Dataset Information

Network-based Biased Tree Ensembles (NetBiTE) for Drug Sensitivity Prediction and Drug Sensitivity Biomarker Identification in Cancer.

ABSTRACT: We present the Network-based Biased Tree Ensembles (NetBiTE) method for drug sensitivity prediction and drug sensitivity biomarker identification in cancer using a combination of prior knowledge and gene expression data. Our devised method consists of a biased tree ensemble that is built according to a probabilistic bias weight distribution. The bias weight distribution is obtained from the assignment of high weights to the drug targets and propagating the assigned weights over a protein-protein interaction network such as STRING. The propagation of weights, defines neighborhoods of influence around the drug targets and as such simulates the spread of perturbations within the cell, following drug administration. Using a synthetic dataset, we showcase how application of biased tree ensembles (BiTE) results in significant accuracy gains at a much lower computational cost compared to the unbiased random forests (RF) algorithm. We then apply NetBiTE to the Genomics of Drug Sensitivity in Cancer (GDSC) dataset and demonstrate that NetBiTE outperforms RF in predicting IC50 drug sensitivity, only for drugs that target membrane receptor pathways (MRPs): RTK, EGFR and IGFR signaling pathways. We propose based on the NetBiTE results, that for drugs that inhibit MRPs, the expression of target genes prior to drug administration is a biomarker for IC50 drug sensitivity following drug administration. We further verify and reinforce this proposition through control studies on, PI3K/MTOR signaling pathway inhibitors, a drug category that does not target MRPs, and through assignment of dummy targets to MRP inhibiting drugs and investigating the variation in NetBiTE accuracy.

SUBMITTER: Oskooei A

PROVIDER: S-EPMC6828742 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Publications

Network-based Biased Tree Ensembles (NetBiTE) for Drug Sensitivity Prediction and Drug Sensitivity Biomarker Identification in Cancer.

Oskooei Ali A Manica Matteo M Mathis Roland R Martínez María Rodríguez MR

Scientific reports 20191104 1

We present the Network-based Biased Tree Ensembles (NetBiTE) method for drug sensitivity prediction and drug sensitivity biomarker identification in cancer using a combination of prior knowledge and gene expression data. Our devised method consists of a biased tree ensemble that is built according to a probabilistic bias weight distribution. The bias weight distribution is obtained from the assignment of high weights to the drug targets and propagating the assigned weights over a protein-protein ...[more]

PMID: 31685861

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Project description:BackgroundDrug sensitivity prediction and drug responsive biomarker selection on high-throughput genomic data is a critical step in drug discovery. Many computational methods have been developed to serve this purpose including several deep neural network models. However, the modular relations among genomic features have been largely ignored in these methods. To overcome this limitation, the role of the gene co-expression network on drug sensitivity prediction is investigated in this study.MethodsIn this paper, we first introduce a network-based method to identify representative features for drug response prediction by using the gene co-expression network. Then, two graph-based neural network models are proposed and both models integrate gene network information directly into neural network for outcome prediction. Next, we present a large-scale comparative study among the proposed network-based methods, canonical prediction algorithms (i.e., Elastic Net, Random Forest, Partial Least Squares Regression, and Support Vector Regression), and deep neural network models for drug sensitivity prediction. All the source code and processed datasets in this study are available at https://github.com/compbiolabucf/drug-sensitivity-prediction .ResultsIn the comparison of different feature selection methods and prediction methods on a non-small cell lung cancer (NSCLC) cell line RNA-seq gene expression dataset with 50 different drug treatments, we found that (1) the network-based feature selection method improves the prediction performance compared to Pearson correlation coefficients; (2) Random Forest outperforms all the other canonical prediction algorithms and deep neural network models; (3) the proposed graph-based neural network models show better prediction performance compared to deep neural network model; (4) the prediction performance is drug dependent and it may relate to the drug's mechanism of action.ConclusionsNetwork-based feature selection method and prediction models improve the performance of the drug response prediction. The relations between the genomic features are more robust and stable compared to the correlation between each individual genomic feature and the drug response in high dimension and low sample size genomic datasets.

Project description:Tumorigenesis is a multi-step process, involving the acquisition of multiple oncogenic mutations that transform cells, resulting in systemic dysregulation that enables proliferation, invasion, and other cancer hallmarks. The goal of precision medicine is to identify therapeutically-actionable mutations from large-scale omic datasets. However, the multiplicity of oncogenes required for transformation, known as oncogenic collaboration, makes assigning effective treatments difficult. Motivated by this observation, we propose a new type of oncogenic collaboration where mutations in genes that interact with an oncogene may contribute to the oncogene's deleterious potential, a new genomic feature that we term "surrogate oncogenes." Surrogate oncogenes are representatives of these mutated subnetworks that interact with oncogenes. By mapping mutations to a protein-protein interaction network, we determine the significance of the observed distribution using permutation-based methods. For a panel of 38 breast cancer cell lines, we identified a significant number of surrogate oncogenes in known oncogenes such as BRCA1 and ESR1, lending credence to this approach. In addition, using Random Forest Classifiers, we show that these significant surrogate oncogenes predict drug sensitivity for 74 drugs in the breast cancer cell lines with a mean error rate of 30.9%. Additionally, we show that surrogate oncogenes are predictive of survival in patients. The surrogate oncogene framework incorporates unique or rare mutations from a single sample, and therefore has the potential to integrate patient-unique mutations into drug sensitivity predictions, suggesting a new direction in precision medicine and drug development. Additionally, we show the prevalence of significant surrogate oncogenes in multiple cancers from The Cancer Genome Atlas, suggesting that surrogate oncogenes may be a useful genomic feature for guiding pancancer analyses and assigning therapies across many tissue types.

Dataset Information

Network-based Biased Tree Ensembles (NetBiTE) for Drug Sensitivity Prediction and Drug Sensitivity Biomarker Identification in Cancer.

Publications

Network-based Biased Tree Ensembles (NetBiTE) for Drug Sensitivity Prediction and Drug Sensitivity Biomarker Identification in Cancer.

Similar Datasets

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