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Register a new userAutomated deconvolution of structured mixtures from bulk tumor genomic data
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Motivation: As cancer researchers have come to appreciate the importance of intratumor heterogeneity, much attention has focused on the challenges of accurately profiling heterogeneity in individual patients. Experimental technologies for directly profiling genomes of single cells are rapidly improving, but they are still impractical for large-scale sampling. Bulk genomic assays remain the standard for population-scale studies, but conflate the influences of mixtures of genetically distinct tumor, stromal, and infiltrating immune cells. Many computational approaches have been developed to deconvolute these mixed samples and reconstruct the genomics of genetically homogeneous clonal subpopulations. All such methods, however, are limited to reconstructing only coarse approximations to a few major subpopulations. In prior work, we showed that one can improve deconvolution of genomic data by leveraging substructure in cellular mixtures through a strategy called simplicial complex inference. This strategy, however, is also limited by the difficulty of inferring mixture structure from sparse, noisy assays. Results: We improve on past work by introducing enhancements to automate learning of substructured genomic mixtures, with specific emphasis on genome-wide copy number variation (CNV) data. We introduce methods for dimensionality estimation to better decompose mixture model substructure; fuzzy clustering to better identify substructure in sparse, noisy data; and automated model inference methods for other key model parameters. We show that these improvements lead to more accurate inference of cell populations and mixture proportions in simulated scenarios. We further demonstrate their effectiveness in identifying mixture substructure in real tumor CNV data. Availability: Source code is available at http://www.cs.cmu.edu/~russells/software/WSCUnmix.zip
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The availability of genomic data is often essential to progress in biomedical research, personalized medicine, drug development, etc. However, its extreme sensitivity makes it problematic, if not outright impossible, to publish or share it. As a result, several initiatives have been launched to experiment with synthetic genomic data, e.g., using generative models to learn the underlying distribution of the real data and generate artificial datasets that preserve its salient characteristics without exposing it. This paper provides the first evaluation of the utility and the privacy protection of six state-of-the-art models for generating synthetic genomic data. We assess the performance of the synthetic data on several common tasks, such as allele population statistics and linkage disequilibrium. We then measure privacy through the lens of membership inference attacks, i.e., inferring whether a record was part of the training data. Our experiments show that no single approach to generate synthetic genomic data yields both high utility and strong privacy across the board. Also, the size and nature of the training dataset matter. Moreover, while some combinations of datasets and models produce synthetic data with distributions close to the real data, there often are target data points that are vulnerable to membership inference. Looking forward, our techniques can be used by practitioners to assess the risks of deploying synthetic genomic data in the wild and serve as a benchmark for future work.
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We present a nonparametric Bayesian method for disease subtype discovery in multi-dimensional cancer data. Our method can simultaneously analyse a wide range of data types, allowing for both agreement and disagreement between their underlying clustering structure. It includes feature selection and infers the most likely number of disease subtypes, given the data. We apply the method to 277 glioblastoma samples from The Cancer Genome Atlas, for which there are gene expression, copy number variation, methylation and microRNA data. We identify 8 distinct consensus subtypes and study their prognostic value for death, new tumour events, progression and recurrence. The consensus subtypes are prognostic of tumour recurrence (log-rank p-value of $3.6 times 10^{-4}$ after correction for multiple hypothesis tests). This is driven principally by the methylation data (log-rank p-value of $2.0 times 10^{-3}$) but the effect is strengthened by the other 3 data types, demonstrating the value of integrating multiple data types. Of particular note is a subtype of 47 patients characterised by very low levels of methylation. This subtype has very low rates of tumour recurrence and no new events in 10 years of follow up. We also identify a small gene expression subtype of 6 patients that shows particularly poor survival outcomes. Additionally, we note a consensus subtype that showly a highly distinctive data signature and suggest that it is therefore a biologically distinct subtype of glioblastoma. The code is available from https://sites.google.com/site/multipledatafusion/
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