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A deep learning framework for high-throughput mechanism-driven phenotype compound screening.

ABSTRACT: Target-based high-throughput compound screening dominates conventional one-drug-one-gene drug discovery process. However, the readout from the chemical modulation of a single protein is poorly correlated with phenotypic response of organism, leading to high failure rate in drug development. Chemical-induced gene expression profile provides an attractive solution to phenotype-based screening. However, the use of such data is currently limited by their sparseness, unreliability, and relatively low throughput. Several methods have been proposed to impute missing values for gene expression datasets. However, few existing methods can perform de novo chemical compound screening. In this study, we propose a mechanism-driven neural network-based method named DeepCE (Deep Chemical Expression) which utilizes graph convolutional neural network to learn chemical representation and multi-head attention mechanism to model chemical substructure-gene and gene-gene feature associations. In addition, we propose a novel data augmentation method which extracts useful information from unreliable experiments in L1000 dataset. The experimental results show that DeepCE achieves the superior performances not only in de novo chemical setting but also in traditional imputation setting compared to state-of-the-art baselines for the prediction of chemical-induced gene expression. We further verify the effectiveness of gene expression profiles generated from DeepCE by comparing them with gene expression profiles in L1000 dataset for downstream classification tasks including drug-target and disease predictions. To demonstrate the value of DeepCE, we apply it to patient-specific drug repurposing of COVID-19 for the first time, and generate novel lead compounds consistent with clinical evidences. Thus, DeepCE provides a potentially powerful framework for robust predictive modeling by utilizing noisy omics data as well as screening novel chemicals for the modulation of systemic response to disease.

SUBMITTER: Pham TH

PROVIDER: S-EPMC7386506 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundPhysiological motion, such as respiratory motion, has become a limiting factor in the spatial resolution of positron emission tomography (PET) imaging as the resolution of PET detectors continue to improve. Motion-induced misregistration between PET and CT images can also cause attenuation correction artifacts. Respiratory gating can be used to freeze the motion and to reduce motion induced artifacts.PurposeIn this study, we propose a robust data-driven approach using an unsupervised deep clustering network that employs an autoencoder (AE) to extract latent features for respiratory gating.MethodsWe first divide list-mode PET data into short-time frames. The short-time frame images are reconstructed without attenuation, scatter, or randoms correction to avoid attenuation mismatch artifacts and to reduce image reconstruction time. The deep AE is then trained using reconstructed short-time frame images to extract latent features for respiratory gating. No additional data are required for the AE training. K-means clustering is subsequently used to perform respiratory gating based on the latent features extracted by the deep AE. The effectiveness of our proposed Deep Clustering method was evaluated using physical phantom and real patient datasets. The performance was compared against phase gating based on an external signal (External) and image based principal component analysis (PCA) with K-means clustering (Image PCA).ResultsThe proposed method produced gated images with higher contrast and sharper myocardium boundaries than those obtained using the External gating method and Image PCA. Quantitatively, the gated images generated by the proposed Deep Clustering method showed larger center of mass (COM) displacement and higher lesion contrast than those obtained using the other two methods.ConclusionsThe effectiveness of our proposed method was validated using physical phantom and real patient data. The results showed our proposed framework could provide superior gating than the conventional External method and Image PCA.

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A deep learning framework for high-throughput mechanism-driven phenotype compound screening.

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