Dataset Information

Deep Learning to Predict the Formation of Quinone Species in Drug Metabolism.

ABSTRACT: Many adverse drug reactions are thought to be caused by electrophilically reactive drug metabolites that conjugate to nucleophilic sites within DNA and proteins, causing cancer or toxic immune responses. Quinone species, including quinone-imines, quinone-methides, and imine-methides, are electrophilic Michael acceptors that are often highly reactive and comprise over 40% of all known reactive metabolites. Quinone metabolites are created by cytochromes P450 and peroxidases. For example, cytochromes P450 oxidize acetaminophen to N-acetyl-p-benzoquinone imine, which is electrophilically reactive and covalently binds to nucleophilic sites within proteins. This reactive quinone metabolite elicits a toxic immune response when acetaminophen exceeds a safe dose. Using a deep learning approach, this study reports the first published method for predicting quinone formation: the formation of a quinone species by metabolic oxidation. We model both one- and two-step quinone formation, enabling accurate quinone formation predictions in nonobvious cases. We predict atom pairs that form quinones with an AUC accuracy of 97.6%, and we identify molecules that form quinones with 88.2% AUC. By modeling the formation of quinones, one of the most common types of reactive metabolites, our method provides a rapid screening tool for a key drug toxicity risk. The XenoSite quinone formation model is available at http://swami.wustl.edu/xenosite/p/quinone .

SUBMITTER: Hughes TB

PROVIDER: S-EPMC5871348 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Deep Learning to Predict the Formation of Quinone Species in Drug Metabolism.

Hughes Tyler B TB Swamidass S Joshua SJ

Chemical research in toxicology 20170202 2

Many adverse drug reactions are thought to be caused by electrophilically reactive drug metabolites that conjugate to nucleophilic sites within DNA and proteins, causing cancer or toxic immune responses. Quinone species, including quinone-imines, quinone-methides, and imine-methides, are electrophilic Michael acceptors that are often highly reactive and comprise over 40% of all known reactive metabolites. Quinone metabolites are created by cytochromes P450 and peroxidases. For example, cytochrom ...[more]

PMID: 28099803

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Project description:BackgroundDeep learning algorithms have achieved human-equivalent performance in image recognition. However, the majority of clinical data within electronic health records is inherently in a non-image format. Therefore, creating visual representations of clinical data could facilitate using cutting-edge deep learning models for predicting outcomes such as in-hospital mortality, while enabling clinician interpretability. The objective of this study was to develop a framework that first transforms longitudinal patient data into visual timelines and then utilizes deep learning to predict in-hospital mortality.Methods and findingsAll adult consecutive patient admissions from 2008-2016 at a tertiary care center were included in this retrospective study. Two-dimensional visual representations for each patient were created with clinical variables on one dimension and time on the other. Predictors included vital signs, laboratory results, medications, interventions, nurse examinations, and diagnostic tests collected over the first 48 hours of the hospital stay. These visual timelines were utilized by a convolutional neural network with a recurrent layer model to predict in-hospital mortality. Seventy percent of the cohort was used for model derivation and 30% for independent validation. Of 115,825 hospital admissions, 2,926 (2.5%) suffered in-hospital mortality. Our model predicted in-hospital mortality significantly better than the Modified Early Warning Score (area under the receiver operating characteristic curve [AUC]: 0.91 vs. 0.76, P < 0.001) and the Sequential Organ Failure Assessment score (AUC: 0.91 vs. 0.57, P < 0.001) in the independent validation set. Class-activation heatmaps were utilized to highlight areas of the picture that were most important for making the prediction, thereby providing clinicians with insight into each individual patient's prediction.ConclusionsWe converted longitudinal patient data into visual timelines and applied a deep neural network for predicting in-hospital mortality more accurately than current standard clinical models, while allowing for interpretation. Our framework holds promise for predicting several important outcomes in clinical medicine.

Dataset Information

Deep Learning to Predict the Formation of Quinone Species in Drug Metabolism.

Publications

Deep Learning to Predict the Formation of Quinone Species in Drug Metabolism.

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