The METLIN small molecule dataset for machine learning-based retention time prediction.
Ontology highlight
ABSTRACT:
SUBMITTER: Domingo-Almenara X
PROVIDER: S-EPMC6925099 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:In gas chromatography-mass spectrometry-based untargeted metabolomics, metabolites are identified by comparing mass spectra and chromatographic retention time with reference databases or standard materials. In that sense, machine learning has been used to predict the retention time of metabolites lacking reference data. However, the retention time prediction of trimethylsilyl derivatives of metabolites, typically analyzed in untargeted metabolomics using gas chromatography, has been poorly explored. Here, we provide a rationalized framework for machine learning-based retention time prediction of trimethylsilyl derivatives of metabolites in gas chromatography. We compared different machine learning paradigms, in addition to exploring the influence of the computational molecular structure representation to train the prediction models: fingerprint class and fingerprint calculation software. Our study challenged predicted retention time when using chemical ionization and electron impact ionization sources in simulated and real cases, demonstrating a good correct identity ranking capability by machine learning, despite observing a limited false identity filtering power in cases where a spectrum or a monoisotopic mass match to multiple candidates. Specifically, machine learning prediction yielded median absolute and relative retention index (relative retention time) errors of 37.1 retention index units and 2%, respectively. In addition, fingerprint class and fingerprint calculation software, as well as the molecular structural similarity between the training and test or real case sets, showed to be critical modulators of the prediction performance. Finally, we leveraged the structural similarity between the training and test or real case set to determine the probability that the prediction error is below a specific threshold. Overall, our study demonstrates that predicted retention time can provide insights into the true structure of unknown metabolites by ranking from the most to the least plausible molecular identity, and sets the guidelines to assess the confidence in metabolite identification using predicted retention time data.
2022-05-26 | MTBLS2841 | MetaboLights
Project description:Different types of chemicals and products may exhibit various health risks when administered into the human body. For toxicity reasons, the number of new drugs entering the market through the conventional drug development process has been reduced over the years. However, with the advent of big data and artificial intelligence, machine learning techniques have emerged as a potential solution for predicting toxicity and ensuring efficient drug development and chemical safety. An ML model for toxicity prediction can reduce experimental costs and time while addressing ethical concerns by drastically reducing the need for animals and clinical trials. Herein, MolToxPred, an ML-based tool, has been developed using a stacked model approach to predict the potential toxicity of small molecules and metabolites. The stacked model consists of random forest, multi-layer perceptron, and LightGBM as base classifiers and Logistic Regression as the meta classifier. For training and validation purposes, a comprehensive set of toxic and non-toxic molecules is curated. Different structural and physicochemical-based features in the form of molecular descriptors and fingerprints were employed. MolToxPred utilizes a comprehensive feature selection process and optimizes its hyperparameters through Bayesian optimization with stratified 5-fold cross-validation. In the evaluation phase, MolToxPred achieved an AUROC of 87.76% on the test set and 88.84% on an external validation set. The McNemar test was used as the post-hoc test to determine if the stacked models' performance was significantly different compared to the base learners. The developed stacked model outperformed its base classifiers and an existing tool in the literature, reaffirming its better performance. The hypothesis is that the incorporation of a diverse set of data, the subsequent feature selection, and a stacked ensemble approach give MolToxPred the edge over other methods. In addition to this, an attempt has been made to identify structural alerts responsible for endpoints of the Tox21 data to determine the association of a molecule with a plausible downstream pathway of action. MolToxPred may be helpful for drug discovery and regulatory pipelines in pharmaceutical and other industries for in silico toxicity prediction of small molecule candidates.
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Project description:Peptide retention time (RT) prediction algorithms are tools to study and identify the physicochemical properties that drive the peptide-sorbent interaction. Traditional RT algorithms use multiple linear regression with manually curated parameters to determine the degree of direct contribution for each parameter and improvements to RT prediction accuracies relied on superior feature engineering. Deep learning led to a significant increase in RT prediction accuracy and automated feature engineering via chaining multiple learning modules. However, the significance and the identity of these extracted variables are not well understood due to the inherent complexity when interpreting "relationships-of-relationships" found in deep learning variables. To achieve both accuracy and interpretability simultaneously, we isolated individual modules used in deep learning and the isolated modules are the shallow learners employed for RT prediction in this work. Using a shallow convolutional neural network (CNN) and gated recurrent unit (GRU), we find that the spatial features obtained via the CNN correlate with real-world physicochemical properties namely cross-collisional sections (CCS) and variations of assessable surface area (ASA). Furthermore, we determined that the discovered parameters are "micro-coefficients" that contribute to the "macro-coefficient" - hydrophobicity. Manually embedding CCS and the variations of ASA to the GRU model yielded an R2 = 0.981 using only 525 variables and can represent 88% of the ∼110,000 tryptic peptides used in our dataset. This work highlights the feature discovery process of our shallow learners can achieve beyond traditional RT models in performance and have better interpretability when compared with the deep learning RT algorithms found in the literature.
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Project description:BACKGROUND:Prognostication is an essential tool for risk adjustment and decision making in the intensive care unit (ICU). Research into prognostication in ICU has so far been limited to data from admission or the first 24 hours. Most ICU admissions last longer than this, decisions are made throughout an admission, and some admissions are explicitly intended as time-limited prognostic trials. Despite this, temporal changes in prognostic ability during ICU admission has received little attention to date. Current predictive models, in the form of prognostic clinical tools, are typically derived from linear models and do not explicitly handle incremental information from trends. Machine learning (ML) allows predictive models to be developed which use non-linear predictors and complex interactions between variables, thus allowing incorporation of trends in measured variables over time; this has made it possible to investigate prognosis throughout an admission. METHODS AND FINDINGS:This study uses ML to assess the predictability of ICU mortality as a function of time. Logistic regression against physiological data alone outperformed APACHE-II and demonstrated several important interactions including between lactate & noradrenaline dose, between lactate & MAP, and between age & MAP consistent with the current sepsis definitions. ML models consistently outperformed logistic regression with Deep Learning giving the best results. Predictive power was maximal on the second day and was further improved by incorporating trend data. Using a limited range of physiological and demographic variables, the best machine learning model on the first day showed an area under the receiver-operator characteristic curve (AUC) of 0.883 (σ = 0.008), compared to 0.846 (σ = 0.010) for a logistic regression from the same predictors and 0.836 (σ = 0.007) for a logistic regression based on the APACHE-II score. Adding information gathered on the second day of admission improved the maximum AUC to 0.895 (σ = 0.008). Beyond the second day, predictive ability declined. CONCLUSION:This has implications for decision making in intensive care and provides a justification for time-limited trials of ICU therapy; the assessment of prognosis over more than one day may be a valuable strategy as new information on the second day helps to differentiate outcomes. New ML models based on trend data beyond the first day could greatly improve upon current risk stratification tools.
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Project description:The process of discovering small molecule drugs involves screening numerous compounds and optimizing the most promising ones, both in vitro and in vivo. However, approximately 90% of these optimized candidates fail during trials due to unexpected toxicity or insufficient efficacy. Current concepts with respect to drug-protein interactions suggest that each small molecule interacts with an average of 6-11 targets. This implies that approved drugs and even discontinued compounds could be repurposed by leveraging their interactions with unintended targets. Therefore, we developed a computational repurposing framework for small molecules, which combines artificial intelligence/machine learning (AI/ML)-based and chemical similarity-based target prediction methods with cross-species transcriptomics information. This repurposing methodology incorporates eight distinct target prediction methods, including three machine learning methods. By using multiple orthogonal methods for a "dataset" composed of 2766 FDA-approved drugs targeting multiple therapeutic target classes, we identified 27,371 off-target interactions involving 2013 protein targets (i.e., an average of around 10 interactions per drug). Relative to the drugs in the dataset, we identified 150,620 structurally similar compounds. The highest number of predicted interactions were for drugs targeting G protein-coupled receptors (GPCRs), enzymes, and kinases with 10,648, 4081, and 3678 interactions, respectively. Notably, 17,283 (63%) of the off-target interactions have been confirmed in vitro. Approximately 4000 interactions had an IC50 of <100 nM for 1105 FDA-approved drugs and 1661 interactions had an IC50 of <10 nM for 696 FDA-approved drugs. Together, the confirmation of numerous predicted interactions and the exploration of tissue-specific expression patterns in human and animal tissues offer insights into potential drug repurposing for new therapeutic applications.
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Project description:Reversed-phase liquid chromatography (RPLC) and capillary zone electrophoresis (CZE) are two primary proteoform separation methods in mass spectrometry (MS)-based top-down proteomics. Proteoform retention time (RT) prediction in RPLC and migration time (MT) prediction in CZE provide additional information for accurate proteoform identification and quantification. While existing methods are mainly focused on peptide RT and MT prediction in bottom-up MS, there is still a lack of methods for proteoform RT and MT prediction in top-down MS. We systematically evaluated eight machine learning models and a transfer learning method for proteoform RT prediction and five models and the transfer learning method for proteoform MT prediction. Experimental results showed that a gated recurrent unit (GRU)-based model with transfer learning achieved a high accuracy (R = 0.978) for proteoform RT prediction and that the GRU-based model and a fully connected neural network model obtained a high accuracy of R = 0.982 and 0.981 for proteoform MT prediction, respectively.
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Project description:A re-analysis of published data-dependent acquisition glycoproteomics datasets to demonstrate relative retention time prediction on glycopeptide identification and disambiguation of adduct states.
2020-04-01 | PXD018208 | Pride