Search

In 2018, the Department of Operations, Business Analytics, and Information Systems (OBAIS) in the Carl H. Lindner College of Business at the University of Cincinnati (UC) celebrated its 50th anniversary, and in 2019 the OBAIS department won the INFORMS UPS George D. Smith Prize. The OBAIS department has a long history of excellence in fostering academia-industry collaboration in the area of analytics as well as a track record of continued innovation. In this article, we summarize some of the history of the OBAIS department and describe many of the department’s innovations that enabled the department to win the 2019 Smith Prize. We provide an overview of the department’s curriculum of analytics-focused degree programs, and we explain how the UC Center for Business Analytics serves as the culmination of the department’s efforts to provide a supportive ecosystem in analytics for students, faculty, business leaders, and practitioners. We conclude with some lessons learned along our journey.

Scope Dietary fat composition is an important modulator of vascular function. Non-esterified fatty acids (NEFA) enriched in saturated fatty acids (SFA) are thought to reduce vascular reactivity by attenuating insulin signalling via vasodilator pathways (phosphoinositide 3-kinase (PI3K)/Akt/endothelial nitric oxide synthase (eNOS)) and enhancing signalling via pro-inflammatory pathways. Methods To examine the effects of fatty acids on these pathways, human aortic endothelial cells were incubated with single fatty acids, and mixtures of these fatty acids to mimic typical NEFA composition and concentrations achieved in our previous human study. RNA was extracted to determine gene expression using real-time RT-PCR and cell lysates prepared to assess protein phosphorylation by Western blotting. Results Oleic acid (OA, 100 µM) was shown to down regulate expression of the insulin receptor, PTEN and a PI3K catalytic (p110β) and regulatory (p85α) subunit compared to palmitic, linoleic and stearic acids (P 1177. Both concentration and composition of the SFA and SFA plus n-3 polyunsaturated fatty acids (PUFA) mixtures had significant effects on genes involved in the PI3K/Akt pathway. Greater up-regulation was found with 800 than 400 µM concentration (respective of concentrations in insulin resistant and normal individuals), whereas greater down-regulation was evident with SFA plus n-3 PUFA than SFA mixture alone. Conclusion Our findings provide novel insights into the modulation of the PI3K/Akt/eNOS pathway by single fatty acids and fatty acid mixtures. In particular, OA appears to promote signalling via this pathway, with further work required to determine the primary molecular site(s) of action.

The increasing vulnerability of the population from frequent disasters requires quick and effective responses to provide the required relief through effective humanitarian supply chain distribution networks. We develop scenario-robust optimization models for stocking multiple disaster relief items at strategic facility locations for disaster response. Our models improve the robustness of solutions by easing the difficult, and usually impossible, task of providing exact probability distributions for uncertain parameters in a stochastic programming model. Our models allow decision makers to specify uncertainty parameters (i.e., point and probability estimates) based on their degrees of knowledge, using distribution-free uncertainty sets in the form of ranges. The applicability of our generalized approach is illustrated via a case study of hurricane preparedness in the Southeastern United States. In addition, we conduct simulation studies to show the effectiveness of our approach when conditions deviate from the model assumptions.

The phosphatidylinositol (PI) cycle is central to eukaryotic cell signaling. Its complexity, due to the number of reactions and lipid and inositol phosphate intermediates involved makes it difficult to analyze experimentally. Computational modelling approaches are seen as a way forward to elucidate complex biological regulatory mechanisms when this cannot be achieved solely through experimental approaches. Whilst mathematical modelling is well established in informing biological systems, many models are often informed by data sourced from different cell types (mosaic data), to inform model parameters. For instance, kinetic rate constants are often determined from purified enzyme datain vitroor use experimental concentrations obtained from multiple unrelated cell types. Thus they do not represent any specific cell type nor fully capture cell specific behaviours. In this work, we develop a model of the PI cycle informed byin-vivoomics data taken from a single cell type, namely platelets. Our model recapitulates the known experimental dynamics before and after stimulation with different agonists and demonstrates the importance of lipid- and protein-binding proteins in regulating second messenger outputs. Furthermore, we were able to make a number of predictions regarding the regulation of PI cycle enzymes and the importance of the number of receptors required for successful GPCR signaling. We then consider how pathway behavior differs, when fully informed by data for HeLa cells and show that model predictions remain relatively consistent. However, when informed by mosaic experimental data model predictions greatly vary. Our work illustrates the risks of using mosaic datasets from unrelated cell types which leads to over 75% of outputs not fitting with expected behaviors.Authors summaryComputational models of cellular complexity offer much in terms of understanding cell behaviors and in informing experimental design, but their usefulness is limited in them being built with mosaic data not representing specific cell types and tested against limited experimental outputs. In this work we demonstrate an approach using quantitative proteomic datasets and temporal experimental data from a single cell type (platelets) to inform kinetic rate constants and protein concentrations for a mathematical model of a key signaling pathway - the phosphatidylinositol (PI) cycle; known for its central role in numerous cell functions and diseases. After using our model to make novel predictions regarding how aspects of the pathway are regulated, we demonstrate its versatile nature by utilising proteomic data from other cell types to generate similar predictions for those cells while highlighting the pitfalls of using mosaic data when constructing computational models.

In a tele-ICU center with flexible staff scheduling, interruptions to tasks with lower priority are common, often prolonging the processing time of these tasks. Dedicated staff scheduling, however, can reduce such interruptions. While dedicated staff scheduling is generally perceived to be less efficient than flexible systems according to traditional queueing theory, the reductions in interruptions call this result into question. To investigate when dedicated staff scheduling could be more efficient than flexible systems for tele-ICUs, we build a discrete-event simulation model to analyze the operational process of admissions and interventions at a real tele-ICU center. Our simulation results show that if the dedicated nurse (intensivist) can process admissions at least 31% (26%) faster than the flexible nurse (intensivist), the dedicated staff scheduling will be preferred. Thus, the tele-ICU administrators should choose the scheduling approach (flexible versus dedicated) based on how often interruptions are likely to occur and their anticipated effect on prolonging the medical staff’s processing times of the interrupted tasks. Our simulation model can also help tele-ICU administrators determine a suitable staffing level by providing the estimated waiting times of admissions and interventions under varying staffing levels.

We propose a heuristic approach to address the general class of optimization problems involving the capacitated clustering of observations consisting of variable values that are realizations from respective probability distributions. Based on the expectation-maximization algorithm, our approach unifies Gaussian mixture modeling for clustering analysis and cluster capacity constraints using a posterior regularization framework. To test our algorithm, we consider the capacitated p-median problem in which the observations consist of geographic locations of customers and the corresponding demand of these customers. Our heuristic has superior performance compared to classic geometrical clustering heuristics, with robust performance over a collection of instance types.

Data visualization is the process of visualizing data through tables, charts, graphs, maps, and other visual aids. Data visualization is often thought of as a descriptive tool, but it is also important for use in predictive and prescriptive analytics. It serves as a tool for descriptive data exploration, but also for communicating insights from data and from analytical models. In this tutorial, we provide a concise discussion of best practices for data visualization for effective communication.

This work investigates how fairness concerns influence supply-chain decision making, while examining the effect of private production-cost information and touching on issues related to bounded rationality. We conduct laboratory work utilizing a supply-chain dyad with an upstream supplier feeding a downstream retailer under a simple wholesale-price contract. We perform human–computer (H–C) experiments where human subjects play the role of the supplier paired with the computerized retailer, as well as human–human (H–H) experiments where human subjects play the role of both supplier and retailer. These experiments allow us to isolate other effects like bounded rationality from the effects of fairness concerns on supply-chain decision making. We find that, compared to standard analytical model, the bounded rationality slightly reduces overall supply chain profit without changing its distribution between the supplier and the retailer, while fairness concerns lead to greater supply-chain profits and a more balanced supply-chain profit distribution. We further illustrate that under private cost information, the retailer's fairness concern is suppressed by the lack of reciprocity from not being able to observe her rival's profit information, but that the supplier's fairness concern from altruism persists. Based on our experimental results, we modify classical supply-chain models to include utility functions that incorporate both bounded rationality and fairness concerns. The estimated other-regarding coefficients are significantly lower under private information than under public information for the H–H experiments, and we find no evidence of inequity aversion for the H–C experiments.

In this paper we propose a framework for shift-level container scheduling and resource allocation decisions at a cross-dock facility. The Multi-Mode Resource-Constrained Cross-Dock Scheduling Problem (MRCDSP) approach minimizes material flow and schedules inbound and outbound containers to dock-doors such that the total processing time is minimized subject to the resource constraints at the cross-dock. While container scheduling and resource allocation problems at cross-dock facilities have been studied previously in isolation, our work is the first to consider a complete view of cross-dock operations providing optimal container to dock-door allocation, and a makespan minimizing schedule of containers to the cross-dock. We present a comprehensive framework that includes identification of container clusters to reduce the problem size, a container-to-dock-door assignment algorithm, and a container clusters scheduling model that is solvable for practically sized problems. In a comparative numeric study based on data simulating a cross-dock facility, our approach is shown to outperform current practice, reducing the average time required for processing a set of containers by 37% and reducing the weighted-distance material traveled within the cross-dock by 45%.

Systems biology and modeling approaches require quantitative data-rich temporal experiments to better understand the dynamics and regulation of the components of the signaling pathways that governs cell biology and physiology. Here we present a modified Western blotting method to rapidly analyze and accurately quantify protein copy number, and their respective phosphorylation states at specific sites over detailed time courses.

Systems biology and modeling approaches require quantitative data-rich temporal experiments to better understand the dynamics and regulation of the components of the signaling pathways that governs cell biology and physiology. Here we present a modified Western blotting method to rapidly analyze and accurately quantify protein copy number, and their respective phosphorylation states at specific sites over detailed time courses.

Efficiency and equity are the two crucial factors to be considered when allocating public resources such as voting machines. Existing allocation models are all single-objective, focusing on maximizing either efficiency or equity despite the fact that the actual decision-making process involves both issues simultaneously. We propose a bi-objective integer program to analyse the tradeoff between the two competing objectives. The new model quantifies the sacrifice in efficiency in order to achieve a certain improvement in equity and vice versa. Using data from the 2008 United States Presidential election in Franklin County, Ohio, we demonstrate that our model is capable of producing significantly more balanced allocation plans, in terms of efficiency and equity, than current practice or other competing methods.

In this paper we analyse resource allocation decisions in a Long-Term Home Care (LTHC) program. LTHC programs provide various long-term in-home care services to patients who have been discharged fr...

Intensive Care Units (ICUs) are frequently the bottleneck in a hospital system, limiting patient flow and negatively impacting profits. This article examines admission control policies for a surgical ICU where patients arrive in batches. This problem is formulated as a Markov Decision Process (MDP) with an objective function that allows for varying degrees of emphasis on efficiency versus equity. Equity concerns are driven by a combination of surgery type and operating surgeon and are captured in a robust manner in the proposed models. A simple and efficient heuristic solution method related to our MDP formulation is proposed that provides a performance guarantee. The proposed admissions policy is applied to a real setting motivated by the cardiothoracic surgical ICU at Mount Sinai Medical Center in New York; the results demonstrate that the ICU can achieve large equity gains with no efficiency losses.

Supplemental Digital Content is available in the text., Objectives/Design: Little is known on how to best prioritize various tele-ICU specific tasks and workflows to maximize operational efficiency. We set out to: 1) develop an operational model that accurately reflects tele-ICU workflows at baseline, 2) identify workflow changes that optimize operational efficiency through discrete-event simulation and multi-class priority queuing modeling, and 3) implement the predicted favorable workflow changes and validate the simulation model through prospective correlation of actual-to-predicted change in performance measures linked to patient outcomes. Setting: Tele-ICU of a large healthcare system in New York State covering nine ICUs across the spectrum of adult critical care. Patients: Seven-thousand three-hundred eighty-seven adult critically ill patients admitted to a system ICU (1,155 patients pre-intervention in 2016Q1 and 6,232 patients post-intervention 2016Q3 to 2017Q2) Interventions: Change in tele-ICU workflow process structure and hierarchical process priority based on discrete-event simulation. Measurements and Main Results: Our discrete-event simulation model accurately reflected the actual baseline average time to first video assessment by both the tele-ICU intensivist (simulated 132.8 ± 6.7 min vs 132 ± 12.2 min actual) and the tele-ICU nurse (simulated 128.4 ± 7.6 min vs 123 ± 9.8 min actual). For a simultaneous priority and process change, the model simulated a reduction in average TVFA to 51.3 ± 1.6 min (tele-ICU intensivist) and 50.7 ± 2.1 min (tele-ICU nurse), less than the added simulated reductions for each change alone, suggesting correlation of the changes to some degree. Subsequently implementing both changes simultaneously resulted in actual reductions in average time to first video assessment to values within the 95% CIs of the simulations (50 ± 5.5 min for tele-intensivists and 49 ± 3.9 min for tele-nurses). Conclusions: Discrete-event simulation can accurately predict the effects of contemplated multidisciplinary tele-ICU workflow changes. The value of workflow process and task priority modeling is likely to increase with increasing operational complexities and interdependencies.

We apply service-operations-management concepts to improve the efficiency and equity of voting systems. Recent elections in the United States and elsewhere have been plagued by long lines, excessive waiting times, and perceptions of unfairness. We build models for the waiting lines at voting precincts using both traditional steady-state queueing methods and simulation models. We develop solution methods to allocate voting machines optimally to precincts. Our objective functions consider both the efficiency and the equity of the voting system. We compare our allocation algorithm to several competing methods, including those used in practice. We examine several different strategies for improving voting operations on both the demand and the capacity side of voting systems, and we present a complete case study of applying our method to data from the 2008 election for Franklin County, Ohio. We conclude that our method is superior to existing polices in terms of efficiency and equity and that it is robust in terms of uncertainties regarding turnout rates on Election Day. We also suggest several operational improvements to the voting process drawn from the service-operations literature.

Providing equal access to public service resources is a fundamental goal of democratic societies. Growing research interest in public services (e.g., health care, humanitarian relief, elections) has increased the importance of considering objective functions related to equity. This article studies discrete resource allocation problems where the decision maker is concerned with maintaining equity between some defined subgroups of a customer population and where non-closed-form functions of equity are allowed. Simulation optimization techniques are used to develop rigorous algorithms to allocate resources equitably among these subgroups. The presented solutions are associated with probabilistic bounds on solution quality. A full-factorial experimental design demonstrates that the proposed algorithm outperforms competing heuristics and is robust over various inequity metrics. Additionally, the algorithm is applied to a case study of allocating voting machines to election precincts in Franklin County, Ohio. [...

Objective: To develop queuing and simulation-based models to understand the relationship between ICU bed availability and operating room schedule to maximize the use of critical care resources and minimize case cancellation while providing equity to patients and surgeons. Design: Retrospective analysis of 6-month unit admission data from a cohort of cardiothoracic surgical patients, to create queuing and simulation-based models of ICU bed flow. Three different admission policies (current admission policy, shortest-processing-time policy, and a dynamic policy) were then analyzed using simulation models, representing 10 yr worth of potential admissions. Important output data consisted of the “average waiting time,” a proxy for unit efficiency, and the “maximum waiting time,” a surrogate for patient equity. Setting: A cardiothoracic surgical ICU in a tertiary center in New York, NY. Patients: Six hundred thirty consecutive cardiothoracic surgical patients admitted to the cardiothoracic surgical ICU. Interventions: None. Measurements and Main Results: Although the shortest-processingtime admission policy performs best in terms of unit efficiency (0.4612 days), it did so at expense of patient equity prolonging surgical waiting time by as much as 21 days. The current policy gives the greatest equity but causes inefficiency in unit bed-flow (0.5033 days). The dynamic policy performs at a level (0.4997 days) 8.3% below that of the shortest-processing-time in average waiting time; however, it balances this with greater patient equity (maximum waiting time could be shortened by 4 days compared to the current policy). Conclusions: Queuing theory and computer simulation can be used to model case flow through a cardiothoracic operating room and ICU. A dynamic admission policy that looks at current waiting time and expected ICU length of stay allows for increased equity between patients with only minimum losses of efficiency. This dynamic admission policy would seem to be a superior in maximizing case-flow. These results may be generalized to other surgical ICUs. (Crit Care Med 2013; 41:414–422)

This paper examines the use of price-commitment policies in dynamic contracting in multiple-period, finite-time horizons. Two specific forms of price commitment are considered: one on the part of the retailer through a retail-fixed-markup contract and one on the part of the manufacturer through a price-protection contract. Optimal policies for each form of price commitment are analytically derived, as are optimal policies for the traditional price-only and centralized supply chain scenarios that we use as comparisons. We prove that optimal retail price and order size solutions exist in each period under the assumption of non-increasing price-dependent demand. We show that the existence of retailer inventory between periods causes the optimal policies to differ from a static single-period model. Further, we show that a supplier offers a price-protection policy as a signal to the retailer to resolve the gaming that naturally occurs under price-only; this effectively decouples the multi-period dynamic contracting setting into repeated single-period scenarios. However, the resulting behavior can actually inhibit supply chain performance. On the retail commitment side, we find that retail-fixed-markup policies are quite effective in improving supply chain efficiency. We show that such policies can lead to Pareto-improvement over price-only contracts and can even coordinate the supply chain in some situations.

Sports is a rapidly growing application area for analytics. The use of analytics is pervasive in the professional sports community as evidenced by the increased role for those practicing sports analytics in front-office management and coaching. Part I of this Special Issue on Analytics in Sports is devoted to the application of a variety of methodologies to a broad range of sports. The papers analyze golf, hockey, baseball, motorcycle racing, and college football. The methodologies employed draw from many areas of analytics including optimization, probabilistic modeling, and choice models.

Human breast cancer cells (MCF-7, T-47-D and ZR-75-1) can adapt to circumvent any reduced growth rate during long-term oestrogen deprivation, and this provides three model systems to investigate mechanisms of endocrine resistance in breast cancer. In this paper we report consistent differences in the effects of three growth inhibitors following long-term oestrogen deprivation in all three cell models. Long-term oestrogen deprivation of MCF-7, T-47-D and ZR-75-1 cells resulted in reduced growth inhibition by PD98059 (2-10 μg/ml), implying a loss of dependence on mitogen-activated protein kinase pathways for growth. The growth inhibitor LY294002 (2-10 μM) inhibited growth of both oestrogen-maintained and oestrogen-deprived cells with similar dose-responses, implying continued similar dependence on phosphoinositide 3-kinase (PI3K) pathways with no alteration after adaptation to oestrogen independent growth. However, by contrast, long-term oestrogen deprivation resulted in an increased sensitivity to growth inhibition by rapamycin, which was not reduced by readdition of oestradiol. The enhanced inhibition of long-term oestrogen-deprived MCF-7-ED, T-47-D-ED and ZR-75-1-ED cell growth by combining rapamycin with LY294002 at concentrations where each alone had little effect, offers preclinical support to the development of therapeutic combinations of rapamycin analogues with other PI3K inhibitors in endocrine-resistant breast cancer.

We examine a situation in which a decision-maker executes a sequence of resource allocation decisions over time, but the availability of the indivisible resources at future epochs is uncertain due to actions of competitors. We cast this problem as a specialized type of stochastic knapsack problem in which the uncertainty of item (resource) availability is induced by competitors concurrently filling their own respective knapsacks. Utilizing a multi-period bounded multiple-choice knapsack framework, we introduce a general discrete stochastic optimization model that allows a nonlinear objective function, cardinality constraints, and a knapsack capacity constraint. Utilizing a set of greedy selection rules and agent-based modeling to simulate the competitors' actions, we solve the problem with a stochastic ruler approach that incorporates beam search to determine item selection of the types specified by the solution representation. We illustrate the computational effectiveness of our approach on instances motivated by a sports league draft as well as generic problem instances based on the knapsack literature.

The Help America Vote Act that Congress passed in 2002 required election boards to update their punch card voting systems with new voting technologies by 2006. This change greatly increases the operational and logistical complexities of administering elections in many areas. Because of security concerns and the large physical size of some types of new voting machines, they must be delivered to each polling location during a specified day and time window. Therefore, to generate feasible, cost-effective delivery routes, election boards must solve a difficult vehicle-routing problem. Routes designed by our solution methods have been successfully implemented in Hamilton County, Ohio, to deliver voting machines to polling locations for multiple elections since May 2006. We describe our solution methods and analyze the sensitivity of route costs to time-window and delivery-day constraints. Our sensitivity analysis identified cost-savings strategies that the Hamilton County Board of Elections used to negotiate a new scheduling protocol with poll workers; this protocol reflects a compromise between accommodating poll workers' schedules and reducing the cost of delivering the voting machines. The Board of Elections successfully implemented this new method of specifying delivery time windows, which allowed greater routing flexibility, for the November 2006 midterm election.

Transfreight, LLC, is a third-party logistics provider that supports Toyota Motor Manufacturing's operations in North America. As part of its logistical support, the company operates several crossdocks that facilitate Toyota's focus on lean manufacturing principles. In this paper, we describe our development of a mixed-integer linear program that provides optimal allocation of inbound trailers to docks at a crossdock facility. We focus on improving its operational efficiency and balancing the workload of the crossdock workers. We discuss Transfreight's successful implementation of our model for its inbound trailer assignments at its largest crossdock in Georgetown, Kentucky. Our work has provided Transfreight with significant cost savings and growth opportunities.

We examine periodic review supply chain models where order quantity and shipping frequency are both decision variables and decision-making rights are split between supply chain agents. We address two general questions: (1) when does decentralized decision making result in the greatest loss in supply chain performance; and (2) what effect does the distribution of channel power have on performance loss. We characterize optimal policies where possible in each scenario and we use numerical analysis to generate insights. We find that performance losses from decentralized control are somewhat limited in our results due to risk pooling and that the magnitude of performance loss is strongly influenced by the relative holding and penalty costs, but somewhat invariant to demand uncertainty. Furthermore, we find that concentrating channel power with the supplier can lead to supply chain profits that are very close to a centralized scenario, but also results in lower customer service levels.

We model a situation where a firm wishes to balance workload requirements by creating a portfolio of recurrent insourcing and outsourcing contracts. We use harmonic analysis to decompose an input workload profile into a portfolio of insourcing and outsourcing contracts using rectangular-wave basis functions to better achieve some desired constant workload level. However, this initial selection of contracts may result in impractical options. Therefore, we also develop mathematical programs using principles from goal programming and integer programming to refine the portfolio of contracts to more accurately reflect a realistic environment by placing constraints on the available contracts and explicitly considering operational costs. We consider several modeling extensions including the ability to hold limited amounts of inventory and the use of one-shot contracts to supplement our portfolio of recurrent contracts.

We investigate the operational decisions and resulting profits for a supply chain facing price-dependent demand under a policy where there is an ex-ante commitment made on the retail price markup. We obtain closed-form solutions for this policy under the assumption of a multiplicative demand function and we analytically compare its performance with that of a traditional price-only policy. We compare these results to results obtained when demand follows a linear additive form. These formulations are shown to be qualitatively different as the manufacturer’s wholesale pricing decision is independent of the retail price markup commitment in the multiplicative case, but not when demand is linear additive. We demonstrate that the ex-ante commitment can lead to Pareto-improving solutions under linear additive demand, but not under the multiplicative demand function. We also consider the effect of pricing power in the supply chain by varying who determines the retail price markup.

We consider the problem of routing a fleet of vehicles to pick up components from a network of suppliers and to deliver them to a fixed depot in a lean production system. The pursuit of low work-in-process inventory and production smoothing throughout the system introduces complicating side constraints, creating an enriched case of the vehicle routing problem with time windows and split deliveries. We present a two-phase routing and scheduling approach to address this problem. The routing phase consists of a nested tabu search heuristic that iterates between determining the suppliers' visit frequencies and developing vehicle routes. Given a routing plan, the scheduling phase determines the timing of supplier visits using a binary integer program designed to promote production leveling. Through computational testing on real-world data sets, we compare our solutions to those in the literature and those used by practitioners in the industry.

This paper describes the use of a supply chain management course to teach problem solving techniques to MBA students. An introduction to problem solving techniques and a step-by-step methodology are presented that can be used in supply chain management courses. We discuss two specific supply chain management cases and provide examples of how these cases can be used to illustrate steps in the problem solving methodology. We also describe how problem solving skills can be reinforced and assessed through case study write-ups. We conclude with some feedback from students who have taken this class.

We analyze decentralized supply chains that follow general continuous review (Q, R) inventory policies subject to vendor-managed inventory agreements where the supplier chooses the order quantity Q, and the retailer chooses the reorder point R. Within the VMI scenario, we explore the effect of divisions of channel power on supply chain and individual agent performance by examining different game theoretic models. Optimal policies and analytical results, including existence and uniqueness proofs for equilibrium solutions under VMI, are derived. Numerical results are provided to compare the effectiveness of VMI and to analyze different channel power relationships under a variety of environmental conditions. We find that VMI can result in considerable supply chain savings over traditional relationships and that the relative division of channel power can significantly effect the performance of VMI. Interestingly, we find that the greatest system benefits from VMI arise in asymmetric channel power relationships, but that individual agents lack the incentive to assume a leadership role.

We present a data-driven mathematical model of a key initiating step in platelet activation, a central process in the prevention of bleeding following Injury. In vascular disease, this process is activated inappropriately and causes thrombosis, heart attacks and stroke. The collagen receptor GPVI is the primary trigger for platelet activation at sites of injury. Understanding the complex molecular mechanisms initiated by this receptor is important for development of more effective antithrombotic medicines. In this work we developed a series of nonlinear ordinary differential equation models that are direct representations of biological hypotheses surrounding the initial steps in GPVI-stimulated signal transduction. At each stage model simulations were compared to our own quantitative, high-temporal experimental data that guides further experimental design, data collection and model refinement. Much is known about the linear forward reactions within platelet signalling pathways but knowledge of the roles of putative reverse reactions are poorly understood. An initial model, that includes a simple constitutively active phosphatase, was unable to explain experimental data. Model revisions, incorporating a complex pathway of interactions (and specifically the phosphatase TULA-2), provided a good description of the experimental data both based on observations of phosphorylation in samples from one donor and in those of a wider population. Our model was used to investigate the levels of proteins involved in regulating the pathway and the effect of low GPVI levels that have been associated with disease. Results indicate a clear separation in healthy and GPVI deficient states in respect of the signalling cascade dynamics associated with Syk tyrosine phosphorylation and activation. Our approach reveals the central importance of this negative feedback pathway that results in the temporal regulation of a specific class of protein tyrosine phosphatases in controlling the rate, and therefore extent, of GPVI-stimulated platelet activation., Author Summary Platelets are blood cells that, upon injury, trigger the blood to clot. Following blood vessel damage platelets encounter the extracellular matrix protein collagen to which they respond. They become activated, aggregating to form a major component of blood clots. The platelet collagen receptor GPVI stimulates platelet activation through a complex signalling pathway, and while many of the molecules involved in the activation of this pathway have been identified, their specific roles in determining the rate and extent of the exceptionally rapid platelet response have not been determined. Furthermore, while signalling proteins responsible for forward reactions are known, reverse or negative feedback elements are not well understood. Platelets also trigger thrombosis in diseased arteries, causing heart attacks and strokes, and therefore platelets, and particularly the GPVI signalling pathway, are therapeutic targets. To begin to understand the components in the GPVI signalling pathways that may represent tractable therapeutic targets we have developed a mathematical model of the key initiating events that occur upon stimulation of GPVI. In so doing, we have established the importance of a specific phosphatase-controlled negative feedback in determining the rate of initiation of platelet activation.

Objective— Ibrutinib is an irreversible Bruton tyrosine kinase inhibitor approved for treatment of Waldenstrom macroglobulinemia, chronic lymphocytic leukemia, and mantle cell lymphoma that increases the risk of bleeding among patients. Platelets from ibrutinib-treated patients exhibit deficiencies in collagen-evoked signaling in suspension; however, the significance of this observation and how it relates to bleeding risk is unclear, as platelets encounter immobile collagen in vivo. We sought to clarify the effects of ibrutinib on platelet function to better understand the mechanism underlying bleeding risk. Approach and Results— By comparing signaling in suspension and during adhesion to immobilized ligands, we found that the collagen signaling deficiency caused by ibrutinib is milder during adhesion to immobilized collagen. We also found that platelets in whole blood treated with ibrutinib adhered to collagen under arterial shear but formed unstable thrombi, suggesting that the collagen signaling deficiency caused by ibrutinib may not be the predominant cause of bleeding in vivo. However, clot retraction and signaling evoked by platelet adhesion to immobilized fibrinogen were also inhibited by ibrutinib, indicating that integrin α IIb β 3 outside-in signaling is also effected in addition to GPVI signaling. When ibrutinib was combined with the P2Y 12 inhibitor, cangrelor, thrombus formation under arterial shear was inhibited additively. Conclusions— These findings suggest that (1) ibrutinib causes GPVI and integrin α IIb β 3 platelet signaling deficiencies that result in formation of unstable thrombi and may contribute toward bleeding observed in vivo and (2) combining ibrutinib with P2Y 12 antagonists, which also inhibit thrombus stability, may have a detrimental effect on hemostasis.

The components of many signaling pathways have been identified and there is now a need to conduct quantitative data-rich temporal experiments for systems biology and modeling approaches to better understand pathway dynamics and regulation. Here we present a modified Western blotting method that allows the rapid and reproducible quantification and analysis of hundreds of data points per day on proteins and their phosphorylation state at individual sites. The approach is of particular use where samples show a high degree of sample-to-sample variability such as primary cells from multiple donors. We present a case study on the analysis of >800 phosphorylation data points from three phosphorylation sites in three signaling proteins over multiple time points from platelets isolated from ten donors, demonstrating the technique’s potential to determine kinetic and regulatory information from limited cell numbers and to investigate signaling variation within a population. We envisage the approach being of use in the analysis of many cellular processes such as signaling pathway dynamics to identify regulatory feedback loops and the investigation of potential drug/inhibitor responses, using primary cells and tissues, to generate information about how a cell’s physiological state changes over time.

We examine the behavior of a manufacturer and a retailer in a decentralized supply chain under price-dependent, stochastic demand. We model a retail fixed markup (RFM) policy, which can arise as a form of vertically restrictive pricing in a supply chain, and we examine its effect on supply chain performance. We prove the existence of the optimal pricing and replenishment policies when demand has a linear additive form and the distribution of the uncertainty component has a nondecreasing failure rate. We numerically compare the relative performance of RFM to a price-only contract and we find that RFM results in greater profit for the supply chain than the price-only contract in a variety of scenarios. We find that RFM can lead to Pareto-improving solutions where both the supplier and the retailer earn more profit than under a price-only contract. Finally, we compare RFM to a buyback contract and explore the implications of allowing the fixed markup parameter to be endogenous to the model. © 2006 Wiley Periodicals, Inc. Naval Research Logistics 53: 485-501, 2006.

The lipid products of phosphoinositide 3-kinase (PI3K) are involved in many cellular responses such as proliferation, migration, and survival. Disregulation of PI3K-activated pathways is implicated in different diseases including cancer and diabetes. Among the three classes of PI3Ks, class I is the best characterized, whereas class II has received increasing attention only recently and the precise role of these isoforms is unclear. Similarly, the role of phosphatidylinositol-3-phosphate (PtdIns-3-P) as an intracellular second messenger is only just beginning to be appreciated. Here, we show that lysophosphatidic acid (LPA) stimulates the production of PtdIns-3-P through activation of a class II PI3K (PI3K-C2β). Both PtdIns-3-P and PI3K-C2β are involved in LPA-mediated cell migration. This study is the first identification of PtdIns-3-P and PI3K-C2β as downstream effectors in LPA signaling and demonstration of an intracellular role for a class II PI3K. Defining this novel PI3K-C2β–PtdIns-3-P signaling pathway may help clarify the process of cell migration and may shed new light on PI3K-mediated intracellular events.

In this study we show that both glycogen synthase kinase 3 (GSK3) isoforms, GSK3α and GSK3β, are present in human platelets and are phosphorylated on Ser21 and Ser9, respectively, in platelets stimulated with collagen, convulxin and thrombin. Phosphorylation of GSK3α/β was dependent on phosphoinositide 3-kinase (PI3K) activity and independent of platelet aggregation, and correlated with a decrease in GSK3 activity that was preserved by pre-incubating platelets with PI3K inhibitor LY294002. Three structurally distinct GSK3 inhibitors, lithium, SB415286 and TDZD-8, were found to inhibit platelet aggregation. This implicates GSK3 as a potential regulator of platelet function.

[Figure][1] Phosphoinositide (PI) 3-kinase was first observed in 1984 as a minor inositol lipid kinase activity associated with immunoprecipitated oncogene products (e.g. Src, Abl and polyoma mT antigen) and present in activated growth factor receptor complexes (e.g. PDGF receptor). In 1988

Part II of this Special Issue on Analytics in Sports is devoted to sports scheduling applications. Sports scheduling has proven to be an exceptionally successful application area for operations research. The papers in this issue demonstrate the breadth of applications for sports scheduling. The sports addressed include baseball, volleyball, Canadian football, softball, and soccer. The sports leagues where scheduling methods are applied range from youth recreation leagues to multibillion-dollar professional leagues. In addition, the articles originate from five countries illustrating the international scope of sports scheduling applications.

This paper models a type of vendor-managed inventory (VMI) agreement that occurs in practice called a (z, Z) contract. We investigate the savings due to better coordination of production and delivery facilitated by such an agreement. The optimal behavior of both the supplier and the retailer are characterized. The optimal replenishment and production policies for a supplier are found to be up-to policies, which are shown to be easily computed by decoupling the periods when the supplier outsources from those when the supplier does not outsource. A simple application of the newsvendor relation is used to define the retailer's optimal policy. Numerical analysis is conducted to compare the performance of a single supplier and a single retailer operating under a (z, Z) VMI contract with the performance of those operating under traditional retailer-managed inventory (RMI) with information sharing. Our results verify some observations made in industry about VMI and show that the (z, Z) type of VMI agreement performs significantly better than RMI in many settings, but can perform worse in others.

The assessment of childhood depression is a function of the definition of depression, namely, a single-symptom, symptom cluster, or categorical approach. Furthermore, the assumptions associated with these approaches underpin the development and selection of assessment devices which fall into three main categories: self-report measures, parent, teacher and peer reports, and diagnostic clinical interviews. In describing, exemplifying, and evaluating these measurement techniques, their relationship with the definitional assumptions will be demonstrated through a critical review of the literature. The related and crucial issues of comorbidity and informant variability will also be examined.

Phosphoinositide (PI) 3-kinases have critical roles in diverse cellular signalling processes and in protein trafficking. This suggests that like other intracellular signalling molecules, e.g., phospholipase C and protein kinase C, there might be a large family of PI 3-kinase isoforms with the individual members having discrete signalling roles. Reverse transcription-polymerase chain reaction methods, using degenerate oligonucleotide primers against the lipid kinase consensus region, revealed eight sequences from human cDNA containing a high degree of identity to the family of PI 3-kinases. The sequences obtained included the previously described p110 alpha, p110 beta, and p110 gamma isoforms and HsVps34. Additionally, we have identified four novel sequences which are related to PI 3-kinases. Three of the novel sequences would appear to form a distinct sub-family of PI 3-kinases. We report the expression of these novel PI 3-kinases in human tissues and in cells derived from normal breast.

Phosphoinositide (PI) 3-kinases have been shown to have critical roles in signal transduction, cell transformation and intracellular protein trafficking. Reverse-transcription polymerase chain reaction methods, using degenerate primers derived from the lipid kinase consensus region, were utilised to identify PI 3-kinases in the normal human breast. Here we report the cDNA cloning of a novel human PI 3-kinase isoform, HsC2-PI3K. This PI 3-kinase is most closely related to the recently described C2 domain-containing family of PI 3-kinases which includes Drosophila PI3K_68D/cpk and murine cpk-m/p170. Sequence analysis suggests that HsC2-PI3K is a second distinct mammalian member of the C2 domain-containing PI 3-kinase family. Northern blot analysis of human tissues indicates that HsC2-PI3K is widely expressed. Fluorescence in situ hybridisation has mapped HsC2-PI3K to chromosome 1q32.

In this article, we describe several operational challenges posed by the recent introduction of new voting technologies such as direct-recording electronic and optical-scan voting machines. These new voting technologies significantly complicate the operational and logistical complexity of administering elections. Poor management of the operations associated with these new technologies can negatively impact the voting process by leading to delays in voting, inequitable treatment of voters, and even voter disenfranchisement. Operations-research (OR) methods have proven extremely effective at meeting these operational and logistical challenges. We explain how OR methods can be used to improve the overall voting process when utilizing new voting technologies to increase social welfare. Keywords: voting; elections; queueing; simulation; optimization

The Drosophila gene product Wingless (Wg) is a secreted glycoprotein and a member of the Wnt gene family. Genetic analysis of Drosophila epidermal development has defined a putative paracrine Wg signalling pathway involving the zeste-white 3/shaggy (zw3/sgg) gene product. Although putative components of Wg- (and by inference Wnt-) mediated signalling pathways have been identified by genetic analysis, the biochemical significance of most factors remains unproven. Here we show that in mouse 10T1/2 fibroblasts the activity of glycogen synthase kinase-3 (GSK-3), the murine homologue of Zw3/Sgg, is inactivated by Wg. This occurs through a signalling pathway that is distinct from insulin-mediated regulation of GSK-3 in that Wg signalling to GSK-3 is insensitive to wortmannin. Additionally, Wg-induced inactivation of GSK-3 is sensitive to both the protein kinase C (PKC) inhibitor Ro31-8220 and prolonged pre-treatment of 10T1/2 fibroblasts with phorbol ester. These findings provide the first biochemical evidence in support of the genetically defined pathway from Wg to Zw3/Sgg, and suggest a previously uncharacterized role for a PKC upstream of GSK-3/Zw3 during Wnt/Wg signal transduction.

We examine the question of whether or not momentum exists in an NFL football game. The concept of momentum is often cited by coaches, players, commentators and fans as a major factor in determining the outcome of the game and, consequently, in-game decision making. To examine the existence of momentum, we analyze particular game situations tied to what we consider to be “momentum-changing plays” (MCPs). These MCPs include fourth down conversions/stops, turnovers and scores allowed. We hypothesize that evidence of positive (negative) momentum would be characterized by increases (decreases) in yards gained, higher (lower) probability of converting a first down and greater (lesser) likelihood of scoring after a positive (negative) MCP. Our data set includes all plays from the 2002 to 2007 NFL seasons. We limit our analysis to game situations where the outcome of the game is still in doubt by removing plays that occur when a team is facing an insurmountable score differential. We use a pairwise matching comparison where we control for the game situations of home/away team, field position, time of game and score differential. We find little evidence for the existence of momentum in these events. Our results are in line with previous papers that find little empirical evidence of momentum in sports. While our findings cannot conclusively disprove the existence of momentum in the NFL, they further support the argument that momentum should not be a guiding factor for in-game decision making.

The regulatory (p85 alpha) and catalytic (p110 alpha) subunits of the mammalian phosphatidylinositol 3-kinase have been expressed in insect cells using the baculovirus sytem. The free catalytic subunit p110 alpha and the coexpressed heterodimeric complex of p85 alpha and p110 alpha were purified and their enzymological properties compared. While many kinetic parameters were similar, the coexpressed complex was found to have a 20-fold higher Km for ATP in comparison with the free catalytic subunit p110 alpha using phosphatidylinositol 4,5-bisphosphate as a substrate; no significant difference was detectable when phosphatidylinositol was used. Reconstitution of the p110 alpha.p85 alpha complex in vitro showed that it had the properties of the free p110 alpha and not the p110 alpha.p85 alpha in vivo complex. Therefore, a post-translational modification dependent upon the presence of the regulatory subunit p85 alpha rather than the physical subunit interaction itself is responsible for the observed properties of the lipid kinase activity of the p110 alpha.p85 alpha complex. Phosphatase treatment of the purified lipid kinase complex reduced the high Km for ATP, suggesting that a phosphorylation of the heterodimeric complex (p85 alpha.p110 alpha) caused this effect. This mode of regulation is discussed in the context of lipid kinase activation in vivo.

Phosphatidylinositol 3-kinase (PI 3-kinase) has a regulatory 85 kDa adaptor subunit whose SH2 domains bind phosphotyrosine in specific recognition motifs, and a catalytic 110 kDa subunit. Mutagenesis of the p110 subunit, within a sequence motif common to both protein and lipid kinases, demonstrates a novel intrinsic protein kinase activity which phosphorylates the p85 subunit on serine at a stoichiometry of approximately 1 mol of phosphate per mol of p85. This protein-serine kinase activity is detectable only upon high affinity binding of the p110 subunit with its unique substrate, the p85 subunit. Tryptic phosphopeptide mapping revealed that the same major peptide was phosphorylated in p85 alpha both in vivo in cultured cells and in the purified recombinant enzyme. N-terminal sequence and mass analyses were used to identify Ser608 as the major phosphorylation site on p85 alpha. Phosphorylation of the p85 subunit at this serine causes an 80% decrease in PI 3-kinase activity, which can subsequently be reversed upon treatment with protein phosphatase 2A. These results have implications for the role of inter-subunit serine phosphorylation in the regulation of the PI 3-kinase in vivo.

Vendor-managed inventory (VMI) programs transfer inventory control decisions from the retailer to the supplier. VMI programs rely on information sharing to transmit customer demand and current inventory information to the supplier. The supplier is then in charge of determining the timing and quantity of inventory deliveries to retailers. Most VMI programs contain an initiating contract that specifies elements of the agreement including performance metrics and payment terms. VMI programs have been shown to reduce supply chain costs through shipment consolidation and incentive alignment of decentralized supply chain agents. However, not all VMI programs result in supply chain savings. Even in those cases where VMI can result in system-wide savings, care must be taken to create agreements that are preferable to both suppliers and retailers. Keywords: vendor-managed inventory; VMI; supply chain; contract; retailer replenishment; shipment consolidation; information sharing