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A New Approach to Drug Repurposing with Two-Stage Prediction, Machine Learning, and Unsupervised Clustering of Gene Expression.

ABSTRACT: Drug repurposing has broad importance in planetary health for therapeutics innovation in infectious diseases as well as common or rare chronic human diseases. Drug repurposing has also proved important to develop interventions against the COVID-19 pandemic. We propose a new approach for drug repurposing involving two-stage prediction and machine learning. First, diseases are clustered by gene expression on the premise that similar patterns of altered gene expression imply critical pathways shared in different disease conditions. Next, drug efficacy is assessed by the reversibility of abnormal gene expression, and results are clustered to identify repurposing targets. To cluster similar diseases, gene expression data from 262 cases of 31 diseases and 268 controls were analyzed by Uniform Manifold Approximation and Projection for Dimension Reduction followed by k-means to optimize the number of clusters. For evaluation, we examined disease-specific gene expression data for inclusion, body myositis, polymyositis, and dermatomyositis (DM), and used LINCS L1000 characteristic direction signatures search engine (L1000CDS²) to obtain lists of small-molecule compounds that reversed the expression patterns of these specifically altered genes as candidates for drug repurposing. Finally, the functions of affected genes were analyzed by Gene Set Enrichment Analysis to examine consistency with expected drug efficacy. Consequently, we found disease-specific gene expression, and importantly, identified 20 drugs such as BMS-387032, phorbol-12-myristate-13-acetate, mitoxantrone, alvocidib, and vorinostat as candidates for repurposing. These were previously noted to be effective against two of the three diseases, and have a high probability of being effective against the other. That is, inclusion body myositis and DM. The two-stage prediction approach to drug repurposing presented here offers innovation to inform future drug discovery and clinical trials in a variety of human diseases.

SUBMITTER: Cong Y

PROVIDER: S-EPMC9245788 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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A New Approach to Drug Repurposing with Two-Stage Prediction, Machine Learning, and Unsupervised Clustering of Gene Expression.

Cong Yi Y Shintani Misaki M Imanari Fuga F Osada Naoki N Endo Toshinori T

Omics : a journal of integrative biology 20220603 6

Drug repurposing has broad importance in planetary health for therapeutics innovation in infectious diseases as well as common or rare chronic human diseases. Drug repurposing has also proved important to develop interventions against the COVID-19 pandemic. We propose a new approach for drug repurposing involving two-stage prediction and machine learning. First, diseases are clustered by gene expression on the premise that similar patterns of altered gene expression imply critical pathways share ...[more]

PMID: 35666246

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Project description:BackgroundIdentification of distinct clinical phenotypes of diseases can guide personalized treatment. This study aimed to classify hospitalized COVID-19 pneumonia subgroups using an unsupervised machine learning approach.MethodsWe included hospitalized COVID-19 pneumonia patients from July to September 2021. K-means clustering, an unsupervised machine learning method, was performed to identify clinical phenotypes based on clinical and laboratory variables collected within 24 hours of admission. Variables were normalized before clustering to ensure equal contribution to the analysis. The optimal number of clusters was determined using the elbow method and Silhouette scores. Cox proportional hazard models were used to compare the risk of intubation and 90-day mortality across the identified clusters.ResultsThree clinically distinct clusters were identified among 538 hospitalized COVID-19 pneumonia patients. Cluster 1 (N = 27) consisted predominantly of males and showed significantly elevated serum liver enzymes and LDH levels. Cluster 2 (N = 370) was characterized by lower chest x-ray scores and higher serum albumin levels. Cluster 3 (N = 141) was characterized by older age, diabetes mellitus, higher chest x-ray scores, more severe vital signs, higher creatinine levels, lower hemoglobin levels, lower lymphocyte counts, higher C-reactive protein, higher D-dimer, and higher LDH levels. When compared to cluster 2, cluster 3 was significantly associated with increased risk of 90-day mortality (HR, 6.24; 95% CI, 2.42-16.09) and intubation (HR, 5.26; 95% CI 2.37-11.72). In contrast, cluster 1 had a 100% survival rate with a non-significant increase in intubation risk compared to cluster 2 (HR, 1.40, 95% CI, 0.18-11.04).ConclusionsWe identified three distinct clinical phenotypes of COVID-19 pneumonia patients, with cluster 3 associated with an increased risk of respiratory failure and mortality. These findings may guide tailored clinical management strategies.

Project description:BackgroundDrug repositioning is the process of identifying new uses for existing drugs. Computational drug repositioning methods can reduce the time, costs and risks of drug development by automating the analysis of the relationships in pharmacology networks. Pharmacology networks are large and heterogeneous. Clustering drugs into small groups can simplify large pharmacology networks, these subgroups can also be used as a starting point for repositioning drugs. In this paper, we propose a two-tiered drug-centric unsupervised clustering approach for drug repositioning, integrating heterogeneous drug data profiles: drug-chemical, drug-disease, drug-gene, drug-protein and drug-side effect relationships.ResultsThe proposed drug repositioning approach is threefold; (i) clustering drugs based on their homogeneous profiles using the Growing Self Organizing Map (GSOM); (ii) clustering drugs based on drug-drug relation matrices based on the previous step, considering three state-of-the-art graph clustering methods; and (iii) inferring drug repositioning candidates and assigning a confidence value for each identified candidate. In this paper, we compare our two-tiered clustering approach against two existing heterogeneous data integration approaches with reference to the Anatomical Therapeutic Chemical (ATC) classification, using GSOM. Our approach yields Normalized Mutual Information (NMI) and Standardized Mutual Information (SMI) of 0.66 and 36.11, respectively, while the two existing methods yield NMI of 0.60 and 0.64 and SMI of 22.26 and 33.59. Moreover, the two existing approaches failed to produce useful cluster separations when using graph clustering algorithms while our approach is able to identify useful clusters for drug repositioning. Furthermore, we provide clinical evidence for four predicted results (Chlorthalidone, Indomethacin, Metformin and Thioridazine) to support that our proposed approach can be reliably used to infer ATC code and drug repositioning.ConclusionThe proposed two-tiered unsupervised clustering approach is suitable for drug clustering and enables heterogeneous data integration. It also enables identifying reliable repositioning drug candidates with reference to ATC therapeutic classification. The repositioning drug candidates identified consistently by multiple clustering algorithms and with high confidence have a higher possibility of being effective repositioning candidates.

Project description:BackgroundThe demand for fresh strategies to analyze intricate multidimensional data in neuroscience is increasingly evident. One of the most complex events during our neurodevelopment is adolescence, where our nervous system suffers constant changes, not only in neuroanatomical traits but also in neurophysiological components. One of the most impactful factors we deal with during this time is our environment, especially when encountering external factors such as social behaviors or substance consumption. Binge drinking (BD) has emerged as an extended pattern of alcohol consumption in teenagers, not only affecting their future lifestyle but also changing their neurodevelopment. Recent studies have changed their scope into finding predisposition factors that may lead adolescents into this kind of patterns of consumption.MethodsIn this article, using unsupervised machine learning (UML) algorithms, we analyze the relationship between electrophysiological activity of healthy teenagers and the levels of consumption they had 2 years later. We used hierarchical agglomerative UML techniques based on Ward's minimum variance criterion to clusterize relations between power spectrum and functional connectivity and alcohol consumption, based on similarity in their correlations, in frequency bands from theta to gamma.ResultsWe found that all frequency bands studied had a pattern of clusterization based on anatomical regions of interest related to neurodevelopment and cognitive and behavioral aspects of addiction, highlighting the dorsolateral and medial prefrontal, the sensorimotor, the medial posterior, and the occipital cortices. All these patterns, of great cohesion and coherence, showed an abnormal electrophysiological activity, representing a dysregulation in the development of core resting-state networks. The clusters found maintained not only plausibility in nature but also robustness, making this a great example of the usage of UML in the analysis of electrophysiological activity-a new perspective into analysis that, while contributing to classical statistics, can clarify new characteristics of the variables of interest.

Dataset Information

A New Approach to Drug Repurposing with Two-Stage Prediction, Machine Learning, and Unsupervised Clustering of Gene Expression.

Publications

A New Approach to Drug Repurposing with Two-Stage Prediction, Machine Learning, and Unsupervised Clustering of Gene Expression.

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