An Ensemble Model of QSAR Tools for Regulatory Risk Assessment

Quantitative structure activity relationships (QSARs) are theoretical models that relate a quantitative measure of chemical structure to a physical property or a biological effect. QSAR predictions can be used for chemical risk assessment for protection of human and environmental health, which makes them interesting to regulators, especially in the absence of experimental data. For compatibility with regulatory use, QSAR models should be transparent, reproducible and optimized to minimize the number of false negatives. In silico QSAR tools are gaining wide acceptance as a faster alternative to otherwise time-consuming clinical and animal testing methods. However, different QSAR tools often make conflicting predictions for a given chemical and may also vary in their predictive performance across different chemical datasets. In a regulatory context, conflicting predictions raise interpretation, validation and adequacy concerns. To address these concerns, ensemble learning techniques in the machine learning paradigm can be used to integrate predictions from multiple tools. By leveraging various underlying QSAR algorithms and training datasets, the resulting consensus prediction should yield better overall predictive ability. We present a novel ensemble QSAR model using Bayesian classification. The model allows for varying a cut-off parameter that allows for a selection in the desirable trade-off between model sensitivity and specificity. The predictive performance of the ensemble model is compared with four in silico tools (Toxtree, Lazar, OECD Toolbox, and Danish QSAR) to predict carcinogenicity for a dataset of air toxins (332 chemicals) and a subset of the gold carcinogenic potency database (480 chemicals). Leave-one-out cross validation results show that the ensemble model achieves the best trade-off between sensitivity and specificity (accuracy: 83.8 % and 80.4 %, and balanced accuracy: 80.6 % and 80.8 %) and highest inter-rater agreement [kappa (κ): 0.63 and 0.62] for both the datasets. The ROC curves demonstrate the utility of the cut-off feature in the predictive ability of the ensemble model. This feature provides an additional control to the regulators in grading a chemical based on the severity of the toxic endpoint under study

Predicting Skin Permeability by means of Computational Approaches : Reliability and Caveats in Pharmaceutical Studies

© 2019 American Chemical Society.The skin is the main barrier between the internal body environment and the external one. The characteristics of this barrier and its properties are able to modify and affect drug delivery and chemical toxicity parameters. Therefore, it is not surprising that permeability of many different compounds has been measured through several in vitro and in vivo techniques. Moreover, many different in silico approaches have been used to identify the correlation between the structure of the permeants and their permeability, to reproduce the skin behavior, and to predict the ability of specific chemicals to permeate this barrier. A significant number of issues, like interlaboratory variability, experimental conditions, data set building rationales, and skin site of origin and hydration, still prevent us from obtaining a definitive predictive skin permeability model. This review wants to show the main advances and the principal approaches in computational methods used to predict this property, to enlighten the main issues that have arisen, and to address the challenges to develop in future research.Peer reviewedFinal Accepted Versio

Multi-tier framework for the inferential measurement and data-driven modeling

A framework for the inferential measurement and data-driven modeling has been proposed and assessed in several real-world application domains. The architecture of the framework has been structured in multiple tiers to facilitate extensibility and the integration of new components. Each of the proposed four tiers has been assessed in an uncoupled way to verify their suitability. The first tier, dealing with exploratory data analysis, has been assessed with the characterization of the chemical space related to the biodegradation of organic chemicals. This analysis has established relationships between physicochemical variables and biodegradation rates that have been used for model development. At the preprocessing level, a novel method for feature selection based on dissimilarity measures between Self-Organizing maps (SOM) has been developed and assessed. The proposed method selected more features than others published in literature but leads to models with improved predictive power. Single and multiple data imputation techniques based on the SOM have also been used to recover missing data in a Waste Water Treatment Plant benchmark. A new dynamic method to adjust the centers and widths of in Radial basis Function networks has been proposed to predict water quality. The proposed method outperformed other neural networks. The proposed modeling components have also been assessed in the development of prediction and classification models for biodegradation rates in different media. The results obtained proved the suitability of this approach to develop data-driven models when the complex dynamics of the process prevents the formulation of mechanistic models. The use of rule generation algorithms and Bayesian dependency models has been preliminary screened to provide the framework with interpretation capabilities. Preliminary results obtained from the classification of Modes of Toxic Action (MOA) indicate that this could be a promising approach to use MOAs as proxy indicators of human health effects of chemicals.Finally, the complete framework has been applied to three different modeling scenarios. A virtual sensor system, capable of inferring product quality indices from primary process variables has been developed and assessed. The system was integrated with the control system in a real chemical plant outperforming multi-linear correlation models usually adopted by chemical manufacturers. A model to predict carcinogenicity from molecular structure for a set of aromatic compounds has been developed and tested. Results obtained after the application of the SOM-dissimilarity feature selection method yielded better results than models published in the literature. Finally, the framework has been used to facilitate a new approach for environmental modeling and risk management within geographical information systems (GIS). The SOM has been successfully used to characterize exposure scenarios and to provide estimations of missing data through geographic interpolation. The combination of SOM and Gaussian Mixture models facilitated the formulation of a new probabilistic risk assessment approach.Aquesta tesi proposa i avalua en diverses aplicacions reals, un marc general de treball per al desenvolupament de sistemes de mesurament inferencial i de modelat basats en dades. L'arquitectura d'aquest marc de treball s'organitza en diverses capes que faciliten la seva extensibilitat així com la integració de nous components. Cadascun dels quatre nivells en que s'estructura la proposta de marc de treball ha estat avaluat de forma independent per a verificar la seva funcionalitat. El primer que nivell s'ocupa de l'anàlisi exploratòria de dades ha esta avaluat a partir de la caracterització de l'espai químic corresponent a la biodegradació de certs compostos orgànics. Fruit d'aquest anàlisi s'han establert relacions entre diverses variables físico-químiques que han estat emprades posteriorment per al desenvolupament de models de biodegradació. A nivell del preprocés de les dades s'ha desenvolupat i avaluat una nova metodologia per a la selecció de variables basada en l'ús del Mapes Autoorganitzats (SOM). Tot i que el mètode proposat selecciona, en general, un major nombre de variables que altres mètodes proposats a la literatura, els models resultants mostren una millor capacitat predictiva. S'han avaluat també tot un conjunt de tècniques d'imputació de dades basades en el SOM amb un conjunt de dades estàndard corresponent als paràmetres d'operació d'una planta de tractament d'aigües residuals. Es proposa i avalua en un problema de predicció de qualitat en aigua un nou model dinàmic per a ajustar el centre i la dispersió en xarxes de funcions de base radial. El mètode proposat millora els resultats obtinguts amb altres arquitectures neuronals. Els components de modelat proposat s'han aplicat també al desenvolupament de models predictius i de classificació de les velocitats de biodegradació de compostos orgànics en diferents medis. Els resultats obtinguts demostren la viabilitat d'aquesta aproximació per a desenvolupar models basats en dades en aquells casos en els que la complexitat de dinàmica del procés impedeix formular models mecanicistes. S'ha dut a terme un estudi preliminar de l'ús de algorismes de generació de regles i de grafs de dependència bayesiana per a introduir una nova capa que faciliti la interpretació dels models. Els resultats preliminars obtinguts a partir de la classificació dels Modes d'acció Tòxica (MOA) apunten a que l'ús dels MOA com a indicadors intermediaris dels efectes dels compostos químics en la salut és una aproximació factible.Finalment, el marc de treball proposat s'ha aplicat en tres escenaris de modelat diferents. En primer lloc, s'ha desenvolupat i avaluat un sensor virtual capaç d'inferir índexs de qualitat a partir de variables primàries de procés. El sensor resultant ha estat implementat en una planta química real millorant els resultats de les correlacions multilineals emprades habitualment. S'ha desenvolupat i avaluat un model per a predir els efectes carcinògens d'un grup de compostos aromàtics a partir de la seva estructura molecular. Els resultats obtinguts desprès d'aplicar el mètode de selecció de variables basat en el SOM milloren els resultats prèviament publicats. Aquest marc de treball s'ha usat també per a proporcionar una nova aproximació al modelat ambiental i l'anàlisi de risc amb sistemes d'informació geogràfica (GIS). S'ha usat el SOM per a caracteritzar escenaris d'exposició i per a desenvolupar un nou mètode d'interpolació geogràfica. La combinació del SOM amb els models de mescla de gaussianes dona una nova formulació al problema de l'anàlisi de risc des d'un punt de vista probabilístic

Transcriptomics in Toxicogenomics, Part III: Data Modelling for Risk Assessment

Transcriptomics data are relevant to address a number of challenges in Toxicogenomics (TGx). After careful planning of exposure conditions and data preprocessing, the TGx data can be used in predictive toxicology, where more advanced modelling techniques are applied. The large volume of molecular profiles produced by omics-based technologies allows the development and application of artificial intelligence (AI) methods in TGx. Indeed, the publicly available omics datasets are constantly increasing together with a plethora of different methods that are made available to facilitate their analysis, interpretation and the generation of accurate and stable predictive models. In this review, we present the state-of-the-art of data modelling applied to transcriptomics data in TGx. We show how the benchmark dose (BMD) analysis can be applied to TGx data. We review read across and adverse outcome pathways (AOP) modelling methodologies. We discuss how network-based approaches can be successfully employed to clarify the mechanism of action (MOA) or specific biomarkers of exposure. We also describe the main AI methodologies applied to TGx data to create predictive classification and regression models and we address current challenges. Finally, we present a short description of deep learning (DL) and data integration methodologies applied in these contexts. Modelling of TGx data represents a valuable tool for more accurate chemical safety assessment. This review is the third part of a three-article series on Transcriptomics in Toxicogenomics

Transcriptomics in Toxicogenomics, Part III : Data Modelling for Risk Assessment

Transcriptomics data are relevant to address a number of challenges in Toxicogenomics (TGx). After careful planning of exposure conditions and data preprocessing, the TGx data can be used in predictive toxicology, where more advanced modelling techniques are applied. The large volume of molecular profiles produced by omics-based technologies allows the development and application of artificial intelligence (AI) methods in TGx. Indeed, the publicly available omics datasets are constantly increasing together with a plethora of different methods that are made available to facilitate their analysis, interpretation and the generation of accurate and stable predictive models. In this review, we present the state-of-the-art of data modelling applied to transcriptomics data in TGx. We show how the benchmark dose (BMD) analysis can be applied to TGx data. We review read across and adverse outcome pathways (AOP) modelling methodologies. We discuss how network-based approaches can be successfully employed to clarify the mechanism of action (MOA) or specific biomarkers of exposure. We also describe the main AI methodologies applied to TGx data to create predictive classification and regression models and we address current challenges. Finally, we present a short description of deep learning (DL) and data integration methodologies applied in these contexts. Modelling of TGx data represents a valuable tool for more accurate chemical safety assessment. This review is the third part of a three-article series on Transcriptomics in Toxicogenomics.Peer reviewe