Prediction of drug sensitivity based on multi-omics data using deep learning and similarity network fusion approaches

With the rapid development of multi-omics technologies and accumulation of large-scale bio-datasets, many studies have conducted a more comprehensive understanding of human diseases and drug sensitivity from multiple biomolecules, such as DNA, RNA, proteins and metabolites. Using single omics data is difficult to systematically and comprehensively analyze the complex disease pathology and drug pharmacology. The molecularly targeted therapy-based approaches face some challenges, such as insufficient target gene labeling ability, and no clear targets for non-specific chemotherapeutic drugs. Consequently, the integrated analysis of multi-omics data has become a new direction for scientists to explore the mechanism of disease and drug. However, the available drug sensitivity prediction models based on multi-omics data still have problems such as overfitting, lack of interpretability, difficulties in integrating heterogeneous data, and the prediction accuracy needs to be improved. In this paper, we proposed a novel drug sensitivity prediction (NDSP) model based on deep learning and similarity network fusion approaches, which extracts drug targets using an improved sparse principal component analysis (SPCA) method for each omics data, and construct sample similarity networks based on the sparse feature matrices. Furthermore, the fused similarity networks are put into a deep neural network for training, which greatly reduces the data dimensionality and weakens the risk of overfitting problem. We use three omics of data, RNA sequence, copy number aberration and methylation, and select 35 drugs from Genomics of Drug Sensitivity in Cancer (GDSC) for experiments, including Food and Drug Administration (FDA)-approved targeted drugs, FDA-unapproved targeted drugs and non-specific therapies. Compared with some current deep learning methods, our proposed method can extract highly interpretable biological features to achieve highly accurate sensitivity prediction of targeted and non-specific cancer drugs, which is beneficial for the development of precision oncology beyond targeted therapy

Passenger or Driver: Can Gene Expression Profiling Tell Us Anything about LINE-1 in Cancer?

LINE-1 retrotransposons are expressed in epithelial cancers but not normal adult tissues. Previously, we demonstrated repression of cell proliferation, migration, and invasion genes in L1-reverse transcriptase-inhibited T47D cells, while genes involved in cell projection, formation of vacuolar membranes, and intercellular junctions were upregulated. Extending this, we examined microarray data from L1-silenced and Efavirenz-treated T47D cells by Weighted Gene Correlation Network Analysis and literature mining. Hub genes in the most significant module comparing L1-silenced and untreated controls included HSP90AB2p, DDX39A, PANK2, MT1M, and LIMK2. HSP90AB2p is related to HSP90, a master regulator of cancer, cancer evolvability and chemo-resistance. DDX39A is a known cancer driver gene while PANK2 and MT1M affect multiple pathways. LIMK2 and SYBL1 impact actin cytoskeletal dynamics and the cofilin pathway, cancer cell motility, and the epithelial-to-mesenchymal transition. Also affected were signal transduction, HIF1 pathways, iron/redox metabolism, stress granules and cancer stem cell-related metabolic reprogramming and the eIF4F translation initiation complex. Hub genes in other modules, including BTRC, MDM2, and FBXW7, stabilize oncoproteins like MYC, p53, and NOTCH1 or reflect CXCL12–CXCR4 signalling. Our findings support mounting evidence that L1 activity is a cause, rather than a consequence of oncogenesis, with L1 affecting the formation of cancer stem cells

Penalised regression for high-dimensional data: an empirical investigation and improvements via ensemble learning

In a wide range of applications, datasets are generated for which the number of variables p exceeds the sample size n. Penalised likelihood methods are widely used to tackle regression problems in these high-dimensional settings. In this thesis, we carry out an extensive empirical comparison of the performance of popular penalised regression methods in high-dimensional settings and propose new methodology that uses ensemble learning to enhance the performance of these methods. The relative efficacy of different penalised regression methods in finite-sample settings remains incompletely understood. Through a large-scale simulation study, consisting of more than 1,800 data-generating scenarios, we systematically consider the influence of various factors (for example, sample size and sparsity) on method performance. We focus on three related goals --- prediction, variable selection and variable ranking --- and consider six widely used methods. The results are supported by a semi-synthetic data example. Our empirical results complement existing theory and provide a resource to compare performance across a range of settings and metrics. We then propose a new ensemble learning approach for improving the performance of penalised regression methods, called STructural RANDomised Selection (STRANDS). The approach, that builds and improves upon the Random Lasso method, consists of two steps. In both steps, we reduce dimensionality by repeated subsampling of variables. We apply a penalised regression method to each subsampled dataset and average the results. In the first step, subsampling is informed by variable correlation structure, and in the second step, by variable importance measures from the first step. STRANDS can be used with any sparse penalised regression approach as the ``base learner''. In simulations, we show that STRANDS typically improves upon its base learner, and demonstrate that taking account of the correlation structure in the first step can help to improve the efficiency with which the model space may be explored. We propose another ensemble learning method to improve the prediction performance of Ridge Regression in sparse settings. Specifically, we combine Bayesian Ridge Regression with a probabilistic forward selection procedure, where inclusion of a variable at each stage is probabilistically determined by a Bayes factor. We compare the prediction performance of the proposed method to penalised regression methods using simulated data

Recursive Random Lasso (RRLasso) for Identifying Anti-Cancer Drug Targets.

Uncovering driver genes is crucial for understanding heterogeneity in cancer. L1-type regularization approaches have been widely used for uncovering cancer driver genes based on genome-scale data. Although the existing methods have been widely applied in the field of bioinformatics, they possess several drawbacks: subset size limitations, erroneous estimation results, multicollinearity, and heavy time consumption. We introduce a novel statistical strategy, called a Recursive Random Lasso (RRLasso), for high dimensional genomic data analysis and investigation of driver genes. For time-effective analysis, we consider a recursive bootstrap procedure in line with the random lasso. Furthermore, we introduce a parametric statistical test for driver gene selection based on bootstrap regression modeling results. The proposed RRLasso is not only rapid but performs well for high dimensional genomic data analysis. Monte Carlo simulations and analysis of the "Sanger Genomics of Drug Sensitivity in Cancer dataset from the Cancer Genome Project" show that the proposed RRLasso is an effective tool for high dimensional genomic data analysis. The proposed methods provide reliable and biologically relevant results for cancer driver gene selection

Perceptual quality estimation of H.264/AVC videos using reduced-reference and no-reference models

Reduced-reference (RR) and no-reference (NR) models for video quality estimation, using featuresthat account for the impact of coding artifacts, spatio-temporal complexity, and packet losses, are proposed. Thepurpose of this study is to analyze a number of potentially quality-relevant features in order to select the mostsuitable set of features for building the desired models. The proposed sets of features have not been used in theliterature and some of the features are used for the first time in this study. The features are employed by the leastabsolute shrinkage and selection operator (LASSO), which selects only the most influential of them toward per-ceptual quality. For comparison, we apply feature selection in the complete feature sets and ridge regression onthe reduced sets. The models are validated using a database of H.264/AVC encoded videos that were subjec-tively assessed for quality in an ITU-T compliant laboratory. We infer that just two features selected by RRLASSO and two bitstream-based features selected by NR LASSO are able to estimate perceptual qualitywith high accuracy, higher than that of ridge, which uses more features. The comparisons with competingworks and two full-reference metrics also verify the superiority of our models