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1. Using graph neural networks for site-of-metabolism prediction and its applications to ranking promiscuous enzymatic products

   https://doi.org/10.1093/bioinformatics/btad089  

   Porokhin, Vladimir; Liu, Li-Ping; Hassoun, Soha; Martelli, ed., Pier Luigi (February 2023, Bioinformatics)

   Abstract MotivationWhile traditionally utilized for identifying site-specific metabolic activity within a compound to alter its interaction with a metabolizing enzyme, predicting the site-of-metabolism (SOM) is essential in analyzing the promiscuity of enzymes on substrates. The successful prediction of SOMs and the relevant promiscuous products has a wide range of applications that include creating extended metabolic models (EMMs) that account for enzyme promiscuity and the construction of novel heterologous synthesis pathways. There is therefore a need to develop generalized methods that can predict molecular SOMs for a wide range of metabolizing enzymes. ResultsThis article develops a Graph Neural Network (GNN) model for the classification of an atom (or a bond) being an SOM. Our model, GNN-SOM, is trained on enzymatic interactions, available in the KEGG database, that span all enzyme commission numbers. We demonstrate that GNN-SOM consistently outperforms baseline machine learning models, when trained on all enzymes, on Cytochrome P450 (CYP) enzymes, or on non-CYP enzymes. We showcase the utility of GNN-SOM in prioritizing predicted enzymatic products due to enzyme promiscuity for two biological applications: the construction of EMMs and the construction of synthesis pathways. Availability and implementationA python implementation of the trained SOM predictor model can be found at https://github.com/HassounLab/GNN-SOM. Supplementary informationSupplementary data are available at Bioinformatics online. 

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2. Boost-RS: boosted embeddings for recommender systems and its application to enzyme–substrate interaction prediction

   https://doi.org/10.1093/bioinformatics/btac201  

   Li, Xinmeng; Liu, Li-Ping; Hassoun, Soha; Valencia, ed., Alfonso (April 2022, Bioinformatics)

   Abstract MotivationDespite experimental and curation efforts, the extent of enzyme promiscuity on substrates continues to be largely unexplored and under documented. Providing computational tools for the exploration of the enzyme–substrate interaction space can expedite experimentation and benefit applications such as constructing synthesis pathways for novel biomolecules, identifying products of metabolism on ingested compounds, and elucidating xenobiotic metabolism. Recommender systems (RS), which are currently unexplored for the enzyme–substrate interaction prediction problem, can be utilized to provide enzyme recommendations for substrates, and vice versa. The performance of Collaborative-Filtering (CF) RSs; however, hinges on the quality of embedding vectors of users and items (enzymes and substrates in our case). Importantly, enhancing CF embeddings with heterogeneous auxiliary data, specially relational data (e.g. hierarchical, pairwise or groupings), remains a challenge. ResultsWe propose an innovative general RS framework, termed Boost-RS that enhances RS performance by ‘boosting’ embedding vectors through auxiliary data. Specifically, Boost-RS is trained and dynamically tuned on multiple relevant auxiliary learning tasks Boost-RS utilizes contrastive learning tasks to exploit relational data. To show the efficacy of Boost-RS for the enzyme–substrate prediction interaction problem, we apply the Boost-RS framework to several baseline CF models. We show that each of our auxiliary tasks boosts learning of the embedding vectors, and that contrastive learning using Boost-RS outperforms attribute concatenation and multi-label learning. We also show that Boost-RS outperforms similarity-based models. Ablation studies and visualization of learned representations highlight the importance of using contrastive learning on some of the auxiliary data in boosting the embedding vectors. Availability and implementationA Python implementation for Boost-RS is provided at https://github.com/HassounLab/Boost-RS. The enzyme-substrate interaction data is available from the KEGG database (https://www.genome.jp/kegg/). 

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3. Extending PROXIMAL to predict degradation pathways of phenolic compounds in the human gut microbiota

   https://doi.org/10.1038/s41540-024-00381-1  

   Balzerani, Francesco; Blasco, Telmo; Pérez-Burillo, Sergio; Valcarcel, Luis V; Hassoun, Soha; Planes, Francisco J (December 2024, npj Systems Biology and Applications)

   Abstract Despite significant advances in reconstructing genome-scale metabolic networks, the understanding of cellular metabolism remains incomplete for many organisms. A promising approach for elucidating cellular metabolism is analysing the full scope of enzyme promiscuity, which exploits the capacity of enzymes to bind to non-annotated substrates and generate novel reactions. To guide time-consuming costly experimentation, different computational methods have been proposed for exploring enzyme promiscuity. One relevant algorithm is PROXIMAL, which strongly relies on KEGG to define generic reaction rules and link specific molecular substructures with associated chemical transformations. Here, we present a completely new pipeline, PROXIMAL2, which overcomes the dependency on KEGG data. In addition, PROXIMAL2 introduces two relevant improvements with respect to the former version: i) correct treatment of multi-step reactions and ii) tracking of electric charges in the transformations. We compare PROXIMAL and PROXIMAL2 in recovering annotated products from substrates in KEGG reactions, finding a highly significant improvement in the level of accuracy. We then applied PROXIMAL2 to predict degradation reactions of phenolic compounds in the human gut microbiota. The results were compared to RetroPath RL, a different and relevant enzyme promiscuity method. We found a significant overlap between these two methods but also complementary results, which open new research directions into this relevant question in nutrition. 

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4. Handling Missing Data with Graph Representation Learning

   You, Jiaxuan; Ma, Xiaobai; Ding, Daisy Yi; Kochenderfer, Mykel; Leskovec, Jure. (January 2020, Neural Information Processing Systems (NeurIPS)

   Machine learning with missing data has been approached in two different ways, including feature imputation where missing feature values are estimated based on observed values and label prediction where downstream labels are learned directly from incomplete data. However, existing imputation models tend to have strong prior assumptions and cannot learn from downstream tasks, while models targeting label prediction often involve heuristics and can encounter scalability issues. Here we propose GRAPE, a graph-based framework for feature imputation as well as label prediction. GRAPE tackles the missing data problem using a graph representation, where the observations and features are viewed as two types of nodes in a bipartite graph, and the observed feature values as edges. Under the GRAPE framework, the feature imputation is formulated as an edge-level prediction task and the label prediction as a node-level prediction task. These tasks are then solved with Graph Neural Networks. Experimental results on nine benchmark datasets show that GRAPE yields 20% lower mean absolute error for imputation tasks and 10% lower for label prediction tasks, compared with existing state-of-the-art methods. 

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5. Modeling Label Space Interactions in Multi-label Classification using Box Embeddings

   Patel, Dhruvesh; Dangati, Pavitra; Lee, Jay-Yoon; Boratko, Michael; McCallum, Andrew (January 2022, ICLR 2022 Poster)

   Multi-label classification is a challenging structured prediction task in which a set of output class labels are predicted for each input. Real-world datasets often have natural or latent taxonomic relationships between labels, making it desirable for models to employ label representations capable of capturing such taxonomies. Most existing multi-label classification methods do not do so, resulting in label predictions that are inconsistent with the taxonomic constraints, thus failing to accurately represent the fundamentals of problem setting. In this work, we introduce the multi-label box model (MBM), a multi-label classification method that combines the encoding power of neural networks with the inductive bias and probabilistic semantics of box embeddings (Vilnis, et al 2018). Box embeddings can be understood as trainable Venn-diagrams based on hyper-rectangles. Representing labels by boxes rather than vectors, MBM is able to capture taxonomic relations among labels. Furthermore, since box embeddings allow these relations to be learned by stochastic gradient descent from data, and to be read as calibrated conditional probabilities, our model is endowed with a high degree of interpretability. This interpretability also facilitates the injection of partial information about label-label relationships into model training, to further improve its consistency. We provide theoretical grounding for our method and show experimentally the model's ability to learn the true latent taxonomic structure from data. Through extensive empirical evaluations on both small and large-scale multi-label classification datasets, we show that BBM can significantly improve taxonomic consistency while preserving or surpassing the state-of-the-art predictive performance. 

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