AN ABSTRACT OF THE THESIS OF Nancy Jade Lee for the degree of Honors Baccalaureate of Science in Biochemistry & Biophysics presented on June 5, 2006. Title: Validation of Early Predictors of Outcome in the Dallas Newborn Cohort Abstract approved: ______________________________________________________ Kevin G. Ahern Sickle cell disease (SCD) is a phenotypically variable disorder of hemoglobin that leads to abnormally shaped and dysfunctional red blood cells. Several studies have attempted to construct early predictive models for SCD, including Miller et al.’s (2000) model which uses easily identifiable predictors in early life. The primary aim of this project is to validate the model of Miller et al. in the Dallas Newborn Cohort, the world’s largest newborn inception cohort of sickle cell disease. Specifically, we tested the predictive utility of three clinical findings in the first years of life: painful swelling of the hands and feet (dactylitis), severe anemia (Hgb <7 g/dL), and elevation of white blood cell count (leukocytosis) for later complications, which includes death, stroke, painful episodes, and acute chest syndrome. The predictive utility of the Miller model was found to be fairly poor in the Dallas Newborn Cohort. None of the patients with an adverse outcome was properly identified by the model. Thus, the Miller model is not practical to operate as a guide to influence clinical decisions about early disease-modifying interventions for young children with SCD. Keywords: sickle cell disease ©Copyright by Nancy Jade Lee June 5, 2006 All Rights Reserved Validation of Early Predictors of Outcome in the Dallas Newborn Cohort by Nancy Jade Lee A PROJECT Submitted to Oregon State University University Honors College In partial fulfillment of The requirements for the degree of Honors Bachelor of Science in Biochemistry & Biophysics (Honors Scholar) Presented June 5, 2006 Commencement June 2006 Honors Baccalaureate of Science in Biochemistry & Biophysics project of Nancy Jade Lee presented on June 5, 2006. APPROVED: Mentor, representing the Department of Biochemistry & Biophysics Committee Member, representing Children’s Medical Center Dallas Committee Member, representing the Department of Biochemistry & Biophysics Dean, University Honors College I understand that my project will become part of the permanent collection of Oregon State University, University Honors College. My signature below authorizes release of my project to any reader upon request. Nancy Jade Lee, Author ACKNOWLEDGMENT I would like to express my appreciation and gratitude to Drs. Charles T. Quinn and George Buchanan for providing me with an amazing opportunity to work with children with sickle cell disease at the Center for Cancer and Blood Disorders at Children’s Medical Center on the campus of University of Texas, Southwestern Medical Center at Dallas, Texas. I would also like to acknowledge Dr. Quinn’s support and guidance, which, without, I would not have been able to write this manuscript. I appreciate the patience and help of each of my committee members, and especially Dr. Kevin Ahern, my mentor, for pushing me to excel in everything I do. TABLE OF CONTENTS _______________________________________________________Page INTRODUCTION…………………………………………………..……….. 1 BACKGROUND…………………………………………………..………… 3 SYMPTOMS AND COMPLICATIONS….…………………….…………... 5 AVAILABLE THERAPIES…….……………………………….………….. 8 OBJECTIVE…………..…………………………………………………….. 10 MATERIALS AND METHODS……………………...…………………….. 13 DATA ANALYSIS……………….………………………………..………... 17 DISCUSSION AND CONCLUSION….…………………………..………... 20 BIBLIOGRAPHY…………………………………………...……………….. 21 LIST OF FIGURES Figures Page Figure 1: Sickled erythrocytes……………………………….……..….2 Figure 2: Hemoglobin molecule with 2 α globins and two β globins….4 Figure 3: Ten Redefined by Hertz Nazaire…………………………..... 5 Figure 4: Estimated Probability of Severe Sickle Cell Disease.......…. 11 Figure 5: Receiver operating characteristic..………………………… 19 Tables Page Table 1: Characteristics of Subjects………………….………………. 17 Table 2: Early predictors……………………….…………………….. 17 Table 3: Adverse Events……………………………………………… 17 Table 4: Miller et al Model in the Dallas Newborn Cohort…………... 18