| 1. |
- Mervin, Lewis H., et al.
(författare)
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Probabilistic Random Forest improves bioactivity predictions close to the classification threshold by taking into account experimental uncertainty
- 2021
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Ingår i: Journal of Cheminformatics. - : Springer Science and Business Media LLC. - 1758-2946 .- 1758-2946. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Measurements of protein–ligand interactions have reproducibility limits due to experimental errors. Any model based on such assays will consequentially have such unavoidable errors influencing their performance which should ideally be factored into modelling and output predictions, such as the actual standard deviation of experimental measurements (σ) or the associated comparability of activity values between the aggregated heterogenous activity units (i.e., Ki versus IC50 values) during dataset assimilation. However, experimental errors are usually a neglected aspect of model generation. In order to improve upon the current state-of-the-art, we herein present a novel approach toward predicting protein–ligand interactions using a Probabilistic Random Forest (PRF) classifier. The PRF algorithm was applied toward in silico protein target prediction across ~ 550 tasks from ChEMBL and PubChem. Predictions were evaluated by taking into account various scenarios of experimental standard deviations in both training and test sets and performance was assessed using fivefold stratified shuffled splits for validation. The largest benefit in incorporating the experimental deviation in PRF was observed for data points close to the binary threshold boundary, when such information was not considered in any way in the original RF algorithm. For example, in cases when σ ranged between 0.4–0.6 log units and when ideal probability estimates between 0.4–0.6, the PRF outperformed RF with a median absolute error margin of ~ 17%. In comparison, the baseline RF outperformed PRF for cases with high confidence to belong to the active class (far from the binary decision threshold), although the RF models gave errors smaller than the experimental uncertainty, which could indicate that they were overtrained and/or over-confident. Finally, the PRF models trained with putative inactives decreased the performance compared to PRF models without putative inactives and this could be because putative inactives were not assigned an experimental pXC50 value, and therefore they were considered inactives with a low uncertainty (which in practice might not be true). In conclusion, PRF can be useful for target prediction models in particular for data where class boundaries overlap with the measurement uncertainty, and where a substantial part of the training data is located close to the classification threshold.
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| 2. |
- Mervin, Lewis H., et al.
(författare)
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QSARtuna: An Automated QSAR Modeling Platform for Molecular Property Prediction in Drug Design
- 2024
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Ingår i: Journal of Chemical Information and Modeling. - 1549-960X .- 1549-9596. ; 64:14, s. 5365-5374
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Tidskriftsartikel (refereegranskat)abstract
- Machine-learning (ML) and deep-learning (DL) approaches to predict the molecular properties of small molecules are increasingly deployed within the design-make-test-analyze (DMTA) drug design cycle to predict molecular properties of interest. Despite this uptake, there are only a few automated packages to aid their development and deployment that also support uncertainty estimation, model explainability, and other key aspects of model usage. This represents a key unmet need within the field, and the large number of molecular representations and algorithms (and associated parameters) means it is nontrivial to robustly optimize, evaluate, reproduce, and deploy models. Here, we present QSARtuna, a molecule property prediction modeling pipeline, written in Python and utilizing the Optuna, Scikit-learn, RDKit, and ChemProp packages, which enables the efficient and automated comparison between molecular representations and machine learning models. The platform was developed by considering the increasingly important aspect of model uncertainty quantification and explainability by design. We provide details for our framework and provide illustrative examples to demonstrate the capability of the software when applied to simple molecular property, reaction/reactivity prediction, and DNA encoded library enrichment classification. We hope that the release of QSARtuna will further spur innovation in automatic ML modeling and provide a platform for education of best practices in molecular property modeling. The code for the QSARtuna framework is made freely available via GitHub.
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| 3. |
- Mervin, Lewis H., et al.
(författare)
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Uncertainty quantification in drug design
- 2021
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Ingår i: Drug Discovery Today. - : Elsevier BV. - 1878-5832 .- 1359-6446. ; 26:2, s. 474-489
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Forskningsöversikt (refereegranskat)abstract
- Machine learning and artificial intelligence are increasingly being applied to the drug-design process as a result of the development of novel algorithms, growing access, the falling cost of computation and the development of novel technologies for generating chemically and biologically relevant data. There has been recent progress in fields such as molecular de novo generation, synthetic route prediction and, to some extent, property predictions. Despite this, most research in these fields has focused on improving the accuracy of the technologies, rather than on quantifying the uncertainty in the predictions. Uncertainty quantification will become a key component in autonomous decision making and will be crucial for integrating machine learning and chemistry automation to create an autonomous design–make–test–analyse cycle. This review covers the empirical, frequentist and Bayesian approaches to uncertainty quantification, and outlines how they can be used for drug design. We also outline the impact of uncertainty quantification on decision making.
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| 4. |
- Oldenhof, Martijn, et al.
(författare)
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Industry-Scale Orchestrated Federated Learning for Drug Discovery
- 2023
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Ingår i: Proceedings of the 37th AAAI Conference on Artificial Intelligence, AAAI 2023. ; 37, s. 15576-15584
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Konferensbidrag (refereegranskat)abstract
- To apply federated learning to drug discovery we developed a novel platform in the context of European Innovative Medicines Initiative (IMI) project MELLODDY (grant n°831472), which was comprised of 10 pharmaceutical companies, academic research labs, large industrial companies and startups. The MELLODDY platform was the first industry-scale platform to enable the creation of a global federated model for drug discovery without sharing the confidential data sets of the individual partners. The federated model was trained on the platform by aggregating the gradients of all contributing partners in a cryptographic, secure way following each training iteration. The platform was deployed on an Amazon Web Services (AWS) multi-account architecture running Kubernetes clusters in private subnets. Organisationally, the roles of the different partners were codified as different rights and permissions on the platform and administrated in a decentralized way. The MELLODDY platform generated new scientific discoveries which are described in a companion paper.
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