Computational purification of individual tumor gene expression profiles leads to significant improvements in prognostic prediction.

Tumor heterogeneity is a limiting factor in cancer treatment and in the discovery of biomarkers to personalize it. We describe a computational purification tool, ISOpure, to directly address the effects of variable normal tissue contamination in clinical tumor specimens. ISOpure uses a set of tumor expression profiles and a panel of healthy tissue expression profiles to generate a purified cancer profile for each tumor sample and an estimate of the proportion of RNA originating from cancerous cells. Applying ISOpure before identifying gene signatures leads to significant improvements in the prediction of prognosis and other clinical variables in lung and prostate cancer

Spectral Alignment of Networks

Network alignment refers to the problem of finding a bijective mapping across vertices of two or more graphs to maximize the number of overlapping edges and/or to minimize the number of mismatched interactions across networks. This paper introduces a network alignment algorithm inspired by eigenvector analysis which creates a simple relaxation for the underlying quadratic assignment problem. Our method relaxes binary assignment constraints along the leading eigenvector of an alignment matrix which captures the structure of matched and mismatched interactions across networks. Our proposed algorithm denoted by EigeAlign has two steps. First, it computes the Perron-Frobenius eigenvector of the alignment matrix. Second, it uses this eigenvector in a linear optimization framework of maximum weight bipartite matching to infer bijective mappings across vertices of two graphs. Unlike existing network alignment methods, EigenAlign considers both matched and mismatched interactions in its optimization and therefore, it is effective in aligning networks even with low similarity. We show that, when certain technical conditions hold, the relaxation given by EigenAlign is asymptotically exact over Erdos-Renyi graphs with high probability. Moreover, for modular network structures, we show that EigenAlign can be used to split the large quadratic assignment optimization into small subproblems, enabling the use of computationally expensive, but tight semidefinite relaxations over each subproblem. Through simulations, we show the effectiveness of the EigenAlign algorithm in aligning various network structures including Erdos-Renyi, power law, and stochastic block models, under different noise models. Finally, we apply EigenAlign to compare gene regulatory networks across human, fly and worm species which we infer by integrating genome-wide functional and physical genomics datasets from ENCODE and modENCODE consortia. EigenAlign infers conserved regulatory interactions across these species despite large evolutionary distances spanned. We find strong conservation of centrally-connected genes and some biological pathways, especially for human-fly comparisons

Tissue-specific regulatory circuits reveal variable modular perturbations across complex diseases

Mapping perturbed molecular circuits that underlie complex diseases remains a great challenge. We developed a comprehensive resource of 394 cell type– and tissue-specific gene regulatory networks for human, each specifying the genome-wide connectivity among transcription factors, enhancers, promoters and genes. Integration with 37 genome-wide association studies (GWASs) showed that disease-associated genetic variants—including variants that do not reach genome-wide significance—often perturb regulatory modules that are highly specific to disease-relevant cell types or tissues. Our resource opens the door to systematic analysis of regulatory programs across hundreds of human cell types and tissue

The benefits of selecting phenotype-specific variants for applications of mixed models in genomics

Applications of linear mixed models (LMMs) to problems in genomics include phenotype prediction, correction for confounding in genome-wide association studies, estimation of narrow sense heritability, and testing sets of variants (e.g., rare variants) for association. In each of these applications, the LMM uses a genetic similarity matrix, which encodes the pairwise similarity between every two individuals in a cohort. Although ideally these similarities would be estimated using strictly variants relevant to the given phenotype, the identity of such variants is typically unknown. Consequently, relevant variants are excluded and irrelevant variants are included, both having deleterious effects. For each application of the LMM, we review known effects and describe new effects showing how variable selection can be used to mitigate them.National Institute on Aging (Brain eQTL Study (dbGaP phs000249.v1.p1)

scPair: Boosting single cell multimodal analysis by leveraging implicit feature selection and single cell atlases

Multimodal single-cell assays profile multiple sets of features in the same cells and are widely used for identifying and mapping cell states between chromatin and mRNA and linking regulatory elements to target genes. However, the high dimensionality of input features and shallow sequencing depth compared to unimodal assays pose challenges in data analysis. Here we present scPair, a multimodal single-cell data framework that overcomes these challenges by employing an implicit feature selection approach. scPair uses dual encoder-decoder structures trained on paired data to align cell states across modalities and predict features from one modality to another. We demonstrate that scPair outperforms existing methods in accuracy and execution time, and facilitates downstream tasks such as trajectory inference. We further show scPair can augment smaller multimodal datasets with larger unimodal atlases to increase statistical power to identify groups of transcription factors active during different stages of neural differentiation

ISOpureR: an R implementation of a computational purification algorithm of mixed tumour profiles

Background Tumour samples containing distinct sub-populations of cancer and normal cells present challenges in the development of reproducible biomarkers, as these biomarkers are based on bulk signals from mixed tumour profiles. ISOpure is the only mRNA computational purification method to date that does not require a paired tumour-normal sample, provides a personalized cancer profile for each patient, and has been tested on clinical data. Replacing mixed tumour profiles with ISOpure-preprocessed cancer profiles led to better prognostic gene signatures for lung and prostate cancer. Results To simplify the integration of ISOpure into standard R-based bioinformatics analysis pipelines, the algorithm has been implemented as an R package. The ISOpureR package performs analogously to the original code in estimating the fraction of cancer cells and the patient cancer mRNA abundance profile from tumour samples in four cancer datasets. Conclusions The ISOpureR package estimates the fraction of cancer cells and personalized patient cancer mRNA abundance profile from a mixed tumour profile. This open-source R implementation enables integration into existing computational pipelines, as well as easy testing, modification and extension of the model.Prostate Cancer CanadaMovember Foundation (Grant RS2014-01