Genome-wide analysis captures the determinants of the antibiotic cross-resistance interaction network.

Understanding how evolution of antimicrobial resistance increases resistance to other drugs is a challenge of profound importance. By combining experimental evolution and genome sequencing of 63 laboratory-evolved lines, we charted a map of cross-resistance interactions between antibiotics in Escherichia coli, and explored the driving evolutionary principles. Here, we show that (1) convergent molecular evolution is prevalent across antibiotic treatments, (2) resistance conferring mutations simultaneously enhance sensitivity to many other drugs and (3) 27% of the accumulated mutations generate proteins with compromised activities, suggesting that antibiotic adaptation can partly be achieved without gain of novel function. By using knowledge on antibiotic properties, we examined the determinants of cross-resistance and identified chemogenomic profile similarity between antibiotics as the strongest predictor. In contrast, cross-resistance between two antibiotics is independent of whether they show synergistic effects in combination. These results have important implications on the development of novel antimicrobial strategies.

Antagonism between bacteriostatic and bactericidal antibiotics is prevalent.

Combination therapy is rarely used to counter the evolution of resistance in bacterial infections. Expansion of the use of combination therapy requires knowledge of how drugs interact at inhibitory concentrations. More than 50 years ago, it was noted that, if bactericidal drugs are most potent with actively dividing cells, then the inhibition of growth induced by a bacteriostatic drug should result in an overall reduction of efficacy when the drug is used in combination with a bactericidal drug. Our goal here was to investigate this hypothesis systematically. We first constructed time-kill curves using five different antibiotics at clinically relevant concentrations, and we observed antagonism between bactericidal and bacteriostatic drugs. We extended our investigation by performing a screen of pairwise combinations of 21 different antibiotics at subinhibitory concentrations, and we found that strong antagonistic interactions were enriched significantly among combinations of bacteriostatic and bactericidal drugs. Finally, since our hypothesis relies on phenotypic effects produced by different drug classes, we recreated these experiments in a microfluidic device and performed time-lapse microscopy to directly observe and quantify the growth and division of individual cells with controlled antibiotic concentrations. While our single-cell observations supported the antagonism between bacteriostatic and bactericidal drugs, they revealed an unexpected variety of cellular responses to antagonistic drug combinations, suggesting that multiple mechanisms underlie the interactions.

Bacterial evolution of antibiotic hypersensitivity.

The evolution of resistance to a single antibiotic is frequently accompanied by increased resistance to multiple other antimicrobial agents. In sharp contrast, very little is known about the frequency and mechanisms underlying collateral sensitivity. In this case, genetic adaptation under antibiotic stress yields enhanced sensitivity to other antibiotics. Using large-scale laboratory evolutionary experiments with Escherichia coli, we demonstrate that collateral sensitivity occurs frequently during the evolution of antibiotic resistance. Specifically, populations adapted to aminoglycosides have an especially low fitness in the presence of several other antibiotics. Whole-genome sequencing of laboratory-evolved strains revealed multiple mechanisms underlying aminoglycoside resistance, including a reduction in the proton-motive force (PMF) across the inner membrane. We propose that as a side effect, these mutations diminish the activity of PMF-dependent major efflux pumps (including the AcrAB transporter), leading to hypersensitivity to several other antibiotics. More generally, our work offers an insight into the mechanisms that drive the evolution of negative trade-offs under antibiotic selection.

Semi-automated construction of decision rules to predict morbidities from clinical texts.

OBJECTIVE In this study the authors describe the system submitted by the team of University of Szeged to the second i2b2 Challenge in Natural Language Processing for Clinical Data. The challenge focused on the development of automatic systems that analyzed clinical discharge summary texts and addressed the following question: "Who's obese and what co-morbidities do they (definitely/most likely) have?". Target diseases included obesity and its 15 most frequent comorbidities exhibited by patients, while the target labels corresponded to expert judgments based on textual evidence and intuition (separately). DESIGN The authors applied statistical methods to preselect the most common and confident terms and evaluated outlier documents by hand to discover infrequent spelling variants. The authors expected a system with dictionaries gathered semi-automatically to have a good performance with moderate development costs (the authors examined just a small proportion of the records manually). MEASUREMENTS Following the standard evaluation method of the second Workshop on challenges in Natural Language Processing for Clinical Data, the authors used both macro- and microaveraged Fbeta=1 measure for evaluation. RESULTS The authors submission achieved a microaverage F(beta=1) score of 97.29% for classification based on textual evidence (macroaverage F(beta=1) = 76.22%) and 96.42% for intuitive judgments (macroaverage F(beta=1) = 67.27%). CONCLUSIONS The results demonstrate the feasibility of the authors approach and show that even very simple systems with a shallow linguistic analysis can achieve remarkable accuracy scores for classifying clinical records on a limited set of concepts.

Protein classification based on propagation of unrooted binary trees.

We present two efficient network propagation algorithms that operate on a binary tree, i.e., a sparse-edged substitute of an entire similarity network. TreeProp-N is based on passing increments between nodes while TreeProp-E employs propagation to the edges of the tree. Both algorithms improve protein classification efficiency.

Balanced ROC analysis (BAROC) protocol for the evaluation of protein similarities.

Identification of problematic protein classes (domain types, protein families) that are difficult to predict from sequence is a key issue in genome annotation. ROC (Receiver Operating Characteristic) analysis is routinely used for the evaluation of protein similarities, however its results - the area under curve (AUC) values - are differentially biased for the various protein classes that are highly different in size. We show the bias can be compensated for by adjusting the length of the top list in a class-dependent fashion, so that the number of negatives within the top list will be equal to (or proportional with) the size of the positive class. Using this balanced protocol the problematic classes can be identified by their AUC values, or by a scatter diagram in which the AUC values are plotted against positive/negative ratio of the top list. The use of likelihood-ratio scoring (Kaján et al, Bioinformatics,22, 2865-2869, 2007) the bias caused by class imbalance can be further decreased.

State-of-the-art anonymization of medical records using an iterative machine learning framework.

OBJECTIVE: The anonymization of medical records is of great importance in the human life sciences because a de-identified text can be made publicly available for non-hospital researchers as well, to facilitate research on human diseases. Here the authors have developed a de-identification model that can successfully remove personal health information (PHI) from discharge records to make them conform to the guidelines of the Health Information Portability and Accountability Act. DESIGN: We introduce here a novel, machine learning-based iterative Named Entity Recognition approach intended for use on semi-structured documents like discharge records. Our method identifies PHI in several steps. First, it labels all entities whose tags can be inferred from the structure of the text and it then utilizes this information to find further PHI phrases in the flow text parts of the document. MEASUREMENTS: Following the standard evaluation method of the first Workshop on Challenges in Natural Language Processing for Clinical Data, we used token-level Precision, Recall and F(beta=1) measure metrics for evaluation. RESULTS: Our system achieved outstanding accuracy on the standard evaluation dataset of the de-identification challenge, with an F measure of 99.7534% for the best submitted model. CONCLUSION: We can say that our system is competitive with the current state-of-the-art solutions, while we describe here several techniques that can be beneficial in other tasks that need to handle structured documents such as clinical records.