Mehmet A. Begen

• Okuyan, H. M.; Begen, M. A., (Forthcoming), "miRNAs as attractive diagnostic and therapeutic targets for Familial Mediterranean Fever", Modern Rheumatology.
  Abstract: Familial Mediterranean Fever (FMF) is a hereditary early-onset disease that causes periodical fever attack, excessive release of IL-1β, serositis, arthritis and peritonitis. Genetic analyses conducted on FMF patients (mutated and non-mutated) have highlighted that additional contributing factors such as epigenetics and environment play a role in clinical manifestations of FMF. Recently researchers report that microRNAs (miRNAs), implicated in epigenetic mechanisms, may contribute to the pathogenesis of FMF. miRNAs, a member of the captivating noncoding RNA family, are the single-strand transcripts that work in physiological and pathophysiological processes by regulating target gene expression. Recent studies have shown that miRNAs are associated with various mechanisms involved in the pathogenesis of FMF, such as apoptosis, inflammation and autophagy. Moreover, these miRNAs molecules might have potential use in treatment, therapeutic response monitoring and the diagnosis of subtypes of the disease in the future. Motivated with these potential benefits (diagnostic and therapeutic) of miRNAs, we focus on recent advances of clinical significances and potential action mechanisms of miRNAs in FMF pathogenesis and discuss their potential use for FMF.

  Link(s) to publication:

  http://dx.doi.org/10.1080/14397595.2020.1868674

• Okuyan, H. M.; Dogan, S.; Terzi, Y. T.; Begen, M. A.; Turgut, F. H., (Forthcoming), "Association of serum lncRNA H19 expression with inflammatory and oxidative stress markers and routine biochemical parameters in chronic kidney disease", Clinical and Experimental Nephrology.
  Abstract: Background: Chronic kidney disease (CKD) is a disorder that affects millions worldwide, and current treatment options aimed at inhibiting the progression of kidney damage are limited. Long noncoding RNA (lncRNA) H19 is one of the first explored lncRNAs and its deregulation is associated with renal pathologies such as renal cell injury and nephrotic syndrome. However, there is still no research investigating the connection between serum lncRNA H19 expressions and laboratory parameters and health outcomes in patients with CKD. Therefore, we investigate the relation of serum lncRNA H19 expressions with routine biochemical parameters, inflammatory cytokines, oxidative stress and mineralization markers in patients with advanced CKD.
  
  Methods: LncRNA H19 serum levels from 56 patients with CKD and 20 healthy controls were analyzed with real-time quantitative polymerase chain reaction method. Serum tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6) and osteocalcin (OC) levels were measured by enzyme linked-immunosorbent assay. Total antioxidant status (TAS) and total oxidative status (TOS) levels were evaluated by the automated routine measurement method.
  
  Results: We found that lncRNA H19 expression were upregulated in patients with CKD compared to the healthy controls. Furthermore, lncRNA H19 relative expression levels showed a negative relationship with glomerular filtration rate (GFR) while it was positively correlated with ferritin, parathyroid hormone, TNF-α, IL-6, OC, TAS and TOS levels. Our findings revealed the association of increased serum lncRNA H19 expressions with estimated GFR, inflammation, and mineralization markers in CKD patients.
  
  Conclusions: lncRNA H19 expressions were increased in CKD stage 3-5 and HD patients and elevated lncRNA H19 expressions were associated with biochemical parameters involved in inflammation and mineralization.

  Link(s) to publication:

  https://link.springer.com/article/10.1007/s10157-021-02023-w

  http://dx.doi.org/10.1007/s10157-021-02023-w

• Naderi, B.; Roshanaei, V.; Begen, M. A.; Aleman, D.; Urbach, D., (Forthcoming), "Increased surgical capacity without additional resources: Generalized operating room planning and scheduling", Production and Operations Management.
  Abstract: We study a generalized operating room planning and scheduling (GORPS) problem at the Toronto General Hospital (TGH) in Ontario, Canada. GORPS allocates elective patients and resources (i.e., operating rooms, surgeons, anesthetists) to days, assigns resources to patients, and sequences patients in each day. We consider patients’ due-date, resource eligibility, heterogeneous performances of resources, downstream unit requirements, and lag times between resources. The goal is to create a weekly surgery schedule that minimizes fixed- and over-time costs. We model GORPS using mixed-integer and constraint programming models. To efficiently and effectively solve these models, we develop new‘ multi-featured logic-based Benders decomposition approaches. Using data from TGH, we demonstrate that our best algorithm solves GORPS with an average optimality gap of 2.71% which allows us to provide our practical recommendations. First, we can increase daily OR utilization to reach 80%—25% higher than the status quo in TGH. Second, we do not require to optimize for the daily selection of anesthetists —this finding allows for the development of effective dominance rules that significantly mitigate intractability. Third, solving GORPS without downstream capacities (like many papers in literature) makes GORPS easier to solve, but such OR schedules are only feasible in 24% of instances. Finally, with existing ORs’ safety capacities, TGH can manage 40% increase in its surgical volumes. We provide recommendations on how TGH must adjust its downstream capacities for varying levels of surgical volume increases (e.g., current urgent need for more capacity due to the current Covid-19 pandemic).
• Habbous, S.; Barnieh, L.; Klarenbach, S.; Manns, B.; Sarma, S.; Begen, M. A.; Litchfield, K.; Lentine, K. L.; Singh, S.; Garg, A. X., et al., 2020, "Evaluating multiple living kidney donor candidates simultaneously is more cost-effective than sequentially.", Kidney International, December 98(6): 1578 - 1588.
  Abstract: When multiple living donor candidates come forward to donate a kidney to the same recipient, some living donor programs evaluate one candidate at a time to avoid unnecessary evaluations. Evaluating multiple candidates concurrently rather than sequentially may be cost-effective from a health care system perspective if it reduces the time recipients spend on dialysis. We used a simple decision tree to estimate the cost-effectiveness of evaluating 2 to 4 candidates simultaneously rather than sequentially as potential kidney donors for the same intended recipient. Evaluating 2 donor candidates simultaneously cost $974 ($CAD) more than if they were evaluated sequentially, but living donation occurred 1 month earlier. This translated into $6,931 in averted dialysis costs and a total cost-savings of $5,957 per intended recipient. Simultaneous evaluations also resulted in 1% more living donor transplants. If recipients were free from dialysis at the start of donor candidate evaluations, simultaneous evaluations also reduced the rate of dialysis initiation by 2%. Benefits were also observed in the 3- and 4-candidate scenarios. In conclusion, living donor programs should consider evaluating up to 4 living donor candidates simultaneously when they come forward for the same recipient. Health care system costs incurred are more than offset by avoided dialysis costs.

  Link(s) to publication:

  http://dx.doi.org/10.1016/j.kint.2020.06.015

• Barzanji, R.; Naderi, B.; Begen, M. A., 2020, "Decomposition algorithms for the integrated process-planning and scheduling problem", OMEGA-INTERNATIONAL JOURNAL OF MANAGEMENT SCIENCE, June 93.
  Abstract: There are several algorithms to solve the integrated process planning and scheduling (IPPS) problem (i.e., flexible job shop scheduling with process plan flexibility) in the literature. All the existing algorithms for IPPS are heuristic-based search methods and no research has investigated the use of exact solution methods for this problem. We develop several decomposition approaches based on the logic-based Benders decomposition (LBBD) algorithm. Our LBBD algorithm allows us to partition the decision variables in the IPPS problem into two models, master-problem and sub-problem. The master-problem determines process plan and operation-machine assignment, while the sub-problem optimizes sequencing and scheduling decisions. To achieve faster convergence, we develop two relaxations for the optimal makespan objective function and incorporate them into the master-problem. We analyze the performance and further enhance the algorithm with two ideas, a Benders optimality cut based on the critical path and a faster heuristic way to solve the sub-problem. 16 standard benchmark instances available in the literature are solved to evaluate and compare the performances of our algorithms with those of the state-of-the-art methods in the literature. The proposed algorithm either results in the optimal solution or improves the best-known solutions in all the existing instances, demonstrating its superiority to the existing state-of-the-art methods in literature.

  Link(s) to publication:

  http://dx.doi.org/10.1016/j.omega.2019.01.003

• Sauré, A.; Begen, M. A.; Patrick, J., 2020, "Dynamic Multi-Priority, Multi-Class Patient Scheduling with Stochastic Service Times", European Journal of Operational Research, January 280(1): 254 - 265.
  Abstract: Efficient patient scheduling has significant operational, clinical and economical benefits on health care systems by not only increasing the timely access of patients to care but also reducing costs. However, patient scheduling is complex due to, among other aspects, the existence of multiple priority levels, the presence of multiple service requirements, and its stochastic nature. Patient appointment (allocation) scheduling refers to the assignment of specific appointment start times to a set of patients scheduled for a particular day while advance patient scheduling refers to the assignment of future appointment days to patients. These two problems have generally been addressed separately despite each being highly dependent on the form of the other. This paper develops a framework that incorporates stochastic service times into the advance scheduling problem as a first step towards bridging these two problems. In this way, we not only take into account the waiting time until the day of service but also the idle time/overtime of medical resources on the day of service. We first extend the current literature by providing theoretical and numerical results for the case with multi-class, multi-priority patients and deterministic service times. We then adapt the model to incorporate stochastic service times and perform a comprehensive numerical analysis on a number of scenarios, including a practical application. Results suggest that the advance scheduling policies based on deterministic service times cannot be easily improved upon by incorporating stochastic service times, a finding that has important implications for practice and future research on the combined problem.

  Link(s) to publication:

  http://dx.doi.org/10.1016/j.ejor.2019.06.040

• Begen, M. A.; Puterman, M. L.; Wu, H., 2019, "Development of an Operational and Tactical Decision Support Tool for a Canadian Beverage Firm: A Case Study", European Journal of Industrial Engineering, April 13(2): 245 - 263.
  Abstract: This paper describes a logistics optimization case study for a Canadian beverage manufacturer and distributor. The goal was to determine production, distribution and inventory plans for a given product line to help the company with its challenges due to production shortages, stock-outs and high transportation costs in a new and highly competitive market. We built and implemented an optimization model in Excel with VBA as a customized planning tool. Although we originally designed the tool for operational planning, the beverage company first used it for tactical planning (in price negotiations with the firm’s subcontractors, deciding whether to buy a bankrupt subcontractor production site, and quantification of carrying extra inventory). The tool has changed the way the company conducts its business planning by evaluating “what if” scenarios, finding an optimal operational plan, and forcing the company to think more strategically and for longer horizons.

  Link(s) to publication:

  http://dx.doi.org/10.1504/EJIE.2019.098515

• Habbous,, S.; McArthur, E.; Sarma, S.; Begen, M. A.; Lam, N.; Manns, B.; Lentine, K. L.; Dipchand, C.; Litchfield, K.; Mackenzie, S., et al., 2018, "Potential implications of a more timely living kidney donor evaluation", American Journal of Transplantation, October 18(11): 2719 - 2729.
  Abstract: Living donor kidney transplantation is the most promising way to avoid or minimize the amount of time a recipient spends on dialysis before transplantation. We studied 887 living kidney donors at five transplant centres in Ontario, Canada who started their evaluation and donated between April 2006 and March 2014. Using a series of hypothetical scenarios, we estimated the impact of an earlier living donor evaluation completion and donation on the number pre-emptive transplants, the time spent on dialysis, healthcare cost savings from averted dialysis costs (CAD $2016), and the number of additional transplants. During the study period, if the donor transplants occurred three months earlier, the healthcare system would save on average $12,055 (standard deviation $13,594) per recipient, 21 recipients could have avoided dialysis altogether, and 57 additional transplants (a 26% increase) could have occurred each year. For the 220 living kidney donor transplants performed in Ontario, Canada each year, this translates to total annual cost savings of $2.7M. In conclusion, a more timely evaluation of living donor candidates and their intended recipients may increase the supply of kidneys for transplantation. Improved evaluation efficiency may also yield more pre-emptive transplants and substantial healthcare cost savings through averted dialysis costs.

  Link(s) to publication:

  https://onlinelibrary.wiley.com/doi/abs/10.1111/ajt.14732

  http://dx.doi.org/10.1111/ajt.14732

• Habbous, S.; Arnold, J.; Begen, M. A.; Boudville,, N.; Cooper, M.; Dipchand, C.; Dixon, S.; Feldman,, L. S.; Gozdzik, D.; Karpinski, M., et al., 2018, "Duration of Living Kidney Transplant Donor Evaluations: Findings From 2 Multi-center Cohort Studies", American Journal of Kidney Diseases, October 72(4): 483 - 498.
  Abstract: Background: A prolonged living kidney donor evaluation may result in worse outcomes for transplant recipients. Better knowledge of the duration of this process may help inform future donors and identify opportunities for improvement. br?br Study Design: One prospective and one retrospective cohort study. br?br Setting and Participants: At 16 Canadian and Australian transplant centers (prospective cohort) and 5 Ontario transplant centers (retrospective cohort), we assessed the duration of living kidney donor evaluation and explored donor, recipient, and transplant factors associated with longer evaluation times. Data were obtained from two sources: donor medical records via chart abstraction and healthcare administrative databases. br?br Predictors: Donor and recipient demographics, direct versus paired donation, center-level variables. br?br Outcomes: Duration of living donor evaluation. Results: The median (25th, 75th percentile) total duration of transplant evaluation (time from when the candidate started the evaluation until donation) was 10.3 (6.5, 16.7) months. The median duration from evaluation start until approval to donate was 7.9 (4.6-14.1) months, and from approval until donation was 0.7 (0.3-2.4) months, respectively. The median time between the first and last consultation among donors who completed a nephrology, surgery, and psychosocial assessment in the prospective cohort was 3.0 (1.0, 6.3) months and between computed tomography angiography and donation was 4.8 (2.6, 9.2) months. After adjustment, the total duration of transplant evaluation was longer if the donor participated in paired donation [6.6 (95% confidence interval 1.6, 9.7) months and if the recipient was referred later relative to the donor’s evaluation start date [0.9 (0.8, 1.0) months (per month of delayed referral). Results depended on whether the recipient was receiving dialysis or not. br?br Limitations: Living donor candidates who did not donate were not included and proxy measures were used for some dates in the donor evaluation process. br?br Conclusion: The duration of kidney transplant donor evaluation is quite variable and can be lengthy. A better understanding of the reasons for a prolonged evaluation may inform quality improvement initiatives to reduce unnecessary delays.br?brbr?brbr?brbr?brbr?brbr?br

  Link(s) to publication:

  https://www.sciencedirect.com/science/article/pii/S0272638618301264?via=ihub

  http://dx.doi.org/10.1053/j.ajkd.2018.01.036

• Habbous,, S.; Sarma, S.; Barnieh, L.; McArthur, E.; Klarenbach, S.; Manns,, B.; Begen, M. A.; Lentine, K. L.; Garg, A. X., 2018, "Health care costs for the evaluation, surgery, and follow-up care of living kidney donors", Transplantation, August 102(8): 1367 - 1374.
  Abstract: Background: The health care costs to evaluate, perform surgery, and follow a living kidney donor for the year after donation are poorly described.
  
  Methods: We obtained information on the health care costs of 1099 living kidney donors between April 1, 2004 and March 31, 2014 from Ontario, Canada using comprehensive health care administrative databases. We estimated the cost of three periods of the living donation process: the pre-donation evaluation period (start of evaluation until the day before donation),perioperative period (day of donation until 30-days post-donation), and one year of follow-up period (after perioperative period until 1-year post-donation). We analyzed data for donors and healthy matched non-donor controls using regression-based methods to estimate the incremental cost of living donation. Costs are presented from the perspective of the Canadian health care payer (2017 $CAD).
  
  Results: The incremental health care costs (compared with controls) for the evaluation, perioperative, and follow-up periods were $3,596 (95% confidence interval (CI) $3,350-$3,842), $11,694 ($11,415-$11,973), and $1,011 ($793-$1,230), respectively, totalling $16,290 ($15,814- $16,767). The evaluation cost was higher if the intended recipient started dialysis part-way through the donor evaluation [$886 ($19, $1,752)]. The perioperative cost varied across transplant centres (p<0.0001).
  
  Conclusion: While substantial costs of living donor care are related to the nephrectomy procedure, comprehensive assessment of costs must also include the evaluation and follow-up periods. These estimates are informative for planning future work to support and expand living donation and transplantation, and directing efforts to improve the cost efficiency of living donor care.

  Link(s) to publication:

  http://dx.doi.org/10.1097/TP.0000000000002222

• Lyons, J.; Bell, P. C.; Begen, M. A., 2018, "Solving the Whistler-Blackcomb Mega Day Challenge", Interfaces, July 48(4): 291 - 397.
  Abstract: The Whistler-Blackcomb (WB) Mega Day Challenge requires a skier to ride all 24 lifts at the resort in a single day. Among over two million skiers annually at WB, only 313 completed the challenge in fourteen months following the introduction of a system that tracks lift use by skier. Apart from the physical challenge, the difficulty is to find a route that matches one’s skill level while accounting for variable lift opening and closing times. brbr We use data from WB’s radio-frequency identification (RFID) ticketing system to estimate ski times between lifts for skiers of various skill levels. We then formulate and solve the problem by a combined, iterative integer programming and heuristic approach, up to the highest feasible skier skill level. The problem’s distinctive features preclude use of known solution methods for similar problems, so we use a practical, staged solution approach. brbr Our results include a recommended route that enables the greatest number of skiers, roughly the fastest quartile, to achieve the challenge. We also provide a benchmark, that skiers who can ski a particular common run in 12 minutes or less, should be able to complete the challenge. In three months following communication of our recommended solution, the rate at which Mega Days were successfully completed increased by two-thirds from the previous seven skiing months.

  Link(s) to publication:

  http://dx.doi.org/10.1287/inte.2018.0947

• Habbous, S.; McArthur, E.; Dixon, S.; McKenzie, S.; Garcia-Ochoa, C.; Lam, N.; Lentine, K. L.; Dipchand, C.; Litchfield, K.; Begen, M. A., et al., 2018, "Initiating maintenance dialysis prior to living kidney donor transplantation when a donor candidate evaluation is well underway", Transplantation, July 102(7e345): e345 - e353.
  Abstract: Introduction: Pre-emptive kidney transplants result in better outcomes and patient experiences than transplantation after dialysis onset. It is unknown how often a person initiates maintenance dialysis prior to living kidney donor transplantation when their donor candidate evaluation is well underway. brbr Methods: Using healthcare databases, we retrospectively studied 478 living donor kidney transplants from 2004-2014 across five transplant centres in Ontario, Canada where the recipients were not receiving dialysis when their donor’s evaluation was well underway. We also explored some factors associated with a higher likelihood of dialysis initiation before transplant.brbr Results: A total 167478 (35%) persons with kidney failure initiated dialysis a median 9.7 (25th-75th percentile 5.4-18.7) months after their donor candidate began their evaluation, and received dialysis for a median 8.8 (3.6-16.9) months before kidney transplantation. The total cohort’s dialysis cost was 8.1 million and 44167 (26%) recipients initiated their dialysis urgently in hospital. The median total donor evaluation time (time from evaluation start to donation) was 10.6 (6.4-21.6) months for pre-emptive transplants and 22.4 (13.1-38.7) months for donors whose recipients started dialysis prior to transplant. Recipients were more likely to start dialysis if their donor was female, non-white, lived in a lower-neighbourhood income, and if the transplant centre received the recipient referral later. brbr Conclusion: One-third of persons initiated dialysis prior to receiving their living kidney donor transplant, despite their donor’s evaluation being well underway. Future studies should consider whether some of these events can be prevented by addressing inappropriate delays to improve patient outcomes and reduce healthcare costs.

  Link(s) to publication:

  http://dx.doi.org/10.1097/TP.0000000000002159

• Begen, M. A.; Fung, R.; Granot, D.; Granot, F.; Hall, C.; Kluczny, B., 2018, "Evaluation of a Centralized Transportation Assistance System for Passengers with Special Needs at a Canadian Airport", International Journal of Shipping and Transport Logistics, June 10(3): 355 - 376.
  Abstract: Transportation assistance for travelers with special needs (e.g., disabled, sick, elderly, unaccompanied minors) is provided at most airports around the world, and the demand for this service is increasing every year. At most airports, air carriers are independently responsible for this service, and they set their own service levels and practices. We expect that a centralized system would increase resource efficiency and passenger satisfaction. We conduct an evaluation of such a centralized system at a Canadian airport using two distinct and independent models: simulation and queuing. We find that consolidating the service produces higher levels of service quality for passengers while, at the same time, uses fewer resources. In addition to quantifying the benefits and finding the required resource levels for a given service level, we discuss the pros and cons of a centralized system from the perspectives of the airport authority, the airlines, and the passengers. To the best of our knowledge, this is the first study for consolidating transportation service for special-need passengers. Our methodology may be applied to other airports worldwide to evaluate a centralized transportation assistance system for passengers with special needs.

  Link(s) to publication:

  http://dx.doi.org/10.1504/IJSTL.2018.091678

• Rastpour, A.; Begen, M. A.; Louie, A. V.; Zaric, G. S., 2018, "Variability of Waiting Times for the Four Most Prevalent Cancer Types in Ontario: A Retrospective Population-based Analysis", CMAJ Open, June 6(2): E227 - E234.
  Abstract: Background: Longer waiting times in cancer care are associated with lower care quality and wait-related patient dissatisfaction. We examined and analyzed the variability and median of cancer waiting times, from when a patient seeks care to first treatment, for the four most prevalent cancer types in Ontario. Methods: Using retrospective administrative data, new diagnoses with prostate, breast, lung and colorectal cancers were identified between 2002 and 2012. Treatment interventions were categorized as chemotherapy, radiotherapy or surgery. We used regression analyses to calculate trends for the coefficient of variation, the Gini coefficient, and the median waiting time for each cancer type-treatment type pair over the study period. Results: During the study period, 95,501 new prostate, 89,244 breast, 82,604 lung, and 80,761 colorectal cancer cases were registered. The coefficient of variation and the Gini coefficient of waiting times constantly decreased for all cancer type-treatment type pairs (except for the breast cancer-radiotherapy Gini coefficient) over the study period. However, the median waiting time did not have a consistent trend across cancer type-treatment type pairs over the study period. Interpretation: Variability of waiting time has improved for prostate, breast, colorectal, and lung cancer patients between 2002 and 2012, indicating improvements in waiting time equity for cancer care. This trend aligns with provincial efforts to improve the access and efficiency of cancer care process in Ontario. However, the median waiting times did not consistently have decreasing trends, highlighting the need to identify improvement opportunities for cancer type-treatment type pairs with increasing median waiting times.

  Link(s) to publication:

  http://cmajopen.ca/content/6/2/E227.full.pdf+html

  http://dx.doi.org/10.9778/cmajo.20170118

• Babashov, V.; Aivas, I.; Begen, M. A.; Cao, J. Q.; Rodrigues, G. B.; D'Souza, D.; Lock, M.; Zaric, G. S., 2017, "Reducing Patient Wait Times for Radiation Therapy and Improving Treatment Planning Process: A Discrete-event Simulation Model", Clinical Oncology, June 29(6): 385 - 391.
  Abstract: Background and Purpose We analyzed the radiotherapy planning process at the London Regional Cancer Program (LRCP) to determine the bottlenecks and quantify the impact of specific resource levels with the goal of reducing wait times. Material and Methods We developed a discrete-event simulation (DES) model of a patient’s journey from a point of referral to radiation oncologist to a start of radiotherapy, considering the sequential steps and resources of the treatment planning process. We measured the impact of several resource changes on the ready-to-treat to treatment (RTTT) wait time and on the percent treated within 14-calendar-days target. Results Increasing the number of dosimetrists by one reduced the mean RTTT by 6.55%, leading to 84.92% of patients being treated within the 14-calendar-days target. Adding one more oncologist decreased the mean RTTT from 10.83 to 10.55 days, while a 15% increase in arriving patients increased the wait time by 22.53%. The model was relatively robust to the changes in quantity of other resources. Conclusions Our model identified sensitive and non-sensitive system parameters. A similar approach could be applied by other cancer programs, using their respective data and individualized adjustments, which may be beneficial in making the most effective use of limited resources.

  Link(s) to publication:

  http://dx.doi.org/10.1016/j.clon.2017.01.039

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