hospitals profiled.MethodsWe used State Inpatient Databases from nine states to characterize serious complications after elective cervical and thoracolumbar fusion. Hierarchical logistic regression was used to risk-adjust differences in case mix, along with variability from low case volumes. The reliability of this risk-stratified complication rate (RSCR) was assessed as the variation between hospitals that was not due to chance alone, calculated separately by fusion type and year. Finally, we estimated the proportion of hospitals that had sufficient case volumes to obtain reliable (>0.7) complication estimates.ResultsFrom 2010 to 2017 we identified 154,078 cervical and 213,133 thoracolumbar fusion surgeries. 4.2% of cervical fusion patients had a serious complication, and the median RSCR increased from 4.2% in 2010 to 5.5% in 2017. The reliability of the RSCR for cervical fusion was poor and varied substantially by year (range 0.04-0.28). Overall, 7.7% of thoracolumbar fusion patients experienced a serious complication, and the RSCR varied from 6.8% to 8.0% during the study period. Although still modest, the RSCR reliability was higher for thoracolumbar fusion (range 0.16-0.43). Depending on the study year, 0% to 4.5% of hospitals had sufficient cervical fusion case volume to report reliable (>0.7) estimates, whereas 15% to 36% of hospitals reached this threshold for thoracolumbar fusion.ConclusionA metric of serious complications was unreliable for benchmarking cervical fusion outcomes and only modestly reliable for thoracolumbar fusion. When assessed using administrative datasets, these measures appear inappropriate for high-stakes applications, such as public reporting or pay-for-performance.Level of Evidence: 3.

Project description:BackgroundTo identify differentially expressed genes (DEGs) from microarray data, users of the Affymetrix GeneChip system need to select both a preprocessing algorithm to obtain expression-level measurements and a way of ranking genes to obtain the most plausible candidates. We recently recommended suitable combinations of a preprocessing algorithm and gene ranking method that can be used to identify DEGs with a higher level of sensitivity and specificity. However, in addition to these recommendations, researchers also want to know which combinations enhance reproducibility.ResultsWe compared eight conventional methods for ranking genes: weighted average difference (WAD), average difference (AD), fold change (FC), rank products (RP), moderated t statistic (modT), significance analysis of microarrays (samT), shrinkage t statistic (shrinkT), and intensity-based moderated t statistic (ibmT) with six preprocessing algorithms (PLIER, VSN, FARMS, multi-mgMOS (mmgMOS), MBEI, and GCRMA). A total of 36 real experimental datasets was evaluated on the basis of the area under the receiver operating characteristic curve (AUC) as a measure for both sensitivity and specificity. We found that the RP method performed well for VSN-, FARMS-, MBEI-, and GCRMA-preprocessed data, and the WAD method performed well for mmgMOS-preprocessed data. Our analysis of the MicroArray Quality Control (MAQC) project's datasets showed that the FC-based gene ranking methods (WAD, AD, FC, and RP) had a higher level of reproducibility: The percentages of overlapping genes (POGs) across different sites for the FC-based methods were higher overall than those for the t-statistic-based methods (modT, samT, shrinkT, and ibmT). In particular, POG values for WAD were the highest overall among the FC-based methods irrespective of the choice of preprocessing algorithm.ConclusionOur results demonstrate that to increase sensitivity, specificity, and reproducibility in microarray analyses, we need to select suitable combinations of preprocessing algorithms and gene ranking methods. We recommend the use of FC-based methods, in particular RP or WAD.

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Enhanced ranking of PknB Inhibitors using data fusion methods.

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Enhanced ranking of PknB Inhibitors using data fusion methods.

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