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Multi-resolution modeling of a discrete stochastic process identifies causes of cancer

Adam Yaari · Maxwell Sherman · Oliver C Priebe · Po-Ru Loh · Boris Katz · Andrei Barbu · Bonnie Berger

Keywords: [ probabelistic models ] [ cancer research ] [ non-stationary stochastic processes ] [ Computational Biology ] [ graphical models ] [ deep learning ]


Detection of cancer-causing mutations within the vast and mostly unexplored human genome is a major challenge. Doing so requires modeling the background mutation rate, a highly non-stationary stochastic process, across regions of interest varying in size from one to millions of positions. Here, we present the split-Poisson-Gamma (SPG) distribution, an extension of the classical Poisson-Gamma formulation, to model a discrete stochastic process at multiple resolutions. We demonstrate that the probability model has a closed-form posterior, enabling efficient and accurate linear-time prediction over any length scale after the parameters of the model have been inferred a single time. We apply our framework to model mutation rates in tumors and show that model parameters can be accurately inferred from high-dimensional epigenetic data using a convolutional neural network, Gaussian process, and maximum-likelihood estimation. Our method is both more accurate and more efficient than existing models over a large range of length scales. We demonstrate the usefulness of multi-resolution modeling by detecting genomic elements that drive tumor emergence and are of vastly differing sizes.

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