A general method to determine sampling windows for nonlinear mixed effects models with an application to population pharmacokinetic studies

Optimal design methods have been proposed to determine the best sampling times when sparse blood sampling is required in clinical pharmacokinetic studies. However, the optimal blood sampling time points may not be feasible in clinical practice. Sampling windows, a time interval for blood sample collection, have been proposed to provide flexibility in blood sampling times while preserving efficient parameter estimation. Because of the complexity of the population pharmacokinetic models, which are generally nonlinear mixed effects models, there is no analytical solution available to determine sampling windows. We propose a method for determination of sampling windows based on MCMC sampling techniques. The proposed method attains a stationary distribution rapidly and provides time-sensitive windows around the optimal design points. The proposed method is applicable to determine sampling windows for any nonlinear mixed effects model although our work focuses on an application to population pharmacokinetic models.

Simulation-based fully Bayesian experimental design for mixed effects models

In this paper, we present fully Bayesian experimental designs for nonlinear mixed effects models, in which we develop simulation-based optimal design methods to search over both continuous and discrete design spaces. Although Bayesian inference has commonly been performed on nonlinear mixed effects models, there is a lack of research into performing Bayesian optimal design for nonlinear mixed effects models that require searches to be performed over several design variables. This is likely due to the fact that it is much more computationally intensive to perform optimal experimental design for nonlinear mixed effects models than it is to perform inference in the Bayesian framework. In this paper, the design problem is to determine the optimal number of subjects and samples per subject, as well as the (near) optimal urine sampling times for a population pharmacokinetic study in horses, so that the population pharmacokinetic parameters can be precisely estimated, subject to cost constraints. The optimal sampling strategies, in terms of the number of subjects and the number of samples per subject, were found to be substantially different between the examples considered in this work, which highlights the fact that the designs are rather problem-dependent and require optimisation using the methods presented in this paper.

On the optimal capacity expansion of electric power systems

The analysis of investment in the electric power has been the subject of intensive research for many years. The efficient generation and distribution of electrical energy is a difficult task involving the operation of a complex network of facilities, often located over very large geographical regions. Electric power utilities have made use of an enormous range of mathematical models. Some models address time spans which last for a fraction of a second, such as those that deal with lightning strikes on transmission lines while at the other end of the scale there are models which address time horizons consisting of ten or twenty years; these usually involve long range planning issues. This thesis addresses the optimal long term capacity expansion of an interconnected power system. The aim of this study has been to derive a new, long term planning model which recognises the regional differences which exist for energy demand and which are present in the construction and operation of power plant and transmission line equipment. Perhaps the most innovative feature of the new model is the direct inclusion of regional energy demand curves in the nonlinear form. This results in a nonlinear capacity expansion model. After review of the relevant literature, the thesis first develops a model for the optimal operation of a power grid. This model directly incorporates regional demand curves. The model is a nonlinear programming problem containing both integer and continuous variables. A solution algorithm is developed which is based upon a resource decomposition scheme that separates the integer variables from the continuous ones. The decompostion of the operating problem leads to an interactive scheme which employs a mixed integer programming problem, known as the master, to generate trial operating configurations. The optimum operating conditions of each trial configuration is found using a smooth nonlinear programming model. The dual vector recovered from this model is subsequently used by the master to generate the next trial configuration. The solution algorithm progresses until lower and upper bounds converge. A range of numerical experiments are conducted and these experiments are included in the discussion. Using the operating model as a basis, a regional capacity expansion model is then developed. It determines the type, location and capacity of additional power plants and transmission lines, which are required to meet predicted electicity demands. A generalised resource decompostion scheme, similar to that used to solve the operating problem, is employed. The solution algorithm is used to solve a range of test problems and the results of these numerical experiments are reported. Finally, the expansion problem is applied to the Queensland electricity grid in Australia.

On the optimal capacity expansion of electric power systems

The analysis of investment in the electric power has been the subject of intensive research for many years. The efficient generation and distribution of electrical energy is a difficult task involving the operation of a complex network of facilities, often located over very large geographical regions. Electric power utilities have made use of an enormous range of mathematical models. Some models address time spans which last for a fraction of a second, such as those that deal with lightning strikes on transmission lines while at the other end of the scale there are models which address time horizons consisting of ten or twenty years; these usually involve long range planning issues. This thesis addresses the optimal long term capacity expansion of an interconnected power system. The aim of this study has been to derive a new, long term planning model which recognises the regional differences which exist for energy demand and which are present in the construction and operation of power plant and transmission line equipment. Perhaps the most innovative feature of the new model is the direct inclusion of regional energy demand curves in the nonlinear form. This results in a nonlinear capacity expansion model. After review of the relevant literature, the thesis first develops a model for the optimal operation of a power grid. This model directly incorporates regional demand curves. The model is a nonlinear programming problem containing both integer and continuous variables. A solution algorithm is developed which is based upon a resource decomposition scheme that separates the integer variables from the continuous ones. The decompostion of the operating problem leads to an interactive scheme which employs a mixed integer programming problem, known as the master, to generate trial operating configurations. The optimum operating conditions of each trial configuration is found using a smooth nonlinear programming model. The dual vector recovered from this model is subsequently used by the master to generate the next trial configuration. The solution algorithm progresses until lower and upper bounds converge. A range of numerical experiments are conducted and these experiments are included in the discussion. Using the operating model as a basis, a regional capacity expansion model is then developed. It determines the type, location and capacity of additional power plants and transmission lines, which are required to meet predicted electicity demands. A generalised resource decompostion scheme, similar to that used to solve the operating problem, is employed. The solution algorithm is used to solve a range of test problems and the results of these numerical experiments are reported. Finally, the expansion problem is applied to the Queensland electricity grid in Australia

A flexible optimisation model for the railway crew scheduling problem

Addressing the Crew Scheduling Problem (CSP) in transportation systems can be too complex to capture all details. The designed models usually ignore or simplify features which are difficult to formulate. This paper proposes an alternative formulation using a Mixed Integer Programming (MIP) approach to the problem. The optimisation model integrates the two phases of pairing generation and pairing optimisation by simultaneously sequencing trips into feasible duties and minimising total elapsed time of any duty. Crew scheduling constraints in which the crew have to return to their home depot at the end of the shift are included in the model. The flexibility of this model comes in the inclusion of the time interval of relief opportunities, allowing the crew to be relieved during a finite time interval. This will enhance the robustness of the schedule and provide a better representation of real-world conditions.

A pseudo-marginal sequential Monte Carlo algorithm for random effects models in Bayesian sequential design

A computationally efficient sequential Monte Carlo algorithm is proposed for the sequential design of experiments for the collection of block data described by mixed effects models. The difficulty in applying a sequential Monte Carlo algorithm in such settings is the need to evaluate the observed data likelihood, which is typically intractable for all but linear Gaussian models. To overcome this difficulty, we propose to unbiasedly estimate the likelihood, and perform inference and make decisions based on an exact-approximate algorithm. Two estimates are proposed: using Quasi Monte Carlo methods and using the Laplace approximation with importance sampling. Both of these approaches can be computationally expensive, so we propose exploiting parallel computational architectures to ensure designs can be derived in a timely manner. We also extend our approach to allow for model uncertainty. This research is motivated by important pharmacological studies related to the treatment of critically ill patients.

Statistical and Econometric Methods for Transportation Data Analysis, 2nd edition

Now in its second edition, this book describes tools that are commonly used in transportation data analysis. The first part of the text provides statistical fundamentals while the second part presents continuous dependent variable models. With a focus on count and discrete dependent variable models, the third part features new chapters on mixed logit models, logistic regression, and ordered probability models. The last section provides additional coverage of Bayesian statistical modeling, including Bayesian inference and Markov chain Monte Carlo methods. Data sets are available online to use with the modeling techniques discussed.

Optimal coordination of overcurrent relays in distribution systems with distributed generators based on differential evolution algorithm

Distributed generators (DGs) are defined as generators that are connected to a distribution network. The direction of the power flow and short-circuit current in a network could be changed compared with one without DGs. The conventional protective relay scheme does not meet the requirement in this emerging situation. As the number and capacity of DGs in the distribution network increase, the problem of coordinating protective relays becomes more challenging. Given this background, the protective relay coordination problem in distribution systems is investigated, with directional overcurrent relays taken as an example, and formulated as a mixed integer nonlinear programming problem. A mathematical model describing this problem is first developed, and the well-developed differential evolution algorithm is then used to solve it. Finally, a sample system is used to demonstrate the feasiblity and efficiency of the developed method.

A new approach to automatically producing schedules for cane railways

The scheduling of locomotive movements on cane railways has proven to be a very complex task. Various optimisation methods have been used over the years to try and produce an optimised schedule that eliminates or minimises bin supply delays to harvesters and the factory, while minimising the number of locomotives, locomotive shifts and cane bins, and also the cane age. This paper reports on a new attempt to develop an automatic scheduler using a mathematical model solved using mixed integer programming and constraint programming approaches and blocking parallel job shop scheduling fundamentals. The model solution has been explored using conventional constraint programming search techniques and found to produce a reasonable schedule for small-scale problems with up to nine harvesters. While more effort is required to complete the development of the full model with metaheuristic search techniques, the work completed to date gives confidence that the metaheuristic techniques will provide near optimal solutions in reasonable time.

Scheduling techniques to optimise rail operations

In Australia, railway systems play a vital role in transporting the sugarcane crop from farms to mills. The sugarcane transport system is very complex and uses daily schedules, consisting of a set of locomotives runs, to satisfy the requirements of the mill and harvesters. The total cost of sugarcane transport operations is very high; over 35% of the total cost of sugarcane production in Australia is incurred in cane transport. Efficient schedules for sugarcane transport can reduce the cost and limit the negative effects that this system can have on the raw sugar production system. There are several benefits to formulating the train scheduling problem as a blocking parallel-machine job shop scheduling (BPMJSS) problem, namely to prevent two trains passing in one section at the same time; to keep the train activities (operations) in sequence during each run (trip) by applying precedence constraints; to pass the trains on one section in the correct order (priorities of passing trains) by applying disjunctive constraints; and, to ease passing trains by solving rail conflicts by applying blocking constraints and Parallel Machine Scheduling. Therefore, the sugarcane rail operations are formulated as BPMJSS problem. A mixed integer programming and constraint programming approaches are used to describe the BPMJSS problem. The model is solved by the integration of constraint programming, mixed integer programming and search techniques. The optimality performance is tested by Optimization Programming Language (OPL) and CPLEX software on small and large size instances based on specific criteria. A real life problem is used to verify and validate the approach. Constructive heuristics and new metaheuristics including simulated annealing and tabu search are proposed to solve this complex and NP-hard scheduling problem and produce a more efficient scheduling system. Innovative hybrid and hyper metaheuristic techniques are developed and coded using C# language to improve the solutions quality and CPU time. Hybrid techniques depend on integrating heuristic and metaheuristic techniques consecutively, while hyper techniques are the complete integration between different metaheuristic techniques, heuristic techniques, or both.

A web application to perform linkage disequilibrium and linkage analyses on a computational grid

Motivation: Unravelling the genetic architecture of complex traits requires large amounts of data, sophisticated models and large computational resources. The lack of user-friendly software incorporating all these requisites is delaying progress in the analysis of complex traits. Methods: Linkage disequilibrium and linkage analysis (LDLA) is a high-resolution gene mapping approach based on sophisticated mixed linear models, applicable to any population structure. LDLA can use population history information in addition to pedigree and molecular markers to decompose traits into genetic components. Analyses are distributed in parallel over a large public grid of computers in the UK. Results: We have proven the performance of LDLA with analyses of simulated data. There are real gains in statistical power to detect quantitative trait loci when using historical information compared with traditional linkage analysis. Moreover, the use of a grid of computers significantly increases computational speed, hence allowing analyses that would have been prohibitive on a single computer. © The Author 2009. Published by Oxford University Press. All rights reserved.

Candidate gene analysis for quantitative traits using the transmission disequilibrium test : the example of the melanocortin 4-receptor in pigs

Population-wide associations between loci due to linkage disequilibrium can be used to map quantitative trait loci (QTL) with high resolution. However, spurious associations between markers and QTL can also arise as a consequence of population stratification. Statistical methods that cannot differentiate between loci associations due to linkage disequilibria from those caused in other ways can render false-positive results. The transmission-disequilibrium test (TDT) is a robust test for detecting QTL. The TDT exploits within-family associations that are not affected by population stratification. However, some TDTs are formulated in a rigid-form, with reduced potential applications. In this study we generalize TDT using mixed linear models to allow greater statistical flexibility. Allelic effects are estimated with two independent parameters: one exploiting the robust within-family information and the other the potentially biased between-family information. A significant difference between these two parameters can be used as evidence for spurious association. This methodology was then used to test the effects of the fourth melanocortin receptor (MC4R) on production traits in the pig. The new analyses supported the previously reported results; i.e., the studied polymorphism is either causal of in very strong linkage disequilibrium with the causal mutation, and provided no evidence for spurious association.

Integrated approach to optimize open-pit mine block sequencing

Critical stage in open-pit mining is to determine the optimal extraction sequence of blocks, which has significant impacts on mining profitability. In this paper, a more comprehensive block sequencing optimisation model is developed for the open-pit mines. In the model, material characteristics of blocks, grade control, excavator and block sequencing are investigated and integrated to maximise the short-term benefit of mining. Several case studies are modeled and solved by CPLEX MIP and CP engines. Numerical investigations are presented to illustrate and validate the proposed methodology.

An open pit multistage mine production scheduling model for drilling, blasting and excavating operations

This paper proposes a new multi-resource multi-stage scheduling problem for optimising the open-pit drilling, blasting and excavating operations under equipment capacity constraints. The flow process is analysed based on the real-life data from an Australian iron ore mine site. The objective of the model is to maximise the throughput and minimise the total idle times of equipment at each stage. The following comprehensive mining attributes and constraints have been considered: types of equipment; operating capacities of equipment; ready times of equipment; speeds of equipment; block-sequence-dependent movement times of equipment; equipment-assignment-dependent operation times of blocks; distances between each pair of blocks; due windows of blocks; material properties of blocks; swell factors of blocks; and slope requirements of blocks. It is formulated by mixed integer programming and solved by ILOG-CPLEX optimiser. The proposed model is validated with extensive computational experiments to improve mine production efficiency at the operational level. The model also provides an intelligent decision support tool to account for the availability and usage of equipment units for drilling, blasting and excavating stages.