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Marek Kimmel

Publications and source records attributed to Marek Kimmel.

5 recordsLinked to original sources

An Approximate Maximum Likelihood Estimator for Discretely Observed Linear Birth-and-Death Processes

Linear birth-and-death processes (LBDPs) are foundational stochastic models in population dynamics, evolutionary biology, and hematopoiesis. Estimating parameters from discretely observed data is computationally demanding due to irregular sampling, noise, and missing values. We propose a novel approximate maximum likelihood estimator (MLE) for LBDPs based on a Gaussian approximation to transition probabilities. The approach transforms estimation into a univariate optimization problem, achieving substantial computational gains without sacrificing accuracy. Through simulations, we show that the approximate MLE outperforms Gaussian and saddlepoint-based estimators in speed and precision under realistic noise and sparsity. Applied to longitudinal clonal hematopoiesis data, the method produces biologically meaningful growth estimates even with noisy, compositional input. Unlike Gaussian and saddlepoint approximations, our estimator is invariant to data scaling, making it ideal for real-world applications such as variant allele frequency analyses.

stat.CO

Stochastic dynamics of two-compartment cell proliferation models with regulatory mechanisms for hematopoiesis

We present an asymptotic analysis of a stochastic two-compartmental cell division system with regulatory mechanisms inspired by Getto et al. (2013). The hematopoietic system is modeled as a two-compartment system, where the first compartment consists of dividing cells in the bone marrow, referred to as type $0$ cells, and the second compartment consists of post-mitotic cells in the blood, referred to as type $1$ cells. Division and self-renewal of type $0$ cells are regulated by the population density of type $1$ cells. By scaling up the initial population, we demonstrate that the scaled dynamics converges in distribution to the solution of a system of ordinary differential equations (ODEs). This system of ODEs exhibits a unique non-trivial equilibrium that is globally stable. Furthermore, we establish that the scaled fluctuations of the density dynamics converge in law to a linear diffusion process with time-dependent coefficients. When the initial data is Gaussian, the limit process is a Gauss-Markov process. We analyze its asymptotic properties to elucidate the joint structure of both compartments over large times. This is achieved by proving exponential convergence in the 2-Wasserstein metric for the associated Gaussian measures on an $L^{2}$ Hilbert space. Finally, we apply our results to compare the effects of regulating division and self-renewal of type $0$ cells, providing insights into their respective roles in maintaining hematopoietic system stability.

q-bio.PE

A Countable-Type Branching Process Model for the Tug-of-War Cancer Cell Dynamics

We consider a time-continuous Markov branching process of proliferating cells with a countable collection of types. Among-type transitions are inspired by the Tug-of-War process introduced in McFarland et al. as a mathematical model for competition of advantageous driver mutations and deleterious passenger mutations in cancer cells. We introduce a version of the model in which a driver mutation pushes the type of the cell $L$-units up, while a passenger mutation pulls it $1$-unit down. The distribution of time to divisions depends on the type (fitness) of cell, which is an integer. The extinction probability given any initial cell type is strictly less than $1$, which allows us to investigate the transition between types (type transition) in an infinitely long cell lineage of cells. The analysis leads to the result that under driver dominance, the type transition process escapes to infinity, while under passenger dominance, it leads to a limit distribution. Implications in cancer cell dynamics and population genetics are discussed.

q-bio.PE

Stochastic Models of Stem Cells and Their Descendants under Different Criticality Assumptions

We study time continuous branching processes with exponentially distributed lifetimes, with two types of cells that proliferate according to binary fission. A range of possible system dynamics are considered, each of which is characterized by the mutation rate of the original cells and the survival probability of the altered cells' progeny. For each system, we derive a closed-form expression for the joint probability generating function of cell counts, and perform asymptotic analysis on the behaviors of the cell population with particular focus on probability of extinction. Part of our results confirms known properties of branching processes using a different approach while other are original. While the model is best suited for modeling the fate of differentiating stem cells, we discuss other scenarios in which these system dynamics may be applicable in real life. We also discuss the history of the subject.

math.PR

Thick distribution tails in models of cancer secondary tumors

Recent progress in microdissection and in DNA sequencing has enabled subsampling of multi-focal cancers in organs such as the liver in several hundred spots, helping to determine the pattern of mutations in each of these spots. This has led to the construction of genealogies of the primary, secondary, tertiary and so forth, foci of the tumor. These studies have led to diverse conclusions concerning the Darwinian (selective) or neutral evolution in cancer. Mathematical models of development of multifocal tumors have been developed to support these claims. We report a model of development of a multifocal tumor, which is a mathematically rigorous refinement of a model of Ling et al. (2015). Guided by numerical studies and simulations, we show that the rigorous model, in the form of an infinite-type branching process, displays distributions of tumors size which have heavy tails and moments that become infinite in finite time. To demonstrate these points, we obtain bounds on the tails of the distributions of the process and infinite-series expression for the first moments. In addition to its inherent mathematical interest, the model is corroborated by recent reports of apparent super-exponential growth in cancer metastases.

q-bio.PE