Many problems arising in applications result in the need to probe a probability distribution for functions. Examples include Bayesian nonparametric statistics and conditioned diffusion processes. Standard MCMC algorithms typically become arbitrarily slow under the mesh refinement dictated by nonparametric description of the unknown function. We describe an approach to modifying a whole range of MCMC methods, applicable whenever the target measure has density with respect to a Gaussian process or Gaussian random field reference measure, which ensures that their speed of convergence is robust under mesh refinement. Gaussian processes or random fields are fields whose marginal distributions, when evaluated at any finite set of $N$ points, are $\mathbb{R}^N$-valued Gaussians. The algorithmic approach that we describe is applicable not only when the desired probability measure has density with respect to a Gaussian process or Gaussian random field reference measure, but also to some useful non-Gaussian reference measures constructed through random truncation. In the applications of interest the data is often sparse and the prior specification is an essential part of the overall modelling strategy. These Gaussian-based reference measures are a very flexible modelling tool, finding wide-ranging application. Examples are shown in density estimation, data assimilation in fluid mechanics, subsurface geophysics and image registration. The key design principle is to formulate the MCMC method so that it is, in principle, applicable for functions; this may be achieved by use of proposals based on carefully chosen time-discretizations of stochastic dynamical systems which exactly preserve the Gaussian reference measure. Taking this approach leads to many new algorithms which can be implemented via minor modification of existing algorithms, yet which show enormous speed-up on a wide range of applied problems.Comment: Published in at http://dx.doi.org/10.1214/13-STS421 the Statistical Science (http://www.imstat.org/sts/) by the Institute of Mathematical Statistics (http://www.imstat.org

In this paper we establish a mathematical framework for a range of inverse problems for functions, given a finite set of noisy observations. The problems are hence underdetermined and are often ill-posed. We study these problems from the viewpoint of Bayesian statistics, with the resulting posterior probability measure being defined on a space of functions. We develop an abstract framework for such problems which facilitates application of an infinite-dimensional version of Bayes theorem, leads to a well-posedness result for the posterior measure (continuity in a suitable probability metric with respect to changes in data), and also leads to a theory for the existence of maximizing the posterior probability (MAP) estimators for such Bayesian inverse problems on function space. A central idea underlying these results is that continuity properties and bounds on the forward model guide the choice of the prior measure for the inverse problem, leading to the desired results on well-posedness and MAP estimators; the PDE analysis and probability theory required are thus clearly dileneated, allowing a straightforward derivation of results. We show that the abstract theory applies to some concrete applications of interest by studying problems arising from data assimilation in fluid mechanics. The objective is to make inference about the underlying velocity field, on the basis of either Eulerian or Lagrangian observations. We study problems without model error, in which case the inference is on the initial condition, and problems with model error in which case the inference is on the initial condition and on the driving noise process or, equivalently, on the entire time-dependent velocity field. In order to undertake a relatively uncluttered mathematical analysis we consider the two-dimensional Navier-Stokes equation on a torus. The case of Eulerian observationsdirect observations of the velocity field itself-is then a model for weather forecasting. The case of Lagrangian observations-observations of passive tracers advected by the flow-is then a model for data arising in oceanography. The methodology which we describe herein may be applied to many other inverse problems in which it is of interest to find, given observations, an infinitedimensional object, such as the initial condition for a PDE. A similar approach might be adopted, for example, to determine an appropriate mathematical

Abstract. Inverse problems are often ill posed, with solutions that depend sensitively on data. In any numerical approach to the solution of such problems, regularization of some form is needed to counteract the resulting instability. This paper is based on an approach to regularization, employing a Bayesian formulation of the problem, which leads to a notion of well posedness for inverse problems, at the level of probability measures. The stability which results from this well posedness may be used as the basis for quantifying the approximation, in finite dimensional spaces, of inverse problems for functions. This paper contains a theory which utilizes this stability property to estimate the distance between the true and approximate posterior distributions, in the Hellinger metric, in terms of error estimates for approximation of the underlying forward problem. This is potentially useful as it allows for the transfer of estimates from the numerical analysis of forward problems into estimates for the solution of the related inverse problem. It is noteworthy that, when the prior is a Gaussian random field model, controlling differences in the Hellinger metric leads to control on the differences between expected values of polynomially bounded functions and operators, including the mean and covariance operator. The ideas are applied to some non-Gaussian inverse problems where the goal is determination of the initial condition for the Stokes or Navier-Stokes equation from Lagrangian and Eulerian observations, respectively.

Stochastic simulation of coupled chemical reactions is often computationally intensive, especially if a chemical system contains reactions occurring on different time scales. In this paper, we introduce a multiscale methodology suitable to address this problem, assuming that the evolution of the slow species in the system is well approximated by a Langevin process. It is based on the conditional stochastic simulation algorithm (CSSA) which samples from the conditional distribution of the suitably defined fast variables, given values for the slow variables. In the constrained multiscale algorithm (CMA) a single realization of the CSSA is then used for each value of the slow variable to approximate the effective drift and diffusion terms, in a similar manner to the constrained mean-force computations in other applications such as molecular dynamics. We then show how using the ensuing Fokker-Planck equation approximation, we can in turn approximate average switching times in stochastic chemical systems.

SummaryCell-cell heterogeneity can facilitate lineage choice during embryonic development because it primes cells to respond to differentiation cues. However, remarkably little is known about the origin of heterogeneity or whether intrinsic and extrinsic variation can be controlled to generate reproducible cell type proportioning seen in vivo. Here, we use experimentation and modeling in D. discoideum to demonstrate that population-level cell cycle heterogeneity can be optimized to generate robust cell fate proportioning. First, cell cycle position is quantitatively linked to responsiveness to differentiation-inducing signals. Second, intrinsic variation in cell cycle length ensures cells are randomly distributed throughout the cell cycle at the onset of multicellular development. Finally, extrinsic perturbation of optimal cell cycle heterogeneity is buffered by compensatory changes in global signal responsiveness. These studies thus illustrate key regulatory principles underlying cell-cell heterogeneity optimization and the generation of robust and reproducible fate choice in development.