Parametric inference posits a statistical model that is a specified family of probability distributions. Restricted inference, for example, restricted likelihood ratio testing, attempts to exploit the structure of a statistical submodel that is a subset of the specified family. We consider the problem of testing a simple hypothesis against alternatives from such a submodel. In the case of an unknown submodel, it is not clear how to realize the benefits of restricted inference. To do so, we first construct information tests that are locally asymptotically equivalent to likelihood ratio tests. Information tests are conceptually appealing but (in general) computationally intractable. However, unlike restricted likelihood ratio tests, restricted information tests can be approximated even when the statistical submodel is unknown. We construct approximate information tests using manifold learning procedures to extract information from samples of an unknown (or intractable) submodel, thereby providing a roadmap for computational solutions to a class of previously impenetrable problems in statistical inference. Examples illustrate the efficacy of the proposed methodology.

QNSTOP consists of serial and parallel (OpenMP) Fortran 2003 codes for the quasi-Newton stochastic optimization method of Castle and Trosset for stochastic search problems. A complete description of QNSTOP for both local search with stochastic objective and global search with “noisy” deterministic objective is given here, to the best of our knowledge, for the first time. For stochastic search problems, some convergence theory exists for particular algorithmic choices and parameter values. Both the parallel driver subroutine, which offers several parallel decomposition strategies, and the serial driver subroutine can be used for local stochastic search or global deterministic search, based on an input switch. Some performance data for computational systems biology problems is given.

Parameter estimation in discrete or continuous deterministic cell cycle models is challenging for several reasons, including the nature of what can be observed, and the accuracy and quantity of those observations. The challenge is even greater for stochastic models, where the number of simulations and amount of empirical data must be even larger to obtain statistically valid parameter estimates. The two main contributions of this work are (1) stochastic model parameter estimation based on directly matching multivariate probability distributions, and (2) a new quasi-Newton algorithm class QNSTOP for stochastic optimization problems. QNSTOP directly uses the random objective function value samples rather than creating ensemble statistics. QNSTOP is used here to directly match empirical and simulated joint probability distributions rather than matching summary statistics. Results are given for a current state-of-the-art stochastic cell cycle model of budding yeast, whose predictions match well some summary statistics and one-dimensional distributions from empirical data, but do not match well the empirical joint distributions. The nature of the mismatch provides insight into the weakness in the stochastic model.