Comparing Nonparametric Bayesian Tree Priors for Clonal Reconstruction of Tumors

Statistical machine learning methods, especially nonparametric Bayesian methods, have become increasingly popular to infer clonal population structure of tumors. Here we describe the treeCRP, an extension of the Chinese restaurant process (CRP), a popular construction used in nonparametric mixture models, to infer the phylogeny and genotype of major subclonal lineages represented in the population of cancer cells. We also propose new split-merge updates tailored to the subclonal reconstruction problem that improve the mixing time of Markov chains. In comparisons with the tree-structured stick breaking prior used in PhyloSub, we demonstrate superior mixing and running time using the treeCRP with our new split-merge procedures. We also show that given the same number of samples, TSSB and treeCRP have similar ability to recover the subclonal structure of a tumor.Comment: Preprint of an article submitted for consideration in the Pacific Symposium on Biocomputing \c{opyright} 2015; World Scientific Publishing Co., Singapore, 2015; http://psb.stanford.edu

Inferring clonal evolution of tumors from single nucleotide somatic mutations

High-throughput sequencing allows the detection and quantification of frequencies of somatic single nucleotide variants (SNV) in heterogeneous tumor cell populations. In some cases, the evolutionary history and population frequency of the subclonal lineages of tumor cells present in the sample can be reconstructed from these SNV frequency measurements. However, automated methods to do this reconstruction are not available and the conditions under which reconstruction is possible have not been described. We describe the conditions under which the evolutionary history can be uniquely reconstructed from SNV frequencies from single or multiple samples from the tumor population and we introduce a new statistical model, PhyloSub, that infers the phylogeny and genotype of the major subclonal lineages represented in the population of cancer cells. It uses a Bayesian nonparametric prior over trees that groups SNVs into major subclonal lineages and automatically estimates the number of lineages and their ancestry. We sample from the joint posterior distribution over trees to identify evolutionary histories and cell population frequencies that have the highest probability of generating the observed SNV frequency data. When multiple phylogenies are consistent with a given set of SNV frequencies, PhyloSub represents the uncertainty in the tumor phylogeny using a partial order plot. Experiments on a simulated dataset and two real datasets comprising tumor samples from acute myeloid leukemia and chronic lymphocytic leukemia patients demonstrate that PhyloSub can infer both linear (or chain) and branching lineages and its inferences are in good agreement with ground truth, where it is available

Nested Hierarchical Dirichlet Processes

We develop a nested hierarchical Dirichlet process (nHDP) for hierarchical topic modeling. The nHDP is a generalization of the nested Chinese restaurant process (nCRP) that allows each word to follow its own path to a topic node according to a document-specific distribution on a shared tree. This alleviates the rigid, single-path formulation of the nCRP, allowing a document to more easily express thematic borrowings as a random effect. We derive a stochastic variational inference algorithm for the model, in addition to a greedy subtree selection method for each document, which allows for efficient inference using massive collections of text documents. We demonstrate our algorithm on 1.8 million documents from The New York Times and 3.3 million documents from Wikipedia.Comment: To appear in IEEE Transactions on Pattern Analysis and Machine Intelligence, Special Issue on Bayesian Nonparametric

On Nonparametric Guidance for Learning Autoencoder Representations

Unsupervised discovery of latent representations, in addition to being useful for density modeling, visualisation and exploratory data analysis, is also increasingly important for learning features relevant to discriminative tasks. Autoencoders, in particular, have proven to be an effective way to learn latent codes that reflect meaningful variations in data. A continuing challenge, however, is guiding an autoencoder toward representations that are useful for particular tasks. A complementary challenge is to find codes that are invariant to irrelevant transformations of the data. The most common way of introducing such problem-specific guidance in autoencoders has been through the incorporation of a parametric component that ties the latent representation to the label information. In this work, we argue that a preferable approach relies instead on a nonparametric guidance mechanism. Conceptually, it ensures that there exists a function that can predict the label information, without explicitly instantiating that function. The superiority of this guidance mechanism is confirmed on two datasets. In particular, this approach is able to incorporate invariance information (lighting, elevation, etc.) from the small NORB object recognition dataset and yields state-of-the-art performance for a single layer, non-convolutional network.Comment: 9 pages, 12 figure