Inference for reaction networks using the Linear Noise Approximation

We consider inference for the reaction rates in discretely observed networks such as those found in models for systems biology, population ecology and epidemics. Most such networks are neither slow enough nor small enough for inference via the true state-dependent Markov jump process to be feasible. Typically, inference is conducted by approximating the dynamics through an ordinary differential equation (ODE), or a stochastic differential equation (SDE). The former ignores the stochasticity in the true model, and can lead to inaccurate inferences. The latter is more accurate but is harder to implement as the transition density of the SDE model is generally unknown. The Linear Noise Approximation (LNA) is a first order Taylor expansion of the approximating SDE about a deterministic solution and can be viewed as a compromise between the ODE and SDE models. It is a stochastic model, but discrete time transition probabilities for the LNA are available through the solution of a series of ordinary differential equations. We describe how a restarting LNA can be efficiently used to perform inference for a general class of reaction networks; evaluate the accuracy of such an approach; and show how and when this approach is either statistically or computationally more efficient than ODE or SDE methods. We apply the LNA to analyse Google Flu Trends data from the North and South Islands of New Zealand, and are able to obtain more accurate short-term forecasts of new flu cases than another recently proposed method, although at a greater computational cost

A shared-parameter continuous-time hidden Markov and survival model for longitudinal data with informative dropout

A shared-parameter approach for jointly modeling longitudinal and survival data is proposed. With respect to available approaches, it allows for time-varying random effects that affect both the longitudinal and the survival processes. The distribution of these random effects is modeled according to a continuous-time hidden Markov chain so that transitions may occur at any time point. For maximum likelihood estimation, we propose an algorithm based on a discretization of time until censoring in an arbitrary number of time windows. The observed information matrix is used to obtain standard errors. We illustrate the approach by simulation, even with respect to the effect of the number of time windows on the precision of the estimates, and by an application to data about patients suffering from mildly dilated cardiomyopathy

Stochastic Approximation and Modern Model-Based Designs for Dose-Finding Clinical Trials

In 1951 Robbins and Monro published the seminal article on stochastic approximation and made a specific reference to its application to the "estimation of a quantal using response, nonresponse data." Since the 1990s, statistical methodology for dose-finding studies has grown into an active area of research. The dose-finding problem is at its core a percentile estimation problem and is in line with what the Robbins--Monro method sets out to solve. In this light, it is quite surprising that the dose-finding literature has developed rather independently of the older stochastic approximation literature. The fact that stochastic approximation has seldom been used in actual clinical studies stands in stark contrast with its constant application in engineering and finance. In this article, I explore similarities and differences between the dose-finding and the stochastic approximation literatures. This review also sheds light on the present and future relevance of stochastic approximation to dose-finding clinical trials. Such connections will in turn steer dose-finding methodology on a rigorous course and extend its ability to handle increasingly complex clinical situations.Comment: Published in at http://dx.doi.org/10.1214/10-STS334 the Statistical Science (http://www.imstat.org/sts/) by the Institute of Mathematical Statistics (http://www.imstat.org

Maximally selected chi-square statistics and binary splits of nominal variables

We address the problem of maximally selected chi-square statistics in the case of a binary Y variable and a nominal X variable with several categories. The distribution of the maximally selected chi-square statistic has already been derived when the best cutpoint is chosen from a continuous or an ordinal X, but not when the best split is chosen from a nominal X. In this paper, we derive the exact distribution of the maximally selected chi-square statistic in this case using a combinatorial approach. Applications of the derived distribution to variable selection and hypothesis testing are discussed based on simulations. As an illustration, our method is applied to a pregnancy and birth data set

A latent factor model for spatial data with informative missingness

A large amount of data is typically collected during a periodontal exam. Analyzing these data poses several challenges. Several types of measurements are taken at many locations throughout the mouth. These spatially-referenced data are a mix of binary and continuous responses, making joint modeling difficult. Also, most patients have missing teeth. Periodontal disease is a leading cause of tooth loss, so it is likely that the number and location of missing teeth informs about the patient's periodontal health. In this paper we develop a multivariate spatial framework for these data which jointly models the binary and continuous responses as a function of a single latent spatial process representing general periodontal health. We also use the latent spatial process to model the location of missing teeth. We show using simulated and real data that exploiting spatial associations and jointly modeling the responses and locations of missing teeth mitigates the problems presented by these data.Comment: Published in at http://dx.doi.org/10.1214/09-AOAS278 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org

Maximally selected chi-square statistics and umbrella orderings

Binary outcomes that depend on an ordinal predictor in a non-monotonic way are common in medical data analysis. Such patterns can be addressed in terms of cutpoints: for example, one looks for two cutpoints that define an interval in the range of the ordinal predictor for which the probability of a positive outcome is particularly high (or low). A chi-square test may then be performed to compare the proportions of positive outcomes in and outside this interval. However, if the two cutpoints are chosen to maximize the chi-square statistic, referring the obtained chi-square statistic to the standard chi-square distribution is an inappropriate approach. It is then necessary to correct the p-value for multiple comparisons by considering the distribution of the maximally selected chi-square statistic instead of the nominal chi-square distribution. Here, we derive the exact distribution of the chi-square statistic obtained by the optimal two cutpoints. We suggest a combinatorial computation method and illustrate our approach by a simulation study and an application to varicella data