Competitive exclusion in a model with seasonality: Three species cannot coexist in an ecosystem with two seasons.

Chan, Durrett, and Lanchier introduced a multitype contact process with temporal heterogeneity involving two species competing for space on the d-dimensional integer lattice. Time is divided into two seasons. They proved that there is an open set of the parameters for which both species can coexist when their dispersal range is sufficiently large. Numerical simulations suggested that three species can coexist in the presence of two seasons. The main point of this paper is to prove that this conjecture is incorrect. To do this we prove results for a more general ODE model and contrast its behavior with other related systems that have been studied in order to understand the competitive exclusion principle.

Signatures of neutral evolution in exponentially growing tumors: A theoretical perspective.

Recent work of Sottoriva, Graham, and collaborators have led to the controversial claim that exponentially growing tumors have a site frequency spectrum that follows the 1/f law consistent with neutral evolution. This conclusion has been criticized based on data quality issues, statistical considerations, and simulation results. Here, we use rigorous mathematical arguments to investigate the site frequency spectrum in the two-type model of clonal evolution. If the fitnesses of the two types are λ0 < λ1, then the site frequency spectrum is c/fα where α = λ0/λ1. This is due to the advantageous mutations that produce the founders of the type 1 population. Mutations within the growing type 0 and type 1 populations follow the 1/f law. Our results show that, in contrast to published criticisms, neutral evolution in an exponentially growing tumor can be distinguished from the two-type model using the site frequency spectrum.

Extrapolating weak selection in evolutionary games.

This work is inspired by a 2013 paper from Arne Traulsen's lab at the Max Plank Institute for Evolutionary Biology (Wu et al. in PLoS Comput Biol 9:e1003381, 2013). They studied evolutionary games when the mutation rate is so small that each mutation goes to fixation before the next one occurs. It has been shown that for [Formula: see text] games the ranking of the strategies does not change as strength of selection is increased (Wu et al. in Phys Rev 82:046106, 2010). The point of the 2013 paper is that when there are three or more strategies the ordering can change as selection is increased. Wu et al. (2013) did numerical computations for a fixed population size N. Here, we will instead let the strength of selection [Formula: see text] where c is fixed and let [Formula: see text] to obtain formulas for the invadability probabilities [Formula: see text] that determine the rankings. These formulas, which are integrals on [0, 1], are intractable calculus problems, but can be easily evaluated numerically. Here, we use them to derive simple formulas for the ranking order when c is small or c is large.

Ordinary Differential Equation Models for Adoptive Immunotherapy.

Modified T cells that have been engineered to recognize the CD19 surface marker have recently been shown to be very successful at treating acute lymphocytic leukemias. Here, we explore four previous approaches that have used ordinary differential equations to model this type of therapy, compare their properties, and modify the models to address their deficiencies. Although the four models treat the workings of the immune system in slightly different ways, they all predict that adoptive immunotherapy can be successful to move a patient from the large tumor fixed point to an equilibrium with little or no tumor.

HPV clearance and the neglected role of stochasticity.

Clearance of anogenital and oropharyngeal HPV infections is attributed primarily to a successful adaptive immune response. To date, little attention has been paid to the potential role of stochastic cell dynamics in the time it takes to clear an HPV infection. In this study, we combine mechanistic mathematical models at the cellular level with epidemiological data at the population level to disentangle the respective roles of immune capacity and cell dynamics in the clearing mechanism. Our results suggest that chance-in form of the stochastic dynamics of basal stem cells-plays a critical role in the elimination of HPV-infected cell clones. In particular, we find that in immunocompetent adolescents with cervical HPV infections, the immune response may contribute less than 20% to virus clearance-the rest is taken care of by the stochastic proliferation dynamics in the basal layer. In HIV-negative individuals, the contribution of the immune response may be negligible.

Estimating Tumor Growth Rates In Vivo.

In this paper, we develop methods for inferring tumor growth rates from the observation of tumor volumes at two time points. We fit power law, exponential, Gompertz, and Spratt's generalized logistic model to five data sets. Though the data sets are small and there are biases due to the way the samples were ascertained, there is a clear sign of exponential growth for the breast and liver cancers, and a 2/3's power law (surface growth) for the two neurological cancers.

Some features of the spread of epidemics and information on a random graph.

Random graphs are useful models of social and technological networks. To date, most of the research in this area has concerned geometric properties of the graphs. Here we focus on processes taking place on the network. In particular we are interested in how their behavior on networks differs from that in homogeneously mixing populations or on regular lattices of the type commonly used in ecological models.

POPULATION GENETICS OF NEUTRAL MUTATIONS IN EXPONENTIALLY GROWING CANCER CELL POPULATIONS.

In order to analyze data from cancer genome sequencing projects, we need to be able to distinguish causative, or "driver," mutations from "passenger" mutations that have no selective effect. Toward this end, we prove results concerning the frequency of neutural mutations in exponentially growing multitype branching processes that have been widely used in cancer modeling. Our results yield a simple new population genetics result for the site frequency spectrum of a sample from an exponentially growing population.

A branching process model of ovarian cancer.

Ovarian cancer is usually diagnosed at an advanced stage, rendering the possibility of cure unlikely. To date, no cost-effective screening test has proven effective for reducing mortality. To estimate the window of opportunity for ovarian cancer screening, we develop a branching process model for ovarian cancer growth and progression accounting for three cell populations: Primary (cells in the ovary or fallopian tube), Peritoneal (viable cells in peritoneal fluid), and Metastatic (cells implanted on other intra-abdominal surfaces). Growth and migration parameters were chosen to match results of clinical studies. Using these values, our model predicts a window of opportunity of 2.9 years, indicating that one would have to screen at least every other year to be effective. The model can be used to inform future efforts in designing improved screening and treatment strategies.

Evolution of dispersal distance.

The problem of how often to disperse in a randomly fluctuating environment has long been investigated, primarily using patch models with uniform dispersal. Here, we consider the problem of choice of seed size for plants in a stable environment when there is a trade off between survivability and dispersal range. Ezoe (J Theor Biol 190:287-293, 1998) and Levin and Muller-Landau (Evol Ecol Res 2:409-435, 2000) approached this problem using models that were essentially deterministic, and used calculus to find optimal dispersal parameters. Here we follow Hiebeler (Theor Pop Biol 66:205-218, 2004) and use a stochastic spatial model to study the competition of different dispersal strategies. Most work on such systems is done by simulation or nonrigorous methods such as pair approximation. Here, we use machinery developed by Cox et al. (Voter model perturbations and reaction diffusion equations 2011) to rigorously and explicitly compute evolutionarily stable strategies.

Evolutionary dynamics of tumor progression with random fitness values.

Most human tumors result from the accumulation of multiple genetic and epigenetic alterations in a single cell. Mutations that confer a fitness advantage to the cell are known as driver mutations and are causally related to tumorigenesis. Other mutations, however, do not change the phenotype of the cell or even decrease cellular fitness. While much experimental effort is being devoted to the identification of the functional effects of individual mutations, mathematical modeling of tumor progression generally considers constant fitness increments as mutations are accumulated. In this paper we study a mathematical model of tumor progression with random fitness increments. We analyze a multi-type branching process in which cells accumulate mutations whose fitness effects are chosen from a distribution. We determine the effect of the fitness distribution on the growth kinetics of the tumor. This work contributes to a quantitative understanding of the accumulation of mutations leading to cancer.

Controlling the spread of COVID-19 on college campuses.

This research was done during the DOMath program at Duke University from May 18 to July 10, 2020. At the time, Duke and other universities across the country were wrestling with the question of how to safely welcome students back to campus in the Fall. Because of this, our project focused on using mathematical models to evaluate strategies to suppress the spread of the virus on campus, specifically in dorms and in classrooms. For dorms, we show that giving students single rooms rather than double rooms can substantially reduce virus spread. For classrooms, we show that moving classes with size above some cutoff online can make the basic reproduction number $ R_0 < 1 $, preventing a wide spread epidemic. The cutoff will depend on the contagiousness of the disease in classrooms.

Waiting for two mutations: with applications to regulatory sequence evolution and the limits of Darwinian evolution.

Results of Nowak and collaborators concerning the onset of cancer due to the inactivation of tumor suppressor genes give the distribution of the time until some individual in a population has experienced two prespecified mutations and the time until this mutant phenotype becomes fixed in the population. In this article we apply these results to obtain insights into regulatory sequence evolution in Drosophila and humans. In particular, we examine the waiting time for a pair of mutations, the first of which inactivates an existing transcription factor binding site and the second of which creates a new one. Consistent with recent experimental observations for Drosophila, we find that a few million years is sufficient, but for humans with a much smaller effective population size, this type of change would take > 100 million years. In addition, we use these results to expose flaws in some of Michael Behe's arguments concerning mathematical limits to Darwinian evolution.

Population genetics of polymorphism and divergence under fluctuating selection.

Current methods for detecting fluctuating selection require time series data on genotype frequencies. Here, we propose an alternative approach that makes use of DNA polymorphism data from a sample of individuals collected at a single point in time. Our method uses classical diffusion approximations to model temporal fluctuations in the selection coefficients to find the expected distribution of mutation frequencies in the population. Using the Poisson random-field setting we derive the site-frequency spectrum (SFS) for three different models of fluctuating selection. We find that the general effect of fluctuating selection is to produce a more "U"-shaped site-frequency spectrum with an excess of high-frequency derived mutations at the expense of middle-frequency variants. We present likelihood-ratio tests, comparing the fluctuating selection models to the neutral model using SFS data, and use Monte Carlo simulations to assess their power. We find that we have sufficient power to reject a neutral hypothesis using samples on the order of a few hundred SNPs and a sample size of approximately 20 and power to distinguish between selection that varies in time and constant selection for a sample of size 20. We also find that fluctuating selection increases the probability of fixation of selected sites even if, on average, there is no difference in selection among a pair of alleles segregating at the locus. Fluctuating selection will, therefore, lead to an increase in the ratio of divergence to polymorphism similar to that observed under positive directional selection.

Dependence of paracentric inversion rate on tract length.

BACKGROUND: We develop a Bayesian method based on MCMC for estimating the relative rates of pericentric and paracentric inversions from marker data from two species. The method also allows estimation of the distribution of inversion tract lengths. RESULTS: We apply the method to data from Drosophila melanogaster and D. yakuba. We find that pericentric inversions occur at a much lower rate compared to paracentric inversions. The average paracentric inversion tract length is approx. 4.8 Mb with small inversions being more frequent than large inversions. If the two breakpoints defining a paracentric inversion tract are uniformly and independently distributed over chromosome arms there will be more short tract-length inversions than long; we find an even greater preponderance of short tract lengths than this would predict. Thus there appears to be a correlation between the positions of breakpoints which favors shorter tract lengths. CONCLUSION: The method developed in this paper provides the first statistical estimator for estimating the distribution of inversion tract lengths from marker data. Application of this method for a number of data sets may help elucidate the relationship between the length of an inversion and the chance that it will get accepted.

Temporal profiles of avalanches on networks.

An avalanche or cascade occurs when one event causes one or more subsequent events, which in turn may cause further events in a chain reaction. Avalanching dynamics are studied in many disciplines, with a recent focus on average avalanche shapes, i.e., the temporal profiles of avalanches of fixed duration. At the critical point of the dynamics, the rescaled average avalanche shapes for different durations collapse onto a single universal curve. We apply Markov branching process theory to derive an equation governing the average avalanche shape for cascade dynamics on networks. Analysis of the equation at criticality demonstrates that nonsymmetric average avalanche shapes (as observed in some experiments) occur for certain combinations of dynamics and network topology. We give examples using numerical simulations of models for information spreading, neural dynamics, and behavior adoption and we propose simple experimental tests to quantify whether cascading systems are in the critical state.

Persistence and reversal of plasmid-mediated antibiotic resistance.

In the absence of antibiotic-mediated selection, sensitive bacteria are expected to displace their resistant counterparts if resistance genes are costly. However, many resistance genes persist for long periods in the absence of antibiotics. Horizontal gene transfer (primarily conjugation) could explain this persistence, but it has been suggested that very high conjugation rates would be required. Here, we show that common conjugal plasmids, even when costly, are indeed transferred at sufficiently high rates to be maintained in the absence of antibiotics in Escherichia coli. The notion is applicable to nine plasmids from six major incompatibility groups and mixed populations carrying multiple plasmids. These results suggest that reducing antibiotic use alone is likely insufficient for reversing resistance. Therefore, combining conjugation inhibition and promoting plasmid loss would be an effective strategy to limit conjugation-assisted persistence of antibiotic resistance.

Outcomes of Active Surveillance for Ductal Carcinoma in Situ: A Computational Risk Analysis.

BACKGROUND: Ductal carcinoma in situ (DCIS) is a noninvasive breast lesion with uncertain risk for invasive progression. Usual care (UC) for DCIS consists of treatment upon diagnosis, thus potentially overtreating patients with low propensity for progression. One strategy to reduce overtreatment is active surveillance (AS), whereby DCIS is treated only upon detection of invasive disease. Our goal was to perform a quantitative evaluation of outcomes following an AS strategy for DCIS. METHODS: Age-stratified, 10-year disease-specific cumulative mortality (DSCM) for AS was calculated using a computational risk projection model based upon published estimates for natural history parameters, and Surveillance, Epidemiology, and End Results data for outcomes. AS projections were compared with the DSCM for patients who received UC. To quantify the propagation of parameter uncertainty, a 95% projection range (PR) was computed, and sensitivity analyses were performed. RESULTS: Under the assumption that AS cannot outperform UC, the projected median differences in 10-year DSCM between AS and UC when diagnosed at ages 40, 55, and 70 years were 2.6% (PR = 1.4%-5.1%), 1.5% (PR = 0.5%-3.5%), and 0.6% (PR = 0.0%-2.4), respectively. Corresponding median numbers of patients needed to treat to avert one breast cancer death were 38.3 (PR = 19.7-69.9), 67.3 (PR = 28.7-211.4), and 157.2 (PR = 41.1-3872.8), respectively. Sensitivity analyses showed that the parameter with greatest impact on DSCM was the probability of understaging invasive cancer at diagnosis. CONCLUSION: AS could be a viable management strategy for carefully selected DCIS patients, particularly among older age groups and those with substantial competing mortality risks. The effectiveness of AS could be markedly improved by reducing the rate of understaging.

Phase transitions in the quadratic contact process on complex networks.

The quadratic contact process (QCP) is a natural extension of the well-studied linear contact process where infected (1) individuals infect susceptible (0) neighbors at rate λ and infected individuals recover (1→0) at rate 1. In the QCP, a combination of two 1's is required to effect a 0→1 change. We extend the study of the QCP, which so far has been limited to lattices, to complex networks. We define two versions of the QCP: vertex-centered (VQCP) and edge-centered (EQCP) with birth events 1-0-1→1-1-1 and 1-1-0→1-1-1, respectively, where "-" represents an edge. We investigate the effects of network topology by considering the QCP on random regular, Erdos-Rényi, and power-law random graphs. We perform mean-field calculations as well as simulations to find the steady-state fraction of occupied vertices as a function of the birth rate. We find that on the random regular and Erdos-Rényi graphs, there is a discontinuous phase transition with a region of bistability, whereas on the heavy-tailed power-law graph, the transition is continuous. The critical birth rate is found to be positive in the former but zero in the latter.