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1. Detecting evolutionary patterns of cancers using consensus trees

   https://doi.org/10.1093/bioinformatics/btaa801  

   Christensen, Sarah ; Kim, Juho ; Chia, Nicholas ; Koyejo, Oluwasanmi ; El-Kebir, Mohammed ( December 2020 , Bioinformatics)

   null (Ed.)

   Abstract Motivation While each cancer is the result of an isolated evolutionary process, there are repeated patterns in tumorigenesis defined by recurrent driver mutations and their temporal ordering. Such repeated evolutionary trajectories hold the potential to improve stratification of cancer patients into subtypes with distinct survival and therapy response profiles. However, current cancer phylogeny methods infer large solution spaces of plausible evolutionary histories from the same sequencing data, obfuscating repeated evolutionary patterns. Results To simultaneously resolve ambiguities in sequencing data and identify cancer subtypes, we propose to leverage common patterns of evolution found in patient cohorts. We first formulate the Multiple Choice Consensus Tree problem, which seeks to select a tumor tree for each patient and assign patients into clusters in such a way that maximizes consistency within each cluster of patient trees. We prove that this problem is NP-hard and develop a heuristic algorithm, Revealing Evolutionary Consensus Across Patients (RECAP), to solve this problem in practice. Finally, on simulated data, we show RECAP outperforms existing methods that do not account for patient subtypes. We then use RECAP to resolve ambiguities in patient trees and find repeated evolutionary trajectories in lung and breast cancer cohorts. Availability and implementation https://github.com/elkebir-group/RECAP. Supplementary information Supplementary data are available at Bioinformatics online. 

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2. Meltos: multi-sample tumor phylogeny reconstruction for structural variants

   https://doi.org/10.1093/bioinformatics/btz737  

   Ricketts, Camir ; Seidman, Daniel ; Popic, Victoria ; Hormozdiari, Fereydoun ; Batzoglou, Serafim ; Hajirasouliha, Iman ; Valencia, Alfonso ( October 2019 , Bioinformatics)

   Abstract Motivation We propose Meltos, a novel computational framework to address the challenging problem of building tumor phylogeny trees using somatic structural variants (SVs) among multiple samples. Meltos leverages the tumor phylogeny tree built on somatic single nucleotide variants (SNVs) to identify high confidence SVs and produce a comprehensive tumor lineage tree, using a novel optimization formulation. While we do not assume the evolutionary progression of SVs is necessarily the same as SNVs, we show that a tumor phylogeny tree using high-quality somatic SNVs can act as a guide for calling and assigning somatic SVs on a tree. Meltos utilizes multiple genomic read signals for potential SV breakpoints in whole genome sequencing data and proposes a probabilistic formulation for estimating variant allele fractions (VAFs) of SV events. Results In order to assess the ability of Meltos to correctly refine SNV trees with SV information, we tested Meltos on two simulated datasets with five genomes in both. We also assessed Meltos on two real cancer datasets. We tested Meltos on multiple samples from a liposarcoma tumor and on a multi-sample breast cancer data (Yates et al., 2015), where the authors provide validated structural variation events together with deep, targeted sequencing for a collection of somatic SNVs. We show Meltos has the ability to place high confidence validated SV calls on a refined tumor phylogeny tree. We also showed the flexibility of Meltos to either estimate VAFs directly from genomic data or to use copy number corrected estimates. Availability and implementation Meltos is available at https://github.com/ih-lab/Meltos. Contact imh2003@med.cornell.edu Supplementary information Supplementary data are available at Bioinformatics online. 

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3. A weighted distance-based approach for deriving consensus tumor evolutionary trees

   https://doi.org/10.1093/bioinformatics/btad230  

   Guang, Ziyun ; Smith-Erb, Matthew ; Oesper, Layla ( June 2023 , Bioinformatics)

   The acquisition of somatic mutations by a tumor can be modeled by a type of evolutionary tree. However, it is impossible to observe this tree directly. Instead, numerous algorithms have been developed to infer such a tree from different types of sequencing data. But such methods can produce conflicting trees for the same patient, making it desirable to have approaches that can combine several such tumor trees into a consensus or summary tree. We introduce The Weighted m-Tumor Tree Consensus Problem (W-m-TTCP) to find a consensus tree among multiple plausible tumor evolutionary histories, each assigned a confidence weight, given a specific distance measure between tumor trees. We present an algorithm called TuELiP that is based on integer linear programming which solves the W-m-TTCP, and unlike other existing consensus methods, allows the input trees to be weighted differently.

   On simulated data we show that TuELiP outperforms two existing methods at correctly identifying the true underlying tree used to create the simulations. We also show that the incorporation of weights can lead to more accurate tree inference. On a Triple-Negative Breast Cancer dataset, we show that including confidence weights can have important impacts on the consensus tree identified.

   An implementation of TuELiP and simulated datasets are available at https://bitbucket.org/oesperlab/consensus-ilp/src/main/.

    

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4. Probabilistic Species Tree Distances: Implementing the Multispecies Coalescent to Compare Species Trees Within the Same Model-Based Framework Used to Estimate Them

   https://doi.org/10.1093/sysbio/syz031  

   Adams, Richard H ; Castoe, Todd A ; Burbrink, Frank ( May 2019 , Systematic Biology)

   Abstract Despite the ubiquitous use of statistical models for phylogenomic and population genomic inferences, this model-based rigor is rarely applied to post hoc comparison of trees. In a recent study, Garba et al. derived new methods for measuring the distance between two gene trees computed as the difference in their site pattern probability distributions. Unlike traditional metrics that compare trees solely in terms of geometry, these measures consider gene trees and associated parameters as probabilistic models that can be compared using standard information theoretic approaches. Consequently, probabilistic measures of phylogenetic tree distance can be far more informative than simply comparisons of topology and/or branch lengths alone. However, in their current form, these distance measures are not suitable for the comparison of species tree models in the presence of gene tree heterogeneity. Here, we demonstrate an approach for how the theory of Garba et al. (2018), which is based on gene tree distances, can be extended naturally to the comparison of species tree models. Multispecies coalescent (MSC) models parameterize the discrete probability distribution of gene trees conditioned upon a species tree with a particular topology and set of divergence times (in coalescent units), and thus provide a framework for measuring distances between species tree models in terms of their corresponding gene tree topology probabilities. We describe the computation of probabilistic species tree distances in the context of standard MSC models, which assume complete genetic isolation postspeciation, as well as recent theoretical extensions to the MSC in the form of network-based MSC models that relax this assumption and permit hybridization among taxa. We demonstrate these metrics using simulations and empirical species tree estimates and discuss both the benefits and limitations of these approaches. We make our species tree distance approach available as an R package called pSTDistanceR, for open use by the community. 

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5. A Consensus Approach to Infer Tumor Evolutionary Histories

   https://doi.org/10.1145/3233547.3233584  

   Govek, Kiya ; Sikes, Camden ; Oesper, Layla ( August 2018 , BCB '18 Proceedings of the 2018 ACM International Conference on Bioinformatics, Computational Biology, and Health Informatics)

   Inspired by recent efforts to model cancer evolution with phylogenetic trees, we consider the problem of finding a consensus tumor evolution tree from a set of conflicting input trees. In contrast to traditional phylogenetic trees, the tumor trees we consider contain features such as mutation labels on internal vertices (in addition to the leaves) and allow multiple mutations to label a single vertex. We describe several distance measures between these tumor trees and present an algorithm to solve the consensus problem called GraPhyC. Our approach uses a weighted directed graph where vertices are sets of mutations and edges are weighted using a function that depends on the number of times a parental relationship is observed between their constituent mutations in the set of input trees. We find a minimum weight spanning arborescence in this graph and prove that the resulting tree minimizes the total distance to all input trees for one of our presented distance measures. We evaluate our GraPhyC method using both simulated and real data. On simulated data we show that our method outperforms a baseline method at finding an appropriate representative tree. Using a set of tumor trees derived from both whole-genome and deep sequencing data from a Chronic Lymphocytic Leukemia patient we find that our approach identifies a tree not included in the set of input trees, but that contains characteristics supported by other reported evolutionary reconstructions of this tumor. 

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