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  1. Abstract Motivation

    In metagenomics, the study of environmentally associated microbial communities from their sampled DNA, one of the most fundamental computational tasks is that of determining which genomes from a reference database are present or absent in a given sample metagenome. Existing tools generally return point estimates, with no associated confidence or uncertainty associated with it. This has led to practitioners experiencing difficulty when interpreting the results from these tools, particularly for low-abundance organisms as these often reside in the “noisy tail” of incorrect predictions. Furthermore, few tools account for the fact that reference databases are often incomplete and rarely, if ever, contain exact replicas of genomes present in an environmentally derived metagenome.

    Results

    We present solutions for these issues by introducing the algorithm YACHT: Yes/No Answers to Community membership via Hypothesis Testing. This approach introduces a statistical framework that accounts for sequence divergence between the reference and sample genomes, in terms of ANI, as well as incomplete sequencing depth, thus providing a hypothesis test for determining the presence or absence of a reference genome in a sample. After introducing our approach, we quantify its statistical power and how this changes with varying parameters. Subsequently, we perform extensive experiments using both simulated and real data to confirm the accuracy and scalability of this approach.

    Availability and implementation

    The source code implementing this approach is available via Conda and at https://github.com/KoslickiLab/YACHT. We also provide the code for reproducing experiments at https://github.com/KoslickiLab/YACHT-reproducibles.

     
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  2. Abstract Background

    Computational drug repurposing is a cost- and time-efficient approach that aims to identify new therapeutic targets or diseases (indications) of existing drugs/compounds. It is especially critical for emerging and/or orphan diseases due to its cheaper investment and shorter research cycle compared with traditional wet-lab drug discovery approaches. However, the underlying mechanisms of action (MOAs) between repurposed drugs and their target diseases remain largely unknown, which is still a main obstacle for computational drug repurposing methods to be widely adopted in clinical settings.

    Results

    In this work, we propose KGML-xDTD: a Knowledge Graph–based Machine Learning framework for explainably predicting Drugs Treating Diseases. It is a 2-module framework that not only predicts the treatment probabilities between drugs/compounds and diseases but also biologically explains them via knowledge graph (KG) path-based, testable MOAs. We leverage knowledge-and-publication–based information to extract biologically meaningful “demonstration paths” as the intermediate guidance in the Graph-based Reinforcement Learning (GRL) path-finding process. Comprehensive experiments and case study analyses show that the proposed framework can achieve state-of-the-art performance in both predictions of drug repurposing and recapitulation of human-curated drug MOA paths.

    Conclusions

    KGML-xDTD is the first model framework that can offer KG path explanations for drug repurposing predictions by leveraging the combination of prediction outcomes and existing biological knowledge and publications. We believe it can effectively reduce “black-box” concerns and increase prediction confidence for drug repurposing based on predicted path-based explanations and further accelerate the process of drug discovery for emerging diseases.

     
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