Date on Master's Thesis/Doctoral Dissertation

8-2014

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Electrical and Computer Engineering

Committee Chair

Inanc, Tamer

Committee Member

Brier, Michael

Committee Member

McIntyre, Michael

Committee Member

Xu, Yongzhi Steve

Committee Member

Zurada, Jacek

Subject

Anemia--Treatment; Drugs--Dosage

Abstract

The homeostatic blood hemoglobin (Hb) content of a healthy individual varies between the range of 14-18 g/dL for a male and 12-16 g/dL for a female. This quantity provides an estimate of red blood cell (RBC) count in circulation at any given moment. RBC is a protein carrying substance that transports oxygen from the lungs to other tissues in the body and is synthesized by the kidney through a process known as erythropoiesis where erythropoietin is secreted in response to hypoxia. In this regard, the kidneys act not only as a controller but also as a sensor in regulating RBC levels. Patients with chronic kidney diseases (CKD) have dysfunctional kidneys that compromise these fundamental kidney functions. Consequently, anemia is developed. Anemics of CKD have low levels of Hb that must be controlled and properly regulated to the appropriate therapeutic range. Until the discovery of recombinant human erythropoietin (EPO) over three decades ago, treatment procedure of anemia conditions primarily involved repeated blood transfusions–a process known to be associated with several other health related complications. This discovery resulted in a paradigm shift in anemia management from blood transfusions to dosage therapies. The main objective of anemia management with EPO is to increase patients’ hemoglobin level from low to a suitable therapeutic range as defined by the National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (NKF-KDOI) to be in the range of 10 - 12 g/dL while avoiding response values beyond 14 g/dL to prevent other complications associated with EPO medication. It is therefore imperative that clinicians balance dosage efficacy and toxicity in anemia management therapies. At most treatment facilities, protocols are developed to conform to NKF-KDOI recommendations. These protocols are generally based on EPO packet inserts and the expected Hb responses from the average patient. The inevitable variability within the patient group makes this “one-size-fits-all” dosing scheme non-optimal, at best, and potentially dangerous for certain group of patients that do not adhere to the notion of expected “average” response. A dosing strategy that is tailored to the individual patients’ response to EPO medication could provide a better alternative to the current treatment methods. An objective of this work is to develop EPO dosing strategies tailored to the individual patients using robust identification techniques and modern feedback control methods. First, a unique model is developed based on Hb responses and dosage EPO of the individual patients using semi-blind robust identification techniques. This provides a nominal model and a quantitative information on model uncertainty that accounts for other possible patient’s dynamics not considered in the modeling process. This is in the framework of generalized interpolation theory. Then, from the derived nominal model and the associated uncertainty information, robust controller is designed via the =H1-synthesis methods to provide a new dosing strategies for the individual patients. The H1 control theory has a feature of minimizing the influence of some unknown worst case gain disturbance on a system. Finally, a framework is provided to strategize dosing protocols for newly admitted patients.

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