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Frederick A. Matsen IV

Publications and source records attributed to Frederick A. Matsen IV.

At least 37 records · Page 2Linked to original sources
arXiv2018

Survival analysis of DNA mutation motifs with penalized proportional hazards

Antibodies, an essential part of our immune system, develop through an intricate process to bind a wide array of pathogens. This process involves randomly mutating DNA sequences encoding these antibodies to find variants with improved binding, though mutations are not distributed uniformly across sequence sites. Immunologists observe this nonuniformity to be consistent with "mutation motifs", which are short DNA subsequences that affect how likely a given site is to experience a mutation. Quantifying the effect of motifs on mutation rates is challenging: a large number of possible motifs makes this statistical problem high dimensional, while the unobserved history of the mutation process leads to a nontrivial missing data problem. We introduce an $\ell_1$-penalized proportional hazards model to infer mutation motifs and their effects. In order to estimate model parameters, our method uses a Monte Carlo EM algorithm to marginalize over the unknown ordering of mutations. We show that our method performs better on simulated data compared to current methods and leads to more parsimonious models. The application of proportional hazards to mutation processes is, to our knowledge, novel and formalizes the current methods in a statistical framework that can be easily extended to analyze the effect of other biological features on mutation rates.

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arXiv2018

The Bayesian optimist's guide to adaptive immune receptor repertoire analysis

Probabilistic modeling is fundamental to the statistical analysis of complex data. In addition to forming a coherent description of the data-generating process, probabilistic models enable parameter inference about given data sets. This procedure is well-developed in the Bayesian perspective, in which one infers probability distributions describing to what extent various possible parameters agree with the data. In this paper we motivate and review probabilistic modeling for adaptive immune receptor repertoire data then describe progress and prospects for future work, from germline haplotyping to adaptive immune system deployment across tissues. The relevant quantities in immune sequence analysis include not only continuous parameters such as gene use frequency, but also discrete objects such as B cell clusters and lineages. Throughout this review, we unravel the many opportunities for probabilistic modeling in adaptive immune receptor analysis, including settings for which the Bayesian approach holds substantial promise (especially if one is optimistic about new computational methods). From our perspective the greatest prospects for progress in probabilistic modeling for repertoires concern ancestral sequence estimation for B cell receptor lineages, including uncertainty from germline genotype, rearrangement, and lineage development.

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arXiv2018

Per-sample immunoglobulin germline inference from B cell receptor deep sequencing data

The collection of immunoglobulin genes in an individual's germline, which gives rise to B cell receptors via recombination, is known to vary significantly across individuals. In humans, for example, each individual has only a fraction of the several hundred known V alleles. Furthermore, the currently-accepted set of known V alleles is both incomplete (particularly for non-European samples), and contains a significant number of spurious alleles. The resulting uncertainty as to which immunoglobulin alleles are present in any given sample results in inaccurate B cell receptor sequence annotations, and in particular inaccurate inferred naive ancestors. In this paper we first show that the currently widespread practice of aligning each sequence to its closest match in the full set of IMGT alleles results in a very large number of spurious alleles that are not in the sample's true set of germline V alleles. We then describe a new method for inferring each individual's germline gene set from deep sequencing data, and show that it improves upon existing methods by making a detailed comparison on a variety of simulated and real data samples. This new method has been integrated into the partis annotation and clonal family inference package, available at https://github.com/psathyrella/partis, and is run by default without affecting overall run time.

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arXiv2018

Using genotype abundance to improve phylogenetic inference

Modern biological techniques enable very dense genetic sampling of unfolding evolutionary histories, and thus frequently sample some genotypes multiple times. This motivates strategies to incorporate genotype abundance information in phylogenetic inference. In this paper, we synthesize a stochastic process model with standard sequence-based phylogenetic optimality, and show that tree estimation is substantially improved by doing so. Our method is validated with extensive simulations and an experimental single-cell lineage tracing study of germinal center B cell receptor affinity maturation.

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arXiv2018

Predicting B Cell Receptor Substitution Profiles Using Public Repertoire Data

B cells develop high affinity receptors during the course of affinity maturation, a cyclic process of mutation and selection. At the end of affinity maturation, a number of cells sharing the same ancestor (i.e. in the same "clonal family") are released from the germinal center, their amino acid frequency profile reflects the allowed and disallowed substitutions at each position. These clonal-family-specific frequency profiles, called "substitution profiles", are useful for studying the course of affinity maturation as well as for antibody engineering purposes. However, most often only a single sequence is recovered from each clonal family in a sequencing experiment, making it impossible to construct a clonal-family-specific substitution profile. Given the public release of many high-quality large B cell receptor datasets, one may ask whether it is possible to use such data in a prediction model for clonal-family-specific substitution profiles. In this paper, we present the method "Substitution Profiles Using Related Families" (SPURF), a penalized tensor regression framework that integrates information from a rich assemblage of datasets to predict the clonal-family-specific substitution profile for any single input sequence. Using this framework, we show that substitution profiles from similar clonal families can be leveraged together with simulated substitution profiles and germline gene sequence information to improve prediction. We fit this model on a large public dataset and validate the robustness of our approach on an external dataset. Furthermore, we provide a command-line tool in an open-source software package (https://github.com/krdav/SPURF) implementing these ideas and providing easy prediction using our pre-fit models.

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arXiv2018

Consistency and convergence rate of phylogenetic inference via regularization

It is common in phylogenetics to have some, perhaps partial, information about the overall evolutionary tree of a group of organisms and wish to find an evolutionary tree of a specific gene for those organisms. There may not be enough information in the gene sequences alone to accurately reconstruct the correct "gene tree." Although the gene tree may deviate from the "species tree" due to a variety of genetic processes, in the absence of evidence to the contrary it is parsimonious to assume that they agree. A common statistical approach in these situations is to develop a likelihood penalty to incorporate such additional information. Recent studies using simulation and empirical data suggest that a likelihood penalty quantifying concordance with a species tree can significantly improve the accuracy of gene tree reconstruction compared to using sequence data alone. However, the consistency of such an approach has not yet been established, nor have convergence rates been bounded. Because phylogenetics is a non-standard inference problem, the standard theory does not apply. In this paper, we propose a penalized maximum likelihood estimator for gene tree reconstruction, where the penalty is the square of the Billera-Holmes-Vogtmann geodesic distance from the gene tree to the species tree. We prove that this method is consistent, and derive its convergence rate for estimating the discrete gene tree structure and continuous edge lengths (representing the amount of evolution that has occurred on that branch) simultaneously. We find that the regularized estimator is "adaptive fast converging," meaning that it can reconstruct all edges of length greater than any given threshold from gene sequences of polynomial length. Our method does not require the species tree to be known exactly; in fact, our asymptotic theory holds for any such guide tree.

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arXiv2017

Calculating the Unrooted Subtree Prune-and-Regraft Distance

The subtree prune-and-regraft (SPR) distance metric is a fundamental way of comparing evolutionary trees. It has wide-ranging applications, such as to study lateral genetic transfer, viral recombination, and Markov chain Monte Carlo phylogenetic inference. Although the rooted version of SPR distance can be computed relatively efficiently between rooted trees using fixed-parameter-tractable maximum agreement forest (MAF) algorithms, no MAF formulation is known for the unrooted case. Correspondingly, previous algorithms are unable to compute unrooted SPR distances larger than 7. In this paper, we substantially advance understanding of and computational algorithms for the unrooted SPR distance. First we identify four properties of optimal SPR paths, each of which suggests that no MAF formulation exists in the unrooted case. Then we introduce the replug distance, a new lower bound on the unrooted SPR distance that is amenable to MAF methods, and give an efficient fixed-parameter algorithm for calculating it. Finally, we develop a "progressive A*" search algorithm using multiple heuristics, including the TBR and replug distances, to exactly compute the unrooted SPR distance. Our algorithm is nearly two orders of magnitude faster than previous methods on small trees, and allows computation of unrooted SPR distances as large as 14 on trees with 50 leaves.

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arXiv2017

Probabilistic Path Hamiltonian Monte Carlo

Hamiltonian Monte Carlo (HMC) is an efficient and effective means of sampling posterior distributions on Euclidean space, which has been extended to manifolds with boundary. However, some applications require an extension to more general spaces. For example, phylogenetic (evolutionary) trees are defined in terms of both a discrete graph and associated continuous parameters; although one can represent these aspects using a single connected space, this rather complex space is not suitable for existing HMC algorithms. In this paper, we develop Probabilistic Path HMC (PPHMC) as a first step to sampling distributions on spaces with intricate combinatorial structure. We define PPHMC on orthant complexes, show that the resulting Markov chain is ergodic, and provide a promising implementation for the case of phylogenetic trees in open-source software. We also show that a surrogate function to ease the transition across a boundary on which the log-posterior has discontinuous derivatives can greatly improve efficiency.

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arXiv2017

A surrogate function for one-dimensional phylogenetic likelihoods

Phylogenetics has seen an steady increase in substitution model complexity, which requires increasing amounts of computational power to compute likelihoods. This model complexity motivates strategies to approximate the likelihood functions for branch length optimization and Bayesian sampling. In this paper, we develop an approximation to the one-dimensional likelihood function as parametrized by a single branch length. This new method uses a four-parameter surrogate function abstracted from the simplest phylogenetic likelihood function, the binary symmetric model. We show that it offers a surrogate that can be fit over a variety of branch lengths, that it is applicable to a wide variety of models and trees, and that it can be used effectively as a proposal mechanism for Bayesian sampling. The method is implemented as a stand-alone open-source C library for calling from phylogenetics algorithms; it has proven essential for good performance of our online phylogenetic algorithm sts.

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arXiv2017

Efficiently Inferring Pairwise Subtree Prune-and-Regraft Adjacencies between Phylogenetic Trees

We develop a time-optimal $O(mn^2)$-time algorithm to construct the subtree prune-regraft (SPR) graph on a collection of m phylogenetic trees with n leaves. This improves on the previous bound of $O(mn^3)$. Such graphs are used to better understand the behaviour of phylogenetic methods and recommend parameter choices and diagnostic criteria. The limiting factor in these analyses has been the difficulty in constructing such graphs for large numbers of trees. We also develop the first efficient algorithms for constructing the nearest-neighbor interchange (NNI) and tree bisection-and-reconnection (TBR) graphs

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arXiv2016

Chain Reduction Preserves the Unrooted Subtree Prune-and-Regraft Distance

The subtree prune-and-regraft (SPR) distance metric is a fundamental way of comparing evolutionary trees. It has wide-ranging applications, such as to study lateral genetic transfer, viral recombination, and Markov chain Monte Carlo phylogenetic inference. Although the rooted version of SPR distance can be com puted relatively efficiently between rooted trees using fixed-parameter-tractable algorithms, in the unrooted case previous algorithms are unable to compute distances larger than 7. One important tool for efficient computation in the rooted case is called chain reduction, which replaces an arbitrary chain of subtrees identical in both trees with a chain of three leaves. Whether chain reduction preserves SPR distance in the unrooted case has remained an open question since it was conjectured in 2001 by Allen and Steel, and was presented as a challenge question at the 2007 Isaac Newton Institute for Mathematical Sciences program on phylogenetics. In this paper we prove that chain reduction preserves the unrooted SPR distance. We do so by introducing a structure called a socket agreement forest that restricts edge modification to predetermined socket vertices, permitting detailed analysis and modification of SPR move sequences. This new chain reduction theorem reduces the unrooted distance problem to a linear size problem kernel, substantially improving on the previous best quadratic size kernel.

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arXiv2016

Online Bayesian phylogenetic inference: theoretical foundations via Sequential Monte Carlo

Phylogenetics, the inference of evolutionary trees from molecular sequence data such as DNA, is an enterprise that yields valuable evolutionary understanding of many biological systems. Bayesian phylogenetic algorithms, which approximate a posterior distribution on trees, have become a popular if computationally expensive means of doing phylogenetics. Modern data collection technologies are quickly adding new sequences to already substantial databases. With all current techniques for Bayesian phylogenetics, computation must start anew each time a sequence becomes available, making it costly to maintain an up-to-date estimate of a phylogenetic posterior. These considerations highlight the need for an \emph{online} Bayesian phylogenetic method which can update an existing posterior with new sequences. Here we provide theoretical results on the consistency and stability of methods for online Bayesian phylogenetic inference based on Sequential Monte Carlo (SMC) and Markov chain Monte Carlo (MCMC). We first show a consistency result, demonstrating that the method samples from the correct distribution in the limit of a large number of particles. Next we derive the first reported set of bounds on how phylogenetic likelihood surfaces change when new sequences are added. These bounds enable us to characterize the theoretical performance of sampling algorithms by bounding the effective sample size (ESS) with a given number of particles from below. We show that the ESS is guaranteed to grow linearly as the number of particles in an SMC sampler grows. Surprisingly, this result holds even though the dimensions of the phylogenetic model grow with each new added sequence.

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arXiv2016

The shape of the one-dimensional phylogenetic likelihood function

By fixing all parameters in a phylogenetic likelihood model except for one branch length, one obtains a one-dimensional likelihood function. In this work, we introduce a mathematical framework to characterize the shapes of such one-dimensional phylogenetic likelihood functions. This framework is based on analyses of algebraic structures on the space of all frequency patterns with respect to a polynomial representation of the likelihood functions. Using this framework, we provide conditions under which the one-dimensional phylogenetic likelihood functions are guaranteed to have at most one stationary point, and this point is the maximum likelihood branch length. These conditions are satisfied by common simple models including all binary models, the Jukes-Cantor model and the Felsenstein 1981 model. We then prove that for the simplest model that does not satisfy our conditions, namely, the Kimura 2-parameter model, the one-dimensional likelihood functions may have multiple stationary points. As a proof of concept, we construct a non-degenerate example in which the phylogenetic likelihood function has two local maxima and a local minimum. To construct such examples, we derive a general method of constructing a tree and sequence data with a specified frequency pattern at the root. We then extend the result to prove that the space of all rescaled and translated one-dimensional phylogenetic likelihood functions under the Kimura 2-parameter model is dense in the space of all non-negative continuous functions on $[0, \infty)$ with finite limits. These results indicate that one-dimensional likelihood functions under advanced evolutionary models can be more complex than it is typically assumed by phylogenetic inference algorithms; however, these complexities can be effectively captured by the Kimura 2-parameter model.

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arXiv2016

Likelihood-based inference of B-cell clonal families

The human immune system depends on a highly diverse collection of antibody-making B cells. B cell receptor sequence diversity is generated by a random recombination process called "rearrangement" forming progenitor B cells, then a Darwinian process of lineage diversification and selection called "affinity maturation." The resulting receptors can be sequenced in high throughput for research and diagnostics. Such a collection of sequences contains a mixture of various lineages, each of which may be quite numerous, or may consist of only a single member. As a step to understanding the process and result of this diversification, one may wish to reconstruct lineage membership, i.e. to cluster sampled sequences according to which came from the same rearrangement events. We call this clustering problem "clonal family inference." In this paper we describe and validate a likelihood-based framework for clonal family inference based on a multi-hidden Markov Model (multi-HMM) framework for B cell receptor sequences. We describe an agglomerative algorithm to find a maximum likelihood clustering, two approximate algorithms with various trade-offs of speed versus accuracy, and a third, fast algorithm for finding specific lineages. We show that under simulation these algorithms greatly improve upon existing clonal family inference methods, and that they also give significantly different clusters than previous methods when applied to two real data sets.

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arXiv2015

Ricci-Ollivier Curvature of the Rooted Phylogenetic Subtree-Prune-Regraft Graph

Statistical phylogenetic inference methods use tree rearrangement operations to perform either hill-climbing local search or Markov chain Monte Carlo across tree topologies. The canonical class of such moves are the subtree-prune-regraft (SPR) moves that remove a subtree and reattach it somewhere else via the cut edge of the subtree. Phylogenetic trees and such moves naturally form the vertices and edges of a graph, such that tree search algorithms perform a (potentially stochastic) traversal of this SPR graph. Despite the centrality of such graphs in phylogenetic inference, rather little is known about their large-scale properties. In this paper we learn about the rooted-tree version of the graph, known as the rSPR graph, by calculating the Ricci-Ollivier curvature for pairs of vertices in the rSPR graph with respect to two simple random walks on the rSPR graph. By proving theorems and direct calculation with novel algorithms, we find a remarkable diversity of different curvatures on the rSPR graph for pairs of vertices separated by the same distance. We confirm using simulation that degree and curvature have the expected impact on mean access time distributions, demonstrating relevance of these curvature results to stochastic tree search. This indicates significant structure of the rSPR graph beyond that which was previously understood in terms of pairwise distances and vertex degrees; a greater understanding of curvature could ultimately lead to improved strategies for tree search.

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arXiv2015

Consistency of VDJ rearrangement and substitution parameters enables accurate B cell receptor sequence annotation

VDJ rearrangement and somatic hypermutation work together to produce antibody-coding B cell receptor (BCR) sequences for a remarkable diversity of antigens. It is now possible to sequence these BCRs in high throughput; analysis of these sequences is bringing new insight into how antibodies develop, in particular for broadly-neutralizing antibodies against HIV and influenza. A fundamental step in such sequence analysis is to annotate each base as coming from a specific one of the V, D, or J genes, or from an N-addition (a.k.a. non-templated insertion). Previous work has used simple parametric distributions to model transitions from state to state in a hidden Markov model (HMM) of VDJ recombination, and assumed that mutations occur via the same process across sites. However, codon frame and other effects have been observed to violate these parametric assumptions for such coding sequences, suggesting that a non-parametric approach to modeling the recombination process could be useful. In our paper, we find that indeed large modern data sets suggest a model using parameter-rich per-allele categorical distributions for HMM transition probabilities and per-allele-per-position mutation probabilities, and that using such a model for inference leads to significantly improved results. We present an accurate and efficient BCR sequence annotation software package using a novel HMM "factorization" strategy. This package, called partis (https://github.com/psathyrella/partis/), is built on a new general-purpose HMM compiler that can perform efficient inference given a simple text description of an HMM.

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arXiv2015

Quantifying evolutionary constraints on B cell affinity maturation

The antibody repertoire of each individual is continuously updated by the evolutionary process of B cell receptor mutation and selection. It has recently become possible to gain detailed information concerning this process through high-throughput sequencing. Here, we develop modern statistical molecular evolution methods for the analysis of B cell sequence data, and then apply them to a very deep short-read data set of B cell receptors. We find that the substitution process is conserved across individuals but varies significantly across gene segments. We investigate selection on B cell receptors using a novel method that side-steps the difficulties encountered by previous work in differentiating between selection and motif-driven mutation; this is done through stochastic mapping and empirical Bayes estimators that compare the evolution of in-frame and out-of-frame rearrangements. We use this new method to derive a per-residue map of selection, which provides a more nuanced view of the constraints on framework and variable regions.

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arXiv2014

Quantifying MCMC Exploration of Phylogenetic Tree Space

In order to gain an understanding of the effectiveness of phylogenetic Markov chain Monte Carlo (MCMC), it is important to understand how quickly the empirical distribution of the MCMC converges to the posterior distribution. In this paper we investigate this problem on phylogenetic tree topologies with a metric that is especially well suited to the task: the subtree prune-and-regraft (SPR) metric. This metric directly corresponds to the minimum number of MCMC rearrangements required to move between trees in common phylogenetic MCMC implementations. We develop a novel graph-based approach to analyze tree posteriors and find that the SPR metric is much more informative than simpler metrics that are unrelated to MCMC moves. In doing so we show conclusively that topological peaks do occur in Bayesian phylogenetic posteriors from real data sets as sampled with standard MCMC approaches, investigate the efficiency of Metropolis-coupled MCMC (MCMCMC) in traversing the valleys between peaks, and show that conditional clade distribution (CCD) can have systematic problems when there are multiple peaks.

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