arXiv subjects

Philippe Lemey

Publications and source records attributed to Philippe Lemey.

At least 19 recordsLinked to original sources

arXiv2026

BEAGLE 4.1: A high-performance library for computation on phylogenetic trees across diverse parallel architectures

Efficient evaluation of sequence data likelihoods and their high-dimensional gradients on phylogenetic trees improves inference under both maximum-likelihood and Bayesian frameworks. Here, we present BEAGLE 4.1, a high-performance library for statistical phylogenetics that incorporates new algorithms to evaluate these gradients on phylogenetic trees. We also provide new hardware implementations for both likelihoods and gradients supporting ARM NEON intrinsics and optimized matrix multiplication units -- called tensor cores -- on NVIDIA graphics processing units (GPUs). We benchmark the performance scaling of the library across a number of patterns and taxa on multi-core CPUs and GPUs, and compare the speedup afforded by NVIDIA and AMD GPUs as well as performance scaling with an increasing number of GPUs. We show that multi-core CPU implementations provide up to a fourfold speedup over single-threaded CPU implementations and up to an tenfold speedup for nucleotide and codon models, respectively, with performance generally improving as the number of taxa and site patterns increases. GPUs outperform multi-threaded CPU implementations for a realistic number of patterns, even for nucleotide models with a small state-space size of 4, while for codon models they provide substantially higher performance gains even for a single pattern or four taxa. Tensor cores on GPUs provide up to 2-fold speedup relative to standard CUDA cores for codon models. Using NEON instructions on ARM CPUs affords up to a $\sim 1.3$-fold speedup over non-SIMD implementation with the speedup going down to 1.1-fold at 8 CPU threads. We provide these new algorithms to evaluate the gradient and efficient hardware implementations for both likelihood and gradient calculations through BEAGLE 4.1, such that they can be readily integrated into phylogenetic software packages.

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arXiv2026

Smoothly Time-Varying Continuous Time Markov Chains in Phylogenetics

The dependence of evolutionary rate estimates on the timeframe of sampling poses a fundamental challenge for reconstructing evolutionary histories from molecular sequence data, which is central to evolutionary biology and infectious disease research. We present a novel and flexible approach to accommodate time-varying evolutionary rates by modeling the sequence substitution process using inhomogeneous continuous-time Markov chains (ICTMCs) acting along the branches of the phylogeny, and parameterizing the log transformed rate as a smooth function of time using a cubic B-spline basis expansion. Following the parlance of phylogenetics that refers to rates of molecular substitutions as molecular clocks, we call this a spline clock model. Integrals of the rate function over all branches, required for likelihood evaluation, are approximated efficiently using Gauss-Legendre quadrature, and smoothness is enforced by assigning a Gaussian Markov random field prior to the spline coefficients. Through a simulation study, we demonstrate that the spline clock model recovers the true time-varying rates more accurately and with tighter credible intervals than competing clock models. We apply the spline clock model to examine the evolutionary rate of foamy virus and the rate of spatial diffusion of SARS-CoV-2 across Europe, recovering strong time-varying signal in both settings.

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arXiv2026

Non-Linear Drivers of Population Dynamics: a Nonparametric Coalescent Approach

Effective population size (Ne(t)) is a fundamental parameter in population genetics and phylodynamics that quantifies genetic diversity and reveals demographic history. Coalescent-based methods enable the inference of Ne(t) trajectories through time from phylogenies reconstructed from molecular sequence data. Understanding the ecological and environmental drivers of population dynamics requires linking Ne(t) to external covariates. Existing approaches typically impose log-linear relationships between covariates and Ne(t), which may fail to capture complex biological processes and can introduce bias when the true relationship is nonlinear. We present a flexible Bayesian framework that integrates covariates into coalescent models with piecewise-constant Ne(t) through a Gaussian process (GP) prior. The GP, a distribution over functions, naturally accommodates nonlinear covariate effects without restrictive parametric assumptions. This formulation improves estimation of covariate-Ne(t) relationships, mitigates bias under nonlinear associations, and yields interpretable uncertainty quantification that varies across the covariate space. To balance global covariate-driven patterns with local temporal dynamics, we couple the GP prior with a Gaussian Markov random field that enforces smoothness in Ne(t) trajectories. Through simulation studies and three empirical applications - yellow fever virus dynamics in Brazil (2016-2018), late-Quaternary musk ox demography, and HIV-1 CRF02-AG evolution in Cameroon - we demonstrate that our method both confirms linear relationships where appropriate and reveals nonlinear covariate effects that would otherwise be missed or mischaracterized. This framework advances phylodynamic inference by enabling more accurate and biologically realistic modeling of how environmental and epidemiological factors shape population size through time.

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arXiv2025

Inhomogeneous continuous-time Markov chains to infer flexible time-varying evolutionary rates

Reconstructing evolutionary histories and estimating the rate of evolution from molecular sequence data is of central importance in evolutionary biology and infectious disease research. We introduce a flexible Bayesian phylogenetic inference framework that accommodates changing evolutionary rates over time by modeling sequence character substitution processes as inhomogeneous continuous-time Markov chains (ICTMCs) acting along the unknown phylogeny, where the rate remains as an unknown, positive and integrable function of time. The integral of the rate function appears in the finite-time transition probabilities of the ICTMCs that must be efficiently computed for all branches of the phylogeny to evaluate the observed data likelihood. Circumventing computational challenges that arise from a fully nonparametric function, we successfully parameterize the rate function as piecewise constant with a large number of epochs that we call the polyepoch clock model. This makes the transition probability computation relatively inexpensive and continues to flexibly capture rate change over time. We employ a Gaussian Markov random field prior to achieve temporal smoothing of the estimated rate function. Hamiltonian Monte Carlo sampling enabled by scalable gradient evaluation under this model makes our framework computationally efficient. We assess the performance of the polyepoch clock model in recovering the true timescales and rates through simulations under two different evolutionary scenarios. We then apply the polyepoch clock model to examine the rates of West Nile virus, Dengue virus and influenza A/H3N2 evolution, and estimate the time-varying rate of SARS-CoV-2 spread in Europe in 2020.

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arXiv2025

Detecting Evolutionary Change-Points with Branch-Specific Substitution Models and Shrinkage Priors

Branch-specific substitution models are popular for detecting evolutionary change-points, such as shifts in selective pressure. However, applying such models typically requires prior knowledge of change-point locations on the phylogeny or faces scalability issues with large data sets. To address both limitations, we integrate branch-specific substitution models with shrinkage priors to automatically identify change-points without prior knowledge, while simultaneously estimating distinct substitution parameters for each branch. To enable tractable inference under this high-dimensional model, we develop an analytical gradient algorithm for the branch-specific substitution parameters where the computational time is linear in the number of parameters. We apply this gradient algorithm to infer selection pressure dynamics in the evolution of the BRCA1 gene in primates and mutational dynamics in viral sequences from the recent mpox epidemic. Our novel algorithm enhances inference efficiency, achieving up to a 126-fold speedup per iteration in maximum likelihood optimization when compared to central difference numerical gradient method and up to a 2026-fold improvement in computational performance within a Bayesian framework using Hamiltonian Monte Carlo sampler compared to conventional univariate random walk sampler.

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arXiv2024

Infinite Mixture Models for Improved Modeling of Across-Site Evolutionary Variation

Scientific studies in many areas of biology routinely employ evolutionary analyses based on the probabilistic inference of phylogenetic trees from molecular sequence data. Evolutionary processes that act at the molecular level are highly variable, and properly accounting for heterogeneity in evolutionary processes is crucial for more accurate phylogenetic inference. Nucleotide substitution rates and patterns are known to vary among sites in multiple sequence alignments, and such variation can be modeled by partitioning alignments into categories corresponding to different substitution models. Determining $\textit{a priori}$ appropriate partitions can be difficult, however, and better model fit can be achieved through flexible Bayesian infinite mixture models that simultaneously infer the number of partitions, the partition that each site belongs to, and the evolutionary parameters corresponding to each partition. Here, we consider several different types of infinite mixture models, including classic Dirichlet process mixtures, as well as novel approaches for modeling across-site evolutionary variation: hierarchical models for data with a natural group structure, and infinite hidden Markov models that account for spatial patterns in alignments. In analyses of several viral data sets, we find that different types of infinite mixture models emerge as the best choices in different scenarios. To enable these models to scale efficiently to large data sets, we adapt efficient Markov chain Monte Carlo algorithms and exploit opportunities for parallel computing. We implement this infinite mixture modeling framework in BEAST X, a widely-used software package for Bayesian phylogenetic inference.

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arXiv2024

On the importance of assessing topological convergence in Bayesian phylogenetic inference

Modern phylogenetics research is often performed within a Bayesian framework, using sampling algorithms such as Markov chain Monte Carlo (MCMC) to approximate the posterior distribution. These algorithms require careful evaluation of the quality of the generated samples. Within the field of phylogenetics, one frequently adopted diagnostic approach is to evaluate the effective sample size (ESS) and to investigate trace graphs of the sampled parameters. A major limitation of these approaches is that they are developed for continuous parameters and therefore incompatible with a crucial parameter in these inferences: the tree topology. Several recent advancements have aimed at extending these diagnostics to topological space. In this reflection paper, we present two case studies - one on Ebola virus and one on HIV - illustrating how these topological diagnostics can contain information not found in standard diagnostics, and how decisions regarding which of these diagnostics to compute can impact inferences regarding MCMC convergence and mixing. Our results show the importance of running multiple replicate analyses and of carefully assessing topological convergence using the output of these replicate analyses. To this end, we illustrate different ways of assessing and visualizing the topological convergence of these replicates. Given the major importance of detecting convergence and mixing issues in Bayesian phylogenetic analyses, the lack of a unified approach to this problem warrants further action, especially now that additional tools are becoming available to researchers.

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arXiv2023

Quantum Speedups for Multiproposal MCMC

Multiproposal Markov chain Monte Carlo (MCMC) algorithms choose from multiple proposals to generate their next chain step in order to sample from challenging target distributions more efficiently. However, on classical machines, these algorithms require $\mathcal{O}(P)$ target evaluations for each Markov chain step when choosing from $P$ proposals. Recent work demonstrates the possibility of quadratic quantum speedups for one such multiproposal MCMC algorithm. After generating $P$ proposals, this quantum parallel MCMC (QPMCMC) algorithm requires only $\mathcal{O}(\sqrt{P})$ target evaluations at each step, outperforming its classical counterpart. However, generating $P$ proposals using classical computers still requires $\mathcal{O}(P)$ time complexity, resulting in the overall complexity of QPMCMC remaining $\mathcal{O}(P)$. Here, we present a new, faster quantum multiproposal MCMC strategy, QPMCMC2. With a specially designed Tjelmeland distribution that generates proposals close to the input state, QPMCMC2 requires only $\mathcal{O}(1)$ target evaluations and $\mathcal{O}(\log P)$ qubits when computing over a large number of proposals $P$. Unlike its slower predecessor, the QPMCMC2 Markov kernel (1) maintains detailed balance exactly and (2) is fully explicit for a large class of graphical models. We demonstrate this flexibility by applying QPMCMC2 to novel Ising-type models built on bacterial evolutionary networks and obtain significant speedups for Bayesian ancestral trait reconstruction for 248 observed salmonella bacteria.

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arXiv2023

Random-effects substitution models for phylogenetics via scalable gradient approximations

Phylogenetic and discrete-trait evolutionary inference depend heavily on an appropriate characterization of the underlying character substitution process. In this paper, we present random-effects substitution models that extend common continuous-time Markov chain models into a richer class of processes capable of capturing a wider variety of substitution dynamics. As these random-effects substitution models often require many more parameters than their usual counterparts, inference can be both statistically and computationally challenging. Thus, we also propose an efficient approach to compute an approximation to the gradient of the data likelihood with respect to all unknown substitution model parameters. We demonstrate that this approximate gradient enables scaling of sampling-based inference, namely Bayesian inference via Hamiltonian Monte Carlo, under random-effects substitution models across large trees and state-spaces. Applied to a dataset of 583 SARS-CoV-2 sequences, an HKY model with random-effects shows strong signals of nonreversibility in the substitution process, and posterior predictive model checks clearly show that it is a more adequate model than a reversible model. When analyzing the pattern of phylogeographic spread of 1441 influenza A virus (H3N2) sequences between 14 regions, a random-effects phylogeographic substitution model infers that air travel volume adequately predicts almost all dispersal rates. A random-effects state-dependent substitution model reveals no evidence for an effect of arboreality on the swimming mode in the tree frog subfamily Hylinae. Simulations reveal that random-effects substitution models can accommodate both negligible and radical departures from the underlying base substitution model. We show that our gradient-based inference approach is over an order of magnitude more time efficient than conventional approaches.

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arXiv2023

Many-core algorithms for high-dimensional gradients on phylogenetic trees

The rapid growth in genomic pathogen data spurs the need for efficient inference techniques, such as Hamiltonian Monte Carlo (HMC) in a Bayesian framework, to estimate parameters of these phylogenetic models where the dimensions of the parameters increase with the number of sequences $N$. HMC requires repeated calculation of the gradient of the data log-likelihood with respect to (wrt) all branch-length-specific (BLS) parameters that traditionally takes $\mathcal{O}(N^2)$ operations using the standard pruning algorithm. A recent study proposes an approach to calculate this gradient in $\mathcal{O}(N)$, enabling researchers to take advantage of gradient-based samplers such as HMC. The CPU implementation of this approach makes the calculation of the gradient computationally tractable for nucleotide-based models but falls short in performance for larger state-space size models, such as codon models. Here, we describe novel massively parallel algorithms to calculate the gradient of the log-likelihood wrt all BLS parameters that take advantage of graphics processing units (GPUs) and result in many fold higher speedups over previous CPU implementations. We benchmark these GPU algorithms on three computing systems using three evolutionary inference examples: carnivores, dengue and yeast, and observe a greater than 128-fold speedup over the CPU implementation for codon-based models and greater than 8-fold speedup for nucleotide-based models. As a practical demonstration, we also estimate the timing of the first introduction of West Nile virus into the continental Unites States under a codon model with a relaxed molecular clock from 104 full viral genomes, an inference task previously intractable. We provide an implementation of our GPU algorithms in BEAGLE v4.0.0, an open source library for statistical phylogenetics that enables parallel calculations on multi-core CPUs and GPUs.

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arXiv2022

Accelerating Bayesian inference of dependency between complex biological traits

Inferring dependencies between complex biological traits while accounting for evolutionary relationships between specimens is of great scientific interest yet remains infeasible when trait and specimen counts grow large. The state-of-the-art approach uses a phylogenetic multivariate probit model to accommodate binary and continuous traits via a latent variable framework, and utilizes an efficient bouncy particle sampler (BPS) to tackle the computational bottleneck -- integrating many latent variables from a high-dimensional truncated normal distribution. This approach breaks down as the number of specimens grows and fails to reliably characterize conditional dependencies between traits. Here, we propose an inference pipeline for phylogenetic probit models that greatly outperforms BPS. The novelty lies in 1) a combination of the recent Zigzag Hamiltonian Monte Carlo (Zigzag-HMC) with linear-time gradient evaluations and 2) a joint sampling scheme for highly correlated latent variables and correlation matrix elements. In an application exploring HIV-1 evolution from 535 viruses, the inference requires joint sampling from an 11,235-dimensional truncated normal and a 24-dimensional covariance matrix. Our method yields a 5-fold speedup compared to BPS and makes it possible to learn partial correlations between candidate viral mutations and virulence. Computational speedup now enables us to tackle even larger problems: we study the evolution of influenza H1N1 glycosylations on around 900 viruses. For broader applicability, we extend the phylogenetic probit model to incorporate categorical traits, and demonstrate its use to study Aquilegia flower and pollinator co-evolution.

stat.ME↗

arXiv2021

Scalable Bayesian divergence time estimation with ratio transformations

Divergence time estimation is crucial to provide temporal signals for dating biologically important events, from species divergence to viral transmissions in space and time. With the advent of high-throughput sequencing, recent Bayesian phylogenetic studies have analyzed hundreds to thousands of sequences. Such large-scale analyses challenge divergence time reconstruction by requiring inference on highly-correlated internal node heights that often become computationally infeasible. To overcome this limitation, we explore a ratio transformation that maps the original N - 1 internal node heights into a space of one height parameter and N - 2 ratio parameters. To make analyses scalable, we develop a collection of linear-time algorithms to compute the gradient and Jacobian-associated terms of the log-likelihood with respect to these ratios. We then apply Hamiltonian Monte Carlo sampling with the ratio transform in a Bayesian framework to learn the divergence times in four pathogenic virus phylogenies: West Nile virus, rabies virus, Lassa virus and Ebola virus. Our method both resolves a mixing issue in the West Nile virus example and improves inference efficiency by at least 5-fold for the Lassa and rabies virus examples. Our method also makes it now computationally feasible to incorporate mixed-effects molecular clock models for the Ebola virus example, confirms the findings from the original study and reveals clearer multimodal distributions of the divergence times of some clades of interest.

q-bio.PE↗

arXiv2021

Principled, practical, flexible, fast: a new approach to phylogenetic factor analysis

Biological phenotypes are products of complex evolutionary processes in which selective forces influence multiple biological trait measurements in unknown ways. Phylogenetic factor analysis disentangles these relationships across the evolutionary history of a group of organisms. Scientists seeking to employ this modeling framework confront numerous modeling and implementation decisions, the details of which pose computational and replicability challenges. General and impactful community employment requires a data scientific analysis plan that balances flexibility, speed and ease of use, while minimizing model and algorithm tuning. Even in the presence of non-trivial phylogenetic model constraints, we show that one may analytically address latent factor uncertainty in a way that (a) aids model flexibility, (b) accelerates computation (by as much as 500-fold) and (c) decreases required tuning. We further present practical guidance on inference and modeling decisions as well as diagnosing and solving common problems in these analyses. We codify this analysis plan in an automated pipeline that distills the potentially overwhelming array of modeling decisions into a small handful of (typically binary) choices. We demonstrate the utility of these methods and analysis plan in four real-world problems of varying scales.

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arXiv2021

Shrinkage-based random local clocks with scalable inference

Local clock models propose that the rate of molecular evolution is constant within phylogenetic sub-trees. Current local clock inference procedures scale poorly to large taxa problems, impose model misspecification, or require a priori knowledge of the existence and location of clocks. To overcome these challenges, we present an autocorrelated, Bayesian model of heritable clock rate evolution that leverages heavy-tailed priors with mean zero to shrink increments of change between branch-specific clocks. We further develop an efficient Hamiltonian Monte Carlo sampler that exploits closed form gradient computations to scale our model to large trees. Inference under our shrinkage-clock exhibits an over 3-fold speed increase compared to the popular random local clock when estimating branch-specific clock rates on a simulated dataset. We further show our shrinkage-clock recovers known local clocks within a rodent and mammalian phylogeny. Finally, in a problem that once appeared computationally impractical, we investigate the heritable clock structure of various surface glycoproteins of influenza A virus in the absence of prior knowledge about clock placement.

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arXiv2020

Efficient Bayesian Inference of General Gaussian Models on Large Phylogenetic Trees

Phylogenetic comparative methods correct for shared evolutionary history among a set of non-independent organisms by modeling sample traits as arising from a diffusion process along on the branches of a possibly unknown history. To incorporate such uncertainty, we present a scalable Bayesian inference framework under a general Gaussian trait evolution model that exploits Hamiltonian Monte Carlo (HMC). HMC enables efficient sampling of the constrained model parameters and takes advantage of the tree structure for fast likelihood and gradient computations, yielding algorithmic complexity linear in the number of observations. This approach encompasses a wide family of stochastic processes, including the general Ornstein-Uhlenbeck (OU) process, with possible missing data and measurement errors. We implement inference tools for a biologically relevant subset of all these models into the BEAST phylogenetic software package and develop model comparison through marginal likelihood estimation. We apply our approach to study the morphological evolution in the superfamilly of Musteloidea (including weasels and allies) as well as the heritability of HIV virulence. This second problem furnishes a new measure of evolutionary heritability that demonstrates its utility through a targeted simulation study.

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arXiv2020

Large-scale inference of correlation among mixed-type biological traits with phylogenetic multivariate probit models

Inferring concerted changes among biological traits along an evolutionary history remains an important yet challenging problem. Besides adjusting for spurious correlation induced from the shared history, the task also requires sufficient flexibility and computational efficiency to incorporate multiple continuous and discrete traits as data size increases. To accomplish this, we jointly model mixed-type traits by assuming latent parameters for binary outcome dimensions at the tips of an unknown tree informed by molecular sequences. This gives rise to a phylogenetic multivariate probit model. With large sample sizes, posterior computation under this model is problematic, as it requires repeated sampling from a high-dimensional truncated normal distribution. Current best practices employ multiple-try rejection sampling that suffers from slow-mixing and a computational cost that scales quadratically in sample size. We develop a new inference approach that exploits 1) the bouncy particle sampler (BPS) based on piecewise deterministic Markov processes to simultaneously sample all truncated normal dimensions, and 2) novel dynamic programming that reduces the cost of likelihood and gradient evaluations for BPS to linear in sample size. In an application with 535 HIV viruses and 24 traits that necessitates sampling from a 12,840-dimensional truncated normal, our method makes it possible to estimate the across-trait correlation and detect factors that affect the pathogen's capacity to cause disease. This inference framework is also applicable to a broader class of covariance structures beyond comparative biology.

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arXiv2020

Deep reinforcement learning for large-scale epidemic control

Epidemics of infectious diseases are an important threat to public health and global economies. Yet, the development of prevention strategies remains a challenging process, as epidemics are non-linear and complex processes. For this reason, we investigate a deep reinforcement learning approach to automatically learn prevention strategies in the context of pandemic influenza. Firstly, we construct a new epidemiological meta-population model, with 379 patches (one for each administrative district in Great Britain), that adequately captures the infection process of pandemic influenza. Our model balances complexity and computational efficiency such that the use of reinforcement learning techniques becomes attainable. Secondly, we set up a ground truth such that we can evaluate the performance of the 'Proximal Policy Optimization' algorithm to learn in a single district of this epidemiological model. Finally, we consider a large-scale problem, by conducting an experiment where we aim to learn a joint policy to control the districts in a community of 11 tightly coupled districts, for which no ground truth can be established. This experiment shows that deep reinforcement learning can be used to learn mitigation policies in complex epidemiological models with a large state space. Moreover, through this experiment, we demonstrate that there can be an advantage to consider collaboration between districts when designing prevention strategies.

cs.LG↗

arXiv2020

Online Bayesian phylodynamic inference in BEAST with application to epidemic reconstruction

Reconstructing pathogen dynamics from genetic data as they become available during an outbreak or epidemic represents an important statistical scenario in which observations arrive sequentially in time and one is interested in performing inference in an 'online' fashion. Widely-used Bayesian phylogenetic inference packages are not set up for this purpose, generally requiring one to recompute trees and evolutionary model parameters de novo when new data arrive. To accommodate increasing data flow in a Bayesian phylogenetic framework, we introduce a methodology to efficiently update the posterior distribution with newly available genetic data. Our procedure is implemented in the BEAST 1.10 software package, and relies on a distance-based measure to insert new taxa into the current estimate of the phylogeny and imputes plausible values for new model parameters to accommodate growing dimensionality. This augmentation creates informed starting values and re-uses optimally tuned transition kernels for posterior exploration of growing data sets, reducing the time necessary to converge to target posterior distributions. We apply our framework to data from the recent West African Ebola virus epidemic and demonstrate a considerable reduction in time required to obtain posterior estimates at different time points of the outbreak. Beyond epidemic monitoring, this framework easily finds other applications within the phylogenetics community, where changes in the data -- in terms of alignment changes, sequence addition or removal -- present common scenarios that can benefit from online inference.

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