A Bayesian Nonparametric Model for Inferring Subclonal Populations from Structured DNA Sequencing Data
Author:
He Shai,Schein Aaron,Sarsani Vishal,Flaherty Patrick
Abstract
There are distinguishing features or “hallmarks” of cancer that are found across tumors, individuals, and types of cancer, and these hallmarks can be driven by specific genetic mutations. Yet, within a single tumor there is often extensive genetic heterogeneity as evidenced by single-cell and bulk DNA sequencing data. The goal of this work is to jointly infer the underlying genotypes of tumor subpopulations and the distribution of those subpopulations in individual tumors by integrating single-cell and bulk sequencing data. Understanding the genetic composition of the tumor at the time of treatment is important in the personalized design of targeted therapeutic combinations and monitoring for possible recurrence after treatment.We propose a hierarchical Dirichlet process mixture model that incorporates the correlation structure induced by a structured sampling arrangement and we show that this model improves the quality of inference. We develop a representation of the hierarchical Dirichlet process prior as a Gamma-Poisson hierarchy and we use this representation to derive a fast Gibbs sampling inference algorithm using the augment-and-marginalize method. Experiments with simulation data show that our model outperforms standard numerical and statistical methods for decomposing admixed count data. Analyses of real acute lymphoblastic leukemia cancer sequencing dataset shows that our model improves upon state-of-the-art bioinformatic methods. An interpretation of the results of our model on this real dataset reveals co-mutated loci across samples.
Publisher
Cold Spring Harbor Laboratory
Reference69 articles.
1. Aldous, D. J. (1985). Exchangeability and Related Topics. In Ecole d’Eté de Probabilités de Saint-Flour XIII — 1983, Lecture Notes in Math 1–198. 2. Alizadeh, A. A. , Aranda, V. , Bardelli, A. , Blanpain, C. , Bock, C. , Borowski, C. , Caldas, C. , Califano, A. , Doherty, M. , Elsner, M. , Esteller, M. , Fitzgerald, R. , Korbel, j. O. , Lichter, P. , Mason, C. E. , Navin, N. , Pe’Er, D. , Polyak, K. , Roberts, C. W. M. , Siu, L. , Snyder, A. , Stower, H. , Swanton, C. , Verhaak, R. G. W. , Zenklusen, J. C. , Zuber, J. and Zucman-Rossi, J. (2015). Toward Understanding and Exploiting Tumor Heterogeneity. Nature Medicine. 3. Genome structural variation discovery and genotyping 4. Pan-cancer analysis of the extent and consequences of intratumor heterogeneity 5. Aran, D. , Sirota, M. and Butte, A. J. (2015). Systematic Pan-Cancer Analysis of Tumour Purity. Nature Communications 6.
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