Common use of Conclusions Clause in Contracts

Conclusions. The specificity of QFT-GIT was high and similar to TST at either cutoff. Test discordance observed in recruits with increased risk may be due to lower TST specificity, lower QFT-GIT sensitivity, or both. Negative QFT-GIT results for recruits born in countries with high–TB prevalence and whose TST is > 15mm suggest that QFT-GIT may be less sensitive than TST. Additional studies are needed to determine the risk of developing TB when TST and QFT-GIT results are discordant. Assessing specificity and discordance between the tuberculin skin test and a whole-blood interferon-γ release assay for the detection of Mycobacterium tuberculosis infection among United States Navy recruits. By Xxxxx Xxxxxxx Xxxxx Bachelor of Science in Biology Bachelor of Science in Anthropology University of Utah 2007 Thesis Faculty Advisor: Xxxx X. XxXxxxx, Xx., M.D. Field Advisor: Xxxxxx X. Xxxxxxx, M.D. A thesis submitted to the Faculty of the Xxxxxxx School of Public Health of Emory University in partial fulfillment of the requirements for the degree of Master of Public Health in Epidemiology 2011 Acknowledgements I would like to thank Xx. Xxxxxxx and Xx. XxXxxxx for their efforts in advising and mentoring me through the processes of the thesis and my professional development while at Emory University and with the CDC; the staff at CDC, DTBE, especially Xxxxx Xxxxxxx, Xxxxxx Xxxxx, Kit Xxxxxxxxx, Xxxxxxx Xxxxxxxx and Xxxxx Xxxxxxx, for including me in the branch’s activities and assisting in innumerable ways with my analysis and manuscript; my professors at the Xxxxxxx School of Public Health, particularly Xx. Xxxxxxxxx, who provided council on my statistical analyses; also my friends and colleagues at in the Epidemiology and Behavioral Science and Health Education departments, who have helped make my time in Atlanta a rich experience; my parents, Xxxxxx and Xxxxxxx, for their unwavering love and support; and Xxxxxxx Xxxxx, who has endured the hardships of education with me and has given me such support and freedom, that I may never truly repay her gifts and sacrifices. Table of Contents INTRODUCTION 1 CHAPTER I: BACKGROUND 4 EPIDEMIOLOGY OF TUBERCULOSIS 4 PATHOGENESIS OF MYCOBACTERIUM TUBERCULOSIS INFECTION 6 DIAGNOSTICS FOR MYCOBACTERIUM TUBERCULOSIS INFECTION 11 THE TUBERCULIN SKIN TEST 14 INTERFERON-GAMMA RELEASE ASSAYS 19 WHOLE-BLOOD INTERFERON-GAMMA RELEASE ASSAYS 22 DISCORDANCE IN RESULTS FOR THE DETECTION OF M. TUBERCULOSIS INFECTION 29 LIMITATIONS TO INTERFERON-GAMMA RELEASE ASSAYS 36 TUBERCULOSIS AND THE UNITED STATES NAVY 40 LATENT TUBERCULOSIS INFECTION IN MILITARY RECRUITS 45 CHAPTER II: MANUSCRIPT 52 TITLE PAGE 52 INTRODUCTION 53 MATERIALS AND METHODS 58 RESULTS 64 DISCUSSION 70 LIMITATIONS AND STRENGTHS 83 CONCLUSION 87 REFERENCE LIST 89 TABLES 115 FIGURES 122 CHAPTER III: PUBLIC HEALTH IMPLICATIONS 124 SUMMARY 124 APPLICATIONS OF THE QUANTIFERON-TB GOLD IN-TUBE ASSAY 126 FUTURE DIRECTIONS 128 REFERENCES 131 APPENDICES 173 MILITARY HISTORY FORM FROM STUDY PROTOCOL 173 LINK TO XXXXXXX ET AL. – M. TUBERCULOSIS INFECTION IN NAVY RECRUITS, 2007 175 Tables and Figures TABLE 1. CHARACTERISTICS OF US NAVY RECRUITS 115 TABLE 2. OUTCOMES OF THE TUBERCULIN SKIN TEST VERSUS THE QUANTIFERON®-TB GOLD IN-TUBE ASSAY 116 TABLE 3. OUTCOMES OF THE QUANTIFERON®-TB GOLD ASSAY VERSUS THE QUANTIFERON®-TB GOLD IN-TUBE ASSAY 117 TABLE 4. UNIVARIATE ASSOCIATION OF SUBJECT CHARACTERISTICS WITH TUBERCULIN SKIN TEST OR QUANTIFERON®-TB GOLD IN-TUBE ASSAY RESULTS 118 TABLE 5. UNIVARIATE ASSOCIATION OF SUBJECT CHARACTERISTICS WITH DISCORDANT RESULTS BETWEEN THE QUANTIFERON®-TB GOLD IN-TUBE ASSAY AND THE TUBERCULIN SKIN TEST, USING A 10 MM CUTOFF 119 TABLE 6. UNIVARIATE ASSOCIATION OF SUBJECT CHARACTERISTICS WITH DISCORDANT RESULTS BETWEEN THE QUANTIFERON®-TB GOLD IN-TUBE ASSAY AND THE TUBERCULIN SKIN TEST, USING A 15 MM CUTOFF 120 TABLE 7. MULTIVARIATE ANALYSIS EXAMINING DISCORDANCE BETWEEN NEGATIVE QUANTIFERON®-TB GOLD IN-TUBE ASSAY RESULTS AND TUBERCULIN SKIN TEST RESULTS USING A 15 MM OR A 10 MM CUTOFF 121 FIGURE 1. DIAGRAM OF STUDY PARTICIPATION AND TESTING 122 FIGURE 2. COMPARISON OF TUBERCULIN SKIN TEST RESULTS TO INTERFERON-GAMMA RELEASE ASSAY INTERPRETATIONS, STRATIFIED BY RISK OF INFECTION 123 Introduction Tuberculosis (TB) is a leading cause of death and illness worldwide. The causative agent of TB is the Mycobacterium tuberculosis bacillus. Mycobacterium tuberculosis infection (MTBI) occurs in humans, who act as its primary reservoir. Approximately 2 billion people worldwide have quiescent or latent M. tuberculosis infection (LTBI) and are at risk of developing TB (1). Due to effective treatment and control measures, TB incidence and prevalence rates are declining in the United States (US) and most developed regions of the world (2, 3). However, elimination of TB remains elusive, even in high-resource countries because of continued transmission in groups at high risk of MTBI and progression to TB, difficulties in detecting MTBI, and programmatic complacency (4). Around 4% of the US population is thought to have LTBI, and is a constant source for future TB and MTBI transmission (5). There is continued pressure to improve diagnostic and screening methods for detecting MTBI, including LTBI and infection manifesting as TB (6-8). Identifying and treating LTBI among those at high risk of developing TB is an important component for TB control and elimination in low-TB incidence regions, such as the US and Canada (9, 10). No method exists for accurately detecting LTBI. Historically, the only way to diagnose LTBI was the tuberculin skin test (TST), which involved measuring immunologic delayed hypersensitivity to an intradermal injection of purified protein derivatives (PPD) made from M. tuberculosis (tuberculin PPD) (11). The TST has limitations in detecting LTBI in some settings. For example, where the prevalence of LTBI is low, the positive predictive value (PPV) of TST is hindered by cross reactions induced by sensitization to other mycobacteria (11). The development of interferon-gamma release assays (IGRA) offered an alternative to the TST and addressed some limitations in the TST (12, 13). MTBI typically induces an immune T-lymphocyte response which produces the cytokine interferon gamma (INF-γ) when the T-cells encounter mycobacterial antigens (13). Whole-blood IGRAs such as the 2nd generation, QuantiFERON®-TB Gold test (QFT-G) (Cellestis Limited, Xxxxxxxx, Xxxxxxxx, Australia) measure the amount of INF-γ released when blood is stimulated with specific Mycobacterium antigens (14). In 2007, the US Food and Drug Administration (FDA) approved the 3rd generation of IGRA for the detection of MTBI, the QuantiFERON®-TB Gold In-Tube test (QFT-GIT) (Cellestis Limited, Xxxxxxxx, Xxxxxxxx, Australia) (15). Like the TST, positive QFT-GIT results are highly associated with factors that historically contribute to MTBI (15, 16). However, QFT-GIT can exhibit discordance when compared to TST results and other IGRAs (15, 17-19). Absence of a “gold standard” to confirm MTBI limits IGRA assessments of accuracy and allows only estimates of sensitivity and specificity (15, 16). Approximations of sensitivity have been achieved by comparing the results of diagnostic tests to culture-confirmed cases of TB (15). Previous studies have assessed IGRAs among “assumed negative” populations at low-risk of MTBI, to better approximate specificity, with some consideration of test discordance (20- 22). Further research has been suggested to understand the factors associated with discordant test results (6, 15, 23). In light of the need for more research to understand IGRA accuracy and discordance, this study on QFT-GIT is part of a series of IGRA studies (21, 24- 26). This study was conducted to add to the current discourse on the interpretation of LTBI screening results among low-risk populations when considering multiple testing methods. The analysis of cross-sectional data obtained from US Navy recruits in 2004 will quantify QFT-GIT specificity for a population at low-risk for MTBI. Additionally, this study will identify recruit characteristics and estimate their associations to discordant results between the QFT-GIT and TST. Results for QFT-GIT will also be compared to other IGRA results, performed at the same time (21). Chapter I

Conclusions. The specificity of In a population with prior positive TSTs, TST was more variable than QFT-GIT was high and similar to TST at either cutoffwhen pairs of each test were performed simultaneously. Test discordance observed in recruits with increased risk TSTs may be due to lower TST specificity, lower QFT-GIT sensitivity, or both. Negative QFT-GIT results for recruits born in countries with high–TB prevalence and whose TST is > 15mm suggest that QFT-GIT may be less sensitive than TST. Additional studies are needed to determine the risk trigger conversion of developing TB when subsequent TST and QFT-GIT results are discordantGIT. Assessing specificity The Tuberculin Skin Test: Within-Subject Variability, Boosting, and discordance between Comparison with the tuberculin skin test and a wholeQuantiFERON-blood interferonTB Gold In-γ release assay for the detection of Mycobacterium tuberculosis infection among United States Navy recruits. Tube Test By Xxxxx Xxxxxxx Xxxxx Bachelor of Science in Biology Bachelor of Science in Anthropology Xxxxxx Xxxxxx-Xxxxxx DMD Medical University of Utah 2007 Sofia 1982 Thesis Faculty Advisor: Xxxx X. XxXxxxx, Xx., M.D. Field AdvisorCommittee Chair: Xxxxxx X. Xxxxxxx, M.D. PhD Thesis Field Advisors: Xxxxxx Xxxxxxx, MD and Xxxxxxx X. Xxxxxxxxx, MPH A thesis submitted to the Faculty faculty of the Xxxxxxx School of Public Health of Emory University in partial fulfillment of the requirements for the degree of Master of Public Health in Epidemiology 2011 Acknowledgements the Executive Master of Public Health Program, 2017 Acknowledgments I would like to thank express my sincerest gratitude to my committee chair, Xx. Xxxxxx Xxxxxxx and my field advisors, Xx. Xxxxxx Xxxxxxx and Xx. XxXxxxx Xxxxxxx Xxxxxxxxx. I would also like to express my gratitude to the Centers for their efforts in advising Disease Control and mentoring me through Prevention, Division of Tuberculosis Elimination’s Clinical Research Branch, with whom I had the processes honor and privilege of working and learning. I would also like to thank the thesis students and my professional development while faculty at Emory University and with the CDC; the staff at CDC, DTBE, especially Xxxxx Xxxxxxx, Xxxxxx Xxxxx, Kit Xxxxxxxxx, Xxxxxxx Xxxxxxxx and Xxxxx Xxxxxxx, for including me in the branch’s activities and assisting in innumerable ways with my analysis and manuscript; my professors at the Xxxxxxx School of Public Health, particularly XxHealth – EMPH program for helping me and providing me valuable knowledge and skills. Xxxxxxxxx, who provided council on I would finally like to thank my statistical analyses; also my friends and colleagues at in the Epidemiology and Behavioral Science and Health Education departments, who have helped make my time in Atlanta a rich experience; my parents, Xxxxxx and Xxxxxxx, family for their unwavering love constant understanding, patience, and support; . The findings and Xxxxxxx Xxxxxconclusions in this document are solely those of the author and do not necessarily represent the official views of the Centers for Disease Control and Prevention, who has endured The U. S. Department of Defense, or the hardships of education with me and has given me such support and freedom, that I may never truly repay her gifts and sacrificesU. S. Air Force. Table of Contents INTRODUCTION 1 CHAPTER I: BACKGROUND INTRODUCTION 1 INFECTION AND DISEASE DUE TO MYCOBACTERIUM TUBERCULOSIS 1 Historical Perspective 1 Epidemiology 2 Transmission 4 EPIDEMIOLOGY OF TUBERCULOSIS 4 PATHOGENESIS OF MYCOBACTERIUM TUBERCULOSIS INFECTION 5 Treatment and Control 6 DIAGNOSTICS Targeted Testing 7 IMMUNOLOGIC TESTS FOR MYCOBACTERIUM TUBERCULOSIS INFECTION 9 Tuberculin Skin Test (TST) 9 Interferon-Gamma Release Assay (IGRA) 11 THE TUBERCULIN SKIN TEST PROBLEMS ADDRESSED BY THIS RESEARCH 14 INTERFERONWithin-GAMMA RELEASE ASSAYS 19 WHOLESubject TST Variability 14 TST – QFT Agreement 15 Boosting of Immunologic Responses as Measured by TST 15 Boosting of Immunologic Responses as Measured by QFT-BLOOD INTERFERON-GAMMA RELEASE ASSAYS 22 DISCORDANCE IN RESULTS FOR THE DETECTION OF M. TUBERCULOSIS INFECTION 29 LIMITATIONS TO INTERFERON-GAMMA RELEASE ASSAYS 36 TUBERCULOSIS AND THE UNITED STATES NAVY 40 LATENT TUBERCULOSIS INFECTION IN MILITARY RECRUITS 45 GIT 17 ANALYSIS GOALS CHAPTER II: MANUSCRIPT 52 TITLE PAGE 52 INTRODUCTION 53 MATERIALS LITERATURE REVIEW 19 MEASURES OF VARIABILITY AND METHODS 58 BOOSTING REPORTED IN PRIOR STUDIES 19 WITHIN-SUBJECT TST VARIABILITY (WITHIN-SUBJECT COMPARISON OF TST RESULTS) 20 WITHIN-SUBJECT COMPARISON OF TST AND QFT-GIT RESULTS 64 DISCUSSION 70 LIMITATIONS AND STRENGTHS 83 CONCLUSION 87 REFERENCE LIST 89 TABLES 115 FIGURES 122 22 TST BOOSTING CHAPTER III: PUBLIC HEALTH IMPLICATIONS 124 SUMMARY 124 APPLICATIONS OF THE QUANTIFERON-TB GOLD IN-TUBE ASSAY 126 FUTURE DIRECTIONS 128 REFERENCES 131 APPENDICES 173 MILITARY HISTORY FORM FROM METHODS 28 STUDY PROTOCOL 173 LINK TO XXXXXXX ET AL. – M. TUBERCULOSIS INFECTION IN NAVY RECRUITS, 2007 175 Tables and Figures TABLE 1. CHARACTERISTICS OF US NAVY RECRUITS 115 TABLE 2. OUTCOMES OF THE TUBERCULIN SKIN POPULATION 28 ANALYSIS AND STUDY DESIGN 29 TEST VERSUS THE QUANTIFERON®-TB GOLD IN-TUBE ASSAY 116 TABLE 3. OUTCOMES OF THE QUANTIFERON®-TB GOLD ASSAY VERSUS THE QUANTIFERON®-TB GOLD IN-TUBE ASSAY 117 TABLE 4. UNIVARIATE ASSOCIATION OF METHODS 30 STATISTICAL ANALYSIS METHODS 31 CHAPTER IV: RESULTS 32 SUBJECT CHARACTERISTICS WITH TUBERCULIN SKIN TEST OR QUANTIFERON®-TB GOLD IN-TUBE ASSAY RESULTS 118 TABLE 5. UNIVARIATE ASSOCIATION OF SUBJECT CHARACTERISTICS WITH DISCORDANT RESULTS BETWEEN THE QUANTIFERON®-TB GOLD IN-TUBE ASSAY AND THE TUBERCULIN SKIN TEST, USING A 10 MM CUTOFF 119 TABLE 6. UNIVARIATE ASSOCIATION OF SUBJECT CHARACTERISTICS WITH DISCORDANT RESULTS BETWEEN THE QUANTIFERON®-TB GOLD IN-TUBE ASSAY AND THE TUBERCULIN SKIN TEST, USING A 15 MM CUTOFF 120 TABLE 7. MULTIVARIATE ANALYSIS EXAMINING DISCORDANCE BETWEEN NEGATIVE QUANTIFERON®-TB GOLD IN-TUBE ASSAY RESULTS AND TUBERCULIN SKIN TEST RESULTS USING 33 OBJECTIVE I: ASSESSMENT OF WITHIN-SUBJECT XXX XXXXXXXXXXX 00 XXXXXXXXX XX: ASSESSMENT OF TST - QFT-GIT AGREEMENT 34 OBJECTIVE III: ASSESSMENT OF TST BOOSTING OF A 15 MM OR SUBSEQUENT TST OBJECTIVE IV: ASSESSMENT OF TST BOOSTING OF A 10 MM CUTOFF 121 FIGURE 1. DIAGRAM OF STUDY PARTICIPATION SUBSEQUENT QFT-GIT 35 CHAPTER V: DISCUSSION 36 INTRODUCTION 36 SUMMARY AND TESTING 122 FIGURE 2. COMPARISON OF TUBERCULIN SKIN TEST RESULTS TO INTERFERON-GAMMA RELEASE ASSAY INTERPRETATIONS, STRATIFIED BY RISK OF INFECTION 123 FINDINGS 37 LIMITATIONS 39 IMPLICATIONS 40 RECOMMENDATIONS FOR FUTURE STUDIES 42 CONCLUSIONS 42 FIGURES 43 TABLES 47 REFERENCES 52 Chapter I: Introduction Infection and Disease Due to Mycobacterium Tuberculosis Historical Perspective Tuberculosis (TB) is a leading cause an infectious disease that has ravaged humanity for ages and continues to kill millions of death people each year. TB usually affects the lungs and illness worldwideis transmitted from human-to-human through inhalation. The causative agent of TB bacterium that is the primarily responsible for causing TB, Mycobacterium tuberculosis bacillus(MTB), was first identified and described in 1882 by Xxxxxx Xxxx. Mycobacterium tuberculosis infection Infections with MTB (MTBI) occurs in humanscan be classified as either an active disease (referred to as TB) with clinical symptoms and pathological signs, who act or as its primary reservoir. Approximately 2 billion people worldwide have quiescent or latent M. tuberculosis an asymptomatic non-contagious state, often called “latent” TB infection (LTBI) and are at risk of developing TB (1). Due to effective treatment and control measures, People with TB incidence and prevalence rates are declining in the United States (US) and most developed regions of the world (2, 3). However, elimination of TB remains elusive, even in high-resource countries because of continued transmission in groups at high risk of MTBI and progression to TB, difficulties in detecting MTBI, and programmatic complacency (4). Around 4% of the US population is thought to have LTBI, and is a constant source for future TB and MTBI transmission (5). There is continued pressure to improve diagnostic and screening methods for detecting MTBI, including LTBI and infection manifesting as TB (6-8). Identifying and treating LTBI among those at high risk of developing TB is an important component for TB control and elimination in low-TB incidence regionsmay present with constitutional symptoms, such as weight loss, fever, chills, night sweats, and weakness, but may also present with symptoms associated with disease in specific organs. The lung is most often affected as evidence by symptoms of cough, sputum production, hemoptysis, and chest pain, that are typically accompanied by an abnormal chest x-ray. Pulmonary TB accounts for approximately 80% of newly diagnosed TB in the US and Canada (9, 10)U. S. while 20% to 30% involves extra-pulmonary sites. No method exists for accurately detecting LTBI. Historically, the only way Traditional methods used to diagnose LTBI was TB rely primarily on sputum smear microscopy, bacteriological culture, and clinical examination, although newer and rapid molecular tests are being used with increasing frequency. A combination of sputum culture and clinical exam are considered the tuberculin skin test gold standard for definitive TB diagnosis. TB is curable with a standard six month course of four antimicrobial agents (TSTisoniazid, rifampicin, pyrazinamide, and ethambutol), which involved measuring immunologic delayed hypersensitivity to an intradermal injection but, if left untreated, 70% of purified protein derivatives cases worldwide will not survive 10 years (PPD) made from M. tuberculosis (tuberculin PPD) (11World Health Organization, 2016). The TST has limitations in detecting LTBI in some settings. For example, where the prevalence of LTBI is low, the positive predictive value (PPV) of TST is hindered by cross reactions induced by sensitization to other mycobacteria (11). The development of interferon-gamma release assays (IGRA) offered an alternative to the TST and addressed some limitations in the TST (12, 13). MTBI typically induces an immune T-lymphocyte response which produces the cytokine interferon gamma (INF-γ) when the T-cells encounter mycobacterial antigens (13). Whole-blood IGRAs such as the 2nd generation, QuantiFERON®-TB Gold test (QFT-G) (Cellestis Limited, Xxxxxxxx, Xxxxxxxx, Australia) measure the amount of INF-γ released when blood is stimulated with specific Mycobacterium antigens (14). In 2007, the US Food and Drug Administration (FDA) approved the 3rd generation of IGRA for the detection of MTBI, the QuantiFERON®-TB Gold In-Tube test (QFT-GIT) (Cellestis Limited, Xxxxxxxx, Xxxxxxxx, Australia) (15). Like the TST, positive QFT-GIT results are highly associated with factors that historically contribute to MTBI (15, 16). However, QFT-GIT can exhibit discordance when compared to TST results and other IGRAs (15, 17-19). Absence of a “gold standard” to confirm MTBI limits IGRA assessments of accuracy and allows only estimates of sensitivity and specificity (15, 16). Approximations of sensitivity have been achieved by comparing the results of diagnostic tests to culture-confirmed cases of TB (15). Previous studies have assessed IGRAs among “assumed negative” populations at low-risk of MTBI, to better approximate specificity, with some consideration of test discordance (20- 22). Further research has been suggested to understand the factors associated with discordant test results (6, 15, 23). In light of the need for more research to understand IGRA accuracy and discordance, this study on QFT-GIT is part of a series of IGRA studies (21, 24- 26). This study was conducted to add to the current discourse on the interpretation of LTBI screening results among low-risk populations when considering multiple testing methods. The analysis of cross-sectional data obtained from US Navy recruits in 2004 will quantify QFT-GIT specificity for a population at low-risk for MTBI. Additionally, this study will identify recruit characteristics and estimate their associations to discordant results between the QFT-GIT and TST. Results for QFT-GIT will also be compared to other IGRA results, performed at the same time (21). Chapter I.

Conclusions. The specificity This study finds no evidence indicating an association between nitrosamine exposure from condoms and incidence of QFTcervical and colorectal cancer. Condoms provide substantial and measurable public health benefits, and providers and healthcare organizations should continue to recommend and promote them without hesitation. Lack of ecological association between state-GIT was high level cervical and similar to TST at either cutoff. Test discordance observed in recruits with increased risk may be due to lower TST specificity, lower QFTcolorectal cancer incidence and nitrosamine exposure from condom use for a cross-GIT sensitivity, or both. Negative QFT-GIT results for recruits born in countries with high–TB prevalence and whose TST is > 15mm suggest that QFT-GIT may be less sensitive than TST. Additional studies are needed to determine sectional study of the risk of developing TB when TST and QFT-GIT results are discordant. Assessing specificity and discordance between the tuberculin skin test and a whole-blood interferon-γ release assay for the detection of Mycobacterium tuberculosis infection among United States Navy recruits. By Xxxxx Xxxxxxx Xxxxx Xxxxxx XxXxxxxx Bachelor of Science in Biology Bachelor of Science in Anthropology University of Utah 2007 Arts, Vassar College, 2013 Thesis Faculty AdvisorCommittee Chairs: Xxxx X. XxXxxxxXxxxx Xxxxx, Xx.PhD, M.D. Field Advisor: Xxxxxx X. MPH Xxxxx Xxxxxxx, M.D. PhD, MHS A thesis submitted to the Faculty of the Xxxxxxx School of Public Health of Emory University in partial fulfillment of the requirements for the degree of Master of Public Health in Global Epidemiology 2011 2016 Acknowledgements I would like to thank Xx. express sincere appreciation to my committee chairs Xxxxx Xxxxxxx and XxXxxxx Xxxxx for agreeing to take on another thesis advisee despite their very busy schedules. XxXxxxx Thank you so much for your support and advice during this process, as well as your good humor and very interesting conversations. I would like to thank Xxx X’Xxxxxx at the Emory Center for Digital Scholarship and Xxxxxxx Xxxxxxxx at the Xxxxxxxx Health Science Center Library for their efforts help, including answering emails at 10pm on a Sunday and agreeing to meet frantic MPH students the very next day. I would also like to thank Xxxxx Xxxxxxx for her expertise and infectious enthusiasm for mapping and GIS, as well as her encyclopedic knowledge in advising finding (free) data. Finally, all my love and mentoring me through the processes of the thesis and my professional development while at Emory University and with the CDC; the staff at CDC, DTBE, especially Xxxxx Xxxxxxx, Xxxxxx Xxxxx, Kit Xxxxxxxxx, Xxxxxxx Xxxxxxxx and Xxxxx Xxxxxxx, for including me in the branch’s activities and assisting in innumerable ways with my analysis and manuscript; my professors at the Xxxxxxx School of Public Health, particularly Xx. Xxxxxxxxx, who provided council on my statistical analyses; also gratitude to my friends and colleagues at family. To my Xxxxxxx friends, I could not have done it without you all—we’re (almost) done! To everyone else, I’ll stop talking about this and return calls/emails in the Epidemiology and Behavioral Science and Health Education departmentsa timely manner now, who have helped make my time in Atlanta a rich experience; my parents, Xxxxxx and Xxxxxxx, for their unwavering love and support; and Xxxxxxx Xxxxx, who has endured the hardships of education with me and has given me such support and freedom, that I may never truly repay her gifts and sacrificesswear. Table of Contents INTRODUCTION 1 CHAPTER INitrosamines in food and water 5 Occupational exposure to nitrosamines 9 Nitrosamines in rubber products 13 Colorectal cancer 18 Cervical Cancer 19 METHODS 21 Data Sources 21 Spatial Analysis 23 Bivariate association with cancer incidence 24 Multivariable association with cancer incidence 25 RESULTS 27 Colorectal Cancer Incidence 27 Cervical Cancer Incidence 28 DISCUSSION: BACKGROUND 29 Conclusions 29 Limitations: 30 Future directions 32 APPENDIX 34 Figure 1 34 Figure 2 35 Figure 3 36 Figure 4 EPIDEMIOLOGY OF TUBERCULOSIS 37 Figure 5 38 Figure 6 39 Figure 7 40 Figure 8 41 Table 1 42 Table 2 43 Table 3 44 Table 4 PATHOGENESIS OF MYCOBACTERIUM TUBERCULOSIS INFECTION 6 DIAGNOSTICS FOR MYCOBACTERIUM TUBERCULOSIS INFECTION 11 THE TUBERCULIN SKIN TEST 14 INTERFERON45 Table 5 46 Works Cited 47 Non-GAMMA RELEASE ASSAYS 19 WHOLEprinted sources cited 53 Introduction Condoms are one of the most important public health tools in sexual health, playing roles in human immunodeficiency virus (HIV) prevention, prevention of sexually transmitted infections (STIs), and family planning. There has been substantial investment by local governments, international health agencies and non- governmental organizations (NGOs) to increase supply and uptake of condoms (Xxxxxx et al., 2016; Xxxxxxx et al., 2008; Xxxxxxx et al., 2016; Xxxxx et al., 2015). Increasing access to condoms and education about STI and HIV prevention has resulted in important gains in condom use, especially among high-BLOOD INTERFERON-GAMMA RELEASE ASSAYS 22 DISCORDANCE IN RESULTS FOR THE DETECTION OF M. TUBERCULOSIS INFECTION 29 LIMITATIONS TO INTERFERON-GAMMA RELEASE ASSAYS 36 TUBERCULOSIS AND THE UNITED STATES NAVY 40 LATENT TUBERCULOSIS INFECTION IN MILITARY RECRUITS 45 CHAPTER II: MANUSCRIPT 52 TITLE PAGE 52 INTRODUCTION 53 MATERIALS AND METHODS 58 RESULTS 64 DISCUSSION 70 LIMITATIONS AND STRENGTHS 83 CONCLUSION 87 REFERENCE LIST 89 TABLES 115 FIGURES 122 CHAPTER III: PUBLIC HEALTH IMPLICATIONS 124 SUMMARY 124 APPLICATIONS OF THE QUANTIFERON-TB GOLD IN-TUBE ASSAY 126 FUTURE DIRECTIONS 128 REFERENCES 131 APPENDICES 173 MILITARY HISTORY FORM FROM STUDY PROTOCOL 173 LINK TO XXXXXXX ET AL. – M. TUBERCULOSIS INFECTION IN NAVY RECRUITS, 2007 175 Tables and Figures TABLE 1. CHARACTERISTICS OF US NAVY RECRUITS 115 TABLE 2. OUTCOMES OF THE TUBERCULIN SKIN TEST VERSUS THE QUANTIFERON®-TB GOLD IN-TUBE ASSAY 116 TABLE 3. OUTCOMES OF THE QUANTIFERON®-TB GOLD ASSAY VERSUS THE QUANTIFERON®-TB GOLD IN-TUBE ASSAY 117 TABLE 4. UNIVARIATE ASSOCIATION OF SUBJECT CHARACTERISTICS WITH TUBERCULIN SKIN TEST OR QUANTIFERON®-TB GOLD IN-TUBE ASSAY RESULTS 118 TABLE 5. UNIVARIATE ASSOCIATION OF SUBJECT CHARACTERISTICS WITH DISCORDANT RESULTS BETWEEN THE QUANTIFERON®-TB GOLD IN-TUBE ASSAY AND THE TUBERCULIN SKIN TEST, USING A 10 MM CUTOFF 119 TABLE 6. UNIVARIATE ASSOCIATION OF SUBJECT CHARACTERISTICS WITH DISCORDANT RESULTS BETWEEN THE QUANTIFERON®-TB GOLD IN-TUBE ASSAY AND THE TUBERCULIN SKIN TEST, USING A 15 MM CUTOFF 120 TABLE 7. MULTIVARIATE ANALYSIS EXAMINING DISCORDANCE BETWEEN NEGATIVE QUANTIFERON®-TB GOLD IN-TUBE ASSAY RESULTS AND TUBERCULIN SKIN TEST RESULTS USING A 15 MM OR A 10 MM CUTOFF 121 FIGURE 1. DIAGRAM OF STUDY PARTICIPATION AND TESTING 122 FIGURE 2. COMPARISON OF TUBERCULIN SKIN TEST RESULTS TO INTERFERON-GAMMA RELEASE ASSAY INTERPRETATIONS, STRATIFIED BY RISK OF INFECTION 123 Introduction Tuberculosis risk populations like commercial sex workers (TB) is a leading cause of death and illness worldwide. The causative agent of TB is the Mycobacterium tuberculosis bacillus. Mycobacterium tuberculosis infection (MTBI) occurs in humans, who act as its primary reservoir. Approximately 2 billion people worldwide have quiescent or latent M. tuberculosis infection (LTBICSW) and are at risk of developing TB men who have sex with men (1). Due to effective treatment and control measuresMSM) (Xxxxxxx et al., TB incidence and prevalence rates are declining in the United States (US) and most developed regions of the world (22008; Xxxxxx & Xxxxx, 32016; Xxxxxxxx et al., 2016; Xxxxxxxxxxx et al., 2013). However, elimination of TB remains elusivecondom usage among CSWs continues to face barriers including client preference for unprotected sex, even in high-resource countries because of continued transmission in groups at high risk of MTBI and progression to TB, difficulties in detecting MTBIinconsistent condom supply, and programmatic complacency policies that criminalize sex work (4Xxxxxxxx et al., 2016; Xxxx, 2013). Around 4Among MSM populations, condom use is mediated by perceptions of risk and condom self-efficacy (Xxxxxx & Xxxxx, 2016; Xxxxxxxxxx et al., 2016; Xxxx, 2013). National rates of condom use in the US vary by race, age, gender, and sex act: 24.7% of the US population is thought to have LTBImen and 21.8% of women report condom use at last vaginal intercourse while 26.5% of insertive male partners, 44.1% of receptive male partners and is a constant source for future TB and MTBI transmission 10.8% of receptive female partners report condom use at last anal intercourse (5Xxxxx et al., 2010). There is continued pressure One of the barriers to improve diagnostic and screening methods for detecting MTBI, including LTBI and infection manifesting as TB (6-8). Identifying and treating LTBI among those at high risk of developing TB is an important component for TB control and elimination condom usage in low-TB incidence regionsincome countries is negative perception or rumors about condoms (Xxxxxxx et al., such as the US and Canada 2004); a study in Tanzania found that negative beliefs about condoms were significant predictors of willingness to use condoms (9Xxxxxxx et al., 102012). No method exists for accurately detecting LTBIPerceptions by the public about condom safety and efficacy directly affect their use and thus can adversely affect sexual and reproductive health programs (Xxxxx et al., 2014; Xxxxxxx et al., 2012). HistoricallyNegative beliefs about condoms include the belief that condoms cause cancer (Xxxxxxx et al., 2012). This is actually a concern among some condom manufacturers —specifically, the only way to diagnose LTBI was release of nitrosamines from condoms (ISO/TC 157, 2015). Nitrosamines are a class of carcinogenic compounds that can be produced in the tuberculin skin test manufacturing process of rubber products. Formed by the reaction of nitrites with secondary or tertiary amines, nitrosamines can vary in their carcinogenicity, with two potent carcinogens, N‐nitrosodiethylamine (TSTNDEA) and N- nitrosodimethylamine (NDMA), which involved measuring immunologic delayed hypersensitivity to an intradermal injection often used as indicators of purified protein derivatives nitrosamine presence (PPD) made from M. tuberculosis (tuberculin PPD) (11Xxxxx, 2011). The TST has limitations in detecting LTBI in some settings. For example, where the prevalence of LTBI is lowWorld Health Organization (WHO), the positive predictive value European Union, and the US Environmental Protection Agency (PPVEPA) of TST is hindered by cross reactions induced by sensitization to other mycobacteria classify NDEA and NDMA as probable or presumed human carcinogens (11Xxxxx, 2011). The US Department of Health and Human Services released the 13th Report on Carcinogens in 2014, which included 15 listings of nitrosamines classified as “known or reasonably anticipated” carcinogens (NTP, 2014). Nitrosamines are linked with the development of interferon-gamma release assays multiple different types of cancer in many different animal models, including colon tumors in male rats, female mice and guinea pigs, as well as cervical tumors in female shrews following rectal or oral administration (IGRA) offered an alternative to the TST and addressed some limitations in the TST (12NTP, 132014). MTBI typically induces an immune T-lymphocyte response which produces the cytokine interferon gamma Nitrosamines have been found in food, cosmetics, tobacco products, and rubber goods such as balloons, pacifiers, baby bottle teats, and also condoms (INF-γ) when the T-cells encounter mycobacterial antigens (13NTP, 2007; Xxxx et al., 2015; Xxxxxxxx et al., 2005; Xxxxxxxx et al., 2015; Xxxxxxxx & Xxxxxxxxxxxx, 2011). WholeNitrosamine-blood IGRAs such related cancer studies in humans are relatively scarce, though they include epidemiological studies of cancer mortality for occupational cohorts, as the 2nd generationwell as case-control or ecological studies conducted on dietary exposure (Monarca et al., QuantiFERON®-TB Gold test (QFT-G) (Cellestis Limited2001; de Vocht et al., Xxxxxxxx2007; NTP, Xxxxxxxx, Australia) measure the amount of INF-γ released when blood is stimulated with specific Mycobacterium antigens (142014). In 2007Subsequent sections will discuss studies and regulations regarding nitrosamine exposure in occupational settings, the US Food food and Drug Administration (FDA) approved the 3rd generation of IGRA for the detection of MTBIdrinking water, the QuantiFERON®-TB Gold In-Tube test (QFT-GIT) (Cellestis Limitedas well as rubber products like pacifiers, Xxxxxxxxrubber gloves, Xxxxxxxx, Australia) (15). Like the TST, positive QFT-GIT results are highly associated with factors that historically contribute to MTBI (15, 16). However, QFT-GIT can exhibit discordance when compared to TST results and other IGRAs (15, 17-19). Absence of a “gold standard” to confirm MTBI limits IGRA assessments of accuracy and allows only estimates of sensitivity and specificity (15, 16). Approximations of sensitivity have been achieved by comparing the results of diagnostic tests to culture-confirmed cases of TB (15). Previous studies have assessed IGRAs among “assumed negative” populations at low-risk of MTBI, to better approximate specificity, with some consideration of test discordance (20- 22). Further research has been suggested to understand the factors associated with discordant test results (6, 15, 23). In light of the need for more research to understand IGRA accuracy and discordance, this study on QFT-GIT is part of a series of IGRA studies (21, 24- 26). This study was conducted to add to the current discourse on the interpretation of LTBI screening results among low-risk populations when considering multiple testing methodscondoms1. The analysis migration of cross-sectional data obtained nitrosamines from US Navy recruits in 2004 will quantify QFT-GIT specificity for condoms to mucous membranes like the vagina and rectum, which have higher absorption, is a population at low-possible risk for MTBI. Additionally(Eisenbrand, this study will identify recruit characteristics and estimate their associations to discordant results between the QFT-GIT and TST. Results for QFT-GIT will also be compared to other IGRA results, performed at the same time (212005). Chapter I.

Conclusions. The specificity This pilot study offers the first regional-level characterization of QFT-GIT was high PLWH proceeding through the early steps of transplantation. PLWH were less likely to traverse the steps of kidney transplant compared with those HIV negative, highlighting the need for targeted interventions to improve access to kidney transplant for PLWH. Identifying the barriers and similar disparities for referral to TST at either cutoff. Test discordance observed in recruits kidney transplantation faced by person living with increased risk may be due to lower TST specificity, lower QFT-GIT sensitivity, or both. Negative QFT-GIT results for recruits born in countries with high–TB prevalence HIV and whose TST is > 15mm suggest that QFT-GIT may be less sensitive than TST. Additional studies are needed to determine the risk of developing TB when TST and QFT-GIT results are discordant. Assessing specificity and discordance between the tuberculin skin test and a whole-blood interferon-γ release assay for the detection of Mycobacterium tuberculosis infection among United States Navy recruits. end stage renal disease By Xxxxx Xxxxxxx Xxxxx Bachelor of Science in Biology Bachelor of Science in Anthropology University of Utah 2007 Thesis Faculty Advisor: Xxxx X. XxXxxxxXxxxxxxx ScB, Xx.Monmouth University, M.D. Field 2009 MD, Xxxxxx Xxxxxxxxxx University School of Health Sciences, 2013 Advisor: Xxxxxx X. XxxxxxxXxxxx, M.D. MD A thesis submitted to the Faculty of the Xxxxxxx Xxxxx X. Xxxxx School of Public Health Graduate Studies of Emory University in partial fulfillment of the requirements for the degree of Master of Public Health Science in Epidemiology 2011 Acknowledgements Clinical Research 2020 I would like to thank Xx. Xxxxxx Xxxxx and Xx. Xxxxxx Xxxxxx for serving as research mentors. Their assistance in honing my ideas and interests, providing me with the necessary support and guidance to complete my MSCR application, and informative discussions regarding the implications of this work, not only tremendously developed this work, but helped me to grow as a junior investigator. I am thankful for the help of Dr. Xxxxxxxxx (AKA Xxxxx) Xxxx who assisted me with the analysis and served as my reader and additionally and Xx. Xxxxxxxxx for reviewing the drafts of this thesis. I would like to thank Xx. Xxxxxxx Xxxxx for being instrumental in obtaining the data for this project and Xxbeing so accommodating to additional data requests. XxXxxxx I am also appreciative of Dr. Xxxxx Xxxxxxxxx who has been a fearless leader and program director, and the main reason why I applied to the MSCR program. Lastly, I would like to thank my husband Xxxxxx Xxxxxxxxx for their efforts in advising his patience, love, support, and mentoring me through the processes of the thesis and my professional development while at Emory University and with the CDC; the staff at CDC, DTBE, especially Xxxxx Xxxxxxx, Xxxxxx Xxxxx, Kit Xxxxxxxxx, Xxxxxxx Xxxxxxxx and Xxxxx Xxxxxxx, for including me SAS consultations. TABLE OF CONTENTS INTRODUCTION 1 BACKGROUND 3 METHODS 8 RESULTS 19 DISCUSSION 24 CONCLUSIONS 33 REFERENCES 34 INTRODUCTION‌ End-stage renal disease (ESRD) has increased by 1000% in the branch’s activities and assisting in innumerable ways with my analysis and manuscript; my professors at the Xxxxxxx School of Public Healthpast 3 decades, particularly Xx. Xxxxxxxxx, who provided council on my statistical analyses; also my friends and colleagues at proving to be a significant health concern in the Epidemiology and Behavioral Science and Health Education departmentsUnited Sates. In 1980, who have helped make my time there were 60,000 persons with ESRD though in Atlanta a rich experience; my parents, Xxxxxx and Xxxxxxx, for their unwavering love and support; and Xxxxxxx Xxxxx, who has endured the hardships of education 2018 there were over 700,000 Americans living with me and has given me such support and freedom, that I may never truly repay her gifts and sacrifices. Table of Contents INTRODUCTION 1 CHAPTER I: BACKGROUND 4 EPIDEMIOLOGY OF TUBERCULOSIS 4 PATHOGENESIS OF MYCOBACTERIUM TUBERCULOSIS INFECTION 6 DIAGNOSTICS FOR MYCOBACTERIUM TUBERCULOSIS INFECTION 11 THE TUBERCULIN SKIN TEST 14 INTERFERON-GAMMA RELEASE ASSAYS 19 WHOLE-BLOOD INTERFERON-GAMMA RELEASE ASSAYS 22 DISCORDANCE IN RESULTS FOR THE DETECTION OF M. TUBERCULOSIS INFECTION 29 LIMITATIONS TO INTERFERON-GAMMA RELEASE ASSAYS 36 TUBERCULOSIS AND THE UNITED STATES NAVY 40 LATENT TUBERCULOSIS INFECTION IN MILITARY RECRUITS 45 CHAPTER II: MANUSCRIPT 52 TITLE PAGE 52 INTRODUCTION 53 MATERIALS AND METHODS 58 RESULTS 64 DISCUSSION 70 LIMITATIONS AND STRENGTHS 83 CONCLUSION 87 REFERENCE LIST 89 TABLES 115 FIGURES 122 CHAPTER III: PUBLIC HEALTH IMPLICATIONS 124 SUMMARY 124 APPLICATIONS OF THE QUANTIFERON-TB GOLD IN-TUBE ASSAY 126 FUTURE DIRECTIONS 128 REFERENCES 131 APPENDICES 173 MILITARY HISTORY FORM FROM STUDY PROTOCOL 173 LINK TO XXXXXXX ET AL. – M. TUBERCULOSIS INFECTION IN NAVY RECRUITS, 2007 175 Tables and Figures TABLE 1. CHARACTERISTICS OF US NAVY RECRUITS 115 TABLE 2. OUTCOMES OF THE TUBERCULIN SKIN TEST VERSUS THE QUANTIFERON®-TB GOLD IN-TUBE ASSAY 116 TABLE 3. OUTCOMES OF THE QUANTIFERON®-TB GOLD ASSAY VERSUS THE QUANTIFERON®-TB GOLD IN-TUBE ASSAY 117 TABLE 4. UNIVARIATE ASSOCIATION OF SUBJECT CHARACTERISTICS WITH TUBERCULIN SKIN TEST OR QUANTIFERON®-TB GOLD IN-TUBE ASSAY RESULTS 118 TABLE 5. UNIVARIATE ASSOCIATION OF SUBJECT CHARACTERISTICS WITH DISCORDANT RESULTS BETWEEN THE QUANTIFERON®-TB GOLD IN-TUBE ASSAY AND THE TUBERCULIN SKIN TEST, USING A 10 MM CUTOFF 119 TABLE 6. UNIVARIATE ASSOCIATION OF SUBJECT CHARACTERISTICS WITH DISCORDANT RESULTS BETWEEN THE QUANTIFERON®-TB GOLD IN-TUBE ASSAY AND THE TUBERCULIN SKIN TEST, USING A 15 MM CUTOFF 120 TABLE 7. MULTIVARIATE ANALYSIS EXAMINING DISCORDANCE BETWEEN NEGATIVE QUANTIFERON®-TB GOLD IN-TUBE ASSAY RESULTS AND TUBERCULIN SKIN TEST RESULTS USING A 15 MM OR A 10 MM CUTOFF 121 FIGURE 1. DIAGRAM OF STUDY PARTICIPATION AND TESTING 122 FIGURE 2. COMPARISON OF TUBERCULIN SKIN TEST RESULTS TO INTERFERON-GAMMA RELEASE ASSAY INTERPRETATIONS, STRATIFIED BY RISK OF INFECTION 123 Introduction Tuberculosis (TB) is a leading cause of death and illness worldwide. The causative agent of TB is the Mycobacterium tuberculosis bacillus. Mycobacterium tuberculosis infection (MTBI) occurs in humans, who act as its primary reservoir. Approximately 2 billion people worldwide have quiescent or latent M. tuberculosis infection (LTBI) and are at risk of developing TB ESRD (1). Due The expense of Chronic Kidney Disease (CKD) and ESRD has a significant impact on the United States economy and in 2018, CKD and ESRD accounted for approximately 7% of Medicare expenditure, equating to $114 billion per year (2,3). It is well established that kidney transplantation is the optimal therapy for ESRD as it provides increased survival, better quality of life, and is less costly when compared with conventional dialysis (4–7). Since the advent of effective antiretroviral therapy, persons living with HIV (PLWH) are surviving longer and accumulating comorbidities. While HIV specific mortality has decreased, unfortunately, there continues to be a growing HIV epidemic, particularly in the southeastern United States. In 2017, the south accounted for 52% of the 38,739 new HIV diagnoses (8). As the HIV population ages, ESRD has emerged as a significant cause of morbidity and mortality, with PLWH being three times more likely to develop ESRD compared with the general population and is thought to compromise approximately 1.5% of the dialysis population (9,10). Additionally, compared with HIV- negative counterparts, PLWH experience a lower one- and five- year survival on dialysis (11). Despite this, there is growing evidence that PLWH are less likely to be placed on the organ waitlist and 47% less likely to receive a living donor kidney transplant (12). In order to improve survival and increase transplant rates among PLWH, it is critical to better understand the barriers to achieving a kidney transplant in this high-risk population. The objective of this thesis project was to identify and describe the HIV positive dialysis population in ESRD Network 6, the region with the lowest rates of kidney transplantation in the nation. Additionally, to compare their progression through the early steps (referral, evaluation, and waitlisting) of kidney transplantation to general dialysis population, and highlight patient and dialysis level characteristics that may influence access to kidney transplantation. This was accomplished through creating a novel HIV-ESRD dataset that identifies PLWH as well as those who proceeded through the early steps of transplantation. BACKGROUND‌ PLWH have increasing rates of ESRD. HIV-associated nephropathy (HIVAN) was previously one of the leading causes of renal failure among PLWH. The widespread use of affective antiretroviral therapy (ART) has decreased the prevalence of HIV-associated nephropathies (13,14), however, PLWH are still developing CKD and ESRD faster than HIV negative counterparts. This is largely due to co-morbidities (diabetes mellitus, cardiovascular disease, hypertension, and metabolic syndrome), co- infection with hepatitis C virus (HCV), medication induced injury, and accelerated aging seeing in chronic HIV infection (9,15,16). PLWH of black race are especially at risk for progression from CKD to ESRD. A study performed in Baltimore, Maryland revealed that African-Americans were at an increased risk for incident CKD and developed ESRD markedly faster than white subjects (HR, 17.7 [95% CI 2.5-127.0]) (17). ESRD among PLWH is particularly present in the southeast. In 2000, ESRD Network 6 had the 4th highest percentage of PLWH on dialysis at a proportion of 1.9% compared to an national average of 1.5%(10). Unfortunately, the southeastern region of the US continues to have the highest burden of CKD and ESRD with Georgia, North Carolina and South Carolina being states with some of the highest age-standardized CKD disability-adjusted life years (18,19). This coupled by the ongoing HIV epidemic in the southeast makes ESRD Network 6 a unique region to study the coexistence of ESRD and access to kidney transplantation among PLWH. With significant risk of progression from CKD to ESRD, it is imperative to understand access to transplantation among this vulnerable patient population. Renal transplantation is a feasible treatment option for PLWH with ESRD. In the 1980’s, HIV infection was considered a contraindication for transplantation and control measuresUS legal code was amended to make it a federal crime to transplant tissue from HIV positive donors (20). It was theorized that the effect of immunosuppression would contribute to progression of HIV disease, TB incidence lead to more episodes of infection and prevalence rates are declining increased rate of death; making it an inappropriate allocation of an organ. Between 1987 to 1997, there were 32 kidney transplants performed in the US in PLWH (mostly unintentional transplantation), with reported 3-year graft survival of 53% and patient survival 83% (21,22). These transplants though were prior to significant improvement in medications used to treat PLWH. In 2003, Xxxxx et al published promising outcomes on 14 HIV-positive patients who underwent transplantation. At a mean follow up of 480 days, 10 out of 10 (100%) of patients who received kidney transplants were alive with functioning grafts. There was no evidence of HIV disease progression and HIV did not seem to have an impact on graft survival (23). Around the same time, driven out of lack of access to dialysis, colleagues in South Africa performed the first kidney transplants from HIV-positive organ donors to HIV-positive recipients, showing that transplantation among PLWH was safe and feasible (24). With revived interest in transplanting PLWH, there have been a number of single center studies and a large multicenter study of 150 HIV-positive renal transplant recipients which all reported transplant outcomes for PLWH that were similar to the general transplant population 19(25–28). With better HIV care and improved understanding of medication interactions, PLWH in the United States (US) and most developed regions of the world (2are not only eligible for HIV-negative organs, 3)but HIV-positive organs as well. However, elimination of TB remains elusive, even in high-resource countries because of continued transmission in groups at high risk of MTBI and progression to TB, difficulties in detecting MTBI, and programmatic complacency (4). Around 4% of the US population is thought to have LTBI, and is a constant source for future TB and MTBI transmission (5). There is continued pressure to improve diagnostic and screening methods for detecting MTBI, including LTBI and infection manifesting as TB (6-8). Identifying and treating LTBI among those at high risk of developing TB is an important component for TB control and elimination in low-TB incidence regions, such as the US and Canada (9, 10). No method exists for accurately detecting LTBI. HistoricallyIn 2013, the only way HIV Organ Procurement Equity (HOPE) Act was signed into law, reversing the 1988 amendment, allowing HIV positive organs to diagnose LTBI was be transplanted into HIV positive recipients. This policy change is estimated to increase the tuberculin skin test (TST)donor pool by 300-500 organs, which involved measuring immunologic delayed hypersensitivity providing a unique opportunity to an intradermal injection increase utilization of purified protein derivatives (PPD) made from M. tuberculosis (tuberculin PPD) (11these organs and increase rates of kidney transplantation in HIV positive individuals 20(29). The TST transplant evaluation process is a multifaceted and complex process with the southeastern region performing the least transplants. Though it is possible for patients to be referred for kidney transplant prior to starting dialysis, the majority of ESRD patients start on dialysis before they are referred to a transplant center. Within 60 days of starting dialysis, patients are required by law to be educated on the risks and benefits of transplantation and if eligible, are referred by a dialysis provider to a transplant center. The transplant center then decides on their waitlist candidacy through conducting thorough medical evaluations (often inclusive of multiple studies and specialty evaluations), performing a psychosocial evaluation, assessing their social support network and financial ability to fund kidney transplantation. When this step is completed, the patient can be waitlisted with the eventual hope of receiving a living or deceased donor kidney transplant. To better understand how well dialysis facilities were performing in referring patients to kidney transplant, Xx. Xxxxxx Xxxxxx (co-I; Department of Surgery & Department of Epidemiology) and team reported in 2014 that ESRD Network 6 has limitations the lowest rates of kidney transplantation in detecting LTBI the nation, and that Georgia had the lowest of all 50 states (18,30,31) (Figure 1). Factors associated with decreased access to transplant include demographic differences in the southeast, racial disparities, socioeconomic influences, distance to transplant center, provider knowledge and awareness of transplantation (18,32,33). Because no national surveillance data exist on steps prior to waitlisting, the Southeastern Kidney Transplant Coalition developed a novel data registry for referral and evaluation for transplantation among all 9 transplant centers in Xxxxxxx, Xxxxx Xxxxxxxx xxx Xxxxx Xxxxxxxx (X00XX000000, PI: Xxxxxx). They found substantial variability in transplant access at the dialysis facility level where some settingsfacilities referred 0% of patients and others referred 76% (34). For exampleDialysis facility variability in transplant rates for HIV patients have not been described because currently no data exists linking HIV and ESRD care within a state or region. Factors influencing referral to kidney transplantation in PLWH have yet to be described in ESRD Network 6 and will direct construction of future interventions. Identifying PLWH who are on dialysis is difficult to do. Since 2005, where there are scarce data on the incidence and prevalence of LTBI PLWH requiring dialysis. As part of a condition of participation in the ESRD Medicare program, Centers for Medicare and Medicaid Services (CMS) medical evidence form (CMS 2728 form) is low, completed on every ESRD patient upon initiation of dialysis. CMS funds dialysis for ESRD patient and the positive predictive value (PPV) of TST is hindered by cross reactions induced by sensitization to other mycobacteria (11)surgical procedure and immunosuppressants for those who undergo kidney transplantation. The development medical evidence form provides evidence of interferonan ESRD condition, registers patients into a national renal registry, documents medical co-gamma release assays morbidities and other clinical data in dialysis patients, and ensures quality care for ERSD patients (IGRA) offered an alternative to the TST and addressed some limitations in the TST (12, 13). MTBI typically induces an immune T-lymphocyte response which produces the cytokine interferon gamma (INF-γ) when the T-cells encounter mycobacterial antigens (13). Whole-blood IGRAs such as the 2nd generation, QuantiFERON®-TB Gold test (QFT-G) (Cellestis Limited, Xxxxxxxx, Xxxxxxxx, Australia) measure the amount of INF-γ released when blood is stimulated with specific Mycobacterium antigens (1435). In 20072005, HIV serostatus was removed as an ESRD-related condition on the US Food and Drug Administration medical evidence form due to concerns regarding disclosure of HIV status (FDA) approved the 3rd generation of IGRA for the detection of MTBI, the QuantiFERON®-TB Gold In-Tube test (QFT-GIT) (Cellestis Limited, Xxxxxxxx, Xxxxxxxx, Australia) (1536). Like the TSTPresently, positive QFT-GIT results are highly associated with factors that historically contribute in order to MTBI identity PLWH on dialysis, HIV status is inferred through pharmacy prescription data (15, 16). However, QFT-GIT can exhibit discordance when compared to TST results and other IGRAs (15, 17-19). Absence of a “gold standard” to confirm MTBI limits IGRA assessments of accuracy and allows only estimates of sensitivity and specificity (15, 16). Approximations of sensitivity have been achieved by comparing the results of diagnostic tests to culture-confirmed cases of TB (15). Previous studies have assessed IGRAs among “assumed negative” populations at low-risk of MTBI, to better approximate specificity, with some consideration of test discordance (20- 22). Further research has been suggested to understand the factors associated with discordant test results (6, 15, 23). In light of the need for more research to understand IGRA accuracy and discordance, this study on QFT-GIT is part of a series of IGRA studies (21, 24- 2612). This study ascertainment method is suboptimal, as it may misclassify patients on pre-exposure prophylaxis as being on ART, may fail to identify PLWH not engaged in HIV care, and lacks patient-level epidemiologic and clinical data. Nonetheless, pharmacy prescription data is the only currently available method that can be used. In this study, Medicare prescription part D claims data was conducted used to add to identify PLWH on dialysis. In 2016, there was 81% participation of Medicare part D among hemodialysis patients, suggestive that majority of the current discourse on the interpretation of LTBI screening results among low-risk populations when considering multiple testing methods. The analysis of cross-sectional data obtained from US Navy recruits HIV population is captured in 2004 will quantify QFT-GIT specificity for a population at low-risk for MTBI. Additionally, this study will identify recruit characteristics and estimate their associations (37). METHODS‌ Hypothesis: Persons living with HIV in ESRD Network 6 are less likely to discordant results between traverse through the QFT-GIT and TST. Results for QFT-GIT will also be multistep process of kidney transplantation compared to other IGRA resultsHIV-negative counterparts in the setting of ESRD. Specific Aims Aim 1: To identify and describe the characteristics of PLWH and ESRD in ESRD Network 6. Aim 2: To describe the distribution and timing of early steps of kidney transplant inclusive of referral, performed at the same evaluation, and waitlisting among PLWH compared with HIV negative individuals with ESRD in Network 6. Aim 3: To identify patient-level and dialysis facility-level factors that are associated with time (21). Chapter Ito referral and time to waitlisting.

Conclusions. The specificity of QFT-GIT was high and similar to TST at either cutoff. Test discordance observed in recruits with increased risk may be due to lower TST specificity, lower QFT-GIT sensitivity, or both. Negative QFT-GIT results for recruits born in countries with high–TB prevalence and whose TST is > 15mm suggest that QFTneither pre- nor post-GIT deployment HIV training significantly improves comprehensive HIV knowledge among UN peacekeepers. If confirmed, our observations may be less sensitive than TST. Additional studies are needed to determine the risk of developing TB when TST and QFT-GIT results are discordant. Assessing specificity and discordance between the tuberculin skin test and a whole-blood interferon-γ release assay have important implications for the detection current DPKO HIV training curriculum. HIV Knowledge and Receipt of Mycobacterium tuberculosis infection Targeted Training among United States Navy recruits. UN Peacekeepers in a Post-Conflict Setting By Xxxxx Xxxxxx Xxxx Sc.B., Brown University, 2006 Thesis Committee Chair: Dr. Xxxxxxx Xxxxx Bachelor of Science in Biology Bachelor of Science in Anthropology University of Utah 2007 Thesis Faculty Advisor: Xxxx X. XxXxxxx, Xx., M.D. Field Advisor: Xxxxxx X. Xxxxxxx, M.D. MD, MPH A thesis submitted to the Faculty of the Xxxxxxx School of Public Health of Emory University in partial fulfillment of the requirements for the degree of Master of Public Health in Global Epidemiology 2011 Acknowledgements Acknowledgements: I would like to express my appreciation to my academic instructor Dr. Xxxxxxx Xxxxxxx of the Emory University, and my field advisor Xx. Xxxxx Xxxxxxx of the International Emergency and Refugee Health Branch at the Centers for Disease Control and Prevention for their help with various aspects of this project including development of the research question, analysis of the data, and presentation of results. Thank you Xx. Xxxxxxx for your commitment to the project and technical expertise. Thank you Xx. Xxxxxxx for the opportunity to work on such an important global issue. I very much look forward to our collaboration in the future. I would also like to thank Xx. Xxxxxx Xxxxxxx and Xx. XxXxxxx Xxxx Xxxxxxxxxx for their efforts in advising technical and mentoring me through analytical assistance throughout the processes course of the thesis project. Thank you Xxxxxx for your early work on the project and your invaluable statistical guidance navigating the treacherous waters of SAS and weighted logistic regression. Finally, I would like to express my professional development while gratitude to my additional support at Emory University and with the CDC; the staff at CDC, DTBEespecially Branch Chief Xxxxxxx Xxxxxx, especially Xxxxx XxxxxxxDr. Xxxx Xxxxxxxx, Xxxxxx Xxxxx, Kit Xxxxxxxxx, Xxxxxxx Xxxxxxxx and Xxxxx Xxxxxxx, Xxxx for including me in the branch’s activities opportunity to contribute to this remarkable area of public health research and assisting in innumerable ways with my analysis and manuscript; my professors at the Xxxxxxx School of Public Health, particularly Xx. Xxxxxxxxx, who provided council on my statistical analyses; also my friends and colleagues at in the Epidemiology and Behavioral Science and Health Education departments, who have helped make my time in Atlanta a rich experience; my parents, Xxxxxx and Xxxxxxx, for their unwavering love and support; and Xxxxxxx Xxxxx, who has endured the hardships of education with me and has given me such your continued support and freedom, that I may never truly repay her gifts and sacrificesconfidence in my achievements. Table of Contents INTRODUCTION Introduction and Background 1 CHAPTER I: BACKGROUND 4 EPIDEMIOLOGY OF TUBERCULOSIS 4 PATHOGENESIS OF MYCOBACTERIUM TUBERCULOSIS INFECTION Methods 5 Survey Design and Data Collection 5 Questionnaire and Outcome Measures 6 DIAGNOSTICS FOR MYCOBACTERIUM TUBERCULOSIS INFECTION 11 THE TUBERCULIN SKIN TEST Data analysis 7 Results 8 Discussion 10 Conclusions and Recommendations 14 INTERFERON-GAMMA RELEASE ASSAYS 19 WHOLE-BLOOD INTERFERON-GAMMA RELEASE ASSAYS 22 DISCORDANCE IN RESULTS FOR THE DETECTION OF M. TUBERCULOSIS INFECTION 29 LIMITATIONS TO INTERFERON-GAMMA RELEASE ASSAYS 36 TUBERCULOSIS AND THE UNITED STATES NAVY 40 LATENT TUBERCULOSIS INFECTION IN MILITARY RECRUITS 45 CHAPTER II: MANUSCRIPT 52 TITLE PAGE 52 INTRODUCTION 53 MATERIALS AND METHODS 58 RESULTS 64 DISCUSSION 70 LIMITATIONS AND STRENGTHS 83 CONCLUSION 87 REFERENCE LIST 89 TABLES 115 FIGURES 122 CHAPTER III: PUBLIC HEALTH IMPLICATIONS 124 SUMMARY 124 APPLICATIONS OF THE QUANTIFERON-TB GOLD IN-TUBE ASSAY 126 FUTURE DIRECTIONS 128 REFERENCES 131 APPENDICES 173 MILITARY HISTORY FORM FROM STUDY PROTOCOL 173 LINK TO XXXXXXX ET AL. – M. TUBERCULOSIS INFECTION IN NAVY RECRUITS, 2007 175 References 15 Tables and Figures TABLE 20 Table 1. CHARACTERISTICS OF US NAVY RECRUITS 115 TABLE Associations between Comprehensive HIV Knowledge and Selected Demographic Variables 20 Table 2. OUTCOMES OF THE TUBERCULIN SKIN TEST VERSUS THE QUANTIFERON®-TB GOLD IN-TUBE ASSAY 116 TABLE Multivariable Analyses of Predictors of Comprehensive HIV Knowledge among UN Peacekeepers in Liberia, 2005 21 Table 3. OUTCOMES OF THE QUANTIFERON®-TB GOLD ASSAY VERSUS THE QUANTIFERON®-TB GOLD INMultivariate Analyses of Effect of Pre- and Post-TUBE ASSAY 117 TABLE Deployment Training and other variables on Comprehensive HIV Knowledge 22 Table 4. UNIVARIATE ASSOCIATION OF SUBJECT CHARACTERISTICS WITH TUBERCULIN SKIN TEST OR QUANTIFERON®-TB GOLD INMultivariate Analyses of Effect of Pre and Post-TUBE ASSAY RESULTS 118 TABLE 5Deployment Training on Individual Components of HIV Knowledge 23 Appendix: IRB Approval and Study Questionnaire 24 Introduction and Background Armed conflict, natural disasters, and other emergencies resulting in mass displacement of people are referred to broadly as complex humanitarian emergencies (CHEs). UNIVARIATE ASSOCIATION OF SUBJECT CHARACTERISTICS WITH DISCORDANT RESULTS BETWEEN THE QUANTIFERON®-TB GOLD IN-TUBE ASSAY AND THE TUBERCULIN SKIN TESTCHEs result in acute civic destabilization due to compromised national and local infrastructure, USING A 10 MM CUTOFF 119 TABLE 6separation of families, interruption of health services, increased crowding conditions, decreased access to food and other essentials, and decline in opportunities for employment and income [1, 2]. UNIVARIATE ASSOCIATION OF SUBJECT CHARACTERISTICS WITH DISCORDANT RESULTS BETWEEN THE QUANTIFERON®-TB GOLD IN-TUBE ASSAY AND THE TUBERCULIN SKIN TEST, USING A 15 MM CUTOFF 120 TABLE 7These factors dramatically increase susceptibility to infectious disease and can result in very high mortality rates [3]. MULTIVARIATE ANALYSIS EXAMINING DISCORDANCE BETWEEN NEGATIVE QUANTIFERON®-TB GOLD IN-TUBE ASSAY RESULTS AND TUBERCULIN SKIN TEST RESULTS USING A 15 MM OR A 10 MM CUTOFF 121 FIGURE 1. DIAGRAM OF STUDY PARTICIPATION AND TESTING 122 FIGURE 2. COMPARISON OF TUBERCULIN SKIN TEST RESULTS TO INTERFERON-GAMMA RELEASE ASSAY INTERPRETATIONS, STRATIFIED BY RISK OF INFECTION 123 Introduction Tuberculosis (TB) is a leading cause of death and illness worldwide. The causative agent of TB is While the Mycobacterium tuberculosis bacillus. Mycobacterium tuberculosis infection (MTBI) most critical need occurs in humansthe period immediately following displacement, who act an additional host of health concerns become priorities in the post-emergency phase as its primary reservoirthe conflict progresses, conditions stabilize, and international aid and security are withdrawn. Approximately 2 billion people worldwide have quiescent or latent M. tuberculosis infection (LTBI) and are at Displaced populations may experience a substantial increase in prevalence of health risk factors during the post-conflict stage. Awareness is growing that an increase in HIV transmission is of special importance in post-conflict settings. Although the literature suggests that the extreme level of disruption seen in the emergency phase may actually decrease opportunities for transmission, the risk of developing TB (1)transmission may increase steeply during the post-emergency phase in populations affected by conflict and displacement [4-7]. Due to effective These include interruption of testing and treatment and control measuresservices, TB incidence and prevalence rates are declining the disruption of traditional family units, a rise in the United States (US) and most developed regions of the world (2risk-taking behavior, 3). However, elimination of TB remains elusive, even in high-resource countries because of continued transmission in groups at high risk of MTBI and progression to TB, difficulties in detecting MTBIfood insecurity, and programmatic complacency (4). Around 4% increased vulnerability of the US population is thought women and children leading to have LTBIproliferation of contractual sex and sexual violence [1, and is a constant source for future TB and MTBI transmission (5). There is continued pressure to improve diagnostic and screening methods for detecting MTBI, including LTBI and infection manifesting as TB (6-8)8]. Identifying and treating LTBI among those at These problems are exacerbated in areas with pre- existing high risk of developing TB is an important component for TB control and elimination in low-TB incidence regionsHIV prevalence, such as the US and Canada (Democratic Republic of the Congo [3, 8]. Conversely, transmission can also increase in post-conflict areas of low prevalence but with close contact with high-prevalence areas, as seen, for example, in Mozambique [6, 9, 10]. The risk of HIV transmission is an important issue because of its long-term effects on already destabilized populations. A higher prevalence of HIV among people of working age can undermine post- emergency efforts to rebuild infrastructure and return to self-governance [11]. Special populations of concern regarding HIV transmission in post-conflict settings are deployed members of the military including UN peacekeepers. With high levels of mobility and generally young average age, these groups are at unique risk for acquiring and transmitting sexually transmitted infections (STIs) and HIV [8]. During deployments, military personnel are separated from their families and cultural social structures, are often under high amounts of stress, have frequent contact with local populations, and may be immersed in a culture that encourages risk-taking, all of which can lead to increases in risk behavior [1, 11]. These concerns are particularly relevant in light of reports of increases in contractual sex in communities that host UN peacekeepers and allegations of sexual violence perpetrated by peacekeepers [1, 6, 12]. When compared to civilian populations, military personnel in peacetime are up to five times more likely to have STIs and twice as likely to be infected with HIV, with similar data limited to African military contingents indicating an up to six-fold increase for HIV [13, 14]. This pattern clearly indicates that military groups should be considered as a high priority population for HIV interventions. Furthermore, interventions and education efforts focusing on soldiers may have especially high-impact due to the youth and mobility of the contingents and the military emphasis on discipline and hierarchy [8]. UN peacekeepers represent a particularly promising target for intervention and education. Peacekeepers, organized by the UN Department of Peacekeeping Operations (DPKO), are mostly national military and police personnel seconded to the UN in organized units [15]. No method exists As one of the most mobile populations in the world, peacekeepers have been identified as a unique potential vector for accurately detecting LTBIHIV transmission both in the country they are deployed and in their country of origin [11, 16]. HistoricallyThis concern has been highlighted as a potential security issue in recent years as peacekeepers have been reported to have HIV prevalence estimates double that of civilian populations[10, 17]. Studies have also indicated that the rate of infection correlates directly with duration of deployment. The on-mission incidence of HIV has been reported to increase by up to 5% per year of deployment [10]. Increases in HIV prevalence within a country under the auspices of the UN peacekeeping force can further weaken the disaster-affected region by exacerbating social and political instability and by impairing the country’s long-term reconstruction efforts. What is more, if peacekeepers are perceived to be spreading HIV in the region they are deployed, it could threaten local trust in the mission and reduce willingness of countries to host peacekeepers from high-prevalence countries [18, 19]. Similarly, high HIV rates among military peacekeepers can have negative consequences in the soldiers’ countries of origin by undermining the military strength of the country and their ability to provide national security and maintain domestic stability [11]. This is confirmed in high reported rates of morbidity attributed to HIV among African militaries, some of which report that AIDS is implicated in more military deaths than combat [20, 21]. Furthermore, high HIV rates among military personnel have the potential to affect a large proportion of the country’s population in nations with mandated military service or high overall military involvement [11]. Overall, there is a concern that increasing HIV rates would divert large amounts of resources to the health sector and lead to general state destabilization [17]. Due to these concerns, the only way UN Security Council passed Resolution 1308 in 2000, calling for an HIV training program for UN peacekeepers, and recommending countries that contribute contingents of peacekeepers (Member States) to diagnose LTBI was develop their own HIV training programs and voluntary counseling and testing services [22]. In response, DPKO developed standardized HIV training modules to be conducted in-country for all deployed UN peacekeepers. Voluntary testing and counseling (VCT) is also made available and is encouraged [23]. To date there has been no formal evaluation of the tuberculin skin test impact of the intervention or of the basic HIV knowledge among active peacekeepers following the training [24]. Furthermore, although DPKO dissuades HIV-positive soldiers from deploying, in order to conform to statues of nondiscrimination no mandatory testing is conducted at any time, and Member States have varying policies on testing and deployment of HIV-positive individuals [23, 24]. This leads to a lack of consistency on HIV policy among different peacekeeper contingents and presents difficulties for the development of a standardized education program. With 15,880 peacekeepers on active duty in 2005, Liberia presented an ideal opportunity to assess HIV risk among peacekeepers and to evaluate DPKO’s training program. Liberia is still in a state of post-conflict transition after more than a decade of civil war, which resulted in large-scale infrastructural damage, massive population displacement, and widespread sexual violence [25]. Despite low estimates of HIV prevalence for the region (TSTapproximately 2%), which involved measuring immunologic delayed hypersensitivity Liberia has consistently had some of the worst development indicators in the world; it is currently ranked 162 out of 169 on the Human Development Index [26, 27]. Most recent data show an average of less than four years of school among adults, undernourishment in the population at almost 40%, and high levels of sexual risk-taking among youth [25, 26]. This combination of a high-risk undereducated population, relatively low HIV prevalence, and the country’s continuing struggle for stability indicate that Liberia is at very high risk for an explosive increase in HIV incidence. With continuing presence of UN peacekeepers and the ongoing debate about associated HIV risk, Liberia is a key setting to evaluate DPKO’s educational programs and the HIV-related knowledge of the peacekeepers themselves. In order to accomplish this goal, DPKO, the Joint United Nations Program on HIV/AIDS (UNAIDS) , and the Centers for Disease Control and Prevention (CDC) conducted an intradermal injection HIV knowledge attitude and practice survey in May-June 2005 in a representative sample of purified protein derivatives (PPD) made from M. tuberculosis (tuberculin PPD) (11)English speaking peacekeepers deployed in Liberia. The TST has limitations in detecting LTBI in some settings. For examplepurpose of the survey was to assess the levels of HIV awareness and sexual practices among peacekeepers during deployment, where and to evaluate the prevalence of LTBI is low, the positive predictive value (PPV) of TST is hindered by cross reactions induced by sensitization to other mycobacteria (11)HIV/AIDS program. The development current report will focus on measures of interferon-gamma release assays (IGRA) offered an alternative to HIV knowledge among the TST peacekeepers and addressed some limitations in the TST (12, 13). MTBI typically induces an immune T-lymphocyte response which produces the cytokine interferon gamma (INF-γ) when the T-cells encounter mycobacterial antigens (13). Whole-blood IGRAs such as the 2nd generation, QuantiFERON®-TB Gold test (QFT-G) (Cellestis Limited, Xxxxxxxx, Xxxxxxxx, Australia) measure the amount of INF-γ released when blood is stimulated with specific Mycobacterium antigens (14). In 2007, the US Food and Drug Administration (FDA) approved the 3rd generation of IGRA for the detection of MTBI, the QuantiFERON®-TB Gold In-Tube test (QFT-GIT) (Cellestis Limited, Xxxxxxxx, Xxxxxxxx, Australia) (15). Like the TST, positive QFT-GIT results are highly associated with factors that historically contribute to MTBI (15, 16). However, QFT-GIT can exhibit discordance when compared to TST results and other IGRAs (15, 17-19). Absence of a “gold standard” to confirm MTBI limits IGRA assessments of accuracy and allows only estimates of sensitivity and specificity (15, 16). Approximations of sensitivity have been achieved by comparing the results of diagnostic tests to culture-confirmed cases of TB (15). Previous studies have assessed IGRAs among “assumed negative” populations at low-risk of MTBI, to better approximate specificity, with some consideration of test discordance (20- 22). Further research has been suggested to understand the factors associated with discordant test results (6, 15, 23)influencing their understanding of HIV transmission and prevention. In light of the need for more research to understand IGRA accuracy and discordance, this study on QFT-GIT is part of a series of IGRA studies (21, 24- 26). This study was conducted to add to the current discourse on the interpretation of LTBI screening results among low-risk populations when considering multiple testing methods. The analysis of cross-sectional data obtained from US Navy recruits in 2004 will quantify QFT-GIT specificity for a population at low-risk for MTBI. Additionally, this study will identify recruit characteristics and estimate their associations to discordant results between the QFT-GIT and TST. Results for QFT-GIT will also be compared to other IGRA results, performed at the same time (21). Chapter IMethods

Conclusions. The specificity U.S. needs a national mechanism to systematically identify survey reports and to standardize measures and reporting for Campus Climate Surveys. FTFI and CASI elicited similar rates of QFT-GIT was high sexual violence disclosure, suggesting that colleges and similar universities can conduct robust assessments via CASI. Nonsignificant findings that FTFI elicited more disclosures warrants further study. Colleges and universities need to TST at either cutoffxxxxxx inclusive campus culture for students while implementing Campus Climate Surveys. Test discordance observed in recruits with increased risk may be due to lower TST specificityUnderstanding the Disclosure of Sexual Violence among College Women By Xxxxxxxx Xxxxx Xxxxxx B.A., lower QFT-GIT sensitivityXxxxxxxx College, or both2006 X.Xx. Negative QFT-GIT results for recruits born in countries with high–TB prevalence London School of Hygiene and whose TST is > 15mm suggest that QFT-GIT may be less sensitive than TST. Additional studies are needed to determine the risk of developing TB when TST and QFT-GIT results are discordant. Assessing specificity and discordance between the tuberculin skin test and a whole-blood interferon-γ release assay for the detection of Mycobacterium tuberculosis infection among United States Navy recruits. By Xxxxx Xxxxxxx Xxxxx Bachelor of Science in Biology Bachelor of Science in Anthropology University of Utah 2007 Thesis Faculty Tropical Medicine, 2009 Advisor: Xxxx Xxxxxxx X. XxXxxxxXxxxx, Xx., M.D. Field Advisor: Xxxxxx X. Xxxxxxx, M.D. Ph.D. A thesis dissertation submitted to the Faculty of the Xxxxxxx Xxxxx X. Xxxxx School of Public Health Graduate Studies of Emory University in partial fulfillment of the requirements for the degree of Master Doctor of Public Philosophy in Behavioral Sciences and Health Education 2018 Acknowledgements There are many people to whom I’m grateful for supporting me in Epidemiology 2011 Acknowledgements I would like this work. Thank you to thank Xxmy committee. Xxxxxxx Xxxxxx, thank you for helping me expand this idea into a dissertation through the proposal development class and Xx. XxXxxxx for their efforts in advising and mentoring guiding me through the processes directed study on psychometric measurement. Xxxxxx Xxxxxxxxxx, thank you for encouraging me to pursue the systematic review of Campus Climate Surveys, for providing me with a directed study in structural equation modeling, and for letting me pop-in to your office on a frequent basis. Xxxxxxx Sales, thank you for selecting me to serve as the co-chair of the thesis Campus Climate Survey Subcommittee in 2014, which gave me invaluable insight into these surveys and the practical experience with implementation and communication of results. Thank you for your support throughout my professional development committee work, in figuring out the logistics of this project, and the directed study in screening for experiences of violence, linkages to clinical care, and ethics. Finally, thank you to my advisor, Xxxxxxx Xxxxx. You pushed me to “think big” and prepared me to take on a project of this scope. You encouraged me to work independently while providing consistent support and guidance, removing barriers as I encountered them. It has been a pleasure to have you as my advisor, chair, and mentor. Thank you to the Department of Behavioral Sciences and Health Education for the excellent training that I have received. Thank you to both Director of Graduate Studies who served during my time; Xxx Xxxxx Xxxxxxx and Xxxxx Xxxxx. You both served as the anchor for the doctoral students. Thank you to Xxxxxxx XxXxxxx for leading our department into a new era. Thank you to the faculty members who helped me navigate the world of teaching (you all served as wonderful role models); Xxxx Xxxxxx, Xxxxx Xxxx, and Xxxxx Xxxx. Thank you to Xxx Xxxxx Xxxxxxx, Xxxxx XxXxxxxxxx, and Xxxxxxxx Xxxxx for writing letters of support for my F31 grant. Thank you to all of the department faculty, who xxxxxx an environment of scientific rigor and genuine collegiality. It has made for a happy doctoral experience. I would never have completed this step, or any milestone in the program without the support of my doctoral student colleagues. Thank you to my cohort; Xxxxx Xxxxxxxxx, Xxxxx Xxxxx, Xxxxx Xxxxxxx, and Xxxxxx St. Xxxxx Xxxxxxxx; what a joy to have been through it all together. Thank you to my violence prevention colleagues, Xxxxxxxxx Xxxxxxx, Xxxxx Xxxx, Xxxxxx Xxxxxxx, and Xxxxx Xxxxxx; you inspire me each day through your dedication to the movement. Thank you as well to my peer mentor Xxxxxxxx Hayley; you served as an unparalleled example for hard work and generosity. Thank you to my officemates, who are aforementioned, as well as Xxxxx Xxxxxxx, and unofficial officemate Jing Xxxx Xx, for your willingness to let me “run something by you real quick,” and for all the laughter. I have a reason to thank each doctoral student in this department for a different reason; so again, thank you to all. Thank you to the department administrative staff; Xxxxxx Xxxxxx, Xxxxxxxx Xxxxx, Xxxxxx Xxxxxx, and Yenawa Xxxxxxxx. Our department would not function without you, and I thank you for making it all happen, from signing me up for classes and helping me manage my funding, to making me countless PDF packages, and planning our social gatherings. Thank you for serving as problem fixers and friends. I cannot wait to see what future opportunities await for my excellent research assistants Xxxxxxxx XxXxxxxxx, Xxxxxxxxx Xxxxxxxx, and Xxxxxxx Xxxxxxx. Your enthusiasm and talent kept me motivated throughout the past three years. You are all stars about to launch into the sky. Thank you. Thank you to the Respect Program; Xxxxx Xxxx, Jamechya Xxxxxx, and Xxxxxxx Passono. I see you as my partners in this work. I cannot help but be excited when we meet or collaborate on projects. Thank you for all that you have taught me and for all that you do for the Emory campus. Thank you especially, to Xxxxx, who has written me about six different letters of support for me to pursue funding for this work. Thank you to my colleagues at Emory University and with the CDC; the staff at CDCwho have all contributed to making this work a reality: Xxxxxx Xxxx, DTBEXxxxxx Xxxxxx, especially Xxxxx XxxxxxxXxxxxx Xxxxxx, Xxxxxx Xxxxx, Kit Xxxxxxxxx, Xxxxxxx Xxxxxxxx and Xxxxxx Xxxxxxx. Thank you to my funders. Research reported in this dissertation was supported by National Institute of Child Health and Human Development of the National Institutes of Health under award number 1F31HD086964-01A1. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This work was additionally supported by the Emory Injury Prevention Research Center and Xxxxx Xxxxxxx, for including me in the branch’s activities and assisting in innumerable ways with my analysis and manuscript; my professors at the Xxxxxxx Graduate School Professional Development Support funds. Thank you to all of Public Health, particularly Xx. Xxxxxxxxx, who provided council on my statistical analyses; also my friends who supported me throughout the applying to graduate school, moving to Atlanta, and colleagues at in the Epidemiology finishing this degree. Thank you to my family for your love and Behavioral Science and Health Education departments, who have helped make my time in Atlanta a rich experience; support. Thank you to my parents, Xxxxx and Xxxxx. You have always encouraged me to follow my dreams and you have made achieving them possible by helping me get there. Thank you to my siblings, Xxxxxxx and Xxxxx. Spending a lifetime being known to teachers as “the third Xxxxxx and Xxxxxxxchild” provided me with an endless motivation to live up to your brilliance. Thank you also to Bo, for their unwavering love and support; and Xxxxxxx Xxxxx, who has endured the hardships of education with me and has given me such support and freedom, that I may never truly repay her gifts and sacrifices. Table of Contents INTRODUCTION 1 CHAPTER I: BACKGROUND 4 EPIDEMIOLOGY OF TUBERCULOSIS 4 PATHOGENESIS OF MYCOBACTERIUM TUBERCULOSIS INFECTION 6 DIAGNOSTICS FOR MYCOBACTERIUM TUBERCULOSIS INFECTION 11 THE TUBERCULIN SKIN TEST 14 INTERFERON-GAMMA RELEASE ASSAYS 19 WHOLE-BLOOD INTERFERON-GAMMA RELEASE ASSAYS 22 DISCORDANCE IN RESULTS FOR THE DETECTION OF M. TUBERCULOSIS INFECTION 29 LIMITATIONS TO INTERFERON-GAMMA RELEASE ASSAYS 36 TUBERCULOSIS AND THE UNITED STATES NAVY 40 LATENT TUBERCULOSIS INFECTION IN MILITARY RECRUITS 45 CHAPTER II: MANUSCRIPT 52 TITLE PAGE 52 INTRODUCTION 53 MATERIALS AND METHODS 58 RESULTS 64 DISCUSSION 70 LIMITATIONS AND STRENGTHS 83 CONCLUSION 87 REFERENCE LIST 89 TABLES 115 FIGURES 122 CHAPTER III: PUBLIC HEALTH IMPLICATIONS 124 SUMMARY 124 APPLICATIONS OF THE QUANTIFERON-TB GOLD IN-TUBE ASSAY 126 FUTURE DIRECTIONS 128 REFERENCES 131 APPENDICES 173 MILITARY HISTORY FORM FROM STUDY PROTOCOL 173 LINK TO XXXXXXX ET AL. – M. TUBERCULOSIS INFECTION IN NAVY RECRUITS, 2007 175 Tables and Figures TABLE 1. CHARACTERISTICS OF US NAVY RECRUITS 115 TABLE 2. OUTCOMES OF THE TUBERCULIN SKIN TEST VERSUS THE QUANTIFERON®-TB GOLD IN-TUBE ASSAY 116 TABLE 3. OUTCOMES OF THE QUANTIFERON®-TB GOLD ASSAY VERSUS THE QUANTIFERON®-TB GOLD IN-TUBE ASSAY 117 TABLE 4. UNIVARIATE ASSOCIATION OF SUBJECT CHARACTERISTICS WITH TUBERCULIN SKIN TEST OR QUANTIFERON®-TB GOLD IN-TUBE ASSAY RESULTS 118 TABLE 5. UNIVARIATE ASSOCIATION OF SUBJECT CHARACTERISTICS WITH DISCORDANT RESULTS BETWEEN THE QUANTIFERON®-TB GOLD IN-TUBE ASSAY AND THE TUBERCULIN SKIN TEST, USING A 10 MM CUTOFF 119 TABLE 6. UNIVARIATE ASSOCIATION OF SUBJECT CHARACTERISTICS WITH DISCORDANT RESULTS BETWEEN THE QUANTIFERON®-TB GOLD IN-TUBE ASSAY AND THE TUBERCULIN SKIN TEST, USING A 15 MM CUTOFF 120 TABLE 7. MULTIVARIATE ANALYSIS EXAMINING DISCORDANCE BETWEEN NEGATIVE QUANTIFERON®-TB GOLD IN-TUBE ASSAY RESULTS AND TUBERCULIN SKIN TEST RESULTS USING A 15 MM OR A 10 MM CUTOFF 121 FIGURE 1. DIAGRAM OF STUDY PARTICIPATION AND TESTING 122 FIGURE 2. COMPARISON OF TUBERCULIN SKIN TEST RESULTS TO INTERFERON-GAMMA RELEASE ASSAY INTERPRETATIONS, STRATIFIED BY RISK OF INFECTION 123 Introduction Tuberculosis (TB) is a leading cause of death and illness worldwide. The causative agent of TB is the Mycobacterium tuberculosis bacillus. Mycobacterium tuberculosis infection (MTBI) occurs in humans, who act as its primary reservoir. Approximately 2 billion people worldwide have quiescent or latent M. tuberculosis infection (LTBI) and are at risk of developing TB (1). Due to effective treatment and control measures, TB incidence and prevalence rates are declining in the United States (US) and most developed regions of the world (2, 3). However, elimination of TB remains elusive, even in high-resource countries because of continued transmission in groups at high risk of MTBI and progression to TB, difficulties in detecting MTBIMolly, and programmatic complacency (4)Xxxxx. Around 4% Thank you to my life partner and future husband, Xxxxxxx. Words fall short of the US population is thought all that you mean to have LTBIme. Thank you for inspiring me with your heart, your mind, and is a constant source your cooking. Finally, thank you to my Student Advisory Board, my participants, and survivors. You make this work worthwhile. I am grateful for future TB and MTBI transmission (5)your willingness to participate in my study. There is continued pressure Many students on campuses across the country act to improve diagnostic and screening methods for detecting MTBIcreate change on the issues that matter to them, including LTBI and infection manifesting as TB (6-8)sexual violence. Identifying and treating LTBI among those at high risk I do this work in honor of developing TB is an important component for TB control and elimination in low-TB incidence regions, such as the US and Canada (9, 10). No method exists for accurately detecting LTBI. Historically, the only way to diagnose LTBI was the tuberculin skin test (TST), which involved measuring immunologic delayed hypersensitivity to an intradermal injection of purified protein derivatives (PPD) made from M. tuberculosis (tuberculin PPD) (11). The TST has limitations in detecting LTBI in some settings. For example, where the prevalence of LTBI is low, the positive predictive value (PPV) of TST is hindered by cross reactions induced by sensitization to other mycobacteria (11). The development of interferon-gamma release assays (IGRA) offered an alternative to the TST and addressed some limitations in the TST (12, 13). MTBI typically induces an immune T-lymphocyte response which produces the cytokine interferon gamma (INF-γ) when the T-cells encounter mycobacterial antigens (13). Whole-blood IGRAs such as the 2nd generation, QuantiFERON®-TB Gold test (QFT-G) (Cellestis Limited, Xxxxxxxx, Xxxxxxxx, Australia) measure the amount of INF-γ released when blood is stimulated with specific Mycobacterium antigens (14). In 2007, the US Food and Drug Administration (FDA) approved the 3rd generation of IGRA for the detection of MTBI, the QuantiFERON®-TB Gold In-Tube test (QFT-GIT) (Cellestis Limited, Xxxxxxxx, Xxxxxxxx, Australia) (15). Like the TST, positive QFT-GIT results are highly associated with factors that historically contribute to MTBI (15, 16). However, QFT-GIT can exhibit discordance when compared to TST results and other IGRAs (15, 17-19). Absence of a “gold standard” to confirm MTBI limits IGRA assessments of accuracy and allows only estimates of sensitivity and specificity (15, 16). Approximations of sensitivity have been achieved by comparing the results of diagnostic tests to culture-confirmed cases of TB (15). Previous studies have assessed IGRAs among “assumed negative” populations at low-risk of MTBI, to better approximate specificity, with some consideration of test discordance (20- 22). Further research has been suggested to understand the factors associated with discordant test results (6, 15, 23). In light of the need for more research to understand IGRA accuracy and discordance, this study on QFT-GIT is part of a series of IGRA studies (21, 24- 26). This study was conducted to add to the current discourse on the interpretation of LTBI screening results among low-risk populations when considering multiple testing methods. The analysis of cross-sectional data obtained from US Navy recruits in 2004 will quantify QFT-GIT specificity for a population at low-risk for MTBI. Additionally, this study will identify recruit characteristics and estimate their associations to discordant results between the QFT-GIT and TST. Results for QFT-GIT will also be compared to other IGRA results, performed at the same time (21). Chapter Iyou.

Conclusions. BMI appeared to have a stronger influence on young adult SBP and pre-hypertension / hypertension than all measures of SES, but significant moderation and mediation was observed between BMI and various measures of SES. Further research is needed into the role of BMI as a mediator or moderator on SES and young adult blood pressure, and to investigate whether individual components of SES may predict young adult blood pressure. Influence of Socioeconomic Status and Body Composition on Young Adult Blood Pressure: The specificity of QFT-GIT was high and similar Birth to TST at either cutoff. Test discordance observed in recruits with increased risk may be due to lower TST specificityTwenty Cohort By Chloe W. Eng B.S. Northeastern University 2014 Thesis Committee Chair: Xxxxx X. Xxxxx, lower QFT-GIT sensitivity, or both. Negative QFT-GIT results for recruits born in countries with high–TB prevalence and whose TST is > 15mm suggest that QFT-GIT may be less sensitive than TST. Additional studies are needed to determine the risk of developing TB when TST and QFT-GIT results are discordant. Assessing specificity and discordance between the tuberculin skin test and a whole-blood interferon-γ release assay for the detection of Mycobacterium tuberculosis infection among United States Navy recruits. By Xxxxx Xxxxxxx Xxxxx Bachelor of Science in Biology Bachelor of Science in Anthropology University of Utah 2007 Thesis Faculty Advisor: Xxxx X. XxXxxxx, Xx., M.D. Field Advisor: Xxxxxx X. Xxxxxxx, M.D. PhD A thesis submitted to the Faculty of the Xxxxxxx School of Public Health of Emory University in partial fulfillment of the requirements for the degree of Master of Science in Public Health in Epidemiology 2011 Acknowledgements 2016 I would like to thank Xxextend my sincerest thanks and appreciation to: Xxxxx X. Xxxxx, for allowing me this learning opportunity, as well as his insight, support, and ongoing patience whenever I veer off topic. Xxxxxxx Xxxxx Xxxxxx, PhD, study staff and Xx. XxXxxxx researchers at DPHRU, and University of the Witwatersrand, for their efforts in advising and mentoring towards the continuation of Birth to Twenty, for allowing me the ability to learn from them through the processes practicum experience, and the hospitality that has continued past the culmination of the thesis and my professional development while at Emory University and practicum. The Global Field Experience (GFE) Committee, for providing me with the CDC; funding that allowed me to help clean and analyze this data in the staff at CDC, DTBE, especially Xxxxx Xxxxxxx, Xxxxxx Xxxxx, Kit Xxxxxxxxx, Xxxxxxx Xxxxxxxx and Xxxxx Xxxxxxxcontext in which it was collected. Xxxx Xxxxxx, for including your company in South Africa, your indispensable advice, and for letting me in the branch’s activities rely on you for cell phone access and assisting in innumerable ways with my analysis and manuscript; my professors at the Xxxxxxx School of Public Health, particularly Xxtransportation while abroad. Xxxxxxxxx, who provided council on my statistical analyses; also my My friends and colleagues at in fellow Xxxxxxx classmates, for the Epidemiology laughter, levity, and Behavioral Science and Health Education departmentslate nights that made these past years immensely enjoyable. And finally, who have helped make my time in Atlanta a rich experience; my parents, Xxxxxx for being my ever present anchors and Xxxxxxx, for their unwavering love allowing me the opportunities to learn and support; and Xxxxxxx Xxxxx, who has endured grow so many miles away from home for the hardships of education with me and has given me such support and freedom, that I may never truly repay her gifts and sacrificespast six years. Table of Contents INTRODUCTION 1 CHAPTER Chapter I: BACKGROUND 4 EPIDEMIOLOGY OF TUBERCULOSIS 4 PATHOGENESIS OF MYCOBACTERIUM TUBERCULOSIS INFECTION 6 DIAGNOSTICS FOR MYCOBACTERIUM TUBERCULOSIS INFECTION 11 THE TUBERCULIN SKIN TEST 14 INTERFERON-GAMMA RELEASE ASSAYS 19 WHOLE-BLOOD INTERFERON-GAMMA RELEASE ASSAYS 22 DISCORDANCE IN RESULTS FOR THE DETECTION OF M. TUBERCULOSIS INFECTION 29 LIMITATIONS TO INTERFERON-GAMMA RELEASE ASSAYS 36 TUBERCULOSIS AND THE UNITED STATES NAVY 40 LATENT TUBERCULOSIS INFECTION IN MILITARY RECRUITS 45 CHAPTER Literature Review 1 Chapter II: MANUSCRIPT 52 TITLE PAGE 52 INTRODUCTION 53 MATERIALS AND METHODS 58 RESULTS 64 DISCUSSION 70 LIMITATIONS AND STRENGTHS 83 CONCLUSION 87 REFERENCE LIST 89 TABLES 115 FIGURES 122 CHAPTER Manuscript 15 Abstract 15 Introduction 16 Methods 18 Results 26 Discussion 31 Chapter III: PUBLIC HEALTH IMPLICATIONS 124 SUMMARY 124 APPLICATIONS OF THE QUANTIFERON-TB GOLD IN-TUBE ASSAY 126 FUTURE DIRECTIONS 128 REFERENCES 131 APPENDICES 173 MILITARY HISTORY FORM FROM STUDY PROTOCOL 173 LINK TO XXXXXXX ET AL. – M. TUBERCULOSIS INFECTION IN NAVY RECRUITSSummary, 2007 175 Future Directions, & Public Health Implications 36 Tables and Figures TABLE 1Figures. CHARACTERISTICS OF US NAVY RECRUITS 115 TABLE 237 References. OUTCOMES OF THE TUBERCULIN SKIN TEST VERSUS THE QUANTIFERON®-TB GOLD IN50 Chapter I: Literature Review Introduction Globally, non-TUBE ASSAY 116 TABLE 3. OUTCOMES OF THE QUANTIFERON®-TB GOLD ASSAY VERSUS THE QUANTIFERON®-TB GOLD INcommunicable disease (NCD) has begun to replace communicable, or infectious, disease as the major contributor to mortality.1 One example of this epidemiologic shift seen in South Africa, a middle-TUBE ASSAY 117 TABLE 4. UNIVARIATE ASSOCIATION OF SUBJECT CHARACTERISTICS WITH TUBERCULIN SKIN TEST OR QUANTIFERON®-TB GOLD IN-TUBE ASSAY RESULTS 118 TABLE 5. UNIVARIATE ASSOCIATION OF SUBJECT CHARACTERISTICS WITH DISCORDANT RESULTS BETWEEN THE QUANTIFERON®-TB GOLD IN-TUBE ASSAY AND THE TUBERCULIN SKIN TEST, USING A 10 MM CUTOFF 119 TABLE 6. UNIVARIATE ASSOCIATION OF SUBJECT CHARACTERISTICS WITH DISCORDANT RESULTS BETWEEN THE QUANTIFERON®-TB GOLD IN-TUBE ASSAY AND THE TUBERCULIN SKIN TEST, USING A 15 MM CUTOFF 120 TABLE 7. MULTIVARIATE ANALYSIS EXAMINING DISCORDANCE BETWEEN NEGATIVE QUANTIFERON®-TB GOLD IN-TUBE ASSAY RESULTS AND TUBERCULIN SKIN TEST RESULTS USING A 15 MM OR A 10 MM CUTOFF 121 FIGURE 1. DIAGRAM OF STUDY PARTICIPATION AND TESTING 122 FIGURE 2. COMPARISON OF TUBERCULIN SKIN TEST RESULTS TO INTERFERON-GAMMA RELEASE ASSAY INTERPRETATIONS, STRATIFIED BY RISK OF INFECTION 123 Introduction Tuberculosis (TB) is a leading cause income country that exhibits rates of death and illness worldwide. The causative agent of TB is the Mycobacterium tuberculosis bacillus. Mycobacterium tuberculosis infection (MTBI) occurs in humans, who act chronic diseases such as its primary reservoir. Approximately 2 billion people worldwide have quiescent hypertension as high as or latent M. tuberculosis infection (LTBI) and are at risk of developing TB (1). Due to effective treatment and control measures, TB incidence and prevalence rates are declining in the United States (US) and most developed regions of the world (2, 3). However, elimination of TB remains elusive, even exceeding those seen in high-resource countries because income nations. Hypertension is now regarded as one of continued transmission South Africa and Sub-Saharan Africa’s greatest health challenges after the HIV/AIDs crisis.2 Nationally representative World Health Organization (WHO) data from 2007 to 2010 showed a hypertension prevalence of 77.9% [95% confidence interval (CI): 76.4 – 79.4] in groups at South African adults over age 50, the highest rate reported in this age group of any nation in the world. After stratifying by gender, hypertension prevalence rates were reported to be as high risk as 74.7% [95% CI: 72.6 – 76.8] in males and 80.3% [95% CI: 78.6 – 82.0] for females.3 However despite the similarities in hypertension prevalence with high income countries, South Africa and many other Sub-Saharan African nations report significantly lower rates of MTBI and progression to TBdetection, difficulties in detecting MTBItreatment, and programmatic complacency control than high-income nations.2 South Africa reports some of the highest rates of obesity as well, a condition that has shown consistent associations with hypertension. The WHO Study on Global Aging and Adult Health (4SAGE) compiled data from the six middle-income countries of China, Ghana, India, Mexico, Russia, and South Africa, and found that age and obesity were consistently significant predictors of hypertension prevalence in all six countries (though significance in South Africa data alone was only significant in the 60 – 79 year age group, with an odds ratio of 38.89 and 95% confidence interval of 5.55 to 272.6). Around 4% Socioeconomic factors such as insurance status were also found to be significantly correlated with diagnosis of the US population is thought hypertension, and income was found to have LTBIa significant association with hypertension treatment status, though it showed no effect on prevalence.4, 5 This thesis uses data from the Birth to Twenty Cohort to investigate the effect of socioeconomic status on blood pressure in young adults from South Africa, an age group that remains underrepresented in the study of hypertension in sub-Saharan Africa. Birth to Twenty is distinctive as the longest running longitudinal birth cohort in Africa and has focused on the early expression of metabolic risk factors and conditions as one of its primary domains.6 Because the presence of risk factors such as obesity and hypertension in childhood are strongly associated with adverse health outcomes in later years, the data from this cohort provides a unique opportunity to examine health and development from youth to early adulthood. This cohort is the first to allow for tracking of health throughout early life in South Africa, and is a constant source for future TB and MTBI transmission (5). There is continued pressure past findings have contributed to improve diagnostic and screening methods for detecting MTBInation-wide policies, including LTBI regulation of age for school attendance and infection manifesting as TB (6-8). Identifying and treating LTBI among those at high risk of developing TB is an important component for TB control and elimination in low-TB incidence regionsrestrictions on tobacco purchasing.7 Therefore, such as the US and Canada (9, 10). No method exists for accurately detecting LTBI. Historically, the only way this research aims to diagnose LTBI was the tuberculin skin test (TST), which involved measuring immunologic delayed hypersensitivity to an intradermal injection of purified protein derivatives (PPD) made from M. tuberculosis (tuberculin PPD) (11). The TST has limitations in detecting LTBI in some settings. For example, where the prevalence of LTBI is low, the positive predictive value (PPV) of TST is hindered by cross reactions induced by sensitization to other mycobacteria (11). The development of interferon-gamma release assays (IGRA) offered an alternative to the TST and addressed some limitations explore blood pressure in the TST (12young adult data collection wave, 13). MTBI typically induces an immune Tand to assess how the major risk factor of obesity may mediate observed associations in the unique socioeconomic context of post-lymphocyte response which produces the cytokine interferon gamma (INF-γ) when the T-cells encounter mycobacterial antigens (13). Whole-blood IGRAs such as the 2nd generation, QuantiFERON®-TB Gold test (QFT-G) (Cellestis Limited, Xxxxxxxx, Xxxxxxxx, Australia) measure the amount of INF-γ released when blood is stimulated with specific Mycobacterium antigens (14). In 2007, the US Food and Drug Administration (FDA) approved the 3rd generation of IGRA for the detection of MTBI, the QuantiFERON®-TB Gold In-Tube test (QFT-GIT) (Cellestis Limited, Xxxxxxxx, Xxxxxxxx, Australia) (15). Like the TST, positive QFT-GIT results are highly associated with factors that historically contribute to MTBI (15, 16). However, QFT-GIT can exhibit discordance when compared to TST results and other IGRAs (15, 17-19). Absence of a “gold standard” to confirm MTBI limits IGRA assessments of accuracy and allows only estimates of sensitivity and specificity (15, 16). Approximations of sensitivity have been achieved by comparing the results of diagnostic tests to culture-confirmed cases of TB (15). Previous studies have assessed IGRAs among “assumed negative” populations at low-risk of MTBI, to better approximate specificity, with some consideration of test discordance (20- 22). Further research has been suggested to understand the factors associated with discordant test results (6, 15, 23). In light of the need for more research to understand IGRA accuracy and discordance, this study on QFT-GIT is part of a series of IGRA studies (21, 24- 26). This study was conducted to add to the current discourse on the interpretation of LTBI screening results among low-risk populations when considering multiple testing methods. The analysis of cross-sectional data obtained from US Navy recruits in 2004 will quantify QFT-GIT specificity for a population at low-risk for MTBI. Additionally, this study will identify recruit characteristics and estimate their associations to discordant results between the QFT-GIT and TST. Results for QFT-GIT will also be compared to other IGRA results, performed at the same time (21). Chapter IApartheid South Africa.

Conclusions. The specificity of QFT-GIT was high primary analysis did not support the hypothesis that NAFLD has an association with lower BMD. The secondary analysis suggested the possible relationship between NAFLD and similar lower BMD among people with low to TST at either cutoffnormal BMI. Test discordance observed in recruits with increased risk may be due to lower TST specificity, lower QFT-GIT sensitivity, or both. Negative QFT-GIT results for recruits born in countries with high–TB prevalence Mineral Density -- Results from the Third National Health and whose TST is > 15mm suggest that QFT-GIT may be less sensitive than TST. Additional studies are needed to determine the risk of developing TB when TST and QFT-GIT results are discordant. Assessing specificity and discordance between the tuberculin skin test and a whole-blood interferon-γ release assay for the detection of Mycobacterium tuberculosis infection among United States Navy recruits. Nutrition Examination Survey (NHANES III) By Xxxxx Xxxxxxxxx Xxxxxxx Xxxxx Bachelor of Science in Biology Bachelor of Science in Anthropology Medicine, the University of Utah Tokyo, 2007 Doctor of Philosophy (Medicine), the University of Tokyo, 2014 Thesis Faculty AdvisorCommittee Chair: Xxxx X. XxXxxxxXxxxxxx XxXxxxxxx, Xx.MD, M.D. Field Advisor: Xxxxxx X. Xxxxxxx, M.D. MPH A thesis submitted to the Faculty of the Xxxxxxx School of Public Health of Emory University in partial fulfillment of the requirements for the degree of Master of Public Health in Epidemiology 2011 Acknowledgements 2016 I would first like to thank my thesis adviser Xx. Xxxxxxx XxXxxxxxx of Xxxxxxx School of Public Health at Emory University. He gave me important advices, and steered me in the right direction. I would also like to thank Xx. Xxxxxxx Xxxxxx Xxxxx of Centers for Disease Control and XxPrevention as the second reader of this thesis. XxXxxxx for their efforts I appreciate his valuable comments on this thesis. Finally, I must express my gratitude to my family. My wife, Xxxx Xxxxxxx, provided me with unfailing support and continuous encouragement throughout my study period. I also would like to thank Xxxxxxxx Xxxxxxx, and Xxxxxx Xxxxxxx, who supported me to study in advising and mentoring me through the processes of the thesis and United States. I really appreciate my professional development while at Emory University and with the CDC; the staff at CDCfather, DTBE, especially Xxxxx Xxxxxxx, Xxxxxx Xxxxxwho endured through difficulties and raised me. This accomplishment would not have been possible without them. Thank you. Background/Literature Review 1 Methods 7 Results 17 Discussion 22 Future Directions 27 References 28 Tables 37 Figures and Figure Legends 45 Appendices 50 Supporting Information 50 SAS Source Codes 56 Background/Literature Review In this study, Kit XxxxxxxxxI focused on two chronic health conditions, Xxxxxxx Xxxxxxxx low bone mineral density and Xxxxx Xxxxxxxnonalcoholic fatty liver (NAFLD). These days, chronic health conditions have been attracting more attentions in public health, as the population lives longer and ages. Historically communicable diseases or infectious diseases were the main concerns, contributing to the mortality and morbidity. After the end of 19th century, developing the knowledge and treatments for including me infectious diseases has contributed to the steep declines in the branch’s activities and assisting in innumerable ways with my analysis and manuscript; my professors at the Xxxxxxx School of Public Health, particularly Xx. Xxxxxxxxx, who provided council on my statistical analyses; also my friends and colleagues at in the Epidemiology and Behavioral Science and Health Education departments, who have helped make my time in Atlanta a rich experience; my parents, Xxxxxx and Xxxxxxx, for their unwavering love and support; and Xxxxxxx Xxxxx, who has endured the hardships of education with me and has given me such support and freedom, that I may never truly repay her gifts and sacrifices. Table of Contents INTRODUCTION 1 CHAPTER I: BACKGROUND 4 EPIDEMIOLOGY OF TUBERCULOSIS 4 PATHOGENESIS OF MYCOBACTERIUM TUBERCULOSIS INFECTION 6 DIAGNOSTICS FOR MYCOBACTERIUM TUBERCULOSIS INFECTION 11 THE TUBERCULIN SKIN TEST 14 INTERFERON-GAMMA RELEASE ASSAYS 19 WHOLE-BLOOD INTERFERON-GAMMA RELEASE ASSAYS 22 DISCORDANCE IN RESULTS FOR THE DETECTION OF M. TUBERCULOSIS INFECTION 29 LIMITATIONS TO INTERFERON-GAMMA RELEASE ASSAYS 36 TUBERCULOSIS AND THE UNITED STATES NAVY 40 LATENT TUBERCULOSIS INFECTION IN MILITARY RECRUITS 45 CHAPTER II: MANUSCRIPT 52 TITLE PAGE 52 INTRODUCTION 53 MATERIALS AND METHODS 58 RESULTS 64 DISCUSSION 70 LIMITATIONS AND STRENGTHS 83 CONCLUSION 87 REFERENCE LIST 89 TABLES 115 FIGURES 122 CHAPTER III: PUBLIC HEALTH IMPLICATIONS 124 SUMMARY 124 APPLICATIONS OF THE QUANTIFERON-TB GOLD IN-TUBE ASSAY 126 FUTURE DIRECTIONS 128 REFERENCES 131 APPENDICES 173 MILITARY HISTORY FORM FROM STUDY PROTOCOL 173 LINK TO XXXXXXX ET AL. – M. TUBERCULOSIS INFECTION IN NAVY RECRUITS, 2007 175 Tables and Figures TABLE 1. CHARACTERISTICS OF US NAVY RECRUITS 115 TABLE 2. OUTCOMES OF THE TUBERCULIN SKIN TEST VERSUS THE QUANTIFERON®-TB GOLD IN-TUBE ASSAY 116 TABLE 3. OUTCOMES OF THE QUANTIFERON®-TB GOLD ASSAY VERSUS THE QUANTIFERON®-TB GOLD IN-TUBE ASSAY 117 TABLE 4. UNIVARIATE ASSOCIATION OF SUBJECT CHARACTERISTICS WITH TUBERCULIN SKIN TEST OR QUANTIFERON®-TB GOLD IN-TUBE ASSAY RESULTS 118 TABLE 5. UNIVARIATE ASSOCIATION OF SUBJECT CHARACTERISTICS WITH DISCORDANT RESULTS BETWEEN THE QUANTIFERON®-TB GOLD IN-TUBE ASSAY AND THE TUBERCULIN SKIN TEST, USING A 10 MM CUTOFF 119 TABLE 6. UNIVARIATE ASSOCIATION OF SUBJECT CHARACTERISTICS WITH DISCORDANT RESULTS BETWEEN THE QUANTIFERON®-TB GOLD IN-TUBE ASSAY AND THE TUBERCULIN SKIN TEST, USING A 15 MM CUTOFF 120 TABLE 7. MULTIVARIATE ANALYSIS EXAMINING DISCORDANCE BETWEEN NEGATIVE QUANTIFERON®-TB GOLD IN-TUBE ASSAY RESULTS AND TUBERCULIN SKIN TEST RESULTS USING A 15 MM OR A 10 MM CUTOFF 121 FIGURE 1. DIAGRAM OF STUDY PARTICIPATION AND TESTING 122 FIGURE 2. COMPARISON OF TUBERCULIN SKIN TEST RESULTS TO INTERFERON-GAMMA RELEASE ASSAY INTERPRETATIONS, STRATIFIED BY RISK OF INFECTION 123 Introduction Tuberculosis (TB) is a leading cause of death and illness worldwide. The causative agent of TB is the Mycobacterium tuberculosis bacillus. Mycobacterium tuberculosis infection (MTBI) occurs in humans, who act as its primary reservoir. Approximately 2 billion people worldwide have quiescent or latent M. tuberculosis infection (LTBI) and are at risk of developing TB mortality from infectious diseases (1). Due to effective treatment As a result people live longer but people became suffering from different diseases, such as cancers, heart diseases, diabetes, and control measures, TB incidence and prevalence rates are declining in the United States (US) and most developed regions of the world dementia (2). Low bone mineral density and NAFLD are not directly related to a life-threatening conditions, and they have not attracted so much attention. However, low bone mineral density can increase the rate of bone fracture, which decrease the patients’ quality of life. The number of people with NAFLD is increasing as obesity is becoming more prevalent. Therefore, these two factors can have a great impact on public health, and considering the association can give us a better strategy for prevention and therapy, and must be beneficial for the future researches. Bone Mineral Density Bone mineral density (BMD) is widely used to diagnose osteoporosis (3). HoweverOsteoporosis is a disease “characterized by low bone mass, elimination deterioration of TB remains elusivebone tissue and disruption of bone architecture, even compromised bone strength and an increase in high-resource countries because of continued transmission in groups at high the risk of MTBI fracture.” (3) Xxxxxx reported 10.2 million Americans aged 50 years and progression to TB, difficulties older are affected by osteoporosis in detecting MTBI, and programmatic complacency 2013 (4). Around 4% Maintaining BMD level is beneficial to protect against incidents of the US population is thought to bone fractures. Prospective cohort studies have LTBI, and is a constant source for future TB and MTBI transmission demonstrated that people with low bone mineral density of femur (5, 6). There is continued pressure to improve diagnostic and screening methods for detecting MTBI, including LTBI and infection manifesting as TB lumber spine (5, 7), radius (6, 8) or forearm (9) have higher risk of bone fracture. Meta-8). Identifying and treating LTBI among those at analysis reported -1 S.D. BMD people have 1.5 to 2.6 times as high risk of developing TB is an important component for TB control and elimination in low-TB incidence regions, such as the US and Canada bone fracture (9, 10). No method exists for accurately detecting LTBI. HistoricallyIn the industrialized countries, the only way number of people with osteoporosis or low bone mineral density is increasing, as population is aging. “It is anticipated that the number of fractures will grow proportionally.” (3) “Annually, two million fractures are attributed to diagnose LTBI was the tuberculin skin test (TST)osteoporosis, which involved measuring immunologic delayed hypersensitivity to an intradermal injection of purified protein derivatives (PPD) made from M. tuberculosis (tuberculin PPD) (11). The TST has limitations in detecting LTBI in some settings. For examplecausing more than 432,000 hospital admissions, where the prevalence of LTBI is low, the positive predictive value (PPV) of TST is hindered by cross reactions induced by sensitization to other mycobacteria (11). The development of interferon-gamma release assays (IGRA) offered an alternative to the TST almost 2.5 million medical office visits and addressed some limitations about 180,000 nursing home admissions in the TST U.S.” (123) Therefore, 13). MTBI typically induces an immune T-lymphocyte response which produces keeping bone mineral density is also beneficial from the cytokine interferon gamma (INF-γ) when the T-cells encounter mycobacterial antigens (13). Whole-blood IGRAs such as the 2nd generation, QuantiFERON®-TB Gold test (QFT-G) (Cellestis Limited, Xxxxxxxx, Xxxxxxxx, Australia) measure the amount view of INF-γ released when blood is stimulated with specific Mycobacterium antigens (14). In 2007, the US Food public health and Drug Administration (FDA) approved the 3rd generation of IGRA for the detection of MTBI, the QuantiFERON®-TB Gold In-Tube test (QFT-GIT) (Cellestis Limited, Xxxxxxxx, Xxxxxxxx, Australia) (15). Like the TST, positive QFT-GIT results are highly associated with factors that historically contribute to MTBI (15, 16). However, QFT-GIT can exhibit discordance when compared to TST results and other IGRAs (15, 17-19). Absence of a “gold standard” to confirm MTBI limits IGRA assessments of accuracy and allows only estimates of sensitivity and specificity (15, 16). Approximations of sensitivity have been achieved by comparing the results of diagnostic tests to culture-confirmed cases of TB (15). Previous studies have assessed IGRAs among “assumed negative” populations at low-risk of MTBI, to better approximate specificity, with some consideration of test discordance (20- 22). Further research has been suggested to understand the factors associated with discordant test results (6, 15, 23). In light of the need for more research to understand IGRA accuracy and discordance, this study on QFT-GIT is part of a series of IGRA studies (21, 24- 26). This study was conducted to add to the current discourse on the interpretation of LTBI screening results among low-risk populations when considering multiple testing methods. The analysis of cross-sectional data obtained from US Navy recruits in 2004 will quantify QFT-GIT specificity for a population at low-risk for MTBI. Additionally, this study will identify recruit characteristics and estimate their associations to discordant results between the QFT-GIT and TST. Results for QFT-GIT will also be compared to other IGRA results, performed at the same time (21). Chapter Ihealthcare economy.

Conclusions. The specificity associations between food insecurity and diabetes as well as the high prevalence of QFT-GIT was high both conditions give evidence that food insecurity should be addressed in clinical settings. This study makes the case that electronic medical records should include measures of food insecurity for appropriate referral. More research, especially longitudinal, is necessary to continue to examining this association. Key words‌ Food security, nutrition, type 2 diabetes, hospital, electronic medical records Hunger is Health: The Association Between Food Insecurity and similar to TST Diabetes in the Primary Care Center (PCC) at either cutoff. Test discordance observed Xxxxx Hospital in recruits with increased risk may be due to lower TST specificityAtlanta, lower QFT-GIT sensitivity, or both. Negative QFT-GIT results for recruits born in countries with high–TB prevalence and whose TST is > 15mm suggest that QFT-GIT may be less sensitive than TST. Additional studies are needed to determine the risk of developing TB when TST and QFT-GIT results are discordant. Assessing specificity and discordance between the tuberculin skin test and a whole-blood interferon-γ release assay for the detection of Mycobacterium tuberculosis infection among United States Navy recruits. GA By Xxxxx Xxxxxxx Xxxxx Bachelor of Science in Biology Bachelor of Science in Anthropology X. Xxxxxxxx X.X., American University, 2014 Emory University of Utah 2007 2017 Thesis Faculty AdvisorCommittee Chair: Xxxx X. XxXxxxxXxx Xxxx-Xxxxxx, Xx., M.D. Field Advisor: Xxxxxx X. Xxxxxxx, M.D. PhD A thesis submitted to the Faculty of the Xxxxxxx School of Public Health of Emory University in partial fulfillment of the requirements for the degree of Master of Public Health in Epidemiology 2011 Acknowledgements I would like not have been able to thank complete this thesis without the guidance of Xx. Xxxxxxx Xxx Xxxx- Girard. Thank you, Xxx, for helping me create and Xx. XxXxxxx for their efforts in advising execute a project that I was truly passionate about, and mentoring supporting me through the processes (many) rounds of drafts! A huge thank you also goes to Xxx Xxxxx of Atlanta Community Food Bank for standing by me through every iteration of this project, from when it was just an idea in my head all the thesis and my professional development while at Emory University and with way to the CDC; the staff at CDC, DTBE, especially Xxxxx Xxxxxxx, Xxxxxx Xxxxx, Kit Xxxxxxxxx, Xxxxxxx Xxxxxxxx and Xxxxx Xxxxxxx, for including me in the branch’s activities and assisting in innumerable ways with my analysis and manuscript; my professors at the Xxxxxxx School of Public Health, particularly finish line. Thank you to Xx. XxxxxxxxxXxxx Xxxxxx-Jones, who provided council on my statistical analyses; also without whom I would not have had the clinical nor hospital support to complete this survey. I am incredibly grateful for my friends and colleagues at peers, especially those in the Epidemiology and Behavioral Science and Health Education departmentsnutrition department at Xxxxxxx, who have helped make my time encouraged me to keep moving forward even in Atlanta a rich experience; the face of setbacks. Most of all, thank you to my parents, Xxxxxx Xxxxx and XxxxxxxXxxxx, for their unwavering love and support; and Xxxxxxx Xxxxxbeing my rocks throughout the entire journey that was graduate school. To say, who has endured “I would not be here without you” is a gross understatement. Chapter One: Introduction 1 Chapter Two: Review of the hardships Literature 3 Chapter Three: Methodology 18 Chapter Four: Results 24 Chapter Five: Discussion 31 References 40 Appendices 43 List of education with me and has given me such support and freedom, that I may never truly repay her gifts and sacrifices. Table of Contents INTRODUCTION 1 CHAPTER I: BACKGROUND 4 EPIDEMIOLOGY OF TUBERCULOSIS 4 PATHOGENESIS OF MYCOBACTERIUM TUBERCULOSIS INFECTION 6 DIAGNOSTICS FOR MYCOBACTERIUM TUBERCULOSIS INFECTION 11 THE TUBERCULIN SKIN TEST 14 INTERFERON-GAMMA RELEASE ASSAYS 19 WHOLE-BLOOD INTERFERON-GAMMA RELEASE ASSAYS 22 DISCORDANCE IN RESULTS FOR THE DETECTION OF M. TUBERCULOSIS INFECTION 29 LIMITATIONS TO INTERFERON-GAMMA RELEASE ASSAYS 36 TUBERCULOSIS AND THE UNITED STATES NAVY 40 LATENT TUBERCULOSIS INFECTION IN MILITARY RECRUITS 45 CHAPTER II: MANUSCRIPT 52 TITLE PAGE 52 INTRODUCTION 53 MATERIALS AND METHODS 58 RESULTS 64 DISCUSSION 70 LIMITATIONS AND STRENGTHS 83 CONCLUSION 87 REFERENCE LIST 89 TABLES 115 FIGURES 122 CHAPTER III: PUBLIC HEALTH IMPLICATIONS 124 SUMMARY 124 APPLICATIONS OF THE QUANTIFERON-TB GOLD IN-TUBE ASSAY 126 FUTURE DIRECTIONS 128 REFERENCES 131 APPENDICES 173 MILITARY HISTORY FORM FROM STUDY PROTOCOL 173 LINK TO XXXXXXX ET AL. – M. TUBERCULOSIS INFECTION IN NAVY RECRUITS, 2007 175 Tables and Figures TABLE 1Table No. CHARACTERISTICS OF US NAVY RECRUITS 115 TABLE Description Page Table 1 Incidence and Prevalence of Type 2 Diabetes Across Various Racial/Ethnic Groups 6 Table 2 Descriptive Characteristics Overall and by Diabetes Diagnosis (Prediabetes + Diabetes) 27 Box No. Description Page Box 1 USDA Definition of Food Security 10 Box 2 Pillars of Food Security 11 Box 3 USDA Food Security Module 2-Item Screener 11 Figure No. OUTCOMES OF THE TUBERCULIN SKIN TEST VERSUS THE QUANTIFERON®-TB GOLD INDescription Page Figure 1 Odds of Diabetes with Food Security for 323 Patients Attending the Primary Care Unit at Xxxxx Hospital from January-TUBE ASSAY 116 TABLE 3March 2017. OUTCOMES OF THE QUANTIFERON®-TB GOLD ASSAY VERSUS THE QUANTIFERON®-TB GOLD INOdds ratios and confidence intervals are estimated using logistic regression analysis. 28 Figure 2a Geographic Distribution to USDA 2-TUBE ASSAY 117 TABLE 4Item Screener First Question 29 Figure 2b Geographic Distribution to USDA 2-Item Screener Second Question 30 Figure 2c Geographic Distribution of Diabetes Status by Zip Code 31 Chapter One: Introduction As of 2014, type two diabetes touched the lives of 29.1% of Americans, giving it the status of a public health epidemic. UNIVARIATE ASSOCIATION OF SUBJECT CHARACTERISTICS WITH TUBERCULIN SKIN TEST OR QUANTIFERON®-TB GOLD IN-TUBE ASSAY RESULTS 118 TABLE 5. UNIVARIATE ASSOCIATION OF SUBJECT CHARACTERISTICS WITH DISCORDANT RESULTS BETWEEN THE QUANTIFERON®-TB GOLD IN-TUBE ASSAY AND THE TUBERCULIN SKIN TEST, USING A 10 MM CUTOFF 119 TABLE 6. UNIVARIATE ASSOCIATION OF SUBJECT CHARACTERISTICS WITH DISCORDANT RESULTS BETWEEN THE QUANTIFERON®-TB GOLD IN-TUBE ASSAY AND THE TUBERCULIN SKIN TEST, USING A 15 MM CUTOFF 120 TABLE 7. MULTIVARIATE ANALYSIS EXAMINING DISCORDANCE BETWEEN NEGATIVE QUANTIFERON®-TB GOLD IN-TUBE ASSAY RESULTS AND TUBERCULIN SKIN TEST RESULTS USING A 15 MM OR A 10 MM CUTOFF 121 FIGURE 1. DIAGRAM OF STUDY PARTICIPATION AND TESTING 122 FIGURE 2. COMPARISON OF TUBERCULIN SKIN TEST RESULTS TO INTERFERON-GAMMA RELEASE ASSAY INTERPRETATIONS, STRATIFIED BY RISK OF INFECTION 123 Introduction Tuberculosis (TB) is a leading cause of death and illness worldwide. The causative agent of TB is the Mycobacterium tuberculosis bacillus. Mycobacterium tuberculosis infection (MTBI) occurs in humans, who act as its primary reservoir. Approximately 2 billion people worldwide have quiescent or latent M. tuberculosis infection (LTBI) and are at risk of developing TB (1). Due to effective treatment and control measures, TB incidence and prevalence rates are declining in While the United States (US) and most developed regions spends millions of the world (2, 3). However, elimination of TB remains elusive, even in high-resource countries because of continued transmission in groups at high risk of MTBI and progression to TB, difficulties in detecting MTBI, and programmatic complacency (4). Around 4% of the US population is thought to have LTBI, and is a constant source for future TB and MTBI transmission (5). There is continued pressure to improve diagnostic and screening methods for detecting MTBI, including LTBI and infection manifesting as TB (6-8). Identifying and treating LTBI among those at high risk of developing TB is an important component for TB control and elimination in low-TB incidence regions, such as the US and Canada (9, 10). No method exists for accurately detecting LTBI. Historicallydollars on type two diabetes prevention every year, the only way number of cases continues to diagnose LTBI was the tuberculin skin test (TST), which involved measuring immunologic delayed hypersensitivity to an intradermal injection of purified protein derivatives (PPD) made from M. tuberculosis (tuberculin PPD) (11). The TST has limitations in detecting LTBI in some settings. For example, where the prevalence of LTBI is low, the positive predictive value (PPV) of TST is hindered by cross reactions induced by sensitization to other mycobacteria (11). The development of interferon-gamma release assays (IGRA) offered an alternative to the TST and addressed some limitations in the TST (12, 13). MTBI typically induces an immune T-lymphocyte response which produces the cytokine interferon gamma (INF-γ) when the T-cells encounter mycobacterial antigens (13). Whole-blood IGRAs such as the 2nd generation, QuantiFERON®-TB Gold test (QFT-G) (Cellestis Limited, Xxxxxxxx, Xxxxxxxx, Australia) measure the amount of INF-γ released when blood is stimulated with specific Mycobacterium antigens (14)grow. In 2007, the US Food and Drug Administration (FDA) approved the 3rd generation of IGRA for the detection of MTBI, the QuantiFERON®-TB Gold In-Tube test (QFT-GIT) (Cellestis Limited, Xxxxxxxx, Xxxxxxxx, Australia) (15). Like the TST, positive QFT-GIT results are highly associated with factors that historically contribute to MTBI (15, 16). However, QFT-GIT can exhibit discordance when compared to TST results and other IGRAs (15, 17-19). Absence of a “gold standard” to confirm MTBI limits IGRA assessments of accuracy and allows only estimates of sensitivity and specificity (15, 16). Approximations of sensitivity have been achieved by comparing the results of diagnostic tests to culture-confirmed cases of TB (15). Previous studies have assessed IGRAs among “assumed negative” populations at low-risk of MTBI, to better approximate specificity, with some consideration of test discordance (20- 22). Further research has been suggested to understand the factors associated with discordant test results (6, 15, 23). In light of the need for more research to understand IGRA accuracy and discordance, this study on QFT-GIT is part of a series of IGRA studies (21, 24- 26). This study was conducted to add to the current discourse on the interpretation of LTBI screening results among low-risk populations when considering multiple testing methods. The analysis of cross-sectional data obtained from US Navy recruits in 2004 will quantify QFT-GIT specificity for a population at low-risk for MTBI. Additionally, this study will identify recruit characteristics and estimate their associations to discordant results between the QFT-GIT and TST. Results for QFT-GIT will also be compared to other IGRA results, performed at the same time (21). Chapter Iyear,

Conclusions. The specificity This pilot study offers the first regional-level characterization of QFT-GIT was high PLWH proceeding through the early steps of transplantation. PLWH were less likely to traverse the steps of kidney transplant compared with those HIV negative, highlighting the need for targeted interventions to improve access to kidney transplant for PLWH. Identifying the barriers and similar disparities for referral to TST at either cutoff. Test discordance observed in recruits kidney transplantation faced by person living with increased risk may be due to lower TST specificity, lower QFT-GIT sensitivity, or both. Negative QFT-GIT results for recruits born in countries with high–TB prevalence HIV and whose TST is > 15mm suggest that QFT-GIT may be less sensitive than TST. Additional studies are needed to determine the risk of developing TB when TST and QFT-GIT results are discordant. Assessing specificity and discordance between the tuberculin skin test and a whole-blood interferon-γ release assay for the detection of Mycobacterium tuberculosis infection among United States Navy recruits. end stage renal disease By Xxxxx Xxxxxxx Xxxxx Bachelor of Science in Biology Bachelor of Science in Anthropology University of Utah 2007 Thesis Faculty Advisor: Xxxx X. XxXxxxxXxxxxxxx ScB, Xx.Monmouth University, M.D. Field 2009 MD, Xxxxxx Xxxxxxxxxx University School of Health Sciences, 2013 Advisor: Xxxxxx X. XxxxxxxXxxxx, M.D. MD A thesis submitted to the Faculty of the Xxxxxxx Xxxxx X. Xxxxx School of Public Health Graduate Studies of Emory University in partial fulfillment of the requirements for the degree of Master of Public Health Science in Epidemiology 2011 Acknowledgements Clinical Research 2020 I would like to thank Xx. Xxxxxx Xxxxx and Xx. Xxxxxx Xxxxxx for serving as research mentors. Their assistance in honing my ideas and interests, providing me with the necessary support and guidance to complete my MSCR application, and informative discussions regarding the implications of this work, not only tremendously developed this work, but helped me to grow as a junior investigator. I am thankful for the help of Dr. Zhensheng (AKA Xxxxx) Wang who assisted me with the analysis and served as my reader and additionally and Xx. Xxxxxxxxx for reviewing the drafts of this thesis. I would like to thank Xx. Xxxxxxx Xxxxx for being instrumental in obtaining the data for this project and Xxbeing so accommodating to additional data requests. XxXxxxx I am also appreciative of Dr. Xxxxx Xxxxxxxxx who has been a fearless leader and program director, and the main reason why I applied to the MSCR program. Lastly, I would like to thank my husband Xxxxxx Xxxxxxxxx for their efforts in advising his patience, love, support, and mentoring me through the processes of the thesis and my professional development while at Emory University and with the CDC; the staff at CDC, DTBE, especially Xxxxx Xxxxxxx, Xxxxxx Xxxxx, Kit Xxxxxxxxx, Xxxxxxx Xxxxxxxx and Xxxxx Xxxxxxx, for including me SAS consultations. TABLE OF CONTENTS INTRODUCTION 1 BACKGROUND 3 METHODS 8 RESULTS 19 DISCUSSION 24 CONCLUSIONS 33 REFERENCES 34 INTRODUCTION‌ End-stage renal disease (ESRD) has increased by 1000% in the branch’s activities and assisting in innumerable ways with my analysis and manuscript; my professors at the Xxxxxxx School of Public Healthpast 3 decades, particularly Xx. Xxxxxxxxx, who provided council on my statistical analyses; also my friends and colleagues at proving to be a significant health concern in the Epidemiology and Behavioral Science and Health Education departmentsUnited Sates. In 1980, who have helped make my time there were 60,000 persons with ESRD though in Atlanta a rich experience; my parents, Xxxxxx and Xxxxxxx, for their unwavering love and support; and Xxxxxxx Xxxxx, who has endured the hardships of education 2018 there were over 700,000 Americans living with me and has given me such support and freedom, that I may never truly repay her gifts and sacrifices. Table of Contents INTRODUCTION 1 CHAPTER I: BACKGROUND 4 EPIDEMIOLOGY OF TUBERCULOSIS 4 PATHOGENESIS OF MYCOBACTERIUM TUBERCULOSIS INFECTION 6 DIAGNOSTICS FOR MYCOBACTERIUM TUBERCULOSIS INFECTION 11 THE TUBERCULIN SKIN TEST 14 INTERFERON-GAMMA RELEASE ASSAYS 19 WHOLE-BLOOD INTERFERON-GAMMA RELEASE ASSAYS 22 DISCORDANCE IN RESULTS FOR THE DETECTION OF M. TUBERCULOSIS INFECTION 29 LIMITATIONS TO INTERFERON-GAMMA RELEASE ASSAYS 36 TUBERCULOSIS AND THE UNITED STATES NAVY 40 LATENT TUBERCULOSIS INFECTION IN MILITARY RECRUITS 45 CHAPTER II: MANUSCRIPT 52 TITLE PAGE 52 INTRODUCTION 53 MATERIALS AND METHODS 58 RESULTS 64 DISCUSSION 70 LIMITATIONS AND STRENGTHS 83 CONCLUSION 87 REFERENCE LIST 89 TABLES 115 FIGURES 122 CHAPTER III: PUBLIC HEALTH IMPLICATIONS 124 SUMMARY 124 APPLICATIONS OF THE QUANTIFERON-TB GOLD IN-TUBE ASSAY 126 FUTURE DIRECTIONS 128 REFERENCES 131 APPENDICES 173 MILITARY HISTORY FORM FROM STUDY PROTOCOL 173 LINK TO XXXXXXX ET AL. – M. TUBERCULOSIS INFECTION IN NAVY RECRUITS, 2007 175 Tables and Figures TABLE 1. CHARACTERISTICS OF US NAVY RECRUITS 115 TABLE 2. OUTCOMES OF THE TUBERCULIN SKIN TEST VERSUS THE QUANTIFERON®-TB GOLD IN-TUBE ASSAY 116 TABLE 3. OUTCOMES OF THE QUANTIFERON®-TB GOLD ASSAY VERSUS THE QUANTIFERON®-TB GOLD IN-TUBE ASSAY 117 TABLE 4. UNIVARIATE ASSOCIATION OF SUBJECT CHARACTERISTICS WITH TUBERCULIN SKIN TEST OR QUANTIFERON®-TB GOLD IN-TUBE ASSAY RESULTS 118 TABLE 5. UNIVARIATE ASSOCIATION OF SUBJECT CHARACTERISTICS WITH DISCORDANT RESULTS BETWEEN THE QUANTIFERON®-TB GOLD IN-TUBE ASSAY AND THE TUBERCULIN SKIN TEST, USING A 10 MM CUTOFF 119 TABLE 6. UNIVARIATE ASSOCIATION OF SUBJECT CHARACTERISTICS WITH DISCORDANT RESULTS BETWEEN THE QUANTIFERON®-TB GOLD IN-TUBE ASSAY AND THE TUBERCULIN SKIN TEST, USING A 15 MM CUTOFF 120 TABLE 7. MULTIVARIATE ANALYSIS EXAMINING DISCORDANCE BETWEEN NEGATIVE QUANTIFERON®-TB GOLD IN-TUBE ASSAY RESULTS AND TUBERCULIN SKIN TEST RESULTS USING A 15 MM OR A 10 MM CUTOFF 121 FIGURE 1. DIAGRAM OF STUDY PARTICIPATION AND TESTING 122 FIGURE 2. COMPARISON OF TUBERCULIN SKIN TEST RESULTS TO INTERFERON-GAMMA RELEASE ASSAY INTERPRETATIONS, STRATIFIED BY RISK OF INFECTION 123 Introduction Tuberculosis (TB) is a leading cause of death and illness worldwide. The causative agent of TB is the Mycobacterium tuberculosis bacillus. Mycobacterium tuberculosis infection (MTBI) occurs in humans, who act as its primary reservoir. Approximately 2 billion people worldwide have quiescent or latent M. tuberculosis infection (LTBI) and are at risk of developing TB ESRD (1). Due The expense of Chronic Kidney Disease (CKD) and ESRD has a significant impact on the United States economy and in 2018, CKD and ESRD accounted for approximately 7% of Medicare expenditure, equating to $114 billion per year (2,3). It is well established that kidney transplantation is the optimal therapy for ESRD as it provides increased survival, better quality of life, and is less costly when compared with conventional dialysis (4–7). Since the advent of effective antiretroviral therapy, persons living with HIV (PLWH) are surviving longer and accumulating comorbidities. While HIV specific mortality has decreased, unfortunately, there continues to be a growing HIV epidemic, particularly in the southeastern United States. In 2017, the south accounted for 52% of the 38,739 new HIV diagnoses (8). As the HIV population ages, ESRD has emerged as a significant cause of morbidity and mortality, with PLWH being three times more likely to develop ESRD compared with the general population and is thought to compromise approximately 1.5% of the dialysis population (9,10). Additionally, compared with HIV- negative counterparts, PLWH experience a lower one- and five- year survival on dialysis (11). Despite this, there is growing evidence that PLWH are less likely to be placed on the organ waitlist and 47% less likely to receive a living donor kidney transplant (12). In order to improve survival and increase transplant rates among PLWH, it is critical to better understand the barriers to achieving a kidney transplant in this high-risk population. The objective of this thesis project was to identify and describe the HIV positive dialysis population in ESRD Network 6, the region with the lowest rates of kidney transplantation in the nation. Additionally, to compare their progression through the early steps (referral, evaluation, and waitlisting) of kidney transplantation to general dialysis population, and highlight patient and dialysis level characteristics that may influence access to kidney transplantation. This was accomplished through creating a novel HIV-ESRD dataset that identifies PLWH as well as those who proceeded through the early steps of transplantation. BACKGROUND‌ PLWH have increasing rates of ESRD. HIV-associated nephropathy (HIVAN) was previously one of the leading causes of renal failure among PLWH. The widespread use of affective antiretroviral therapy (ART) has decreased the prevalence of HIV-associated nephropathies (13,14), however, PLWH are still developing CKD and ESRD faster than HIV negative counterparts. This is largely due to co-morbidities (diabetes mellitus, cardiovascular disease, hypertension, and metabolic syndrome), co- infection with hepatitis C virus (HCV), medication induced injury, and accelerated aging seeing in chronic HIV infection (9,15,16). PLWH of black race are especially at risk for progression from CKD to ESRD. A study performed in Baltimore, Maryland revealed that African-Americans were at an increased risk for incident CKD and developed ESRD markedly faster than white subjects (HR, 17.7 [95% CI 2.5-127.0]) (17). ESRD among PLWH is particularly present in the southeast. In 2000, ESRD Network 6 had the 4th highest percentage of PLWH on dialysis at a proportion of 1.9% compared to an national average of 1.5%(10). Unfortunately, the southeastern region of the US continues to have the highest burden of CKD and ESRD with Georgia, North Carolina and South Carolina being states with some of the highest age-standardized CKD disability-adjusted life years (18,19). This coupled by the ongoing HIV epidemic in the southeast makes ESRD Network 6 a unique region to study the coexistence of ESRD and access to kidney transplantation among PLWH. With significant risk of progression from CKD to ESRD, it is imperative to understand access to transplantation among this vulnerable patient population. Renal transplantation is a feasible treatment option for PLWH with ESRD. In the 1980’s, HIV infection was considered a contraindication for transplantation and control measuresUS legal code was amended to make it a federal crime to transplant tissue from HIV positive donors (20). It was theorized that the effect of immunosuppression would contribute to progression of HIV disease, TB incidence lead to more episodes of infection and prevalence rates are declining increased rate of death; making it an inappropriate allocation of an organ. Between 1987 to 1997, there were 32 kidney transplants performed in the US in PLWH (mostly unintentional transplantation), with reported 3-year graft survival of 53% and patient survival 83% (21,22). These transplants though were prior to significant improvement in medications used to treat PLWH. In 2003, Stock et al published promising outcomes on 14 HIV-positive patients who underwent transplantation. At a mean follow up of 480 days, 10 out of 10 (100%) of patients who received kidney transplants were alive with functioning grafts. There was no evidence of HIV disease progression and HIV did not seem to have an impact on graft survival (23). Around the same time, driven out of lack of access to dialysis, colleagues in South Africa performed the first kidney transplants from HIV-positive organ donors to HIV-positive recipients, showing that transplantation among PLWH was safe and feasible (24). With revived interest in transplanting PLWH, there have been a number of single center studies and a large multicenter study of 150 HIV-positive renal transplant recipients which all reported transplant outcomes for PLWH that were similar to the general transplant population 19(25–28). With better HIV care and improved understanding of medication interactions, PLWH in the United States (US) and most developed regions of the world (2are not only eligible for HIV-negative organs, 3)but HIV-positive organs as well. However, elimination of TB remains elusive, even in high-resource countries because of continued transmission in groups at high risk of MTBI and progression to TB, difficulties in detecting MTBI, and programmatic complacency (4). Around 4% of the US population is thought to have LTBI, and is a constant source for future TB and MTBI transmission (5). There is continued pressure to improve diagnostic and screening methods for detecting MTBI, including LTBI and infection manifesting as TB (6-8). Identifying and treating LTBI among those at high risk of developing TB is an important component for TB control and elimination in low-TB incidence regions, such as the US and Canada (9, 10). No method exists for accurately detecting LTBI. HistoricallyIn 2013, the only way HIV Organ Procurement Equity (HOPE) Act was signed into law, reversing the 1988 amendment, allowing HIV positive organs to diagnose LTBI was be transplanted into HIV positive recipients. This policy change is estimated to increase the tuberculin skin test (TST)donor pool by 300-500 organs, which involved measuring immunologic delayed hypersensitivity providing a unique opportunity to an intradermal injection increase utilization of purified protein derivatives (PPD) made from M. tuberculosis (tuberculin PPD) (11these organs and increase rates of kidney transplantation in HIV positive individuals 20(29). The TST transplant evaluation process is a multifaceted and complex process with the southeastern region performing the least transplants. Though it is possible for patients to be referred for kidney transplant prior to starting dialysis, the majority of ESRD patients start on dialysis before they are referred to a transplant center. Within 60 days of starting dialysis, patients are required by law to be educated on the risks and benefits of transplantation and if eligible, are referred by a dialysis provider to a transplant center. The transplant center then decides on their waitlist candidacy through conducting thorough medical evaluations (often inclusive of multiple studies and specialty evaluations), performing a psychosocial evaluation, assessing their social support network and financial ability to fund kidney transplantation. When this step is completed, the patient can be waitlisted with the eventual hope of receiving a living or deceased donor kidney transplant. To better understand how well dialysis facilities were performing in referring patients to kidney transplant, Xx. Xxxxxx Xxxxxx (co-I; Department of Surgery & Department of Epidemiology) and team reported in 2014 that ESRD Network 6 has limitations the lowest rates of kidney transplantation in detecting LTBI the nation, and that Georgia had the lowest of all 50 states (18,30,31) (Figure 1). Factors associated with decreased access to transplant include demographic differences in the southeast, racial disparities, socioeconomic influences, distance to transplant center, provider knowledge and awareness of transplantation (18,32,33). Because no national surveillance data exist on steps prior to waitlisting, the Southeastern Kidney Transplant Coalition developed a novel data registry for referral and evaluation for transplantation among all 9 transplant centers in Xxxxxxx, Xxxxx Xxxxxxxx xxx Xxxxx Xxxxxxxx (X00XX000000, PI: Xxxxxx). They found substantial variability in transplant access at the dialysis facility level where some settingsfacilities referred 0% of patients and others referred 76% (34). For exampleDialysis facility variability in transplant rates for HIV patients have not been described because currently no data exists linking HIV and ESRD care within a state or region. Factors influencing referral to kidney transplantation in PLWH have yet to be described in ESRD Network 6 and will direct construction of future interventions. Identifying PLWH who are on dialysis is difficult to do. Since 2005, where there are scarce data on the incidence and prevalence of LTBI PLWH requiring dialysis. As part of a condition of participation in the ESRD Medicare program, Centers for Medicare and Medicaid Services (CMS) medical evidence form (CMS 2728 form) is low, completed on every ESRD patient upon initiation of dialysis. CMS funds dialysis for ESRD patient and the positive predictive value (PPV) of TST is hindered by cross reactions induced by sensitization to other mycobacteria (11)surgical procedure and immunosuppressants for those who undergo kidney transplantation. The development medical evidence form provides evidence of interferonan ESRD condition, registers patients into a national renal registry, documents medical co-gamma release assays morbidities and other clinical data in dialysis patients, and ensures quality care for ERSD patients (IGRA) offered an alternative to the TST and addressed some limitations in the TST (12, 13). MTBI typically induces an immune T-lymphocyte response which produces the cytokine interferon gamma (INF-γ) when the T-cells encounter mycobacterial antigens (13). Whole-blood IGRAs such as the 2nd generation, QuantiFERON®-TB Gold test (QFT-G) (Cellestis Limited, Xxxxxxxx, Xxxxxxxx, Australia) measure the amount of INF-γ released when blood is stimulated with specific Mycobacterium antigens (1435). In 20072005, HIV serostatus was removed as an ESRD-related condition on the US Food and Drug Administration medical evidence form due to concerns regarding disclosure of HIV status (FDA) approved the 3rd generation of IGRA for the detection of MTBI, the QuantiFERON®-TB Gold In-Tube test (QFT-GIT) (Cellestis Limited, Xxxxxxxx, Xxxxxxxx, Australia) (1536). Like the TSTPresently, positive QFT-GIT results are highly associated with factors that historically contribute in order to MTBI identity PLWH on dialysis, HIV status is inferred through pharmacy prescription data (15, 16). However, QFT-GIT can exhibit discordance when compared to TST results and other IGRAs (15, 17-19). Absence of a “gold standard” to confirm MTBI limits IGRA assessments of accuracy and allows only estimates of sensitivity and specificity (15, 16). Approximations of sensitivity have been achieved by comparing the results of diagnostic tests to culture-confirmed cases of TB (15). Previous studies have assessed IGRAs among “assumed negative” populations at low-risk of MTBI, to better approximate specificity, with some consideration of test discordance (20- 22). Further research has been suggested to understand the factors associated with discordant test results (6, 15, 23). In light of the need for more research to understand IGRA accuracy and discordance, this study on QFT-GIT is part of a series of IGRA studies (21, 24- 2612). This study ascertainment method is suboptimal, as it may misclassify patients on pre-exposure prophylaxis as being on ART, may fail to identify PLWH not engaged in HIV care, and lacks patient-level epidemiologic and clinical data. Nonetheless, pharmacy prescription data is the only currently available method that can be used. In this study, Medicare prescription part D claims data was conducted used to add to identify PLWH on dialysis. In 2016, there was 81% participation of Medicare part D among hemodialysis patients, suggestive that majority of the current discourse on the interpretation of LTBI screening results among low-risk populations when considering multiple testing methods. The analysis of cross-sectional data obtained from US Navy recruits HIV population is captured in 2004 will quantify QFT-GIT specificity for a population at low-risk for MTBI. Additionally, this study will identify recruit characteristics and estimate their associations (37). METHODS‌ Hypothesis: Persons living with HIV in ESRD Network 6 are less likely to discordant results between traverse through the QFT-GIT and TST. Results for QFT-GIT will also be multistep process of kidney transplantation compared to other IGRA resultsHIV-negative counterparts in the setting of ESRD. Specific Aims Aim 1: To identify and describe the characteristics of PLWH and ESRD in ESRD Network 6. Aim 2: To describe the distribution and timing of early steps of kidney transplant inclusive of referral, performed at the same evaluation, and waitlisting among PLWH compared with HIV negative individuals with ESRD in Network 6. Aim 3: To identify patient-level and dialysis facility-level factors that are associated with time (21). Chapter Ito referral and time to waitlisting.