Few amino acid positions in rpoB are associated with most of the rifampin resistance in Mycobacterium tuberculosis

dc.contributor.authorCummings, Michael P
dc.contributor.authorSegal, Mark R
dc.description.abstractMutations in rpoB, the gene encoding the β subunit of DNA-dependent RNA polymerase, are associated with rifampin resistance in Mycobacterium tuberculosis. Several studies have been conducted where minimum inhibitory concentration (MIC, which is defined as the minimum concentration of the antibiotic in a given culture medium below which bacterial growth is not inhibited) of rifampin has been measured and partial DNA sequences have been determined for rpoB in different isolates of M. tuberculosis. However, no model has been constructed to predict rifampin resistance based on sequence information alone. Such a model might provide the basis for quantifying rifampin resistance status based exclusively on DNA sequence data and thus eliminate the requirements for time consuming culturing and antibiotic testing of clinical isolates. Sequence data for amino acid positions 511–533 of rpoB and associated MIC of rifampin for different isolates of M. tuberculosis were taken from studies examining rifampin resistance in clinical samples from New York City and throughout Japan. We used tree-based statistical methods and random forests to generate models of the relationships between rpoB amino acid sequence and rifampin resistance. The proportion of variance explained by a relatively simple tree-based cross-validated regression model involving two amino acid positions (526 and 531) is 0.679. The first partition in the data, based on position 531, results in groups that differ one hundredfold in mean MIC (1.596 μg/ml and 159.676 μg/ml). The subsequent partition based on position 526, the most variable in this region, results in a > 354-fold difference in MIC. When considered as a classification problem (susceptible or resistant), a cross-validated tree-based model correctly classified most (0.884) of the observations and was very similar to the regression model. Random forest analysis of the MIC data as a continuous variable, a regression problem, produced a model that explained 0.861 of the variance. The random forest analysis of the MIC data as discrete classes produced a model that correctly classified 0.942 of the observations with sensitivity of 0.958 and specificity of 0.885. Highly accurate regression and classification models of rifampin resistance can be made based on this short sequence region. Models may be better with improved (and consistent) measurements of MIC and more sequence data.en_US
dc.identifier.citationCummings, M.P., Segal, M.R. Few amino acid positions in rpoB are associated with most of the rifampin resistance in Mycobacterium tuberculosis. BMC Bioinformatics 5, 137 (2004).en_US
dc.publisherSpringer Natureen_US
dc.relation.isAvailableAtCollege of Computer, Mathematical & Physical Sciencesen_us
dc.relation.isAvailableAtDigital Repository at the University of Marylanden_us
dc.relation.isAvailableAtUniversity of Maryland (College Park, MD)en_us
dc.subjectMinimum Inhibitory Concentrationen_US
dc.subjectRandom Foresten_US
dc.subjectAmino Acid Positionen_US
dc.subjectRandom Forest Analysisen_US
dc.titleFew amino acid positions in rpoB are associated with most of the rifampin resistance in Mycobacterium tuberculosisen_US


Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
220.79 KB
Adobe Portable Document Format
License bundle
Now showing 1 - 1 of 1
No Thumbnail Available
1.57 KB
Item-specific license agreed upon to submission