Gholamreza Haffari

The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups

The elucidation of breast cancer subgroups and their molecular drivers requires integrated views of the genome and transcriptome from representative numbers of patients. We present an integrated analysis of copy number and gene expression in a discovery and validation set of 997 and 995 primary breast tumours, respectively, with long-term clinical follow-up. Inherited variants (copy number variants and single nucleotide polymorphisms) and acquired somatic copy number aberrations (CNAs) were associated with expression in ∼40% of genes, with the landscape dominated by cis- and trans-acting CNAs. By delineating expression outlier genes driven in cis by CNAs, we identified putative cancer genes, including deletions in PPP2R2A, MTAP and MAP2K4. Unsupervised analysis of paired DNA–RNA profiles revealed novel subgroups with distinct clinical outcomes, which reproduced in the validation cohort. These include a high-risk, oestrogen-receptor-positive 11q13/14 cis-acting subgroup and a favourable prognosis subgroup devoid of CNAs. Trans-acting aberration hotspots were found to modulate subgroup-specific gene networks, including a TCR deletion-mediated adaptive immune response in the ‘CNA-devoid’ subgroup and a basal-specific chromosome 5 deletion-associated mitotic network. Our results provide a novel molecular stratification of the breast cancer population, derived from the impact of somatic CNAs on the transcriptome.

The clonal and mutational evolution spectrum of primary triple-negative breast cancers.

Primary triple-negative breast cancers (TNBCs), a tumour type defined by lack of oestrogen receptor, progesterone receptor and ERBB2 gene amplification, represent approximately 16% of all breast cancers. Here we show in 104 TNBC cases that at the time of diagnosis these cancers exhibit a wide and continuous spectrum of genomic evolution, with some having only a handful of coding somatic aberrations in a few pathways, whereas others contain hundreds of coding somatic mutations. High-throughput RNA sequencing (RNA-seq) revealed that only approximately 36% of mutations are expressed. Using deep re-sequencing measurements of allelic abundance for 2,414 somatic mutations, we determine for the first time—to our knowledge—in an epithelial tumour subtype, the relative abundance of clonal frequencies among cases representative of the population. We show that TNBCs vary widely in their clonal frequencies at the time of diagnosis, with the basal subtype of TNBC showing more variation than non-basal TNBC. Although p53 (also known as TP53), PIK3CA and PTEN somatic mutations seem to be clonally dominant compared to other genes, in some tumours their clonal frequencies are incompatible with founder status. Mutations in cytoskeletal, cell shape and motility proteins occurred at lower clonal frequencies, suggesting that they occurred later during tumour progression. Taken together, our results show that understanding the biology and therapeutic responses of patients with TNBC will require the determination of individual tumour clonal genotypes.

DriverNet: uncovering the impact of somatic driver mutations on transcriptional networks in cancer

Simultaneous interrogation of tumor genomes and transcriptomes is underway in unprecedented global efforts. Yet, despite the essential need to separate driver mutations modulating gene expression networks from transcriptionally inert passenger mutations, robust computational methods to ascertain the impact of individual mutations on transcriptional networks are underdeveloped. We introduce a novel computational framework, DriverNet, to identify likely driver mutations by virtue of their effect on mRNA expression networks. Application to four cancer datasets reveals the prevalence of rare candidate driver mutations associated with disrupted transcriptional networks and a simultaneous modulation of oncogenic and metabolic networks, induced by copy number co-modification of adjacent oncogenic and metabolic drivers. DriverNet is available on Bioconductor or at http://compbio.bccrc.ca/software/drivernet/.

Feature-based classifiers for somatic mutation detection in tumour–normal paired sequencing data

Motivation: The study of cancer genomes now routinely involves using next-generation sequencing technology (NGS) to profile tumours for single nucleotide variant (SNV) somatic mutations. However, surprisingly few published bioinformatics methods exist for the specific purpose of identifying somatic mutations from NGS data and existing tools are often inaccurate, yielding intolerably high false prediction rates. As such, the computational problem of accurately inferring somatic mutations from paired tumour/normal NGS data remains an unsolved challenge. Results: We present the comparison of four standard supervised machine learning algorithms for the purpose of somatic SNV prediction in tumour/normal NGS experiments. To evaluate these approaches (random forest, Bayesian additive regression tree, support vector machine and logistic regression), we constructed 106 features representing 3369 candidate somatic SNVs from 48 breast cancer genomes, originally predicted with naive methods and subsequently revalidated to establish ground truth labels. We trained the classifiers on this data (consisting of 1015 true somatic mutations and 2354 non-somatic mutation positions) and conducted a rigorous evaluation of these methods using a cross-validation framework and hold-out test NGS data from both exome capture and whole genome shotgun platforms. All learning algorithms employing predictive discriminative approaches with feature selection improved the predictive accuracy over standard approaches by statistically significant margins. In addition, using unsupervised clustering of the ground truth ‘false positive’ predictions, we noted several distinct classes and present evidence suggesting non-overlapping sources of technical artefacts illuminating important directions for future study. Availability: Software called MutationSeq and datasets are available from http://compbio.bccrc.ca. Contact: saparicio@bccrc.ca Supplementary information: Supplementary data are available at Bioinformatics online.

Active Learning for Statistical Phrase-based Machine Translation

Statistical machine translation (SMT) models need large bilingual corpora for training, which are unavailable for some language pairs. This paper provides the first serious experimental study of active learning for SMT. We use active learning to improve the quality of a phrase-based SMT system, and show significant improvements in translation compared to a random sentence selection baseline, when test and training data are taken from the same or different domains. Experimental results are shown in a simulated setting using three language pairs, and in a realistic situation for Bangla-English, a language pair with limited translation resources.

Incorporating Structural Alignment Biases into an Attentional Neural Translation Model

Neural encoder-decoder models of machine translation have achieved impressive results, rivalling traditional translation models. However their modelling formulation is overly simplistic, and omits several key inductive biases built into traditional models. In this paper we extend the attentional neural translation model to include structural biases from word based alignment models, including positional bias, Markov conditioning, fertility and agreement over translation directions. We show improvements over a baseline attentional model and standard phrase-based model over several language pairs, evaluating on difficult languages in a low resource setting.

Semi-supervised model adaptation for statistical machine translation

Statistical machine translation systems are usually trained on large amounts of bilingual text (used to learn a translation model), and also large amounts of monolingual text in the target language (used to train a language model). In this article we explore the use of semi-supervised model adaptation methods for the effective use of monolingual data from the source language in order to improve translation quality. We propose several algorithms with this aim, and present the strengths and weaknesses of each one. We present detailed experimental evaluations on the French–English EuroParl data set and on data from the NIST Chinese–English large-data track. We show a significant improvement in translation quality on both tasks.

PREvaIL, an integrative approach for inferring catalytic residues using sequence, structural, and network features in a machine-learning framework

Determining the catalytic residues in an enzyme is critical to our understanding the relationship between protein sequence, structure, function, and enhancing our ability to design novel enzymes and their inhibitors. Although many enzymes have been sequenced, and their primary and tertiary structures determined, experimental methods for enzyme functional characterization lag behind. Because experimental methods used for identifying catalytic residues are resource- and labor-intensive, computational approaches have considerable value and are highly desirable for their ability to complement experimental studies in identifying catalytic residues and helping to bridge the sequence-structure-function gap. In this study, we describe a new computational method called PREvaIL for predicting enzyme catalytic residues. This method was developed by leveraging a comprehensive set of informative features extracted from multiple levels, including sequence, structure, and residue-contact network, in a random forest machine-learning framework. Extensive benchmarking experiments on eight different datasets based on 10-fold cross-validation and independent tests, as well as side-by-side performance comparisons with seven modern sequence- and structure-based methods, showed that PREvaIL achieved competitive predictive performance, with an area under the receiver operating characteristic curve and area under the precision-recall curve ranging from 0.896 to 0.973 and from 0.294 to 0.523, respectively. We demonstrated that this method was able to capture useful signals arising from different levels, leveraging such differential but useful types of features and allowing us to significantly improve the performance of catalytic residue prediction. We believe that this new method can be utilized as a valuable tool for both understanding the complex sequence-structure-function relationships of proteins and facilitating the characterization of novel enzymes lacking functional annotations.

A Latent Variable Recurrent Neural Network for Discourse-Driven Language Models

This paper presents a novel latent variable recurrent neural network architecture for jointly modeling sequences of words and (possibly latent) discourse relations between adjacent sentences. A recurrent neural network generates individual words, thus reaping the benefits of discriminatively-trained vector representations. The discourse relations are represented with a latent variable, which can be predicted or marginalized, depending on the task. The resulting model can therefore employ a training objective that includes not only discourse relation classification, but also word prediction. As a result, it outperforms state-of-the-art alternatives for two tasks: implicit discourse relation classification in the Penn Discourse Treebank, and dialog act classification in the Switchboard corpus. Furthermore, by marginalizing over latent discourse relations at test time, we obtain a discourse informed language model, which improves over a strong LSTM baseline.

Modeling the temporal dynamics of social rating networks using bidirectional effects of social relations and rating patterns

In this paper we first observe and analyze the temporal behavior of users in a social rating network on expressing ratings and creating social relations. Then, we model the temporal dynamics of a SRN based on our observations and using bidirectional effects of ratings and social relationships. While existing models for other types of social networks have captured some of the factors, our model is the first one to represent all four factors, i.e. social relations-on-ratings (social influence), social relations-on-social relations (transitivity), ratings-on-social relations (selection), and ratings-on-ratings (correlational influence). We also model the strength of each effect throughout the evolution of a SRN. Using our model, we develop a generative model for SRNs. Such a model can serve as basis for several purposes, in particular link prediction, rating prediction and prediction of future community structures. Given the sensitive nature of social network data, there are only very few public social rating network datasets. This motivates the development of generative models to create such synthetic datasets for research purposes. Our experimental study on the Epinions dataset demonstrates that the proposed model produces social rating networks that agree with real world data on a comprehensive set of evaluation criteria much better than existing models.