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Publications

Our faculty members have published widely in both clinical and operations research journals. The papers below either apply operations research to address a specific health care problem or discuss how a certain operations research methodolgy is applicable to a variety of health care settings.



2011-present

Huh, W.T., Janakiraman, G., Magarajan M. (forthcoming). Capacitated Multi-Echelon Inventory Systems: Policies & Bounds. Manufacturing & Service Operations Management. [Accepted on Jan. 25 2016]

"Walking in My Shoes: How Expectations of Role Reversal in Future Negotiations Impact Present Behaviors". Journal of Marketing Research. (2016) Co-Authors: M. Nagarajan R. Bagchi., H. Gurnani, N, Koukova

Hong, T., Huh, W.T., Kang, C., (forthcoming). Sourcing assemble-to-order inventores under supplier risk uncertainty. Omega. http://dx.doi.org/10.1016/j.omega.2015.06.011

Kocaman, A.S., Abad, C., Troy, T.J. Huh, W.T., Modi, V. (2016). A Stochastic Model for a Macroscale Hybrid Renewable Energy System. Renewable and Sustainable Energy Reviews, 54, 688-703. 

Kang, W., Kang, C., Hong, Y., Huh, W.T. (2015). Risk Propagation through a Platform: The Failure Risk Perspective on Platform Sharing. IEEE Transactions on Engineering Management, 62(3): 372-383

Ekeland, I., Queyranne, M. (to appear).  Optimal pits and optimal transportation. Mathematical Modelling and Numerical Analysis (accepted, April 2, 2015).

Skandari R, Shechter SM, Zalunardo N. Optimal vascular access choice for patients on hemodialysis. Manufacturing and Service Operations Management, 17(4): 608-619, 2015.

Sabouri A*, Shechter SM, Huh WT. Inspecting a vital component needed upon emergency. Production and Operations Management, 24(12): 1839-1851, 2015.

Shechter SM, Gocgun Y*, Ghassemi F*, Puterman ML. Trading off quick versus slow actions in optimal search. Operations Research, 63(2): 353-362, 2015.

Nagarajan M, Shechter S. Prospect theory and the newsvendor problem. Management Science, 60(4): 1057-1062, 2014.

Shechter SM, Skandari MR*, Zalunardo N. Timing of arteriovenous fistula creation in patients with chronic kidney disease: A decision analysis. American Journal of Kidney Diseases, 63(1): 95-103, 2014.

Chen, Jing, Anjali Awasthi, Steven Shechter, Derek Atkins, Linda Lemke, Les Fisher, Peter Dodek.  "Using Operations Research to Plan Improvement of the Transport of Critically ill Patients", J. Prehospital Emergency care, 2013, 17.4, 466-474.

Liping, Liang, Derek Atkins, "Designing Service Level Agreements for Inventory Management", Production and Operations Management 2013 (to appear). 


Huh WT, Liu N, Truong V. “Multiresource allocation scheduling in dynamic environments”. Manufacturing & Service Operations Management, (Forthcoming).

 Abstract

Motivated by service capacity-management problems in health care contexts, we consider a multi-resource allocation problem with two classes of jobs (elective and emergency) in a dynamic and non-stationary environment. Emergency jobs need to be served immediately, while elective jobs can wait. Distributional information about demand and resource availability is continually updated, and we allow jobs to renege. We prove that our formulation is convex, and the optimal amount of capacity reserved for emergency jobs in each period decreases with the number of elective jobs waiting for service. However, the optimal policy is difficult to compute exactly. We develop the idea of a limit policy starting at a particular time, and use this policy to obtain upper and lower bounds on the decisions of an optimal policy in each period, and also to develop several computationally-efficient policies. We show in computational experiments that our best policy performs within 1.8% of an optimal policy on average.

http://dx.doi.org/10.1287/msom.1120.0415


Regnier ED, Shechter S. “State-space size considerations for disease-progression models”. To appear in Statistics in Medicine.

 Abstract

Markov models of disease progression are widely used to model transitions in patients' health state over time. Usually, patients' health status may be classified according to a set of ordered health states. Modelers lump together similar health states into a finite and usually small, number of health states that form the basis of a Markov chain disease-progression model. This increases the number of observations used to estimate each parameter in the transition probability matrix. However, lumping together observably distinct health states also obscures distinctions among them and may reduce the predictive power of the model. Moreover, as we demonstrate, precision in estimating the model parameters does not necessarily improve as the number of states in the model declines. This paper explores the tradeoff between lumping error introduced by grouping distinct health states and sampling error that arises when there are insufficient patient data to precisely estimate the transition probability matrix.

http://dx.doi.org/10.1002/sim.5808


Dürr C, Queyranne M, Spieksma FCR, Talla Nobibon F, Woeginger GJ. “The interval ordering problem”. Discrete Applied Mathematics, 160(7-8): 1094-1103, 2012.

 Abstract

For a given set of intervals on the real line, we consider the problem of ordering the intervals with the goal of minimizing an objective function that depends on the exposed interval pieces (that is, the pieces that are not covered by earlier intervals in the ordering). This problem is motivated by an application in molecular biology that concerns the determination of the structure of the backbone of a protein. We present polynomial-time algorithms for several natural special cases of the problem that cover the situation where the interval boundaries are agreeably ordered and the situation where the interval set is laminar. Also the bottleneck variant of the problem is shown to be solvable in polynomial time. Finally we prove that the general problem is NP-hard, and that the existence of a constant-factor-approximation algorithm is unlikely.

http://dx.doi.org/10.1016/j.dam.2011.12.020


Begen MA, Levi R, Queyranne M. “A sampling-based approach to appointment scheduling”. Operations Research, 60(3): 675-681, 2012.

 Abstract

We consider the problem of appointment scheduling with discrete random durations but under the more realistic assumption that the duration probability distributions are not known and only a set of independent samples is available, e.g., historical data. For a given sequence of appointments (jobs, tasks), the goal is to determine the planned starting time of each appointment such that the expected total underage and overage costs due to the mismatch between allocated and realized durations is minimized. We use the convexity and subdifferential of the objective function of the appointment scheduling problem to determine bounds on the number of independent samples required to obtain a provably near-optimal solution with high probability.

http://dx.doi.org/10.1287/opre.1120.1053


Zhang Y, Puterman ML, Atkins D. “Residential long-term care capacity planning: The shortcomings of ratio based forecasts”. Healthcare Policy, 7(4): 68-81, 2012.

 Abstract

This paper uses observations from two British Columbia studies to illustrate the shortcomings of widely used ratio-based approaches for residential long-term care capacity planning. It shows that capacity plans based on a fixed ratio of beds per population over age 75 may result in either excess capacity or long wait times for admission. It then investigates the use of linear regression models to obtain a “best” ratio by relating optimal plans derived by rigorous analytical methods to population characteristics and shows that no single ratio applies broadly. While the use of regression is promising, finding these “best” ratios is too analytically complex for general practice. The paper concludes by providing and evaluating an easy-to-use planning method, which we call the average flow model (AFM). The AFM combines demand forecasts with length-of-stay estimates to produce enhanced capacity plans. The AFM is transparent, easily implemented in a spreadsheet and well suited for “what if?” analyses.

http://www.ncbi.nlm.nih.gov/pubmed/23634164


Zhang Y, Puterman ML, Nelson M, Atkins D. “A simulation optimization approach to long-term care capacity planning”. Operations Research, 60(2): 249-261, 2012.

 Abstract

This paper describes a methodology for setting long-term care capacity levels over a multi-year planning horizon, to achieve target wait time service levels. Our approach integrates demographic and survival analysis, discrete event simulation, and optimization. Based on this methodology, a decision support system was developed for use in practice. We illustrate this approach through two case studies: one for a regional health authority in British Columbia, Canada, and the other for a long-term care facility. We also compare our approach to the xed ratio approach used in practice and the SIPP (stationary, independent, period by period) approach developed in the call center literature. In addition, a state-dependent model and an adaptive system for capacity planning are considered to achieve better resource utilization. We conclude the paper with policy recommendations.

http://dx.doi.org/10.1287/opre.1110.1026


Noonan V, Santos A, Lewis R, Singh A, Fehlings M, Soril L, Dvorak M, Atkins D. “The application of operations research methodologies to the delivery of care model for traumatic spinal cord injury: The access to care and timing (ACT) project”. Journal of Neurotrauma, 29(13): 2272-2282, 2012.

 Abstract

The long-term impact of spinal cord injury (SCI) on the health care system imposes a need for greater efficiency in the use of resources and the management of care. The Access to Care and Timing (ACT) project was developed to model the health care delivery system in Canada for patients with traumatic SCI. Techniques from Operations Research, such as simulation modeling, were used to predict the impact of best practices and policy initiatives on outcomes related to both the system and patients. These methods have been used to solve similar problems in business and engineering and may offer a unique solution to the complexities encountered in SCI care delivery. Findings from various simulated scenarios, from the patients' point of injury to community re-integration, can be used to inform decisions on optimizing practice across the care continuum. This article describes specifically the methodology and implications of producing such simulations for the care of traumatic SCI in Canada. Future publications will report on specific practices pertaining to the access to specialized services and the timing of interventions evaluated using the ACT model. Results from this type of research will provide the evidence required to support clinical decision making, inform standards of care, and provide an opportunity to engage policymakers.

http://dx.doi.org/10.1089/neu.2012.2317


Atkins D, Noonan V, Santos A, Lewis R, Fehlings M, Burns A, Dvorak M. “Secondary complications in SCI across the continuum: Using operations research to predict the impact and optimize management strategies”. Topics in Spinal Cord and Injury Rehabilitation, 18(1): 57-60, 2012.

 Abstract

Secondary complications following traumatic spinal cord injury (tSCI) have a tremendous impact on quality of life and health care costs. Although some complications result from the injury itself, many originate from the care provided; complications arising early in the tSCI journey can predispose an individual to recurrence later. To measure the total impact of secondary complications on patient outcomes and health care costs, all the stages of care, from first response to life in the community, must be spanned. Interventions to ameliorate secondary complications need to consider the effects on the whole system and not just individual phases of care; however, such an approach is not common in the literature. To measure the impact of complications as well as the effect of proposed interventions, a partnership between clinical researchers and operations research professionals was formed to develop a discrete-event simulation model of the entire continuum of tSCI care. In this article, we focus on the part of the model concerning common secondary complications (eg, pressure ulcers, pneumonia). We first describe early results from the model, discuss how the effects from the complications impact care throughout the tSCI continuum, and review assumptions of the model. The article concludes with a discussion as to the possible uses of the model, their strengths/limitations, and future directions.

http://dx.doi.org/10.1310/sci1801-57


Sauré A, Patrick J, Tyldesley S, Puterman ML. “Dynamic multi-appointment patient scheduling for radiation therapy”. European Journal of Operational Research, 223(2): 573-584, 2012.

 Abstract

Seeking to reduce the potential impact of delays on radiation therapy cancer patients such as psychological distress, deterioration in quality of life and decreased cancer control and survival, and motivated by inefficiencies in the use of expensive resources, we undertook a study of scheduling practices at the British Columbia Cancer Agency (BCCA). As a result, we formulated and solved a discounted infinite-horizon Markov decision process for scheduling cancer treatments in radiation therapy units. The main purpose of this model is to identify good policies for allocating available treatment capacity to incoming demand, while reducing wait times in a cost-effective manner. We use an affine architecture to approximate the value function in our formulation and solve an equivalent linear programming model through column generation to obtain an approximate optimal policy for this problem. The benefits from the proposed method are evaluated by simulating its performance for a practical example based on data provided by the BCCA.

http://dx.doi.org/10.1016/j.ejor.2012.06.046


Saveh-Shemshaki F*, Shechter S, Tang P, Isaac-Renton J. “Setting sites for faster results: Optimizing locations and capacities of new tuberculosis testing laboratories”. IIE Transactions in Health Systems Engineering, 2(4): 248-258, 2012.

 Abstract

A reduced turnaround time to obtain initial test results for detecting the bacterial agent that causes tuberculosis (TB) can significantly improve the management of this communicable disease. We propose a new facility location modeling approach for designing a network of TB testing laboratories so as to reduce transportation times and thereby decrease overall test turnaround time. Our mathematical formulation chooses new laboratory facility locations, the capacities of those laboratories, as well as the assignment of TB samples to regional laboratories so as to minimize total sample transportation time, while considering constraints on the laboratory capacities, budget, and maximum transportation times between any origin and the testing laboratory. We ran the model using the TB testing demand and laboratory data for the TB reference laboratory in the Canadian province of British Columbia (BC), and demonstrate its potential to improve patient care and population health by optimizing the locations of additional testing laboratories. Furthermore, we explored data limitations and assumptions through several sensitivity analyses.

http://dx.doi.org/10.1080/19488300.2012.736119


Lowsky DJ, Ding Y, Lee DKK, McCulloch CE, Ross LF, Thistlethwaite JR, Zenios SA. “A K-nearest-neighbors survival probability prediction method”. Statistics in Medicine, 32(12): 2063-2069, 2012.

 Abstract

We introduce a nonparametric survival prediction method for right-censored data. The method generates a survival curve prediction by constructing a (weighted) Kaplan–Meier estimator using the outcomes of the K most similar training observations. Each observation has an associated set of covariates, and a metric on the covariate space is used to measure similarity between observations. We apply our method to a kidney transplantation data set to generate patient-specific distributions of graft survival and to a simulated data set in which the proportional hazards assumption is explicitly violated. We compare the performance of our method with the standard Cox model and the random survival forests method.

http://dx.doi.org/10.1002/sim.5673


Chow VS, Puterman ML, Huang K, Atkins D, Salehirad N. “Reducing surgical ward congestion through improved surgical scheduling and uncapacitated simulation”. Production Operations Management, 20(3): 418-430, 2011.

 Abstract

High surgical bed occupancy levels often result in heightened staff stress, frequent surgical cancellations and long surgical wait times. This congestion is in part attributable to surgical scheduling practices which often focus on the efficient use of operating rooms but ignore resulting downstream bed utilization. This paper describes a transparent and portable approach to improve scheduling practices which combines a Monte Carlo simulation model and a mixed integer optimization model. For any surgical schedule, the simulation samples from historical case records and predicts bed requirements assuming no resource constraints. The mixed integer optimization model compliments the simulation model by scheduling both surgeon blocks and patient types to reduce peak bed occupancies. Scheduling guidelines were developed from the optimized schedules to provide surgical planners with a simple and implementable alternative to the optimization model. This approach has been tested and delivered to planners at a health authority in British Columbia, Canada. The models have been used to propose new surgical schedules and to evaluate the impact of proposed system changes on ward congestion. Insights from the models are guiding future surgical schedule revisions.

http://dx.doi.org/10.1111/j.1937-5956.2011.01226.x


Soril L, Santos A, Noonan V, Lewis R, Singh A, Fehlings M, Atkins D, Dvorak M. “Modeling the processes of care for patients with traumatic SCI in British Columbia”. The Spine Journal, 11(10): S49, 2011.

 Abstract

A patient’s journey through the healthcare system is influenced by clinical and system processes which are integrated across the entire continuum of care. To optimize the access to care and patient flow for individuals with traumatic SCI (tSCI), factors that may govern the performance of healthcare delivery across the continuum of tSCI care must be empirically evaluated.

http://dx.doi.org/10.1016/j.spinee.2011.08.128


Begen M, Queyranne M. “Appointment scheduling with discrete random durations”. Mathematics of Operations Research, 36(2): 240-257, 2011.

 Abstract

We consider the problem of determining optimal appointment schedule for a given sequence of jobs (e.g., medical procedures) on a single processor (e.g., operating room, ex- amination facility), to minimize the expected total underage and overage costs when each job has a random processing duration given by a joint discrete probability distribution. Simple conditions on the cost rates imply that the objective function is submodular and L-convex. Then there exists an optimal appointment schedule which is integer and can be found in polynomial time. Our model can handle a given due date for the total processing (e.g., end of day for an operating room) after which overtime is incurred and, no-shows and emergencies.

http://dx.doi.org/10.1287/moor.1110.0489


2001-2010


Ayvaz N, Huh WT. “Allocation of hospital capacity to multiple types of patients”. Journal of Revenue and Pricing Management, 9(5): 386-398, 2010.

 Abstract

Allocation of a limited capacity of resources among several customer types is a critical decision encountered by many manufacturing and service firms. We tackle this problem by focusing on a hospital setting and formulate a general model that is applicable to various resource allocation problems of a hospital. To this end, we consider a system with multiple customer classes that display different reactions to the delays in service. By adopting a dynamic-programming approach, we show that the optimal policy for a system involving both lost sales and backorders is not simple but exhibits desirable monotonicity properties. Furthermore, we propose a simple threshold heuristic policy that performs well in our experiments.

http://dx.doi.org/10.1057/rpm.2010.30


Shechter SM. “Treatment evolution and new standards of care: Implications for cost-effectiveness analysis”. Medical Decision Making, 31(1): 35-42, 2010.

 Abstract

Background. Traditional approaches to cost-effectiveness analysis have not considered the downstream possibility of a new standard of care coming out of the research and development pipeline. However, the treatment landscape for patients may change significantly over the course of their lifetimes. Objective. To present a Markov modeling framework that incorporates the possibility of treatment evolution into the incremental cost-effectiveness ratio (ICER) that compares treatments available at the present time. Design. Markov model evaluated by matrix algebra. Measurements. The author evaluates the difference between the new and traditional ICER calculations for patients with chronic diseases facing a lifetime of treatment. Results. The bias of the traditional ICER calculation may be substantial, with further testing revealing that it may be either positive or negative depending on the model parameters. The author also performs probabilistic sensitivity analyses with respect to the possible timing of a new treatment discovery and notes the increase in the magnitude of the bias when the new treatment is likely to appear sooner rather than later. Limitations. The modeling framework is intended as a proof of concept and therefore makes simplifying assumptions such as time stationarity of model parameters and consideration of a single new drug discovery. Conclusions. For diseases with a more active research and development pipeline, the possibility of a new treatment paradigm may be at least as important to consider in sensitivity analysis as other parameters that are often considered.

http://dx.doi.org/10.1177/0272989X10364849


Shechter SM, Alagoz O, Roberts MS. “Irreversible treatment decisions under consideration of the research and development pipeline for new therapies”. IIE Transactions, 42(9): 632-642, 2010.

 Abstract

This paper addresses a topic not considered in previous models of patient treatment: the possible downstream availability of improved treatment options coming out of the medical research and development (R&D) pipeline. We provide clinical examples in which a patient may prefer to wait and take the chance that an improved therapy comes to market rather than choose an irreversible treatment option that has serious quality of life ramifications and would render future treatment discoveries meaningless for that patient. We then develop a Markov Decision Process model of the optimal time to initiate treatment, which incorporates uncertainty around the development of new therapies and their effects. After deriving structural properties for the model, we provide a numerical example that demonstrates how models that do not have any foresight of the R&D pipeline may result in optimal policies that differ from models that have such foresight, implying erroneous decisions in the former models. Our example quantifies the effects of such errors.

http://dx.doi.org/10.1080/07408170903468589

Santibáñez P, Chow V, French J, Puterman M, Tyldesley S. “Reducing patient wait times and improving resource utilization at British Columbia Cancer Agency’s ambulatory care unit through simulation”. Health Care Management Science, 12(4): 392-407, 2009.

 Abstract

We consider an ambulatory care unit (ACU) in a large cancer centre, where operational and resource utilization challenges led to overcrowding, excessive delays, and concerns regarding safety of critical patient care duties. We use simulation to analyze the simultaneous impact of operations, scheduling, and resource allocation on patient wait time, clinic overtime, and resource utilization. The impact of these factors has been studied before, but usually in isolation. Further, our model considers multiple clinics operating concurrently, and includes the extra burden of training residents and medical students during patient consults. Through scenario analyses we found that the best outcomes were obtained when not one but multiple changes were implemented simultaneously. We developed configurations that achieve a reduction of up to 70% in patient wait times and 25% in physical space requirements, with the same appointment volume. The key findings of the study are the importance of on time clinic start, the need for improved patient scheduling; and the potential improvements from allocating examination rooms flexibly and dynamically among individual clinics within each of the oncology programs. These findings are currently being evaluated for implementation by senior management.

http://dx.doi.org/10.1007/s10729-009-9103-1


Lavieri M, Puterman M. “Optimal nurse workforce planning”. Health Care Management Science, 12(2): 119-128, 2009.

 Abstract

This paper describes a linear programming hierarchical planning model that determines the optimal number of nurses to train, promote to management and recruit over a 20 year planning horizon to achieve specified workforce levels. Age dynamics attrition rates of the nursing workforce are key model components. The model was developed to help policy makers plan a sustainable nursing work force for British Columbia, Canada. An easy to use interface and considerable flexibility makes it ideal for scenario and “What-If” analyses.

http://dx.doi.org/10.1007/s10729-008-9097-0


Werker G, Sauré A, French J, Shechter S. “The use of discrete-event simulation modelling to improve radiation therapy planning processes”. Radiotherapy and Oncology, 92(1): 76-82, 2009.

 Abstract

The planning portion of the radiation therapy treatment process at the British Columbia Cancer Agency is efficient but nevertheless contains room for improvement. The purpose of this study is to show how a discrete-event simulation (DES) model can be used to represent this complex process and to suggest improvements that may reduce the planning time and ultimately reduce overall waiting times. BACKGROUND AND PURPOSE: A simulation model of the radiation therapy (RT) planning process was constructed using the Arena simulation software, representing the complexities of the system. Several types of inputs feed into the model; these inputs come from historical data, a staff survey, and interviews with planners. RESULTS: The simulation model was validated against historical data and then used to test various scenarios to identify and quantify potential improvements to the RT planning process. CONCLUSIONS: Simulation modelling is an attractive tool for describing complex systems, and can be used to identify improvements to the processes involved. It is possible to use this technique in the area of radiation therapy planning with the intent of reducing process times and subsequent delays for patient treatment. In this particular system, reducing the variability and length of oncologist-related delays contributes most to improving the planning time.

http://dx.doi.org/10.1016/j.radonc.2009.03.012


Lavieri M, Regan S, Ratner P, Puterman M. “Applying operations research to health human resource planning: A case study of registered nurse workforce planning in British Columbia”. Healthcare Policy, 4(2): 117-135, 2008.

 Abstract

The authors explore the power and flexibility of using an operations research methodology known as linear programming to support health human resources (HHR) planning. The model takes as input estimates of the future need for healthcare providers and, in contrast to simulation, compares all feasible strategies to identify a long-term plan for achieving a balance between supply and demand at the least cost to the system. The approach is illustrated by using it to plan the British Columbia registered nurse (RN) workforce over a 20-year horizon. The authors show how the model can be used for scenario analysis by investigating the impact of decreasing attrition from educational programs, changing RN-to-manager ratios in direct care and exploring how other changes might alter planning recommendations. In addition to HHR policy recommendations, their analysis also points to new research opportunities.

http://www.ncbi.nlm.nih.gov/pubmed/19377361/


Patrick J, Puterman ML, Queyranne M. “Dynamic multi-priority patient scheduling for a diagnostic resource”. Operations Research, 56(6): 1507-1525, 2008.

 Abstract

We present a method to dynamically schedule patients with different priorities to a diagnostic facility in a public health-care setting. Rather than maximizing revenue, the challenge facing the resource manager is to dynamically allocate available capacity to incoming demand to achieve wait-time targets in a cost-effective manner. We model the scheduling process as a Markov decision process. Because the state space is too large for a direct solution, we solve the equivalent linear program through approximate dynamic programming. For a broad range of cost parameter values, we present analytical results that give the form of the optimal linear value function approximation and the resulting policy. We investigate the practical implications and the quality of the policy through simulation.

http://dx.doi.org/10.1287/opre.1080.0590


Patrick J, Puterman M. “Reducing wait times through operations research: Optimizing the use of surge capacity”. Healthcare Policy, 3(3): 75-88, 2008.

 Abstract

Widespread public demand for improved access, political pressure for shorter wait times, a stretched workforce, an aging population and overutilized equipment and facilities challenge healthcare leaders to adopt new management approaches. This paper highlights the significant benefits that can be achieved by applying operations research (OR) methods to healthcare management. It shows how queuing theory provides managers with insights into the causes for excessive wait times and the relationship between wait times and capacity. It provides a case study of the use of several OR methods, including Markov decision processes, linear programming and simulation, to optimize the scheduling of patients with multiple priorities. The study shows that by applying this approach, wait time targets can be attained with the judicious use of surge capacity in the form of overtime. It concludes with some policy insights.

http://www.ncbi.nlm.nih.gov/pubmed/19305770/


Braithwaite RS, Roberts MS, Chang CCH, Goetz MB, Gilbert CL, Rodriguez-Barradas MC, Shechter S, Schaefer A, Nucifora K, Koppenhaver R, Justice AC. “Influence of alternative thresholds for initiating HIV treatment on quality-adjusted life expectancy: A decision model”. Annals of Internal Medicine, 148(3): 178-185, 2008.

 Abstract

Background: The optimal threshold for initiating HIV treatment is unclear. Objective: To compare different thresholds for initiating HIV treatment. Design: A validated computer simulation was used to weigh important harms from earlier initiation of antiretroviral therapy (toxicity, side effects, and resistance accumulation) against important benefits (decreased HIV-related mortality). Data sources: Veterans Aging Cohort Study (5742 HIV-infected patients and 11 484 matched uninfected controls) and published reports. Target population: Individuals with newly diagnosed chronic HIV infection and varying viral loads (10,000, 30,000, 100,000, and 300,000 copies/mL) and ages (30, 40, and 50 years). Time horizon: Unlimited. Perspective: Societal. Intervention: Alternative thresholds for initiating antiretroviral therapy (CD4 counts of 200, 350, and 500 cells/mm3). Outcome measures: Life-years and quality-adjusted life-years (QALYs). Results Of Base-Case Analysis: Although the simulation was biased against earlier treatment initiation because it used an upper-bound assumption for therapy-related toxicity, earlier treatment increased life expectancy and QALYs at age 30 years regardless of viral load (life expectancies with CD4 initiation thresholds of 500, 350, and 200 cells/mm3 were 18.2 years, 17.6 years, and 17.2 years, respectively, for a viral load of 10,000 copies/mL and 17.3 years, 15.9 years, and 14.5 years, respectively, for a viral load of 300,000 copies/mL), and increased life expectancies at age 40 years if viral loads were greater than 30 000 copies/mL (life expectancies were 12.5 years, 12.0 years, and 11.4 years, respectively, for a viral load of 300,000 copies/mL). Results of Sensitivity Analysis: Findings favoring early treatment were generally robust. Limitations: Results favoring later treatment may not be valid. The findings may not be generalizable to women. Conclusion: This simulation suggests that earlier initiation of combination antiretroviral therapy is often favored compared with current recommendations.

http://dx.doi.org/10.7326/0003-4819-148-3-200802050-00004


Shechter SM, Bailey MD, Schaefer AJ, Roberts MS. “The optimal time to initiate HIV therapy under ordered health states”. Operations Research, 56(1): 20-33, 2008.

 Abstract

The question of when to initiate HIV treatment is considered the most important question in HIV care today. Benefits of delaying therapy include avoiding the negative side effects and toxicities associated with the drugs, delaying selective pressures that induce the development of resistant strains of the virus, and preserving a limited number of treatment options. On the other hand, the risks of delayed therapy include the possibility of irreversible damage to the immune system, development of AIDS-related complications, and death. We use Markov decision processes to develop the first HIV optimization models that aim to maximize the expected lifetime or quality-adjusted lifetime of a patient. We prove conditions that establish structural properties of the optimal solution and compare them to our data and results. Model solutions, based on clinical data, support a strategy of treating HIV earlier in its course as opposed to recent trends toward treating it later.

http://dx.doi.org/10.1287/opre.1070.0480

Shechter SM, Bailey MD, Schaefer AJ. “A modeling framework for replacing medical therapies." IIE Transactions, 40(9): 861-869, 2008.

 Abstract

A common application of Markov Decision Processes (MDPs) is to determine when to replace machines that stochastically degrade over time. Typical assumptions are that there exists an infinite supply of identical replacements, each of which, upon installation, immediately renews the system to the best state, from which stochastic deterioration proceeds. This paper considers a situation for which these assumptions no longer apply: the replacement of medical therapies so as to maximize a patient's expected lifetime (or quality-adjusted lifetime). For example, upon taking HIV therapy, levels of the virus gradually decrease; however, viral resistance accrues over time, leading to an eventual increase of viral levels. This prompts a switch in therapy; however, there are only a finite number of effective therapies. A model is presented that addresses these challenges to a stationary MDP framework and a general algorithm for scheduling therapies is discussed.

http://dx.doi.org/10.1080/07408170802165898


 


Braithwaite RS, Conigliaro J, Roberts MS, Shecter S, Schaefer A, McGinnis K, Rodriguez MC, Rabenek L, Bryant K, Justic AC. Estimating the impact of alcohol consumption on survival for HIV+ individuals." AIDS Care, 19(4): 459-466, 2007.

 Abstract

Alcohol consumption is associated with decreased antiretroviral adherence, and decreased adherence results in poorer outcomes. However the magnitude of alcohol's impact on survival is unknown. Our objective was to use a calibrated and validated simulation of HIV disease to estimate the impact of alcohol on survival. We incorporated clinical data describing the temporal and dose-response relationships between alcohol consumption and adherence in a large observational cohort (N=2,702). Individuals were categorized as nondrinkers (no alcohol consumption), hazardous drinkers (consume > 5 standard drinks on drinking days), and nonhazardous drinkers (consume <5 standard drinks on drinking days). Our results showed that nonhazardous alcohol consumption decreased survival by more than 1 year if the frequency of consumption was once per week or greater, and by 3.3 years (from 21.7 years to 18.4 years) with daily consumption. Hazardous alcohol consumption decreased overall survival by more than 3 years if frequency of consumption was once per week or greater, and by 6.4 years (From 16.1 years to 9.7 years) with daily consumption. Our results suggest that alcohol is an underappreciated yet modifiable risk factor for poor survival among individuals with HIV. 

http://dx.doi.org/10.1080/09540120601095734


Braithwaite RS, Shecter S, Chang CCH, Schaefer A, Roberts MS. "Estimating the rate of accumulating drug resistance mutations in the HIV genome.Value in Health, 10(3): 204-213, 2007.

Abstract

HIV mutation accumulation has great implications for pharmacoeconomics and clinical care, yet scarcity of data has hindered its representation in decision analytic models. Our objective is to determine the accuracy with which mutation accumulation and other unmeasured parameters could be estimated during model calibration.

http://dx.doi.org/10.1111/j.1524-4733.2007.00170.x


Patrick J, Puterman M. “Improving resource utilization for diagnostic services through flexible inpatient scheduling”. Journal of the Operational Research Society, 58(2): 235-245, 2007.
 Abstract

We present a method to increase the utilization of and reduce the waiting times for an under-capacitated diagnostic resource in the presence of uncertain demand with several priority levels. We consider the case of a computed tomography (CT) scanning department that services both high-priority in-patients and lower priority outpatients. Current practice calls for all in-patient demand to be met on the day of the request. Our proposal looks at the benefit of reserving space for carrying over a percentage of non-emergency in-patient demand to the next day and utilizing a pool of on-call outpatients who can respond quickly to available capacity. We formulate and solve an optimization problem that returns a reservation policy that minimizes unused capacity subject to an overtime constraint. We use a simulation to demonstrate a significant reduction in the growth rate of outpatient waiting time resulting from using the proposed method and investigate the sensitivity of results to several model assumptions.

http://dx.doi.org/10.1057/palgrave.jors.2602242


Odegaard F, Chen L, Quee R, Puterman M. “Improving the efficiency of hospital porter services, Part 2: Schedule optimization and simulation model study objectives and results”. Journal for Healthcare Quality, 29(1): 12-18, 2007.

 Abstract

This article is the second of a 2-part series on a study of porter operations at Vancouver General Hospital, Vancouver, British Columbia, Canada. Part 1 describes the importance of efficient porter services, the system's operation at the time of the study, the challenges faced in carrying out the study, the performance measures developed, the recommendations, and the outcomes. Part 2 describes the simulation model that measured the impact of system changes and the linear programming model developed to improve porter schedules.

http://dx.doi.org/10.1111/j.1945-1474.2007.tb00170.x


Odegaard F, Chen L, Quee R, Puterman M. “Improving the efficiency of hospital porter services, Part 1: Study objectives and results”. Journal for Healthcare Quality, 29(1): 4-11, 2007.

Abstract

This article is the first of a 2-part series reporting the results of a 7-month study of porter operations at Vancouver General Hospital, Vancouver, British Columbia, Canada. Part 1 describes the importance of efficient porter services, the system's operation at the time of the study, the challenges faced in carrying out the study, the performance measures developed, the recommendations, and the outcomes. Part 2 describes the simulation model that measured the impact of system changes and the linear programming model developed to improve porter schedules.

http://dx.doi.org/10.1111/j.1945-1474.2007.tb00169.x

Braithwaite RS, Shecter S, Roberts MS, Schaefer A, Brangsberg DR, Harrigan PR, Justice AC. "Explaining variability in the relationship between antiretroviral adherence and HIV mutation accumulation." Journal of Antimicrobial Chemotherapy, 58: 1036-1043, 2006.

Abstract

Determining the relationship between antiretroviral adherence and resistance accumulation is important for the design and evaluation of adherence interventions. Our objective was to explain heterogeneity observed in this relationship.

http://dx.doi.org/10.1093/jac/dkl386


Shechter SM, Schaefer AJ, Braithwaite RS, Roberts MS. “Increasing the efficiency of Monte Carlo cohort simulations with variance reduction techniques.” Medical Decision Making, 26(5): 550-553, 2006.


Abstract

The authors discuss techniques for Monte Carlo (MC) cohort simulations that reduce the number of simulation replications required to achieve a given degree of precision for various output measures. known as variance reduction techniques, they are often used in industrial engineering and operations research models, but they are seldom used in medical models. However, most MC cohort simulations are well suited to the implementation of these techniques. The authors discuss the cost of implementation versus the benefit of reduced replications. 

http://dx.doi.org/10.1177/0272989X06290489



Shechter SM, Bryce CL, Alagoz O, Kreke JE, Stahl JE, Schaefer AJ, Angus DC, Roberts MS. “A clinically based discrete-event simulation of end-stage liver disease and the organ allocation process”. Medical Decision Making, 25(2): 199-209, 2005.


 Abstract

Background. The optimal allocation of scarce donor livers is a contentious health care issue requiring careful analysis. The objective of this article was to design a biologically based discrete-event simulation to test proposed changes in allocation policies. Methods. The authors used data from multiple sources to simulate end-stage liver disease and the complex allocation system. To validate the model, they compared simulation output with historical data. Results. Simulation outcomes were within 1% to 2% of actual results for measures such as new candidates, donated livers, and transplants by year. The model overestimated the yearly size of the waiting list by 5% in the last year of the simulation and the total number of pretransplant deaths by 10%. Conclusion. The authors created a discrete-event simulation model that represents the biology of end-stage liver disease and the health care organization of transplantation in the United States.

http://dx.doi.org/10.1177/0272989X04268956


Stahl JE, Kong N, Shechter SM, Schaefer AJ, Roberts MS. "A methodological framework for optimally reorganizing liver transplant regions." Medical Decision Making, 25(1): 35-46, 2005.

Abstract

Background. The United States is divided currently into 11 transplant regions, which vary in area and number of organ procurement organizations (OPOs). Region size affects organ travel time and organ viability at transplant. Purpose. To develop a methodologic framework for determining optimal configurations of regions maximizing transplant allocation efficiency and geographic parity. 

http://dx.doi.org/10.1177/0272989X04273137


Alagoz O, Bryce CL, Shechter S, Schaefer A, Chang CCH, Angus DC, Roberts MS. "Incorporating biological natural history in simulation models: Empirical estimates of the progression of end-stage liver disease.Medical Decision Making, 25(6): 620-632, 2005.

Abstract

To develop an empiric natural-history model that can predict quantitative changes in the values and clinical characteristics of patients with end-stage liver disease (ESLD), to be used to calibrate an individual microsimulation model. 

http://dx.doi.org/10.1177/0272989X05282719


Wang P, Puterman ML. “Analysis of longitudinal data of epileptic seizure counts – A two-state hidden Markov regression approach”. Biometrical Journal, 43(8): 941-962, 2001.


 Abstract

This paper discusses a two-state hidden Markov Poisson regression (MPR) model for analyzing longitudinal data of epileptic seizure counts, which allows for the rate of the Poisson process to depend on covariates through an exponential link function and to change according to the states of a two-state Markov chain with its transition probabilities associated with covariates through a logit link function. This paper also considers a two-state hidden Markov negative binomial regression (MNBR) model, as an alternative, by using the negative binomial instead of Poisson distribution in the proposed MPR model when there exists extra-Poisson variation conditional on the states of the Markov chain. The two proposed models in this paper relax the stationary requirement of the Markov chain, allow for overdispersion relative to the usual Poisson regression model and for correlation between repeated observations. The proposed methodology provides a plausible analysis for the longitudinal data of epileptic seizure counts, and the MNBR model fits the data much better than the MPR model. Maximum likelihood estimation using the EM and quasi-Newton algorithms is discussed. A Monte Carlo study for the proposed MPR model investigates the reliability of the estimation method, the choice of probabilities for the initial states of the Markov chain, and some finite sample behaviors of the maximum likelihood estimates, suggesting that (1) the estimation method is accurate and reliable as long as the total number of observations is reasonably large, and (2) the choice of probabilities for the initial states of the Markov process has little impact on the parameter estimates.

http://dx.doi.org/10.1002/1521-4036(200112)43:8<941::AID-BIMJ941>3.0.CO;2-#


1991-2000


Dear K, Dobson A, Puterman ML. "Estimated correlations from epidemiological data in the presence of measurement error". Statistics in Medicine, 16(19): 2177-2189, 1997.

 Abstract

Analysis of a major multi-site epidemiologic study of heart disease has required estimation of the pairwise correlation of several measurements across subpopulations. Because the measurements from each subpopulation were subject to sampling variability, the Pearson product moment estimator of these correlations produces biased estimates. This paper proposes a model that takes into account within and between sub-population variation, provides algorithms for obtaining maximum likelihood estimates of these correlations and discusses several approaches for obtaining interval estimates.

http://dx.doi.org/10.1002/(SICI)1097-0258(19971015)16:19<2177::AID-SIM646>3.0.CO;2-N


Cherukupalli K, Larson JE, Puterman ML. "Comparative biochemistry of gestational and postnatal lung growth and development in the rat and human". Pediatric Pulmonology, 24(1): 12-21, 1997.

 Abstract

We compared the ontogeny of collagen (hydroxyproline), elastin (desmosine), soluble protein, and DNA in the lungs of rate and humans during gestation and postnatal life. In humans, lung weight/body weight ratios declined faster during gestation than postnatally, whereas in rats lung weight/body weight ratio declined little during gestation and then suddenly on the first day of life. Lung weight/body weight ratios may be lower than expected around term in humans, and prediction data are given to assess human pulmonary hypoplasia. Rats and humans differed in water content of their lungs, with rats showing a sharper decline during gestation. In the human lung, collagen and elastin made their appearance at an early stage of gestation; elastin. In particular, increased rapidly during gestation, suggesting a role in intrauterine alveolar formation. In the rat, elastin accumulation is primarily a postnatal event, as is alveolar formation. Hydroxyproline concentrations increased with conceptual age and continued to increase rapidly postnatally between 4 and 7 weeks in the rat, but slowed in the human after 60 weeks of conceptual age. Desmosine concentrations level off at the end of the study period in rats, while these are still increasing, although slowly, in humans. Overall lung growth, as assessed by weight, was linear in humans, but phases of lung growth were apparent in the rat, including one of minimal growth in the immediate postnatal period.

http://dx.doi.org/10.1002/(SICI)1099-0496(199707)24:1<12::AID-PPUL3>3.0.CO;2-L


Rotschild A, Massoud EA, Puterman ML, Sekhon HS, Thurlbeck WM. "Development of the pulmonary airways in the fetal rat and its relationship to prenatal environment". Pediatric Pulmonology, 21(4): 219-226, 1996.

 Abstract

We studied the left lung using multi-focus microphotography in 378 rat fetuses, assessing airway branching from day 13 to day 19 of gestation, and lung growth variables from day 13 to day 21. Longitudinal growth, and monopodial and dichotomous branching brought about a consistent airway pattern with variations within each day of gestation and a small overlap between adjacent days. Amniotic fluid weight and pole to pole (PTP) distance of the lung increased quadratically with age, while fetal weight and the peripheral airway count (PAC) increased exponentially. The location of the fetus within the uterus had no effect on fetal variables, but correlations were found between maternal weight gain and both fetal weight and PTP. Fetal weight was the best predictor of PAC from gestational ages 15 to 19 days (P < 0.008). The method described allows for observations that are reproducible within the environmental variations present in normal gestation and can be used to study the effect of external factors on lung development.

http://dx.doi.org/10.1002/(SICI)1099-0496(199604)21:4<219::AID-PPUL3>3.0.CO;2-J


Ko CW, Lee J, Queyranne M. "An exact algorithm for maximum entropy sampling". Operations Research, 43(4): 684-691, 1995.

 Abstract

We study the experimental design problem of selecting a most informative subset, having prespecified size, from a set of correlated random variables. The problem arises in many applied domains, such as meteorology, environmental statistics, and statistical geology. In these applications, observations can be collected at different locations, and possibly, at different times. Information is measured by "entropy." In the Gaussian case, the problem is recast as that of maximizing the determinant of the covariance matrix of the chosen subset. We demonstrate that this problem is NP-hard. We establish an upper bound for the entropy, based on the eigenvalue interlacing property, and we incorporate this bound in a branch-and-bound algorithm for the exact solution of the problem. We present computational results for estimated covariance matrices that correspond to sets of environmental monitoring stations in the United States.

http://dx.doi.org/10.1287/opre.43.4.684


Speert DP, Puterman ML et. al. "A multicenter comparison of methods for typing strains of Pseudomona Aeruginosa predominantly from patients with Cystic Fibrosis". Journal of Infectious Diseases, 169(1): 134-142, 1994.

 Abstract

Typing methods in seven laboratories were compared for their ability to type reproducibly 200 strains of Pseudomonas aeruginosa, predominantly from patients with cystic fibrosis (CF). Methods included lipopolysaccharide (LPS) serotyping, phage susceptibility typing, bacteriocini production, pilin gene typing, and analysis by restriction fragment length polymorphism (RFLP) with a probe upstream from the exotoxin A gene. The methods differed substantially in their capacity to identify unique typing patterns and to type each strain reproducibly on three occasions. For strains from patients with CF, the RFLP typing method had the greatest discriminatory power (30 unique patterns, 105 [70%] of 150 typed reproducibly). LPS serotyping appeared to be equivalent to RFLP typing for discriminating among P. aeruginosa strains from the environment and from clinical sources other than CF patients. RFLP analysis appears to be the best method for typing P. aeruginosa strains with rough LPS (such as from patients with CF). LPS serotyping appears preferable for other indications as it is simpler to perform.

http://dx.doi.org/10.1093/infdis/169.1.134


Gribble MJ, Puterman ML. "Prophylaxis of urinary tract infection in persons with recent spinal cord injury: A prospective, randomized, double-blind, placebo-controlled study of Trimethoprim-Sulfamethoxazole". American Journal of Medicine, 95(2): 151- 162, 1993.

 Abstract

Purpose: To determine the efficacy of trimethopriin-sulfamethoxazole (TMP-SMX) for prophylaxis of urinary tract infection in persons with recent spinal cord injury, during the first 4 months of intermittent catheterization. Patients and methods: One hundred twenty nine adults (112 men, 17 women) with recent acute spinal cord injury participated in a randomized, double-blind, placebo-controlled trial, and were studied for up to 16 weeks. Low-dose TMP-SMX (TMP 40 mg, SMX 200 mg) or placebo was given once daily. Clinical observations, urine cultures, and cultures of rectal and urethral swabs were made weekly. Subjects who developed breakthrough bacteriuria received conventional antimicrobial therapy and prophylaxis was continued. Results: Sixty-six TMP-SMX recipients (57 men, 9 women) and 60 placebo recipients (52 men, 8 women) are evaluable for efficacy. Among male subjects, bacteriuria was present during 50% or more of study weeks in 30% of TMP-SMX recipients and in 56% of placebo recipients (p = 0.003). The interval to the onset of bacteriuria was prolonged in TMP-SMX recipients (p <0.0001). TMP-SMX recipients without bacteriuria in any given week had a lower probability of having bacteriuria the subsequent week (0.26) than did placebo recipients (0.49) (p <0.0001). At least 1 episode of definite symptomatic bacteriuria (bacteriuria and fever and at least 1 classical manifestation of urinary infection) occurred in 4 of 57 TMP-SMX-treated men and in 18 of 52 placebo-treated men (p <0.0003). We observed similar trends in women, but differences did not reach statistical significance, perhaps because the number of females was small. Adverse events suspected to be due to medications were frequent in this population of patients with recent severe injuries and led to discontinuation of the study in 10% of the TMPSMX group and 8% of the placebo group. Adverse events included neutropenia (TMP-SMX: two; placebo: three), pseudomembranous colitis (TMP-SMX: one), severe skin rash (TMP-SMX: two; placebo: one), and drug fever (TMP-SMX: one). The proportion of all episodes of bacteriuria that were due to TMP-SMX-resistant organisms was unexpectedly high in the placebo group (51%), and increased progressively according to year of enrollment in the study. By Year 3, all subjects in the placebo group had at least one episode of TMP-SMX-resistant bacteriuria. Gram-negative enteric bacilli resistant to TMP-SMX were recovered from rectal swabs (TMP-SMX 49%, placebo 42%) and urethral swabs (TMP-SMX 33%, placebo 26%) in similar proportions of subjects in the two study groups. Conclusions: Prophylaxis with TMP-SMX significantly reduces bacteriuria and symptomatic urinary tract infection in persons with recent acute spinal cord injury during bladder retraining using intermittent catheterization. However, adverse reactions attributable to TMP-SMX are common in this population. Colonization and breakthrough bacteriuria with TMP-SMX-resistant organisms are frequent and may seriously limit the usefulness of this strategy, particularly in an institutional setting.

http://dx.doi.org/10.1016/0002-9343(93)90254-M


Massoud EA, Sekhon HS, Rotschild A, Puterman ML, Matsui R, Thurlbeck WM. "In vitro branching morphogenesis of the fetal rat lung". Pediatric Pulmonology, 15(2): 89-97, 1993.

 Abstract

We studied the pattern of airways branching in the fetal rat lung in vitro. Lung primordia of gestational ages 13, 14, and 15 days were allowed to grow in culture to a gestational age equivalent to 21 days. The first generation airways appear by a single new bud (monopodial budding) from the left main airway (lateral appearing before the medial). They elongate to form branches and then bud dichotomously (2 buds occurring simultaneously and adjacent to each other) at their tips. Then monopodial branching takes place along their sides. The same cycle of budding and branching seems to be repeated for the following generation of the airways. The total number of the peripheral (subpleural) buds was greatest in the day 15 explants and least in day 13 explants throughout the whole culture period, but the statistical model used indicated faster budding in the 13 day explants. Morphometric assessment showed no difference in the ratios between the lung components in the 3 age groups and that the peripheral epithelial measurements were the same in the 3 groups at an equivalent gestational age of 21 days. We have also shown that lobes do not form in the right lung, although appropriate airways do. This may indicate the importance of mesothelial covering of the lung in the process of lobe formation. The method is useful for studying the control of lung morphogenesis.

http://dx.doi.org/10.1002/ppul.1950150205


Sandor GS, Puterman ML, Rogers P, Chan KW, Pritchard S, Popov R. "Early prediction of anthracycline cardionyapthy using standard M-mode and digitized echocardiography". American Journal of Pediatric Hematology/Oncology, 14(2): 151-157, 1992.

 Abstract

In this study, we attempted to identify echocardiographic findings that can be used as early predictors of left ventricular dysfunction due to anthracyclines in 26 pediatric oncology patients. Retrospective review identified six patients (group 1 mean anthracycline dose = 337 +/- 123 mg/m2) who developed clinical evidence of cardiomyopathy and 20 consecutive patients followed prospectively (group 2 mean anthracycline dose = 298 +/- 102 mg/m2) who did not. All of the patients had serial m-mode echocardiography before and at approximately every 50 mg/ m2 of anthracycline treatment depending on the dosage schedule. The following measurements were recorded: left ventricular dimensions and wall thickness, indices of left ventricular function, including systolic time intervals, shortening fraction, and ejection fraction. Using digitized echocardiography, the following parameters were recorded: peak and normalized systolic and diastolic velocities of the left ventricular chamber, posterior and septal wall velocities, and percent of posterior wall thickening. Variations from established normal longitudinal bounds and actual changes from pre-anthracycline values were compared for the two groups throughout the course of therapy. At 70 mg/m2 of anthracycline, group 1 showed significant deterioration in shortening fraction (mean change = 8.8 versus 2.5, p = .03), left ventricular velocity in diastole (2.9 versus 0.21, p = .04), left ventricular normalized velocity in systole (.65 versus 0.03, p = .02), and left ventricular normalized velocity in diastole (1.15 versus 0.002, p = .04) compared to group 2. These values were mostly compensated by 125 mg/m2, but they slowly deteriorated again at higher doses of anthracycline, leading to the appearance of clinical evidence of cardiomyopathy. These early changes were 100%, 75%, 75%, 100% sensitive; 82%, 91%, 91%, 73% specific for subsequent cardiomyopathy; and had a predictive accuracy of 67%, 75%, 75%, 57%, respectively. Thus, a transient early deterioration in left ventricular function may be a sensitive predictor of subsequent clinical manifestations of anthracycline cardiotoxicity. This change in left ventricular function may be detected by standard m-mode echocardiography as easily as with digitized echocardiography.

http://www.ncbi.nlm.nih.gov/pubmed/1530119


Rotschild A, Chitiyat D, Puterman ML, Phang MS, Ling E, Baldwin V. "Optimal positioning of endotracheal tubes for ventilation of preterm infants". American Journal of Diseases of Children, 145(9): 1007-1012, 1991.

 Abstract

Accurate knowledge of upper-airway dimensions is required to prevent malpositioning of endotracheal tubes in preterm infants. We measured vocal cord—carina, oralcarina, and nasal-carina distances in situ at autopsy of two groups of infants (<1000 and ≥1000 g). In all 24 infants, crown-heel length, crown-rump length, and occipitofrontal circumference were better than weight in predicting upper-airway dimensions. Flexion of the neck decreased and extension increased both nasal-carina and oral-carina distances. Lateral rotation produced no significant changes. The postmortem data were not different from nasal-carina distances measured radiologically in 40 living, nasally intubated and ventilated infants, confirming the clinical validity of our findings. Regression equations were derived to predict optimal endotracheal tube lengths based on the external measurements of crown-rump length and crown-heel length.

http://dx.doi.org/10.1001/archpedi.1991.02160090059023


1981-1990


Puterman ML, Schumacher P, Sandor GSS. "Optimal choice of prognostic variables with an application to cardiac monitoring using M-mode echocardiography". Statistics in Medicine, 9(3): 273-286, 1990.

 Abstract

This paper provides a methodology for the optimal choice of a subset from a large number of interrelated diagnostic variables. We use predetermined abnormal ranges for each measurement and code subjects as abnormal or normal on this basis. We present a procedure to determine the smallest subset of measurements that identifies any subject abnormal on at least one measurement. We formulate and solve the problem using integer programming. We then apply this methodology to study the use of M-mode echocardiography to determine potentially cardiotoxic side effects of chemotherapy and compare its performance to several multivariate methods. Extensions and modifications are discussed.

http://dx.doi.org/10.1002/sim.4780090310


Rotschild A, Ling E, Puterman ML, Farquharson D. "Neonatal outcome of prolonged rupture of membranes". American Journal of Obstetrics and Gynaecology, 162(1): 46-52, 1989.

 Abstract

Pulmonary hypoplasia was diagnosed in 14 of 88 infants (16%) delivered in 1983 to 1986 after rupture of the membranes of >= 7 days with onset before 29 weeks' gestation. Logistic regression analysis applied to examine the relative importance of perinatal risk factors in the prediction of pulmonary hypoplasia showed that gestational age at onset of rupture of the membranes had a significant effect (p = 0.002) on the odds that pulmonary hypoplasia developed in the neonate, whereas the duration of rupture of the membranes (p = 0.11) and the degree of oligohydramnios (p = 0.65) did not. Postnatally, the presence of pulmonary hypoplasia was associated with the severity of skeletal compression deformities (p > 0.0001). The development of skeletal compression deformities was associated with severe oligohydramnios (p = 0.05) and duration of rupture of the membranes (p = 0.02) but not gestational age at rupture of the membranes (p = 0.77). Gestational age at onset of rupture of the membranes being the best single predictor of pulmonary hypoplasia suggests that the stage of lung development at rupture of the membranes may be important.

http://dx.doi.org/10.1016/0002-9378(90)90818-R


Tingle AJ, Pot KH, Yong FP, Puterman ML, Hancock EJ. "Kinetics of isotype-specific humoral immunity in Rubella vaccine-associated arthropathy". Clinical Immunology and Immunopathology, 53(2): S99-S106, 1989.

 Abstract

The present study documents the relationship between the development of rubella vaccine-associated arthropathy and isotype-specific rubella antibody responses in a prospectively studied population of 44 adult rubella hemagglutination inhibition (HAI) seronegative females undergoing rubella immunization. Rubella-specific IgM, IgG, and IgA antibody responses were evaluated prior to and at 1, 2, 3, 4, 5, 6, 12, and 24 weeks postvaccine. Detectable preimmunization rubella antibody of the IgG or IgA class was present using ELISA techniques in 6 of 6 individuals developing acute arthritis, 13 of 17 developing acute arthralgia, and in 15 of 21 with no joint manifestations postvaccine. Significantly elevated HAI IgM responses were noted 3 and 4 weeks postvaccine in the acute arthritis group but no significant differences were found in IgG and IgA rubella antibody levels postvaccine in relation to the presence or absence of joint manifestations at any time period postvaccine. The data support rubella reinfection as an important feature of rubella vaccine-associated arthropathy but do not support a role for quantitative differences in rubella IgG and IgA antibody in the pathogenesis of this syndrome.

http://dx.doi.org/10.1016/0090-1229(89)90075-5


Hrboticky N, MacKinnon MJ, Puterman ML, Innis SM. "Effect of a linoleic acid rich vegetable oil ‘infant‘ formula on brain synaptosomal lipid accretion and enzyme thermotropic behavior in the newborn piglet". Journal of Lipid Research, 30(8): 1173-1184, 1989.

 Abstract

The effects of a vegetable oil-based infant formula, virtually devoid of n-6 and n-3 long chain polyenoid fatty acids (LCP) and high in 18:2(n-6) and 18:2(n-6)/18:3(n-3) ratio, on brain synaptosome lipid composition and enzyme thermotropic behavior were studied in neonatal piglets. Term gestation piglets were fed either sow milk (SMF) or formula (FF) from birth for 5, 10, 15, or 25 days. Synaptosomal cholesterol, total lipid phosphorus, and phospholipid class composition did not differ between SMF and FF piglets. Synaptosomal fatty acid composition, however, was influenced by diet. The proportion of n-3 LCP, especially 22:6(n-3), was decreased, while the n-6 LCP, especially 22:4(n-6) and 22:5(n-6), were increased in FF compared to SMF piglets. These diet-related changes were most pronounced in the ethanolamine glycerophospholipid fraction and increased with the duration of feeding. FF thus reversed an apparent developmental increase in the synaptosomal n-3/n-6 LCP ratio. The monoenei content, especially 18:1, was also reduced in the synaptosomes of FF compared to SMF pigs. FF had no effect on the activity of synaptosomal acetylcholinesterase. However, higher transition temperatures for this enzyme, indicating decreased membrane fluidity, were found in the FF compared to SMF piglets. The data suggest that exclusive feeding of proprietary formulae, devoid of LCP and high in 18:2(n-6) and/or the 18:2 (n-6)/18:3(n-3) ratio, may compromise normal fatty acid accretion and physical properties of brain synaptosomal membranes.

http://www.ncbi.nlm.nih.gov/pubmed/2769072


Lokitch G, Puterman ML, Godolphin WJ, Sheps S, Tingle AJ, Quigley G. "Infection and immunity in Down Syndrome: A trial of long term low dose oral zinc". Journal of Pediatrics, 114(5): 781 787, 1989.

 Abstract

To determine whether orally administered zinc supplements could correct the abnormal humoral and cell-mediated immunity of Down syndrome, we randomly assigned 64 children with Down syndrome, aged 1 to 19 years and living at home, to receive either zinc gluconate or placebo daily for 6-month periods with crossover from one regimen to another. Control subjects were siblings and age-matched, unrelated children. Serum zinc, copper, and measures of immune system competence were tested at 3- or 6-month intervals. Parents kept daily logs of clinical symptoms such as cough and diarrhea and of physician visits. Mean serum zinc concentrations increased to about 150% of baseline during zinc supplementation, but we found no effect on serum levels of copper, immunoglobulins, or complement; on lymphocyte number or subset distribution; or on in vitro response to mitogens. Children with Down syndrome who were receiving zinc had a trend toward fewer days or episodes of cough and fever but no change in other clinical variables. Long-term, low-dose oral zinc supplementation to improve depressed immune response or to decrease infections in children with Down syndrome cannot be recommended.

http://dx.doi.org/10.1016/S0022-3476(89)80136-2


Magil AB, Puterman ML, Ballow MS, Chan V, Lirenman DS, Rae A, Sutton RAL. "Prognostic factors in diffuse proliferative lupus glomerulonehritus". Kidney International, 34(4): 511 517, 1988.

 Abstract

Prognostic factors in diffuse proliferative lupus glomerulonephritis. A number of clinical laboratory and biopsy-derived parameters were assessed for their prognostic significance in the short (24 months), intermediate (60 months) and long terms in 45 patients (43 female, 2 male) with diffuse proliferative lupus glomerulonephritis (DPGN). The factors evaluated were serum creatinine (SCr) and urinary protein at time of biopsy, initial dose of prednisone and immunosuppressive after biopsy, activity index (AI), chronicity index (CI), their individual components, extent of extraglomerular (tubulo-interstitial) immune deposits (EGD) and mean number of intraglomerular monocytes per glomerulus (NSE index). Using proportional hazards analysis to evaluate the parameters, SCr (P = 0.003), AI (P = 0.005) and NSE index (P = 0.038) were shown to be significant predictors of outcome when all variables except the components of AI and CI were considered. When AI and CI were omitted but their components included, SCr (P = 0.0005), NSE index (P = 0.024), extent of karyorrhexis (P = 0.035) and glomerulosclerosis (P = 0.033) were then demonstrated to be significant prognostic factors of DPGN. The results suggest that intraglomerular monocyte infiltration has a protective effect and confirm that AI index is a relatively powerful predictor of outcome. Histologic and nonhistologic biopsy factors contribute significant additional prognostic information to that provided by Scr.

http://dx.doi.org/10.1038/ki.1988.211


Thomas EE, Puterman ML, Kawano E, Curran M. "Evaluation of immunoassays for the detection of Rotavirus in stool samples from a pediatric population". Journal of Clinical Microbiology, 26(6): 1189 1193, 1988.

 Abstract

The performance of seven commercially manufactured rotavirus assays was evaluated with 144 pediatric stool specimens and compared with electron microscopy (EM) findings. The four enzyme-linked immunosorbent assays used were Rotazyme Il, Pathfinder, IDL rotavirus immunoassay, and Enzygnost (Behring) rotavirus assay. The three latex tests were Meritec rotavirus detection test, Virogen Rotatest, and Bartels rotavirus latex test. Test outcomes were compared with EM on the basis of sensitivity, specificity, positive negative predictive value, and the kappa statistic. Relative to EM, Meritec had the highest specificity (97%), followed by Virogen (95%), IDL (91%), Pathfinder (85%), Behring (81%), Bartels (72%), and Rotazyme (71%). The sensitivities were as follows: Rotazyme (92%), Pathfinder (89%), Bartels (86%), Virogen (86%), Behring (82%), Meritec (71%), and IDL (75%). Patient age and sex did not influence test results. Owing to the absence of a true standard, the tests were also compared with each other on the basis of the kappa statistic, the frequency of positive test results, and the frequency of samples in which a test differed from all other tests. Using these measures, the assays could be classified into three groups with progressively decreasing utility: group 1 (Virogen, Meritec, IDL, and EM), group 2 (Pathfinder and Behring), and group 3 (Rotazyme and Bartels). Laboratory criteria were also compared. Latex tests were faster and required less equipment than enzyme-linked immunosorbent assays. The Virogen latex assay showed the best overall performance, which made it our choice for rapid and accurate rotavirus diagnosis. However, in children who have gastrointestinal symptoms with negative rotavirus test results, EM will be useful until such time as immunological tests for other enteric viruses are available.

http://www.ncbi.nlm.nih.gov/pubmed/2838516/


Lokitch G, Singh V, Puterman ML, Godolphin WJ, Sheps S, Tingle AJ, Wong J, Quigley G. "Age related changes in humoral and cell mediated immunity in Down syndrome children living at home". Pediatric Research, 22(5): 536 540, 1987.

 Abstract

Abnormalities of humoral and cell-mediated immunity have been described in Down syndrome but reported findings have been inconsistent. Confounding factors have included age, institutional versus home life, hepatitis B antigenemia, and zinc deficiency. To clarify this problem, we studied 64 children with Down syndrome (DS) compared with an age-matched control group. All children had always lived at home. All the DS children were negative for hepatitis B surface antigen. Serum zinc concentration in the DS group was on average 12 micrograms/dl lower than age-matched control children. They also had significantly lower levels of immunoglobulin M, total lymphocyte count, T and B lymphocytes, and T helper and suppressor cells. In vitro lymphocyte response to phytohemagglutinin and concanavalin A was significantly reduced at all ages in the DS group. Lymphocyte response to pokeweed mitogen increased with age in control children but decreased in the DS children. By 18 year, the mean response for DS was 60000 cpm lower than controls. The DS group had significantly higher concentrations of immunoglobulins A and G than controls and the difference increased with age. Complement fractions C3 and C4 were also higher in the DS group at all ages. The number of HNK-1 positive cells was higher in the DS group than controls at all ages. When hepatitis and institutionalization are excluded as confounding factors, DS children still differ in both humoral and cell-mediated immunity from an age-matched control group.

http://dx.doi.org/10.1203/00006450-198711000-00013


Sandor G, Schumacher P, Puterman ML, Popov R. "Normal serial variability for M mode and digitized echocardiography in a paediatric population". Paediatric Cardiology, 8(1): 23 26, 1987.

 Abstract

The normal serial variability of M-mode and digitized echocardiography was assessed in 18 healthy children aged 3-16 years. M-mode echocardiograms were done one month apart in each child and two sets of three beats were analyzed twice for each month's tracing. Ejection fraction and shortening fraction were obtained in the standard manner and the tracing digitized and analyzed for peak and normalized left ventricular velocities, and for posterior wall and septal wall velocities in systole and diastole. The component variabilities were determined by a univariate four-factor hierarchical variance components analysis and the sum of these variability limits established. Standard M-mode echocardiographic measurements of shortening fraction and ejection fraction (15% and 10% of mean) were the least variable. Peak and normalized velocities were more variable with left ventricular velocities (18%-29% of mean), posterior wall velocities (26%-45% of mean) and septal velocities (38%-68% of mean) showing increasing variabilities. Thus there is less variability in M-mode echocardiography than digitized echocardiography. The normal limits of variability are established and should be used for follow-up studies.

http://dx.doi.org/10.1007/BF02308380


Hancock EJ, Pot K, Puterman ML, Tingle AJ. "Dissociation between Rubella HAI Titers and whole virus ELISA values in congenital Rubella syndrome". The Journal of Infectious Diseases, 154(6): 1031 1033, 1986.

 Abstract

Current rubella serological assays detect antibody to rubella virus HA antigens by using HAl assays, passive HA assays, single radial hemolysis, or ELISAs[I, 2]. However, recent studies [3-6] have established that the rubella virus virion contains three structural proteins: two envelope glycoproteins(E, and E2) and a nonglycosylated nucleocapsid protein (NC). E1 is believed to contain the principal HA activity [3, 4, 6]. Assays detecting only antibody to E1 (HA) antigenic determinants will therefore miss potentially abnormal patterns of antibody reactivity directed against the other major structural viral proteins of rubella virus (E2 and NC) [7]. Previous studies have characterized the development ofrubella virus ELISA techniques that use whole rubella virions as target antigens [8, 9] and have the capability of detecting antibody to all three structural proteins of rubella virus. Using this assay, we have carried out preliminary studies examining the relation between titers of HAl antibody to rubella virus and levels of antibody to whole rubella virus (as measured by ELISA) in sera obtained from randomly selected adult controls and from patients after immunization with RA27/3 rubella vaccine, wild rubella infection, or congenital rubella infection.

http://dx.doi.org/10.1093/infdis/154.6.1031


Petty RE, Hunt DWC, Rollins DF, Schroeder ML, Puterman ML. "Immunity to soluble retinal antigen in patients with uveitis accompanying juvenile rheumatoid arthritis". Arthritis and Rheumatism, 30(3): 287 293, 1987.

 Abstract

Studies of immunity to bovine soluble retinal antigen (antigen S) were carried out using serum and peripheral blood lymphocytes from children with juvenile rheumatoid arthritis and chronic anterior uveitis (JRA-uveitis), children with JRA alone, children with nonrheumatic diseases, and controls who had no ocular or rheumatic disease. Enzyme-linked immunosorbent assay and the lymphocyte transformation assay were used to determine immunity. Antibody to antigen S was present significantly more frequently in children with JRA-uveitis than in children with JRA alone, children with nonrheumatic disorders, or controls. These latter groups did not differ in positivity for this antibody. Lymphocyte transformation occurred more frequently in children with JRA-uveitis than in children with JRA alone or controls. Children with JRA alone and controls had similar frequencies of lymphocyte transformation positivity. Enzyme-linked immunosorbent assay positivity and lymphocyte transformation positivity tended to occur in different children. Children with JRA-uveitis who had HLA-B35 had the highest frequency of antibody to antigen S. Immunity to antigen S may be the result of ocular damage by mechanisms other than a pathogenic mechanism per se.

http://dx.doi.org/10.1002/art.1780300307


Junker A, Clark EA, Ochs HD, Puterman ML, Wedgewood RJ. "Transient immune deficiency in patients with acute Epstein-Barr virus infection". Journal of Immunology and Immunopathology, 40(3): 436 446, 1986.

 Abstract

To study the effect of primary Epstein-Barr virus (EBV) infection on antigen-specific antibody production, we immunized 17 college students who had developed acute infectious mononucleosis with the T-cell dependent neoantigen bacteriophage φX174. During the early phase of infectious mononucleosis, the proportion of peripheral blood lymphocytes displaying la and T8 (CD8) phenotypes was increased and the T helper/suppressor ratio was decreased (<1). These abnormalities disappeared during the convalescent phase. Correlating with EBV-induced changes in T lymphocytes, we demonstrated depressed humoral immune responses to bacteriophage φX174 both in vivo and in vitro, In vitro coculture experiments indicated that the la+ suppressor T cells could inhibit antibody production and isotype switch. Removal of T8+lymphocytes from patient T cells normalized in vitro antibody synthesis. In addition, impaired B-cell function was shown to be in part responsible for deficient antibody production. These studies demonstrate that infection with EBV affects both B and T lymphocytes and causes a broad-based transient immune deficiency in patients with uncomplicated infections mononucleosis.

http://dx.doi.org/10.1016/0090-1229(86)90188-1


Sandor G, Puterman ML, Patterson MW, Tipple MA, Vince DJ. "The effect of pressure loading, volume loading and cardiomyopathy on left ventricular diastolic operant chamber stiffness and myocardial stiffness in congenital heart disease, With re evaluation of normal paediatric values". Journal of the American College of Cardiology, 8(2): 371 378, 1986.

 Abstract

This study assessed the effect of pressure load, volume load and surgery on left ventricular chamber stiffness (b) and myocardial stiffness (k). A normal range for chamber stiffness and myocardial stiffness was also established. A total of 44 patients were studied: 8 were control subjects, 12 had volume load and 24 had pressure load. At cardiac catheterization simultaneous high fidelity pressures (P) and left ventricular volumes (V) were obtained in one diastolic cycle. From the relation P = aVb, operant chamber stiffness (b) was estimated for each patient. Similarly, the relation between stress (σ) and radius (B) was approximated by σ = cBf and the myocardial stiffness (k) derived for each patient. Mean values for chamber or myocardial stiffness for the diagnostic groups were not significantly different but differed within the operative groups. Mean values for b and k were greater in the post-open heart surgery group than in the post-closed heart surgery or nonsurgical group. Although the mean values for chamber stiffness and myocardial stiffness for the diagnostic groups were not different, there were more abnormal patients in the pressure load group (9 of 24) than in the volume load group (2 of 8) when the normal range was obtained from the control group. Thus, left ventricular operant chamber and myocardial stiffness are often preserved with volume loading, less frequently with pressure loading and rarely after open heart surgery.

http://dx.doi.org/10.1016/S0735-1097(86)80053-5


Kastrukoff LF, Lau AS, Puterman ML. "Genetics of natural resistance to herpes simplex virus 1: Latent infection of the peripheral nervous system in mice". The Journal of General Virology, 67(4): 613 631, 1986.

 Abstract

The genetics of natural resistance to the development of latent infection in the trigeminal ganglia of mice inoculated in the lip with herpes simplex virus type 1 (HSV-1) was examined. Based on coefficients of a logistic regression relating latency to strain and HSV-1 concentration, inbred strains of mice formed a continuum of resistance ranging from most resistant (C57BL/6J) to most susceptible (PL/J). When these results were analysed along with latency data derived from studies employing a non-fatal concentration of HSV-1, three subpopulations were identified among these strains: resistant (C57BL/10J, BALB/cByJ, C57BL/6J), moderately resistant (DBA/2J, SWR/J, A/J, AKR/J, DBA/1J) and susceptible (PL/J, LP/J, CBA/J). Results from F1 hybrids between resistant and moderately resistant strains (B6D2F1/J, B6AF1/J) and between resistant and susceptible strains [(C57BL/6J × CBA/J)F1, (C57BL/6J × LP/J)F1)] indicated that resistance is dominant. Data from both inbred and congenic strains failed to show an association between H-2 and resistance to the development of a latent infection. Studies of mortality also indicated that a continuum was present, with C57BL/10J, C57BL/6J and DBA/1J being most resistant and PL/J mice most susceptible. When inbred strains were categorized on the basis of resistance to the development of latent infection and mortality, five groups could be identified. Group A are strains resistant to both mortality and latency (C57BL/6J, C57BL/10J, DBA/1J) while group B consists of one strain (BALB/cByJ) intermediate in resistance to mortality but resistant to latency. Group C are strains intermediate in resistance to mortality and susceptible to latency (LP/J, CBA/J) while Group D are strains susceptible to mortality and intermediate in susceptibility to latency (AKR/J, SWR/J, DBA/2J). Group E consists of one strain (PL/J) susceptible to both mortality and latency. These results indicate that host factors play an important role in the establishment of latent infection in vivo.

http://dx.doi.org/10.1099/0022-1317-67-4-613


Kao EPC, Queyranne M. "Aggregation in a two-stage stochastic program for manpower planning in the service sector". TIMS Studies in the Management Sciences, 22: 205-225, 1986.

 Abstract

None


Kao EPC, Queyranne M. "Budgeting costs of nursing in a hospital". Management Science, 31(5): 608-621, 1985.

 Abstract

This paper examines issues in building decision support models for budgeting nursing workforce requirements in a hospital. We determine regular-time, overtime, and agency workforce levels for various skill classes in a budget cycle. We introduce a family of eight models ranging from a single-period, aggregate and deterministic model to a multiperiod, disaggregate and probabilistic model. In a single-period model, we ignore the time-varying nature of demand for nursing hours. Aggregation is done over the nurse skill class mix. For probabilistic models, we consider demand uncertainty. Using empirical data, we evaluate the effects of level of sophistication in model building and in information requirements on their relative performances. The results suggest that ignoring the time-varying nature of demand does not induce gross errors in budget estimates. However, ignoring demand uncertainty produces underestimates (about five to six percent) of budget needs—a consequence of a Madansky (Madansky, A. 1960. Inequalities for stochastic linear programming problem. Management Sci. 6 197–204.) inequality. It also induces added costs to the system due to implementing nonoptimal regular-time workforce levels. Finally, we find that a simple formula using a single-period demand estimate gives excellent approximations to the budget estimates obtainable from the more precise models.

http://dx.doi.org/10.1287/mnsc.31.5.608


Speert DP, Eftekhar F, Puterman ML. "Non opsonic phagocytosis of pseudomonas aeruginosa strains from cystic fibrosis patients". Infection and Immunity, 43(3): 1006 1011, 1984.

 Abstract

Pseudomonas aeruginosa is the predominant respiratory pathogen in patients with cystic fibrosis, but its mechanism of persisting in pulmonary secretions is poorly understood. We observed that three nonmucoid cystic fibrosis P. aeruginosa strains were phagocytized and one strain resisted phagocytosis by human polymorphonuclear leukocytes in the absence of serum. Phagocytosis was assessed by luminol-enhanced chemiluminescence, inspection of stained smears, bactericidal assay, reduction of nitroblue tetrazolium dye, and electron microscopy. Phagocytosis, determined by visual inspection, occurred at 35 degrees C but not at 4 degrees C. Nonopsonic phagocytosis was inhibited most efficiently by D-mannose, mannose-containing saccharides, and D-fructose. Opsonin-dependent phagocytosis of P. aeruginosa and of zymosan was not markedly inhibited by mannose, suggesting different leukocyte receptors for nonopsonic and opsonic phagocytosis.

http://www.ncbi.nlm.nih.gov/pubmed/6421734


Picard J-C, Queyranne M. "On the one-dimensional space allocation problem". Operations Research, 29(2): 371-391, 1981.

 Abstract

The One-Dimensional Space Allocation Problem (ODSAP) arises when locating rooms along a corridor, when setting books on a shelf, when allocating information items among the "cylinders" of a magnetic disk, or when storing products in certain warehouses. The rooms (objects) to be located have a known length (or width) and, for each pair of rooms, there is a given number of "trips" between them; the problem is to find a sequencing of the rooms which minimizes the total traveled distance. This paper deals first with two particular cases. In the rooted tree case, previous results obtained by Adolphson and T. C. Hu for the Linear Ordering Problem are extended and provide efficient solution methods. In addition, it is shown that most of the assumptions made by Adolphson and Hu are necessary, since relaxing any of them leads to an NP-complete problem. In the case of independent destinations (solved by Bergmans and Pratt when all lengths are equal), a unimodality property is shown for an optimum solution, but this is not sufficient to lead to a "good" algorithm and the problem is shown to be NP-complete. For the general problem, an exact algorithm using dynamic programming is described and computationally tested.

http://dx.doi.org/10.1287/opre.29.2.371

*denotes a student coauthor