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Register a new userA Systematic Approach to Featurization for Cancer Drug Sensitivity Predictions with Deep Learning
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By combining various cancer cell line (CCL) drug screening panels, the size of the data has grown significantly to begin understanding how advances in deep learning can advance drug response predictions. In this paper we train >35,000 neural network models, sweeping over common featurization techniques. We found the RNA-seq to be highly redundant and informative even with subsets larger than 128 features. We found the inclusion of single nucleotide polymorphisms (SNPs) coded as count matrices improved model performance significantly, and no substantial difference in model performance with respect to molecular featurization between the common open source MOrdred descriptors and Dragon7 descriptors. Alongside this analysis, we outline data integration between CCL screening datasets and present evidence that new metrics and imbalanced data techniques, as well as advances in data standardization, need to be developed.
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Thanks to the increasing availability of genomics and other biomedical data, many machine learning approaches have been proposed for a wide range of therapeutic discovery and development tasks. In this survey, we review the literature on machine learning applications for genomics through the lens of therapeutic development. We investigate the interplay among genomics, compounds, proteins, electronic health records (EHR), cellular images, and clinical texts. We identify twenty-two machine learning in genomics applications across the entire therapeutics pipeline, from discovering novel targets, personalized medicine, developing gene-editing tools all the way to clinical trials and post-market studies. We also pinpoint seven important challenges in this field with opportunities for expansion and impact. This survey overviews recent research at the intersection of machine learning, genomics, and therapeutic development.
The emerging field of precision oncology relies on the accurate pinpointing of alterations in the molecular profile of a tumor to provide personalized targeted treatments. Current methodologies in the field commonly include the application of next generation sequencing technologies to a tumor sample, followed by the identification of mutations in the DNA known as somatic variants. The differentiation of these variants from sequencing error poses a classic classification problem, which has traditionally been approached with Bayesian statistics, and more recently with supervised machine learning methods such as neural networks. Although these methods provide greater accuracy, classic neural networks lack the ability to indicate the confidence of a variant call. In this paper, we explore the performance of deep Bayesian neural networks on next generation sequencing data, and their ability to give probability estimates for somatic variant calls. In addition to demonstrating similar performance in comparison to standard neural networks, we show that the resultant output probabilities make these better suited to the disparate and highly-variable sequencing data-sets these models are likely to encounter in the real world. We aim to deliver algorithms to oncologists for which model certainty better reflects accuracy, for improved clinical application. By moving away from point estimates to reliable confidence intervals, we expect the resultant clinical and treatment decisions to be more robust and more informed by the underlying reality of the tumor molecular profile.
Drug repurposing can accelerate the identification of effective compounds for clinical use against SARS-CoV-2, with the advantage of pre-existing clinical safety data and an established supply chain. RNA viruses such as SARS-CoV-2 manipulate cellular pathways and induce reorganization of subcellular structures to support their life cycle. These morphological changes can be quantified using bioimaging techniques. In this work, we developed DEEMD: a computational pipeline using deep neural network models within a multiple instance learning (MIL) framework, to identify putative treatments effective against SARS-CoV-2 based on morphological analysis of the publicly available RxRx19a dataset. This dataset consists of fluorescence microscopy images of SARS-CoV-2 non-infected cells and infected cells, with and without drug treatment. DEEMD first extracts discriminative morphological features to generate cell morphological profiles from the non-infected and infected cells. These morphological profiles are then used in a statistical model to estimate the applied treatment efficacy on infected cells based on similarities to non-infected cells. DEEMD is capable of localizing infected cells via weak supervision without any expensive pixel-level annotations. DEEMD identifies known SARS-CoV-2 inhibitors, such as Remdesivir and Aloxistatin, supporting the validity of our approach. DEEMD is scalable to process and screen thousands of treatments in parallel and can be explored for other emerging viruses and datasets to rapidly identify candidate antiviral treatments in the future.
How to produce expressive molecular representations is a fundamental challenge in AI-driven drug discovery. Graph neural network (GNN) has emerged as a powerful technique for modeling molecular data. However, previous supervised approaches usually suffer from the scarcity of labeled data and have poor generalization capability. Here, we proposed a novel Molecular Pre-training Graph-based deep learning framework, named MPG, that leans molecular representations from large-scale unlabeled molecules. In MPG, we proposed a powerful MolGNet model and an effective self-supervised strategy for pre-training the model at both the node and graph-level. After pre-training on 11 million unlabeled molecules, we revealed that MolGNet can capture valuable chemistry insights to produce interpretable representation. The pre-trained MolGNet can be fine-tuned with just one additional output layer to create state-of-the-art models for a wide range of drug discovery tasks, including molecular properties prediction, drug-drug interaction, and drug-target interaction, involving 13 benchmark datasets. Our work demonstrates that MPG is promising to become a novel approach in the drug discovery pipeline.
The genomic profile underlying an individual tumor can be highly informative in the creation of a personalized cancer treatment strategy for a given patient; a practice known as precision oncology. This involves next generation sequencing of a tumor sample and the subsequent identification of genomic aberrations, such as somatic mutations, to provide potential candidates of targeted therapy. The identification of these aberrations from sequencing noise and germline variant background poses a classic classification-style problem. This has been previously broached with many different supervised machine learning methods, including deep-learning neural networks. However, these neural networks have thus far not been tailored to give any indication of confidence in the mutation call, meaning an oncologist could be targeting a mutation with a low probability of being true. To address this, we present here a deep bayesian recurrent neural network for cancer variant calling, which shows no degradation in performance compared to standard neural networks. This approach enables greater flexibility through different priors to avoid overfitting to a single dataset. We will be incorporating this approach into software for oncologists to obtain safe, robust, and statistically confident somatic mutation calls for precision oncology treatment choices.
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