Title: Exact and efficient hybrid Monte Carlo algorithm for accelerated Bayesian inference of gene expression models from snapshots of single-cell transcripts

Abstract

Single cells exhibit a significant amount of variability in transcript levels, which arises from slow, stochastic transitions between gene expression states. Elucidating the nature of these states and understanding how transition rates are affected by different regulatory mechanisms require state-of-the-art methods to infer underlying models of gene expression from single cell data. A Bayesian approach to statistical inference is the most suitable method for model selection and uncertainty quantification of kinetic parameters using small data sets. However, this approach is impractical because current algorithms are too slow to handle typical models of gene expression. To solve this problem, we first show that time-dependent mRNA distributions of discrete-state models of gene expression are dynamic Poisson mixtures, whose mixing kernels are characterized by a piecewise deterministic Markov process. Here, we combined this analytical result with a kinetic Monte Carlo algorithm to create a hybrid numerical method that accelerates the calculation of time-dependent mRNA distributions by 1000-fold compared to current methods. We then integrated the hybrid algorithm into an existing Monte Carlo sampler to estimate the Bayesian posterior distribution of many different, competing models in a reasonable amount of time. We demonstrate that kinetic parameters can be reasonably constrained for modestly sampled datamore » sets if the model is known a priori. If there are many competing models, Bayesian evidence can rigorously quantify the likelihood of a model relative to other models from the data. We demonstrate that Bayesian evidence selects the true model and outperforms approximate metrics typically used for model selection.« less

Authors:

Lin, Yen Ting  ^[1];

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• Search DOE PAGES for ORCID "0000-0001-6893-8423"
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Buchler, Nicolas E.  ^[2]

• Search DOE PAGES for author "Buchler, Nicolas E."
• Search DOE PAGES for ORCID "0000-0003-3940-3432"
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+ Show Author Affiliations

1. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
2. North Carolina State Univ., Raleigh, NC (United States)

Publication Date:

2019-07-14

Research Org.:

Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

Sponsoring Org.:

USDOE Laboratory Directed Research and Development (LDRD) Program

OSTI Identifier:

1557757

Alternate Identifier(s):

OSTI ID: 1532586

Report Number(s):

LA-UR-18-31392
Journal ID: ISSN 0021-9606

Grant/Contract Number:  

89233218CNA000001

Resource Type:

Accepted Manuscript

Journal Name:

Journal of Chemical Physics

Additional Journal Information:

Journal Volume: 151; Journal Issue: 2; Journal ID: ISSN 0021-9606

Publisher:

American Institute of Physics (AIP)

Country of Publication:

United States

Language:

English

Subject:

59 BASIC BIOLOGICAL SCIENCES; Biological Science; Mathematics