Design and Analytic Methods for Time‐Varying Exposures in Perinatal Epidemiology By Anthony Philip Nunes MS, University of Massachusetts at Amherst, 2006 A Dissertation Submitted in Partial Fulfillment of the Requirements for Degree of Doctor of Philosophy in the Division of Biology and Medicine at Brown University Providence, Rhode Island May 2011 © Copyright 2011 by Anthony Philip Nunes This dissertation by Anthony Philip Nunes is accepted in its present form by the Division of Biology and Medicine as satisfying the dissertation requirement for the Degree of Doctor of Philosophy. Date________________ _________________________________ Elizabeth W. Triche, PhD, Advisor Recommended to the Graduate Council Date________________ _________________________________ E. Andres Houseman, ScD (Reader) Date________________ _________________________________ Maureen G. Phipps, MD, MPH (Reader) Date________________ _________________________________ Gregory A. Wellenius, ScD (Reader) Approved by the Graduate Council Date________________ _________________________________ Peter Weber, Dean of the Graduate School III Curriculum Vitae Anthony Nunes was born in Fall River, MA in September of 1980. He attended the University of Massachusetts at Amherst where he received a Bachelors of Science degree in Environmental Science with a concentration in Toxicology and Chemistry. Anthony then received his Master of Science degree in Epidemiology from the School of Public Health and Health Sciences at the University of Massachusetts at Amherst. Anthony’s Master’s thesis assessed the association between stress and motor vehicle injuries among active duty US Army personnel. Anthony then worked as a researcher for the US Army Research Institute for Environmental Medicine, assisting in data analysis within the substantive area of injury prevention epidemiology, and as an associate epidemiologist for Environ International, assisting with grant writing, data collection, data analysis, and drafting of manuscripts and expert reports. He entered the Doctoral Program in Epidemiology in the Department of Community Health at Brown University in September of 2007 to pursue research within the substantive area of perinatal and reproductive epidemiology. He received funding through a National Institute on Aging Training Grant and through a research assistantship in the Division of Research at Women & Infants Hospital in Providence, RI. In addition, Anthony worked as a statistical and methodological consultant for the Community Health Clerkship rotation in the Warren Alpert Medical School. During his graduate training, Anthony was honored by receiving an invitation to attend the NICHD IV Summer Institute in Reproductive and Perinatal Epidemiology. He has contributed to publications within the substantive areas of adolescent pregnancy, pharmaco‐ epidemiology, and injury/environmental epidemiology. Anthony’s research has been presented at conferences for the International Society for Pharmacoepidemiology, the American College of Obstetricians and Gynecologists, and the Society for Epidemiologic Research. V Acknowledgments Throughout my graduate training at Brown, I have been blessed to have mentors who have been as caring and kind as they have been knowledgeable. I would like to thank Dr. Beth Triche, my advisor and mentor, for her commitment, guidance, and support throughout this investigation. To Dr. Maureen Phipps, Dr. E. Andres Houseman, and Dr. Gregory Wellenius, I would like to express my appreciation for each of their unique perspectives and insights they provided to help shape the methods and clinical relevance of my research. I am grateful to my academic advisors and research mentors Dr. Stephen Buka, Dr. Melissa Clark, Dr. Kate Lapane, Dr. Martin Weinstock, Dr. Joseph Hogan, and Dr. Vincent Mor; each of whom have helped to develop the questions and analytic approaches addressed in this dissertation. I would like to acknowledge Dr. Enrique Schisterman, who served as an external reader; and Dr. Michael Bracken, Dr. Theodore Holford, Dr. Kathleen Belanger, and Dr. Brian Leaderer from the Yale Center for Perinatal, Pediatric, and Environmental Epidemiology for granting access to the data utilized in this research. Lastly, none of this would have been possible without the support of my family, friends, and colleagues. I would like to specifically thank my parents, Anthony and Gail Nunes; my wife, Heather Nunes; and my children, Anthony and Daniel Nunes; for the support and encouragement they have provided and the sacrifices they have made to allow me to pursue higher education. VI Table of Contents Signature Page ................................................................................................................... III Curriculum Vitae ................................................................................................................ IV Acknowledgments ............................................................................................................. VI List or Tables .................................................................................................................... VIII List of Figures ..................................................................................................................... IX Introduction ........................................................................................................................ 1 Overview ................................................................................................................. 1 Analytic Solution ................................................................................................................. 3 Design Solution ................................................................................................................... 4 Specific Aims ........................................................................................................... 5 Chapter 1: TIME‐DEPENDENT BIAS OF AVERAGE AND JOINTLY MODELED EXPOSURES: EXAMPLES IN PERINATAL EPIDEMIOLOGY .................................................................................... 6 Abstract ................................................................................................................... 7 Introduction ........................................................................................................................ 8 Simulation Methods .......................................................................................................... 14 Simulation Results ............................................................................................................. 17 Bias Correction Methods .................................................................................................. 18 Bias Correction Illustration ............................................................................................... 19 Discussion.............................................................................................................. 22 Chapter 2: EVALUATING MISSING DATA DESIGNS IN THE PRESENCE OF NON‐DESIGNED MISSING DATA: APPLICATIONS IN PERINATAL EPIDEMIOLOGY ................................... 34 Abstract ................................................................................................................. 35 Introduction ...................................................................................................................... 37 Methods ............................................................................................................................ 40 Results ............................................................................................................................... 48 Discussion.............................................................................................................. 50 Chapter 3: TIME DEPENDENT ASSOCIATIONS BETWEEN MATERNAL CAFFEINE CONSUMPTION AND FETAL GROWTH ............................................................................ 63 Abstract ................................................................................................................. 64 Introduction ...................................................................................................................... 65 Methods ............................................................................................................................ 67 Results ............................................................................................................................... 74 Discussion.............................................................................................................. 77 General Discussion ........................................................................................................... 89 References ........................................................................................................................ 95 VII List of Tables Table 1.1, Average Effect Estimates for 1000 Simulations of 10,000 Pregnancies Using Time‐Invariant and Time‐Varying Methods ..................................................................... 28 Table 1.2, Average Effect Estimates for 1000 Simulations of 10,000 Pregnancies Using Time‐Invariant and Time‐Varying Methods .................................................. 29 Table 1.3, Simulation of Average Exposure and Preterm Birth: Average Effect Estimates for 1000 Simulations of 10,000 Pregnancies Using Time‐Invariant and Time‐ Varying Methods ........................................................................................... 30 Table 1.4, Association Between Prenatal Care Initiation and Preterm Birth and Low Birth Weight, 2006 US Natality Data ...................................................................... 31 Table 2.1, Sample Size and Cost Parameters Used for Data Simulations ......................... 56 Table 2.2, Characteristics of Study Participants Within Protocols of the Nutrition in Pregnancy Study Prior to and After Weighting ............................................. 57 Table 2.3, Bias and Relative Efficiency of Missing Data Designs (MDD) in the Presence of Non‐Designed Missing Data Relative to Complete Ascertainment Designs (CAD), 1000 Data Simulations ....................................................................... 58 Table 2.4, Cost‐Fixed Sample Size and Compliance Within Study Protocols Among Participants in the Nutrition in Pregnancy Study .......................................... 59 Table 2.5, Association Between Measures of Smoking and Small for Gestational Age by Week of Pregnancy and Study Design Among Participants in the Nutrition in Pregnancy Study ............................................................................................ 60 Table 3.1, Distribution of Baseline Characteristics by Levels of First Trimester Caffeine Consumption, Health and Nutrition in Pregnancy Study, 1996‐2001 .......... 83 Table 3.2, Association Between Caffeine Consumption and Intrauterine Growth Retardation Among Full Term Live Births, Health and Nutrition in Pregnancy Study, 1996‐2001 .......................................................................................... 85 Table 3.3, Associations Between Joint Effects of Self Reported Caffeine Intake and Potential Effect Modifiers and Intrauterine Growth Retardation Among Full Term Live Births, Health and Nutrition in Pregnancy Study, 1996‐2001 ...... 86 Table 3.4, Association Between Caffeine Consumption and Birth Weight Among Full Term Live Births, Health and Nutrition in Pregnancy Study, 1996‐2001 ...... 87 VIII List of Figures Figure 1.1, Calculation of the Incidence Rate Ratio from a 2X2 Table ............................ 32 Figure 1.2, Calculation of the Incidence Rate Ratio of Jointly Modeled Exposures ......... 32 Figure 1.3, Dose‐Response Patterns for (a) Constant Probability of Exposure Initiation, (b) Declining Probability of Exposure Initiation, and (c) Increasing Probability of Exposure Initiation .................................................................................... 33 Figure 2.1, Candidate Missing Data Designs ..................................................................... 61 Figure 2.2, Distribution of the Predicted Probability of Being Assigned to the Intensive Protocol Prior to Weighting (a) and After Weighting (b) ............................. 62 Figure 3.1, Directed Acyclic Graph for Confounders of the Association Between Caffeine and Fetal Growth ........................................................................................... 88 IX INTRODUCTION In epidemiological investigations of time varying exposures, repeat assessments of exposures are necessary to accurately characterize exposed person‐time and to quantify time‐dependent effects. Though time‐dependent effects are not unique to perinatal epidemiology, the sensitivity of exposure effects are magnified more so than any other time during human development due to the physiologic changes experienced by the mother and fetus. The profound changes in maternal metabolic, hematologic, cardiovascular, and respiratory physiology are rivaled only by that experience in the embryonic and fetal periods of development.[1] As a consequence of the maternal and fetal physiological changes, associations between perinatal exposures and adverse pregnancy outcomes are timing sensitive.[2, 3] That is, the same exposure may result in different outcomes depending on the gestational age at which the exposure occurred. This has been well documented for fetal/neonatal outcomes such as spontaneous abortion, birth defects, low birth weight, growth restriction, and fetal programming [2, 3]. In mothers, outcomes such as preeclampsia, eclampsia, maternal hemorrhage, and maternal mortality are sensitive to exposure timing[4]. Without assessment and evaluation of timing specific exposures, epidemiological investigations can not sufficiently describe the exposure/disease association nor will is validly estimate the underlying causal effect. 1
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