Precise asymptotics of small eigenvalues of reversible diffusions in the metastable regime

We investigate the close connection between metastability of the reversible diffusion process X defined by the stochastic differential equation dX_t=-\nabla F(X_t) dt+\sqrt2\epsilon dW_t,\qquad \epsilon >0, and the spectrum near zero of its generator -L_{\epsilon}\equiv \epsilon \Delta -\nabla F\cdot\nabla, where F:R^d\to R and W denotes Brownian motion on R^d. For generic F to each local minimum of F there corresponds a metastable state. We prove that the distribution of its rescaled relaxation time converges to the exponential distribution as \epsilon \downarrow 0 with optimal and uniform error estimates. Each metastable state can be viewed as an eigenstate of L_{\epsilon} with eigenvalue which converges to zero exponentially fast in 1/\epsilon. Modulo errors of exponentially small order in 1/\epsilon this eigenvalue is given as the inverse of the expected metastable relaxation time. The eigenstate is highly concentrated in the basin of attraction of the corresponding trap.Comment: Published at http://dx.doi.org/10.1214/009117904000000991 in the Annals of Probability (http://www.imstat.org/aop/) by the Institute of Mathematical Statistics (http://www.imstat.org

Mass campaigns with antimalarial drugs: a modelling comparison of artemether-lumefantrine and DHA-piperaquine with and without primaquine as tools for malaria control and elimination

Antimalarial drugs are a powerful tool for malaria control and elimination. Artemisinin-based combination therapies (ACTs) can reduce transmission when widely distributed in a campaign setting. Modelling mass antimalarial campaigns can elucidate how to most effectively deploy drug-based interventions and quantitatively compare the effects of cure, prophylaxis, and transmission-blocking in suppressing parasite prevalence. A previously established agent-based model that includes innate and adaptive immunity was used to simulate malaria infections and transmission. Pharmacokinetics of artemether, lumefantrine, dihydroartemisinin, piperaquine, and primaquine were modelled with a double-exponential distribution-elimination model including weight-dependent parameters and age-dependent dosing. Drug killing of asexual parasites and gametocytes was calibrated to clinical data. Mass distribution of ACTs and primaquine was simulated with seasonal mosquito dynamics at a range of transmission intensities. A single mass campaign with antimalarial drugs is insufficient to permanently reduce malaria prevalence when transmission is high. Current diagnostics are insufficiently sensitive to accurately identify asymptomatic infections, and mass-screen-and-treat campaigns are much less efficacious than mass drug administrations. Improving campaign coverage leads to decreased prevalence one month after the end of the campaign, while increasing compliance lengthens the duration of protection against reinfection. Use of a long-lasting prophylactic as part of a mass drug administration regimen confers the most benefit under conditions of high transmission and moderately high coverage. Addition of primaquine can reduce prevalence but exerts its largest effect when coupled with a long-lasting prophylactic.Comment: 14 pages, 5 figure

Metastability and low lying spectra in reversible Markov chains

We study a large class of reversible Markov chains with discrete state space and transition matrix $P_N$. We define the notion of a set of {\it metastable points} as a subset of the state space \G_N such that (i) this set is reached from any point x\in \G_N without return to x with probability at least $b_N$, while (ii) for any two point x,y in the metastable set, the probability $T^{-1}_{x,y}$ to reach y from x without return to x is smaller than $a_N^{-1}\ll b_N$. Under some additional non-degeneracy assumption, we show that in such a situation: \item{(i)} To each metastable point corresponds a metastable state, whose mean exit time can be computed precisely. \item{(ii)} To each metastable point corresponds one simple eigenvalue of $1-P_N$ which is essentially equal to the inverse mean exit time from this state. The corresponding eigenfunctions are close to the indicator function of the support of the metastable state. Moreover, these results imply very sharp uniform control of the deviation of the probability distribution of metastable exit times from the exponential distribution.Comment: 44pp, AMSTe

Metastability in stochastic dynamics of disordered mean-field models

We study a class of Markov chains that describe reversible stochastic dynamics of a large class of disordered mean field models at low temperatures. Our main purpose is to give a precise relation between the metastable time scales in the problem to the properties of the rate functions of the corresponding Gibbs measures. We derive the analog of the Wentzell-Freidlin theory in this case, showing that any transition can be decomposed, with probability exponentially close to one, into a deterministic sequence of ``admissible transitions''. For these admissible transitions we give upper and lower bounds on the expected transition times that differ only by a constant. The distribution rescaled transition times are shown to converge to the exponential distribution. We exemplify our results in the context of the random field Curie-Weiss model.Comment: 73pp, AMSTE

Finding levers for innovation in diverse teams

Lange, P.A.M. van [Promotor]Voelpel, S.C. [Promotor]Homan, A.C. [Copromotor

The challenges and opportunities in tuberculosis control, from Texas to Afghanistan

Tuberculosis is one of the most ancient human pathogens. Very early in the history of humans, tuberculosis spread throughout the world and currently infects one third of the world’s population1. Tuberculosis, both as a pathogen and a disease state, is fascinating in its own right. Considering the global public health significance of tuberculosis, which infects one third of the world’s population and kills over 1.5 million people per year, tuberculosis remains a threat and demands further research. For these reasons, my undergraduate research has largely centered on tuberculosis. Chapter 1 gives a broad overview of tuberculosis, applicable but not specific to my research. Each subsequent chapter focuses on a research project, with relevant additional background on tuberculosis. Chapter 2 is based on an internship at the Texas Department of State Health Services analyzing reasons for delayed completion of tuberculosis therapy for patients whose therapy initiated in Texas in 2006. Chapter 3 examines the potential for molecular methods of tuberculosis in low-resource setting, building off of my experience using mutations in the rpoB gene as a surrogate marker of rifampin resistance in Afghanistan. Chapter 4 briefly expands upon further work done in the lab of Dr. Andrew Ellington at the University of Texas at Austin under the supervision of Xi Chen, developing non-enzymatic methods of nucleic acid detection to indicate the presence of tuberculosis and other pathogens.Biological Sciences, School o

Fractional diffusion emulates a human mobility network during a simulated disease outbreak

From footpaths to flight routes, human mobility networks facilitate the spread of communicable diseases. Control and elimination efforts depend on characterizing these networks in terms of connections and flux rates of individuals between contact nodes. In some cases, transport can be parameterized with gravity-type models or approximated by a diffusive random walk. As a alternative, we have isolated intranational commercial air traffic as a case study for the utility of non-diffusive, heavy-tailed transport models. We implemented new stochastic simulations of a prototypical influenza-like infection, focusing on the dense, highly-connected United States air travel network. We show that mobility on this network can be described mainly by a power law, in agreement with previous studies. Remarkably, we find that the global evolution of an outbreak on this network is accurately reproduced by a two-parameter space-fractional diffusion equation, such that those parameters are determined by the air travel network.Comment: 26 pages, 4 figure