23,954 research outputs found
Modeling reactivity to biological macromolecules with a deep multitask network
Most
small-molecule drug candidates fail before entering the market,
frequently because of unexpected toxicity. Often, toxicity is detected
only late in drug development, because many types of toxicities, especially
idiosyncratic adverse drug reactions (IADRs), are particularly hard
to predict and detect. Moreover, drug-induced liver injury (DILI)
is the most frequent reason drugs are withdrawn from the market and
causes 50% of acute liver failure cases in the United States. A common
mechanism often underlies many types of drug toxicities, including
both DILI and IADRs. Drugs are bioactivated by drug-metabolizing enzymes
into reactive metabolites, which then conjugate to sites in proteins
or DNA to form adducts. DNA adducts are often mutagenic and may alter
the reading and copying of genes and their regulatory elements, causing
gene dysregulation and even triggering cancer. Similarly, protein
adducts can disrupt their normal biological functions and induce harmful
immune responses. Unfortunately, reactive metabolites are not reliably
detected by experiments, and it is also expensive to test drug candidates
for potential to form DNA or protein adducts during the early stages
of drug development. In contrast, computational methods have the potential
to quickly screen for covalent binding potential, thereby flagging
problematic molecules and reducing the total number of necessary experiments.
Here, we train a deep convolution neural networkî—¸the XenoSite
reactivity modelî—¸using literature data to accurately predict
both sites and probability of reactivity for molecules with glutathione,
cyanide, protein, and DNA. On the site level, cross-validated predictions
had area under the curve (AUC) performances of 89.8% for DNA and 94.4%
for protein. Furthermore, the model separated molecules electrophilically
reactive with DNA and protein from nonreactive molecules with cross-validated
AUC performances of 78.7% and 79.8%, respectively. On both the site-
and molecule-level, the model’s performances significantly
outperformed reactivity indices derived from quantum simulations that
are reported in the literature. Moreover, we developed and applied
a selectivity score to assess preferential reactions with the macromolecules
as opposed to the common screening traps. For the entire data set
of 2803 molecules, this approach yielded totals of 257 (9.2%) and
227 (8.1%) molecules predicted to be reactive only with DNA and protein,
respectively, and hence those that would be missed by standard reactivity
screening experiments. Site of reactivity data is an underutilized
resource that can be used to not only predict if molecules are reactive,
but also show where they might be modified to reduce toxicity while
retaining efficacy. The XenoSite reactivity model is available at http://swami.wustl.edu/xenosite/p/reactivity
Using Machine Learning On Diverse Datasets To Predict Drug-Induced Liver Injury
A major challenge in drug development is safety and toxicity concerns due to drug sideeffects. One such side effect, drug-induced liver injury (DILI), is considered a primary factor in regulatory clearance. To develop prediction models of DILI, the Critical Assessment of Massive Data Analysis (CAMDA) 2020 CMap Drug Safety Challenge goal was established with an ultimate goal to develop prediction models based on gene perturbation of six preselected cell-lines (CMap L1000), extended structural information (MOLD2), toxicity data (TOX21), and FDA reporting of adverse events (FAERS). Four types of DILI classes were targeted, including two clinically relevant scores and two control classifications, designed by the CAMDA organizers. The L1000 gene expression data had variable drug coverage across cell lines with only 247 out of 617 drugs in the study measured in all six cell types. We addressed this coverage issue by using Kru-Bor ranked merging to generate a singular drug expression signature across all six cell lines. These merged signatures were then narrowed down to the top and bottom 100, 250, 500, or 1,000 genes most perturbed by drug treatment. These signatures were subject to feature selection using Fisher’s exact test to identify genes predictive of DILI status. Models based solely on expression signatures had varying results for clinical DILI subtypes with an accuracy ranging from 0.49 to 0.67 and Matthews Correlation Coefficient (MCC) values ranging from -0.03 to 0.1. Models built using FAERS, MOLD2 and TOX21 also had similar results in predicting clinical DILI scores with accuracy ranging from 0.56 to 0.67 with MCC scores ranging from 0.12 to 0.36. To incorporate these various data types with expression-based models, we utilized soft, hard, and weighted ensemble voting methods using the top three performing models for each DILI classification. These voting models achieved a balanced accuracy up to 0.54 and 0.60 for the clinically relevant DILI subtypes. Overall, from our experiment, traditional machine learning approaches may not be optimal as a classification method for the current data
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Reliably Filter Drug-Induced Liver Injury Literature With Natural Language Processing and Conformal Prediction
Drug-induced liver injury describes the adverse effects of drugs that damage the liver. Life-threatening results were also reported in severe cases. Therefore, liver toxicity is an important assessment for new drug candidates. These reports are documented in research papers that contain preliminary in vitro and in vivo experiments. Conventionally, data extraction from publications relies on resource-demanding manual labeling, which restricts the efficiency of the information extraction. The development of natural language processing techniques enables the automatic processing of biomedical texts. Herein, based on around 28,000 papers (titles and abstracts) provided by the Critical Assessment of Massive Data Analysis challenge, this study benchmarked model performances on filtering liver-damage-related literature. Among five text embedding techniques, the model using term frequency-inverse document frequency (TF-IDF) and logistic regression outperformed others with an accuracy of 0.957 on the validation set. Furthermore, an ensemble model with similar overall performances was developed with a logistic regression model on the predicted probability given by separate models with different vectorization techniques. The ensemble model achieved a high accuracy of 0.954 and an F1 score of 0.955 in the hold-out validation data in the challenge. Moreover, important words in positive/negative predictions were identified via model interpretation. The prediction reliability was quantified with conformal prediction, which provides users with a control over the prediction uncertainty. Overall, the ensemble model and TF-IDF model reached satisfactory classification results, which can be used by researchers to rapidly filter literature that describes events related to liver injury induced by medications
Investigation of a Data Split Strategy Involving the Time Axis in Adverse Event Prediction Using Machine Learning
Adverse events are a serious issue in drug development and many prediction
methods using machine learning have been developed. The random split
cross-validation is the de facto standard for model building and evaluation in
machine learning, but care should be taken in adverse event prediction because
this approach tends to be overoptimistic compared with the real-world
situation. The time split, which uses the time axis, is considered suitable for
real-world prediction. However, the differences in model performance obtained
using the time and random splits are not fully understood. To understand the
differences, we compared the model performance between the time and random
splits using eight types of compound information as input, eight adverse events
as targets, and six machine learning algorithms. The random split showed higher
area under the curve values than did the time split for six of eight targets.
The chemical spaces of the training and test datasets of the time split were
similar, suggesting that the concept of applicability domain is insufficient to
explain the differences derived from the splitting. The area under the curve
differences were smaller for the protein interaction than for the other
datasets. Subsequent detailed analyses suggested the danger of confounding in
the use of knowledge-based information in the time split. These findings
indicate the importance of understanding the differences between the time and
random splits in adverse event prediction and suggest that appropriate use of
the splitting strategies and interpretation of results are necessary for the
real-world prediction of adverse events.Comment: 20 pages, 4 figure
Prediction is a balancing act: importance of sampling methods to balance sensitivity and specificity of predictive models based on imbalanced chemical data sets
Increase in the number of new chemicals synthesized in past decades has resulted in constant growth in the development and application of computational models for prediction of activity as well as safety profiles of the chemicals. Most of the time, such computational models and its application must deal with imbalanced chemical data. It is indeed a challenge to construct a classifier using imbalanced data set. In this study, we analyzed and validated the importance of different sampling methods over non-sampling method, to achieve a well-balanced sensitivity and specificity of a machine learning model trained on imbalanced chemical data. Additionally, this study has achieved an accuracy of 93.00%, an AUC of 0.94, F1 measure of 0.90, sensitivity of 96.00% and specificity of 91.00% using SMOTE sampling and Random Forest classifier for the prediction of Drug Induced Liver Injury (DILI). Our results suggest that, irrespective of data set used, sampling methods can have major influence on reducing the gap between sensitivity and specificity of a model. This study demonstrates the efficacy of different sampling methods for class imbalanced problem using binary chemical data sets
An ensemble learning approach for modeling the systems biology of drug-induced injury
Background: Drug-induced liver injury (DILI) is an adverse reaction caused by the intake of drugs of common use that produces liver damage. The impact of DILI is estimated to affect around 20 in 100,000 inhabitants worldwide each year. Despite being one of the main causes of liver failure, the pathophysiology and mechanisms of DILI are poorly understood. In the present study, we developed an ensemble learning approach based on different features (CMap gene expression, chemical structures, drug targets) to predict drugs that might cause DILI and gain a better understanding of the mechanisms linked to the adverse reaction. Results: We searched for gene signatures in CMap gene expression data by using two approaches: phenotype-gene associations data from DisGeNET, and a non-parametric test comparing gene expression of DILI-Concern and No-DILI-Concern drugs (as per DILIrank definitions). The average accuracy of the classifiers in both approaches was 69%. We used chemical structures as features, obtaining an accuracy of 65%. The combination of both types of features produced an accuracy around 63%, but improved the independent hold-out test up to 67%. The use of drug-target associations as feature obtained the best accuracy (70%) in the independent hold-out test. Conclusions: When using CMap gene expression data, searching for a specific gene signature among the landmark genes improves the quality of the classifiers, but it is still limited by the intrinsic noise of the dataset. When using chemical structures as a feature, the structural diversity of the known DILI-causing drugs hampers the prediction, which is a similar problem as for the use of gene expression information. The combination of both features did not improve the quality of the classifiers but increased the robustness as shown on independent hold-out tests. The use of drug-target associations as feature improved the prediction, specially the specificity, and the results were comparable to previous research studies.The authors received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreements TransQST and eTRANSAFE (refs: 116030, 777365). This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA companies in kind contribution. The authors also received support from Spanish Ministry of Economy (MINECO, refs: BIO2017–85329-R (FEDER, EU), RYC-2015-17519) as well as EU H2020 Programme 2014–2020 under grant agreement No. 676559 (Elixir-Excelerate) and from Agència de GestiĂł D’ajuts Universitaris i de Recerca Generalitat de Catalunya (AGAUR, ref.: 2017SGR01020). L.I.F. received support from ISCIII-FEDER (ref: CPII16/00026). The Research Programme on Biomedical Informatics (GRIB) is a member of the Spanish National Bioinformatics Institute (INB), PRB2-ISCIII and is supported by grant PT13/0001/0023, of the PE I + D + i 2013–2016, funded by ISCIII and FEDER. The DCEXS is a “Unidad de Excelencia MarĂa de Maeztu”, funded by the MINECO (ref: MDM-2014-0370). J.A.P. received support from the CAMDA Travel Fellowship
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