Refinement Type Inference via Horn Constraint Optimization

We propose a novel method for inferring refinement types of higher-order functional programs. The main advantage of the proposed method is that it can infer maximally preferred (i.e., Pareto optimal) refinement types with respect to a user-specified preference order. The flexible optimization of refinement types enabled by the proposed method paves the way for interesting applications, such as inferring most-general characterization of inputs for which a given program satisfies (or violates) a given safety (or termination) property. Our method reduces such a type optimization problem to a Horn constraint optimization problem by using a new refinement type system that can flexibly reason about non-determinism in programs. Our method then solves the constraint optimization problem by repeatedly improving a current solution until convergence via template-based invariant generation. We have implemented a prototype inference system based on our method, and obtained promising results in preliminary experiments.Comment: 19 page

Efficient Solving of Quantified Inequality Constraints over the Real Numbers

Let a quantified inequality constraint over the reals be a formula in the first-order predicate language over the structure of the real numbers, where the allowed predicate symbols are $\leq$ and $<$. Solving such constraints is an undecidable problem when allowing function symbols such $\sin$ or $\cos$. In the paper we give an algorithm that terminates with a solution for all, except for very special, pathological inputs. We ensure the practical efficiency of this algorithm by employing constraint programming techniques

Certainty Closure: Reliable Constraint Reasoning with Incomplete or Erroneous Data

Constraint Programming (CP) has proved an effective paradigm to model and solve difficult combinatorial satisfaction and optimisation problems from disparate domains. Many such problems arising from the commercial world are permeated by data uncertainty. Existing CP approaches that accommodate uncertainty are less suited to uncertainty arising due to incomplete and erroneous data, because they do not build reliable models and solutions guaranteed to address the user's genuine problem as she perceives it. Other fields such as reliable computation offer combinations of models and associated methods to handle these types of uncertain data, but lack an expressive framework characterising the resolution methodology independently of the model. We present a unifying framework that extends the CP formalism in both model and solutions, to tackle ill-defined combinatorial problems with incomplete or erroneous data. The certainty closure framework brings together modelling and solving methodologies from different fields into the CP paradigm to provide reliable and efficient approches for uncertain constraint problems. We demonstrate the applicability of the framework on a case study in network diagnosis. We define resolution forms that give generic templates, and their associated operational semantics, to derive practical solution methods for reliable solutions.Comment: Revised versio

Flux imbalance analysis and the sensitivity of cellular growth to changes in metabolite pools

Stoichiometric models of metabolism, such as flux balance analysis (FBA), are classically applied to predicting steady state rates - or fluxes - of metabolic reactions in genome-scale metabolic networks. Here we revisit the central assumption of FBA, i.e. that intracellular metabolites are at steady state, and show that deviations from flux balance (i.e. flux imbalances) are informative of some features of in vivo metabolite concentrations. Mathematically, the sensitivity of FBA to these flux imbalances is captured by a native feature of linear optimization, the dual problem, and its corresponding variables, known as shadow prices. First, using recently published data on chemostat growth of Saccharomyces cerevisae under different nutrient limitations, we show that shadow prices anticorrelate with experimentally measured degrees of growth limitation of intracellular metabolites. We next hypothesize that metabolites which are limiting for growth (and thus have very negative shadow price) cannot vary dramatically in an uncontrolled way, and must respond rapidly to perturbations. Using a collection of published datasets monitoring the time-dependent metabolomic response of Escherichia coli to carbon and nitrogen perturbations, we test this hypothesis and find that metabolites with negative shadow price indeed show lower temporal variation following a perturbation than metabolites with zero shadow price. Finally, we illustrate the broader applicability of flux imbalance analysis to other constraint-based methods. In particular, we explore the biological significance of shadow prices in a constraint-based method for integrating gene expression data with a stoichiometric model. In this case, shadow prices point to metabolites that should rise or drop in concentration in order to increase consistency between flux predictions and gene expression data. In general, these results suggest that the sensitivity of metabolic optima to violations of the steady state constraints carries biologically significant information on the processes that control intracellular metabolites in the cell.Published versio