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Chapter 3.1 128 METHODS Study design Japanese academic hospitals and major general hospitals were invited to participate in the study. Additional entry criteria were availability of data on previous treatment with interferon and on clinical outcomes. All consecutive chronic hepatitis C patients who received interferon alpha treatment between January 1, 1990 and December 31, 1995 and who did not show a sustained virological response were included. Sustained virological response was defi ned as normal alanine aminotransferase (ALT) and negative HCV-RNA at the end of treatment and six months thereafter. The ethics committees of all participating centers approved the protocol. In order to ensure privacy of the patients, the treating physician replaced patient names by a code before entry in the database. Patient selection Data of all consecutive patients with chronic hepatitis C with non-response to previous interferon treatment were collected. Data were collected on separate case record forms, one per patient, by the local investigator. The case record forms were sent to the co-ordination center in <strong>Rotterdam</strong>, where the data were entered in a central database. Before the data were entered, they were checked and in case of doubt, contact was made with the local investigator. Data recorded Information was obtained on demographics (age, gender) and on details of the interferon treatment (starting date, duration, and total dose) as well as the glycyrrhizin treatment (starting date, duration, total dose). Virological data (genotype, viremia), hematological (platelet count) and biochemical data (aminotransferase levels, bilirubin, and gamma glutamyltransferase) were measured in the certifi ed laboratories of the participating hospitals and added to the case record form by the local investigator. Centrally, the results were corrected for local normal values. Follow-up data were recorded every four weeks if available and included ALT-levels, start of glycyrrhizin treatment and the occurrence of HCC. Patients were considered to have a HCC if biopsy proved so or if ultrasound or computed tomography showed a focal lesion in the presence of a serum alpha-fetoprotein of > 400.
Statistics Glycyrrhizin for IFN-non responders 129 A data analysis plan was developed before closure of the database. The Kaplan Meier method was used to assess the occurrence of HCC over time in the overall population. Risk factors for development of hepatocellular carcinoma over time were assessed by time-dependent Cox-regression analysis. Baseline factors and medication during followup after interferon treatment were included in this analysis. The latter factor necessitated the time dependent form of Cox regression analysis. In order to avoid bias, cases were censured at the time of a second interferon-based treatment. According to the data analysis plan, a second analysis was done to assess the effect of glycyrrhizin according to response. Response to glycyrrhizin was defi ned as ALT levels < 1.5 x upper limit of normal at the fi rst measurement 3 months after initiation of treatment. Statistical analyses were performed using SPSS Windows version 11 (SPSS Inc, Chicago, IL, USA). Findings showed a strong infl uence of fi brosis and ALT elevation on development of HCC. Therefore, an additional analysis was done in a more homogeneous group of patients with advanced fi brosis. Simply adjusting for ALT as a time-dependent covariate in a Cox model may lead to a biased estimate of the treatment effect, since higher ALT levels were associated with a higher probability of developing HCC and also of starting glycyrrhizin therapy (fi gure 1). In order to estimate the causal effect of time-dependent glycyrrhizin treatment in the presence of a time-dependent covariate ALT, we used the G-estimation described by Robins. 9 This method is designed to get an unbiased estimate of a treatment effect in Risk of HCC High ALT Low ALT Glycyrrhizin exposure Figure 1. Elevated ALT-levels during follow-up were associated with a higher probability of receiving glycyrrhizin, but also lead to a higher probability of developing HCC. As ALT-levels are lowered by glycyrrhizin treatment, ALT is regarded as a time-dependent covariate which is both a confounder and an intermediate. In order to investigate whether glycyrrhizin reduces the risk of developing HCC by lowering ALT levels (dotted arrow), sophisticated statistical analyses were required and a G-estimation was performed ?
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Statistical Models of Treatment Eff
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ISBN: 978-90-8559-069-9 © Bettina
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PROMOTIECOMMISSIE Promotor: Prof.dr
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CONTENTS Chapter 1. Introduction 11
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Cha pter 1 Introduction
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Chapter 1 14 Epidemiology Worldwide
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Chapter 1 16 Prediction models with
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Chapter 1 18 standard method fails
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Chapter 1 20 The extended non-linea
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Chapter 1 22 References 1. Blumberg
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Cha pter 2 Prediction of response t
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Chapter 2.1 28 ABSTRACT The aim of
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Chapter 2.1 30 been hepatitis B sur
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Chapter 2.1 32 HBV DNA decline The
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Chapter 2.1 34 Figure 2 continued.
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Chapter 2.1 36 Figure 4. Estimated
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Chapter 2.1 38 DNA was observed in
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Chapter 2.1 40 15. Kao JH. Role of
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Chapter 2.2 44 ABSTRACT Background:
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Chapter 2.2 46 low baseline HBV DNA
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Chapter 2.2 48 patient subgroups wa
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Chapter 2.2 50 p=0.002). Previous I
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Chapter 2.2 52 Application of the m
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Chapter 2.2 54 PEG-IFN, the proport
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Chapter 2.2 56 References 1. Lavanc
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Chapter 2.2 58 26. Bonino F, Lau GK
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Chap ter 2.3 Prediction of the resp
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INTRODUCTION Dynamic prediction of
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Statistical analysis Dynamic predic
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Dynamic prediction of response to P
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References Dynamic prediction of re
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Page 118 and 119: Chapter 2.5 116 hepatocellular carc
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Page 129: INTRODUCTION Glycyrrhizin for IFN-n
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Page 135 and 136: Table 2. Time dependent Cox regress
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Page 145 and 146: Introduction Discriminant analysis
Page 147 and 148: Discriminant analysis using a MLMM
Page 149 and 150: Estimation Discriminant analysis us
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Page 178 and 179: Chapter 4.1 176 ABSTRACT Nucleoside
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Chapter 4.1 178 at day 1 at t =0 an
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Chapter 4.1 180 Table 1. Baseline c
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Chapter 4.1 182 Figure 1.
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Chapter 4.1 184 Figure 1. Viral dec
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Chapter 4.1 186 suppression in seru
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Chapter 4.1 188 13. Seifer M, Hamat
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Cha pter 4.2 Viral dynamics during
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INTRODUCTION Viral dynamics during
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Viral dynamics during tenofovir the
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log HBV DNA (copies/mL) 10.0 9.0 8.
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Chap ter 4.3 Modelling of early vir
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INTRODUCTION HBV viral kinetics dur
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HBV viral kinetics during PEG-IFN 2
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SUMMARY AND CONCLUSION Summary and
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Summary and conclusion 233 The mode
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Summary and conclusion 235 The infe
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Summary and conclusion 237 Early st
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SAMENVATTING EN CONCLUSIE Samenvatt
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Samenvatting en conclusie 243 Er we
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Samenvatting en conclusie 245 Data
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Samenvatting en conclusie 247 Behan
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Dan kwoord
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Dankwoord 254 Lieve Marion en Margr
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BIBLI OGRAPHY Bibliography 257 1. K
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Bibliography 259 Interferon-ribavir
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Bibliography 261 Long term clinical
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Bibliography 263 Flares in chronic
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Bibliography 265 Genetic characteri
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Bibliography 267 106. Reijnders JG,
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