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

Dynamic Clustering via Asymptotics of the Dependent Dirichlet Process Mixture

This paper presents a novel algorithm, based upon the dependent Dirichlet process mixture model (DDPMM), for clustering batch-sequential data containing an unknown number of evolving clusters. The algorithm is derived via a low-variance asymptotic analysis of the Gibbs sampling algorithm for the DDPMM, and provides a hard clustering with convergence guarantees similar to those of the k-means algorithm. Empirical results from a synthetic test with moving Gaussian clusters and a test with real ADS-B aircraft trajectory data demonstrate that the algorithm requires orders of magnitude less computational time than contemporary probabilistic and hard clustering algorithms, while providing higher accuracy on the examined datasets.Comment: This paper is from NIPS 2013. Please use the following BibTeX citation: @inproceedings{Campbell13_NIPS, Author = {Trevor Campbell and Miao Liu and Brian Kulis and Jonathan P. How and Lawrence Carin}, Title = {Dynamic Clustering via Asymptotics of the Dependent Dirichlet Process}, Booktitle = {Advances in Neural Information Processing Systems (NIPS)}, Year = {2013}

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

Probabilistic Clustering of Time-Evolving Distance Data

We present a novel probabilistic clustering model for objects that are represented via pairwise distances and observed at different time points. The proposed method utilizes the information given by adjacent time points to find the underlying cluster structure and obtain a smooth cluster evolution. This approach allows the number of objects and clusters to differ at every time point, and no identification on the identities of the objects is needed. Further, the model does not require the number of clusters being specified in advance -- they are instead determined automatically using a Dirichlet process prior. We validate our model on synthetic data showing that the proposed method is more accurate than state-of-the-art clustering methods. Finally, we use our dynamic clustering model to analyze and illustrate the evolution of brain cancer patients over time

Adaptive Evolutionary Clustering

In many practical applications of clustering, the objects to be clustered evolve over time, and a clustering result is desired at each time step. In such applications, evolutionary clustering typically outperforms traditional static clustering by producing clustering results that reflect long-term trends while being robust to short-term variations. Several evolutionary clustering algorithms have recently been proposed, often by adding a temporal smoothness penalty to the cost function of a static clustering method. In this paper, we introduce a different approach to evolutionary clustering by accurately tracking the time-varying proximities between objects followed by static clustering. We present an evolutionary clustering framework that adaptively estimates the optimal smoothing parameter using shrinkage estimation, a statistical approach that improves a naive estimate using additional information. The proposed framework can be used to extend a variety of static clustering algorithms, including hierarchical, k-means, and spectral clustering, into evolutionary clustering algorithms. Experiments on synthetic and real data sets indicate that the proposed framework outperforms static clustering and existing evolutionary clustering algorithms in many scenarios.Comment: To appear in Data Mining and Knowledge Discovery, MATLAB toolbox available at http://tbayes.eecs.umich.edu/xukevin/affec