Predicting drug response of tumors from integrated genomic profiles by deep neural networks

The study of high-throughput genomic profiles from a pharmacogenomics viewpoint has provided unprecedented insights into the oncogenic features modulating drug response. A recent screening of ~1,000 cancer cell lines to a collection of anti-cancer drugs illuminated the link between genotypes and vulnerability. However, due to essential differences between cell lines and tumors, the translation into predicting drug response in tumors remains challenging. Here we proposed a DNN model to predict drug response based on mutation and expression profiles of a cancer cell or a tumor. The model contains a mutation and an expression encoders pre-trained using a large pan-cancer dataset to abstract core representations of high-dimension data, followed by a drug response predictor network. Given a pair of mutation and expression profiles, the model predicts IC50 values of 265 drugs. We trained and tested the model on a dataset of 622 cancer cell lines and achieved an overall prediction performance of mean squared error at 1.96 (log-scale IC50 values). The performance was superior in prediction error or stability than two classical methods and four analog DNNs of our model. We then applied the model to predict drug response of 9,059 tumors of 33 cancer types. The model predicted both known, including EGFR inhibitors in non-small cell lung cancer and tamoxifen in ER+ breast cancer, and novel drug targets. The comprehensive analysis further revealed the molecular mechanisms underlying the resistance to a chemotherapeutic drug docetaxel in a pan-cancer setting and the anti-cancer potential of a novel agent, CX-5461, in treating gliomas and hematopoietic malignancies. Overall, our model and findings improve the prediction of drug response and the identification of novel therapeutic options.Comment: Accepted for presentation in the International Conference on Intelligent Biology and Medicine (ICIBM 2018) at Los Angeles, CA, USA. Currently under consideration for publication in a Supplement Issue of BMC Genomic

Gene function finding through cross-organism ensemble learning

Background: Structured biological information about genes and proteins is a valuable resource to improve discovery and understanding of complex biological processes via machine learning algorithms. Gene Ontology (GO) controlled annotations describe, in a structured form, features and functions of genes and proteins of many organisms. However, such valuable annotations are not always reliable and sometimes are incomplete, especially for rarely studied organisms. Here, we present GeFF (Gene Function Finder), a novel cross-organism ensemble learning method able to reliably predict new GO annotations of a target organism from GO annotations of another source organism evolutionarily related and better studied. Results: Using a supervised method, GeFF predicts unknown annotations from random perturbations of existing annotations. The perturbation consists in randomly deleting a fraction of known annotations in order to produce a reduced annotation set. The key idea is to train a supervised machine learning algorithm with the reduced annotation set to predict, namely to rebuild, the original annotations. The resulting prediction model, in addition to accurately rebuilding the original known annotations for an organism from their perturbed version, also effectively predicts new unknown annotations for the organism. Moreover, the prediction model is also able to discover new unknown annotations in different target organisms without retraining.We combined our novel method with different ensemble learning approaches and compared them to each other and to an equivalent single model technique. We tested the method with five different organisms using their GO annotations: Homo sapiens, Mus musculus, Bos taurus, Gallus gallus and Dictyostelium discoideum. The outcomes demonstrate the effectiveness of the cross-organism ensemble approach, which can be customized with a trade-off between the desired number of predicted new annotations and their precision.A Web application to browse both input annotations used and predicted ones, choosing the ensemble prediction method to use, is publicly available at http://tiny.cc/geff/. Conclusions: Our novel cross-organism ensemble learning method provides reliable predicted novel gene annotations, i.e., functions, ranked according to an associated likelihood value. They are very valuable both to speed the annotation curation, focusing it on the prioritized new annotations predicted, and to complement known annotations available

DEEPred: Automated Protein Function Prediction with Multi-task Feed-forward Deep Neural Networks

Automated protein function prediction is critical for the annotation of uncharacterized protein sequences, where accurate prediction methods are still required. Recently, deep learning based methods have outperformed conventional algorithms in computer vision and natural language processing due to the prevention of overfitting and efficient training. Here, we propose DEEPred, a hierarchical stack of multi-task feed-forward deep neural networks, as a solution to Gene Ontology (GO) based protein function prediction. DEEPred was optimized through rigorous hyper-parameter tests, and benchmarked using three types of protein descriptors, training datasets with varying sizes and GO terms form different levels. Furthermore, in order to explore how training with larger but potentially noisy data would change the performance, electronically made GO annotations were also included in the training process. The overall predictive performance of DEEPred was assessed using CAFA2 and CAFA3 challenge datasets, in comparison with the state-of-the-art protein function prediction methods. Finally, we evaluated selected novel annotations produced by DEEPred with a literature-based case study considering the 'biofilm formation process' in Pseudomonas aeruginosa. This study reports that deep learning algorithms have significant potential in protein function prediction; particularly when the source data is large. The neural network architecture of DEEPred can also be applied to the prediction of the other types of ontological associations. The source code and all datasets used in this study are available at: https://github.com/cansyl/DEEPred

On Computable Protein Functions

Proteins are biological machines that perform the majority of functions necessary for life. Nature has evolved many different proteins, each of which perform a subset of an organism’s functional repertoire. One aim of biology is to solve the sparse high dimensional problem of annotating all proteins with their true functions. Experimental characterisation remains the gold standard for assigning function, but is a major bottleneck due to resource scarcity. In this thesis, we develop a variety of computational methods to predict protein function, reduce the functional search space for proteins, and guide the design of experimental studies. Our methods take two distinct approaches: protein-centric methods that predict the functions of a given protein, and function-centric methods that predict which proteins perform a given function. We applied our methods to help solve a number of open problems in biology. First, we identified new proteins involved in the progression of Alzheimer’s disease using proteomics data of brains from a fly model of the disease. Second, we predicted novel plastic hydrolase enzymes in a large data set of 1.1 billion protein sequences from metagenomes. Finally, we optimised a neural network method that extracts a small number of informative features from protein networks, which we used to predict functions of fission yeast proteins

タンパク質の機能予測のための深層転移学習法に関する研究

早大学位記番号:新9098早稲田大

Cell Type Classification Via Deep Learning On Single-Cell Gene Expression Data

Single-cell sequencing is a recently advanced revolutionary technology which enables researchers to obtain genomic, transcriptomic, or multi-omics information through gene expression analysis. It gives the advantage of analyzing highly heterogenous cell type information compared to traditional sequencing methods, which is gaining popularity in the biomedical area. Moreover, this analysis can help for early diagnosis and drug development of tumor cells, and cancer cell types. In the workflow of gene expression data profiling, identification of the cell types is an important task, but it faces many challenges like the curse of dimensionality, sparsity, batch effect, and overfitting. However, these challenges can be overcome by performing a feature selection technique which selects more relevant features by reducing feature dimensions. In this research work, recurrent neural network-based feature selection model is proposed to extract relevant features from high dimensional, and low sample size data. Moreover, a deep learning-based gene embedding model is also proposed to reduce data sparsity of single-cell data for cell type identification. The proposed frameworks have been implemented with different architectures of recurrent neural networks, and demonstrated via real-world micro-array datasets and single-cell RNA-seq data and observed that the proposed models perform better than other feature selection models. A semi-supervised model is also implemented using the same workflow of gene embedding concept since labeling data is very cumbersome, time consuming, and requires manual effort and expertise in the field. Therefore, different ratios of labeled data are used in the experiment to validate the concept. Experimental results show that the proposed semi-supervised approach represents very encouraging performance even though a limited number of labeled data is used via the gene embedding concept. In addition, graph attention based autoencoder model has also been studied to learn the latent features by incorporating prior knowledge with gene expression data for cell type classification. Index Terms — Single-Cell Gene Expression Data, Gene Embedding, Semi-Supervised model, Incorporate Prior Knowledge, Gene-gene Interaction Network, Deep Learning, Graph Auto Encode