Data-Driven Management of Post-transplant Medications: An APOMDP Approach

Organ-transplanted patients typically receive high amounts of immunosuppressive drugs (e.g., tacrolimus) as a mechanism to reduce their risk of organ rejection. However, due to the diabetogenic effect of these drugs, this practice exposes them to greater risk of New-Onset Diabetes After Trans-plant (NODAT), and hence, becoming insulin-dependent. This common conundrum of balancing the risk of organ rejection versus that of NODAT is further complicated due to various factors that create ambiguity in quantifying risks: (1) false-positive and false-negative errors of medical tests,(2) inevitable estimation errors when data sets are used, (3) variability among physicians’ attitudes towards ambiguous outcomes, and (4) dynamic and patient risk-profile dependent progression of health conditions. To address these challenges, we propose an ambiguous partially observable Markov decision process (APOMDP) framework, where dynamic optimization with respect to a “cloud†of possible models allows us to make decisions that are robust to misspecifications of risks. We first provide various structural results that facilitate characterizing the optimal policy. Using a clinical data set, we then compare the optimal policy to the current practice as well as some other bench-marks, and discuss various implications for both policy makers and physicians. In particular, our results show that substantial improvements are achievable in two important dimensions: (a) the quality-adjusted life expectancy (QALE) of patients, and (b) medical expenditures.

[1]  Murat Kurt,et al.  The structure of optimal statin initiation policies for patients with Type 2 diabetes , 2011 .

[2]  John N. Tsitsiklis,et al.  The Complexity of Markov Decision Processes , 1987, Math. Oper. Res..

[3]  Kunam S Reddy,et al.  Hyperglycemia during the immediate period after kidney transplantation. , 2009, Clinical journal of the American Society of Nephrology : CJASN.

[4]  Oguzhan Alagoz,et al.  Incorporating Biological Natural History in Simulation Models: Empirical Estimates of the Progression of End-Stage Liver Disease , 2005, Medical decision making : an international journal of the Society for Medical Decision Making.

[5]  Wojciech Piekoszewski,et al.  Pharmacokinetics of tacrolimus in liver transplant patients , 1995, Clinical pharmacology and therapeutics.

[6]  Nephrology, dialysis, transplantation. In this issue. , 2008, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[7]  Milos Hauskrecht,et al.  Value-Function Approximations for Partially Observable Markov Decision Processes , 2000, J. Artif. Intell. Res..

[8]  George E. Schreiner,et al.  The American Society of Nephrology , 1967 .

[9]  Y. Jang,et al.  Standards of Medical Care in Diabetes-2010 by the American Diabetes Association: Prevention and Management of Cardiovascular Disease , 2010 .

[10]  David Moore,et al.  Data Uncertainty in Markov Chains: Application to Cost-Effectiveness Analyses of Medical Innovations , 2018, Oper. Res..

[11]  D. Brennan,et al.  The role of tacrolimus in renal transplantation , 2008, Expert opinion on pharmacotherapy.

[12]  Laurent El Ghaoui,et al.  Robust Control of Markov Decision Processes with Uncertain Transition Matrices , 2005, Oper. Res..

[13]  Steven L. Shafer,et al.  Comparison of Some Suboptimal Control Policies in Medical Drug Therapy , 1996, Oper. Res..

[14]  Lisa M. Maillart,et al.  Assessing Dynamic Breast Cancer Screening Policies , 2008, Oper. Res..

[15]  Dimitris Bertsimas,et al.  Fairness, Efficiency, and Flexibility in Organ Allocation for Kidney Transplantation , 2013, Oper. Res..

[16]  Raymond Vanholder,et al.  New-Onset Diabetes After Renal Transplantation , 2011, Diabetes Care.

[17]  P Taylor,et al.  Low tacrolimus concentrations and increased risk of early acute rejection in adult renal transplantation. , 2001, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[18]  C. Staatz,et al.  Clinical Pharmacokinetics and Pharmacodynamics of Tacrolimus in Solid Organ Transplantation , 2004, Clinical pharmacokinetics.

[19]  Massimo Marinacci,et al.  Differentiating ambiguity and ambiguity attitude , 2004, J. Econ. Theory.

[20]  Alexander Peysakhovich,et al.  Asymmetric Effects of Favorable and Unfavorable Information on Decision Making Under Ambiguity , 2016, Manag. Sci..

[21]  Faruk Gul,et al.  EXPECTED UNCERTAIN UTILITY THEORY , 2014 .

[22]  Soroush Saghafian,et al.  Ambiguous Partially Observable Markov Decision Processes: Structural Results and Applications , 2017, J. Econ. Theory.

[23]  A. Terzic,et al.  Clinical pharmacology: the science of therapeutics , 2007, Clinical pharmacology and therapeutics.

[24]  Edward Cole,et al.  Therapeutic monitoring of calcineurin inhibitors for the nephrologist. , 2007, Clinical journal of the American Society of Nephrology : CJASN.

[25]  Syngjoo Choi,et al.  Estimating Ambiguity Aversion in a Portfolio Choice Experiment , 2009 .

[26]  F. Sassi Calculating QALYs, comparing QALY and DALY calculations. , 2006, Health policy and planning.

[27]  Ayala Arad,et al.  Imprecise Data Sets as a Source of Ambiguity: A Model and Experimental Evidence , 2012, Manag. Sci..

[28]  Stef van Buuren,et al.  MICE: Multivariate Imputation by Chained Equations in R , 2011 .

[29]  Fatih Safa Erenay,et al.  Optimizing Colonoscopy Screening for Colorectal Cancer Prevention and Surveillance , 2014, Manuf. Serv. Oper. Manag..

[30]  I. Gilboa,et al.  Maxmin Expected Utility with Non-Unique Prior , 1989 .

[31]  Soroush Saghafian,et al.  Characterization of Remitting and Relapsing Hyperglycemia in Post-Renal-Transplant Recipients , 2015, PloS one.

[32]  L Zhang,et al.  The Role of Ethnicity in Variability in Response to Drugs: Focus on Clinical Pharmacology Studies , 2008, Clinical pharmacology and therapeutics.

[33]  C Revillard,et al.  [Clinical pharmacokinetics]. , 1976, Schweizerische medizinische Wochenschrift.

[34]  Brian T. Denton,et al.  Optimizing the simultaneous management of blood pressure and cholesterol for type 2 diabetes patients , 2014, Eur. J. Oper. Res..

[35]  W. Whitt Multivariate monotone likelihood ratio and uniform conditional stochastic order , 1982 .

[36]  David B. Portnoy,et al.  Physicians’ attitudes about communicating and managing scientific uncertainty differ by perceived ambiguity aversion of their patients , 2013, Health expectations : an international journal of public participation in health care and health policy.

[37]  Yuanhui Zhang,et al.  Robust Optimal Control for Medical Treatment Decisions , 2014 .

[38]  L. Eeckhoudt,et al.  Treatment decisions under ambiguity. , 2013, Journal of health economics.

[39]  Andrew J. Schaefer,et al.  The Optimal Timing of Living-Donor Liver Transplantation , 2004, Manag. Sci..

[40]  Edward J. Sondik,et al.  The Optimal Control of Partially Observable Markov Processes over a Finite Horizon , 1973, Oper. Res..

[41]  Shie Mannor,et al.  Percentile Optimization for Markov Decision Processes with Parameter Uncertainty , 2010, Oper. Res..

[42]  Nilay D Shah,et al.  Optimizing the Start Time of Statin Therapy for Patients with Diabetes , 2009, Medical decision making : an international journal of the Society for Medical Decision Making.

[43]  Xuanming Su,et al.  Patient Choice in Kidney Allocation: A Sequential Stochastic Assignment Model , 2005, Oper. Res..

[44]  Paul K J Han,et al.  Aversion to Ambiguity Regarding Medical Tests and Treatments: Measurement, Prevalence, and Relationship to Sociodemographic Factors , 2009, Journal of health communication.

[45]  Turgay Ayer,et al.  OR Forum - A POMDP Approach to Personalize Mammography Screening Decisions , 2012, Oper. Res..

[46]  E D Lehmann,et al.  A physiological model of glucose-insulin interaction in type 1 diabetes mellitus. , 1992, Journal of biomedical engineering.

[47]  G. Monahan State of the Art—A Survey of Partially Observable Markov Decision Processes: Theory, Models, and Algorithms , 1982 .

[48]  Garud Iyengar,et al.  Robust Dynamic Programming , 2005, Math. Oper. Res..

[49]  Shie Mannor,et al.  Distributionally Robust Markov Decision Processes , 2010, Math. Oper. Res..

[50]  S. Dharmage,et al.  HbA1c as a screening tool for detection of Type 2 diabetes: a systematic review , 2007 .

[51]  Sridhar R. Tayur,et al.  OrganJet: Overcoming Geographical Disparities in Access to Deceased Donor Kidneys in the United States , 2017, Manag. Sci..

[52]  J. Yates,et al.  Characterizing Physicians' Perceptions of Ambiguity , 1989, Medical decision making : an international journal of the Society for Medical Decision Making.

[53]  Yan Chen,et al.  Sealed Bid Auctions with Ambiguity: Theory and Experiments , 2007, J. Econ. Theory.

[54]  Timothy Van Zandt An Introduction to Monotone Comparative Statics , 2002 .

[55]  C. Duvoux,et al.  Evaluation of the Architect tacrolimus assay in kidney, liver, and heart transplant recipients. , 2010, Journal of pharmaceutical and biomedical analysis.

[56]  B. Denton,et al.  PARTIALLY OBSERVABLE MARKOV DECISION PROCESSES FOR PROSTATE CANCER SCREENING, SURVEILLANCE, AND TREATMENT , 2018 .

[57]  Ambiguity Attitudes in a Large Representative Sample , 2015 .

[58]  E A Gale,et al.  Unnecessary insulin treatment for diabetes. , 1981, British medical journal.

[59]  B. Denton,et al.  Robust Markov Decision Processes for Medical Treatment Decisions , 2015 .