Skin Doctor: Machine Learning Models for Skin Sensitization Prediction that Provide Estimates and Indicators of Prediction Reliability.
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ABSTRACT:
SUBMITTER: Wilm A
PROVIDER: S-EPMC6801714 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Skin sensitization potential or potency is an important end point in the safety assessment of new chemicals and new chemical mixtures. Formerly, animal experiments such as the local lymph node assay (LLNA) were the main form of assessment. Today, however, the focus lies on the development of nonanimal testing approaches (i.e., in vitro and in chemico assays) and computational models. In this work, we investigate, based on publicly available LLNA data, the ability of aggregated, Mondrian conformal prediction classifiers to differentiate between non- sensitizing and sensitizing compounds as well as between two levels of skin sensitization potential (weak to moderate sensitizers, and strong to extreme sensitizers). The advantage of the conformal prediction framework over other modeling approaches is that it assigns compounds to activity classes only if a defined minimum level of confidence is reached for the individual predictions. This eliminates the need for applicability domain criteria that often are arbitrary in their nature and less flexible. Our new binary classifier, named Skin Doctor CP, differentiates nonsensitizers from sensitizers with a higher reliability-to-efficiency ratio than the corresponding nonconformal prediction workflow that we presented earlier. When tested on a set of 257 compounds at the significance levels of 0.10 and 0.30, the model reached an efficiency of 0.49 and 0.92, and an accuracy of 0.83 and 0.75, respectively. In addition, we developed a ternary classification workflow to differentiate nonsensitizers, weak to moderate sensitizers, and strong to extreme sensitizers. Although this model achieved satisfactory overall performance (accuracies of 0.90 and 0.73, and efficiencies of 0.42 and 0.90, at significance levels 0.10 and 0.30, respectively), it did not obtain satisfying class-wise results (at a significance level of 0.30, the validities obtained for nonsensitizers, weak to moderate sensitizers, and strong to extreme sensitizers were 0.70, 0.58, and 0.63, respectively). We argue that the model is, in consequence, unable to reliably identify strong to extreme sensitizers and suggest that other ternary models derived from the currently accessible LLNA data might suffer from the same problem. Skin Doctor CP is available via a public web service at https://nerdd.zbh.uni-hamburg.de/skinDoctorII/.
| S-EPMC7887802 | biostudies-literature
Project description:The replacement of animal use in testing for regulatory classification of skin sensitizers is a priority for US federal agencies that use data from such testing. Machine learning models that classify substances as sensitizers or non-sensitizers without using animal data have been developed and evaluated. Because some regulatory agencies require that sensitizers be further classified into potency categories, we developed statistical models to predict skin sensitization potency for murine local lymph node assay (LLNA) and human outcomes. Input variables for our models included six physicochemical properties and data from three non-animal test methods: direct peptide reactivity assay; human cell line activation test; and KeratinoSens™ assay. Models were built to predict three potency categories using four machine learning approaches and were validated using external test sets and leave-one-out cross-validation. A one-tiered strategy modeled all three categories of response together while a two-tiered strategy modeled sensitizer/non-sensitizer responses and then classified the sensitizers as strong or weak sensitizers. The two-tiered model using the support vector machine with all assay and physicochemical data inputs provided the best performance, yielding accuracy of 88% for prediction of LLNA outcomes (120 substances) and 81% for prediction of human test outcomes (87 substances). The best one-tiered model predicted LLNA outcomes with 78% accuracy and human outcomes with 75% accuracy. By comparison, the LLNA predicts human potency categories with 69% accuracy (60 of 87 substances correctly categorized). These results suggest that computational models using non-animal methods may provide valuable information for assessing skin sensitization potency. Copyright © 2017 John Wiley & Sons, Ltd.
| S-EPMC5435511 | biostudies-literature
Project description:One of the Interagency Coordinating Committee on the Validation of Alternative Method's (ICCVAM) top priorities is the development and evaluation of non-animal approaches to identify potential skin sensitizers. The complexity of biological events necessary to produce skin sensitization suggests that no single alternative method will replace the currently accepted animal tests. ICCVAM is evaluating an integrated approach to testing and assessment based on the adverse outcome pathway for skin sensitization that uses machine learning approaches to predict human skin sensitization hazard. We combined data from three in chemico or in vitro assays - the direct peptide reactivity assay (DPRA), human cell line activation test (h-CLAT) and KeratinoSens™ assay - six physicochemical properties and an in silico read-across prediction of skin sensitization hazard into 12 variable groups. The variable groups were evaluated using two machine learning approaches, logistic regression and support vector machine, to predict human skin sensitization hazard. Models were trained on 72 substances and tested on an external set of 24 substances. The six models (three logistic regression and three support vector machine) with the highest accuracy (92%) used: (1) DPRA, h-CLAT and read-across; (2) DPRA, h-CLAT, read-across and KeratinoSens; or (3) DPRA, h-CLAT, read-across, KeratinoSens and log P. The models performed better at predicting human skin sensitization hazard than the murine local lymph node assay (accuracy 88%), any of the alternative methods alone (accuracy 63-79%) or test batteries combining data from the individual methods (accuracy 75%). These results suggest that computational methods are promising tools to identify effectively the potential human skin sensitizers without animal testing. Published 2016. This article has been contributed to by US Government employees and their work is in the public domain in the USA.
| S-EPMC5243794 | biostudies-literature
Project description:In recent years, a number of machine learning models for the prediction of the skin sensitization potential of small organic molecules have been reported and become available. These models generally perform well within their applicability domains but, as a result of the use of molecular fingerprints and other non-intuitive descriptors, the interpretability of the existing models is limited. The aim of this work is to develop a strategy to replace the non-intuitive features by predicted outcomes of bioassays. We show that such replacement is indeed possible and that as few as ten interpretable, predicted bioactivities are sufficient to reach competitive performance. On a holdout data set of 257 compounds, the best model ("Skin Doctor CP:Bio") obtained an efficiency of 0.82 and an MCC of 0.52 (at the significance level of 0.20). Skin Doctor CP:Bio is available free of charge for academic research. The modeling strategies explored in this work are easily transferable and could be adopted for the development of more interpretable machine learning models for the prediction of the bioactivity and toxicity of small organic compounds.
| S-EPMC8402010 | biostudies-literature
Project description:Tools to estimate brain connectivity offer the potential to enhance our understanding of brain functioning. The behavior of neuronal networks, including functional connectivity and induced connectivity changes by external stimuli, can be studied using models of cultured neurons. Cultured neurons tend to be active in groups, and pairs of neurons are said to be functionally connected when their firing patterns show significant synchronicity. Methods to infer functional connections are often based on pair-wise cross-correlation between activity patterns of (small groups of) neurons. However, these methods are not very sensitive to detect inhibitory connections, and they were not designed for use during stimulation. Maximum Entropy (MaxEnt) models may provide a conceptually different method to infer functional connectivity. They have the potential benefit to estimate functional connectivity during stimulation, and to infer excitatory as well as inhibitory connections. MaxEnt models do not involve pairwise comparison, but aim to capture probability distributions of sets of neurons that are synchronously active in discrete time bins. We used electrophysiological recordings from in vitro neuronal cultures on micro electrode arrays to investigate the ability of MaxEnt models to infer functional connectivity. Connectivity estimates provided by MaxEnt models correlated well with those obtained by conditional firing probabilities (CFP), an established cross-correlation based method. In addition, stimulus-induced connectivity changes were detected by MaxEnt models, and were of the same magnitude as those detected by CFP. Thus, MaxEnt models provide a potentially powerful new tool to study functional connectivity in neuronal networks.
| S-EPMC9187636 | biostudies-literature
Project description:Skin permeability is widely considered to be mechanistically implicated in chemically-induced skin sensitization. Although many chemicals have been identified as skin sensitizers, there have been very few reports analyzing the relationships between molecular structure and skin permeability of sensitizers and non-sensitizers. The goals of this study were to: (i) compile, curate, and integrate the largest publicly available dataset of chemicals studied for their skin permeability; (ii) develop and rigorously validate QSAR models to predict skin permeability; and (iii) explore the complex relationships between skin sensitization and skin permeability. Based on the largest publicly available dataset compiled in this study, we found no overall correlation between skin permeability and skin sensitization. In addition, cross-species correlation coefficient between human and rodent permeability data was found to be as low as R(2)=0.44. Human skin permeability models based on the random forest method have been developed and validated using OECD-compliant QSAR modeling workflow. Their external accuracy was high (Q(2)ext=0.73 for 63% of external compounds inside the applicability domain). The extended analysis using both experimentally-measured and QSAR-imputed data still confirmed the absence of any overall concordance between skin permeability and skin sensitization. This observation suggests that chemical modifications that affect skin permeability should not be presumed a priori to modulate the sensitization potential of chemicals. The models reported herein as well as those developed in the companion paper on skin sensitization suggest that it may be possible to rationally design compounds with the desired high skin permeability but low sensitization potential.
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Project description:Nitrogen is the most limiting nutrient for turfgrass growth. Instead of pursuing the maximum yield, most turfgrass managers use nitrogen (N) to maintain a sub-maximal growth rate. Few tools or soil tests exist to help managers guide N fertilizer decisions. Turf growth prediction models have the potential to be useful, but the currently existing turf growth prediction model only takes temperature into account, limiting its accuracy. This study developed machine-learning-based turf growth models using the random forest (RF) algorithm to estimate short-term turfgrass clipping yield. To build the RF model, a large set of variables were extracted as predictors including the 7-day weather, traffic intensity, soil moisture content, N fertilization rate, and the normalized difference red edge (NDRE) vegetation index. In this study, the data were collected from two putting greens where the turfgrass received 0 to 1,800 round/week traffic rates, various irrigation rates to maintain the soil moisture content between 9 and 29%, and N fertilization rates of 0 to 17.5 kg ha-1 applied biweekly. The RF model agreed with the actual clipping yield collected from the experimental results. The temperature and relative humidity were the most important weather factors. Including NDRE improved the prediction accuracy of the model. The highest coefficient of determination (R2) of the RF model was 0.64 for the training dataset and was 0.47 for the testing data set upon the evaluation of the model. This represented a large improvement over the existing growth prediction model (R 2 = 0.01). However, the machine-learning models created were not able to accurately predict the clipping production at other locations. Individual golf courses can create customized growth prediction models using clipping volume to eliminate the deviation caused by temporal and spatial variability. Overall, this study demonstrated the feasibility of creating machine-learning-based yield prediction models that may be able to guide N fertilization decisions on golf course putting greens and presumably other turfgrass areas.
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Project description:BackgroundAccurate and reliable predictions of infectious disease can be valuable to public health organizations that plan interventions to decrease or prevent disease transmission. A great variety of models have been developed for this task. However, for different data series, the performance of these models varies. Hepatitis E, as an acute liver disease, has been a major public health problem. Which model is more appropriate for predicting the incidence of hepatitis E? In this paper, three different methods are used and the performance of the three methods is compared.MethodsAutoregressive integrated moving average(ARIMA), support vector machine(SVM) and long short-term memory(LSTM) recurrent neural network were adopted and compared. ARIMA was implemented by python with the help of statsmodels. SVM was accomplished by matlab with libSVM library. LSTM was designed by ourselves with Keras, a deep learning library. To tackle the problem of overfitting caused by limited training samples, we adopted dropout and regularization strategies in our LSTM model. Experimental data were obtained from the monthly incidence and cases number of hepatitis E from January 2005 to December 2017 in Shandong province, China. We selected data from July 2015 to December 2017 to validate the models, and the rest was taken as training set. Three metrics were applied to compare the performance of models, including root mean square error(RMSE), mean absolute percentage error(MAPE) and mean absolute error(MAE).ResultsBy analyzing data, we took ARIMA(1, 1, 1), ARIMA(3, 1, 2) as monthly incidence prediction model and cases number prediction model, respectively. Cross-validation and grid search were used to optimize parameters of SVM. Penalty coefficient C and kernel function parameter g were set 8, 0.125 for incidence prediction, and 22, 0.01 for cases number prediction. LSTM has 4 nodes. Dropout and L2 regularization parameters were set 0.15, 0.001, respectively. By the metrics of RMSE, we obtained 0.022, 0.0204, 0.01 for incidence prediction, using ARIMA, SVM and LSTM. And we obtained 22.25, 20.0368, 11.75 for cases number prediction, using three models. For MAPE metrics, the results were 23.5%, 21.7%, 15.08%, and 23.6%, 21.44%, 13.6%, for incidence prediction and cases number prediction, respectively. For MAE metrics, the results were 0.018, 0.0167, 0.011 and 18.003, 16.5815, 9.984, for incidence prediction and cases number prediction, respectively.ConclusionsComparing ARIMA, SVM and LSTM, we found that nonlinear models(SVM, LSTM) outperform linear models(ARIMA). LSTM obtained the best performance in all three metrics of RSME, MAPE, MAE. Hence, LSTM is the most suitable for predicting hepatitis E monthly incidence and cases number.
| S-EPMC7497991 | biostudies-literature
Project description:Stratum corneum is the outermost layer of the skin preventing external substances from entering human body. Microneedles (MNs) are sharp protrusions of a few hundred microns in length, which can penetrate the stratum corneum to facilitate drug permeation through skin. To determine the amount of drug delivered through skin, in vitro drug permeation testing is commonly used, but the testing is costly and time-consuming. To address this issue, machine learning methods were employed to predict drug permeation through the skin, circumventing the need of conducting skin permeation experiments. By comparing the experimental data and simulated results, it was found extreme gradient boosting (XGBoost) was the best among the four simulation methods. It was also found that drug loading, permeation time, and MN surface area were critical parameters in the models. In conclusion, machine learning is useful to predict drug permeation profiles for MN-facilitated transdermal drug delivery.
| S-EPMC10658566 | biostudies-literature
Project description:The assessment of skin sensitization has evolved over the past few years to include in vitro assessments of key events along the adverse outcome pathway and opportunistically capitalize on the strengths of in silico methods to support a weight of evidence assessment without conducting a test in animals. While in silico methods vary greatly in their purpose and format; there is a need to standardize the underlying principles on which such models are developed and to make transparent the implications for the uncertainty in the overall assessment. In this contribution, the relationship between skin sensitization relevant effects, mechanisms, and endpoints are built into a hazard assessment framework. Based on the relevance of the mechanisms and effects as well as the strengths and limitations of the experimental systems used to identify them, rules and principles are defined for deriving skin sensitization in silico assessments. Further, the assignments of reliability and confidence scores that reflect the overall strength of the assessment are discussed. This skin sensitization protocol supports the implementation and acceptance of in silico approaches for the prediction of skin sensitization.
| S-EPMC7518315 | biostudies-literature