META-ANALYSIS IN CANCER EPIDEMIOLOGY by SARA GANDINI A thesis submitted to The University of Birmingham for the degree of DOCTOR OF PHILOSOPHY Division of Cancer Studies School of Medicine The University of Birmingham August 2003 University of Birmingham Research Archive e-theses repository This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder. Abstract A published meta-analysis on breast cancer and vegetables and fruit consumption was described to present a methodology used on meta-analysis in Epidemiology. Meta-analysis confirmed the association between intake of vegetables (RR=0.74; 95%CI 0.65-0.84) and, to a lesser extent, fruit and breast cancer risk (RR=0.93; 95%CI 0.79-1.09). Using this methodology, present in a peer-reviewed journal, a systematic meta-analysis on melanoma was conducted extracting RRs from published studies. Fully adjusted estimates were obtained from those studies, when available; RRs adjusted for confounders not related to sun exposure, such as naevi, were considered for sun exposure and sunburns pooled estimates. Pooled estimates were obtained for all main risk factors for melanoma: sun exposure (total, intermittent and chronic), sunburns (in childhood and in adulthood), indicators of actinic damage, family history of melanoma and phenotype characteristics. Investigation of biases and inconsistencies among studies was one of the key phases of the meta-analysis to look for patterns among studies that might explain discrepant findings. The analyses on pigmented lesions and sun exposure showed that the choice of sources of cases and controls influenced significantly the estimate. An indication of a protective effect of chronic sun exposure came from studies that did not include subjects with dermatological problems (significantly different from the other studies: p=0.01). Publication year was an important factor for total sun exposure (p=0.005). Latitude of the study seemed to be an important factor for sunburns (p=0.002) and for high density of freckles (p=0.04). Estimates for hair colour and eye colour adjusted for phenotype and/or photo-type were significantly lower than unadjusted ones (p=0.06 and p=0.06, respectively). This study highlighted how several features of study design, type of analysis, categorization of exposures, study location and populations significantly explained between-study heterogeneity. II To my beloved Mum, Sergio and Eleonora III Acknowledgements I would like to thank my research advisor, Prof. Peter Boyle, not only for his excellent ideas and scientific advice, but also for the opportunity that he gave me to immerse myself in a wonderful job. Thanks also to the European Institute of Oncology for the financial support and the chance to improve my skills. I would like to thank Prof. Langman MJ, for his wise and generous suggestions in the drafting of the thesis. My thanks also go to Francesco Sera of “Congregazione Figli dell’Immacolata Concezione IDI Istituto di Ricovero e Cura a Carattere Scientifico (IDI-IRCCS)”. I would like to thank him for his invaluable help in retrieving and reviewing the relevant literature. This work was carried out within the framework of support of “Associazione Italiana per la Ricerca sul Cancro” (Italian Association for Cancer Research) and “Programma Nazionale di Ricerca e Formazione per le tecnologie in oncologia” (National Research and Education Programme for Cancer Technology) under the auspices of the “Ministero italiano dell'Università e della Ricerca Scientifica e Tecnologica” (Italian Ministry for Universities and Scientific and Technological Research). For the part on breast cancer, published in the European Journal of Cancer, I need to thank Chris Robertson and Hiltrud Merzenich for their scientific advise as valuable statistician and nutritionist, respectively. Thanks also to two special friends of mine: Cristina Pecoraro and Robert Landon who help me in revising my English. IV Table of Contents Table of Contents v List of Figures xi List of Tables xiv Abbreviations xvi Chapter 1. Meta-analysis in Epidemiology 1.1 Introduction Pag. 1 1.2 Meta-analysis of observational studies Pag. 3 1.3 Main aims of the thesis Pag. 6 1.4 Previous works Pag. 8 1.5 Conclusions Pag. 10 Chapter 2. Heterogeneity and bias: Statistical methods 2.1 Introduction Pag. 13 2.2 Bias in meta-analysis Pag. 14 2.2.1 Funnel plots and graphical tests to detect bias Pag. 16 2.3 Meta-analysis dilemma: heterogeneity Pag. 19 2.3.1 Fixed effects models Pag. 22 2.3.2 Random effects models Pag. 23 2.3.3 Dose-response models Pag. 24 2.4 Multiple endpoints Pag. 26 2.5 Bayesian approach Pag. 27 2.6 Conclusions Pag. 28 Chapter 3. Breast cancer and fruit and vegetables consumption 3.1 Introduction Pag. 31 3.2 Material and methods 3.2.1 Selection of studies Pag. 31 3.2.2 Extraction and unification of the data Pag. 35 3.2.3 Analysis Pag. 38 V 3.2.3.1 Heterogeneity analysis Pag. 40 3.2.3.2 Sensitivity analysis Pag. 40 3.3 Results 3.3.1 Characteristics of studies Pag. 41 3.3.2 Pooled Relative Risk estimates Pag. 41 3.3.3 Results from heterogeneity analysis Pag. 42 2.3.4 Results from sensitivity analysis Pag. 43 3.3.5 Publication bias Pag. 44 3.4 Discussion Pag. 44 3.5 Tables Pag. 51 3.4 Figures Pag. 54 Chapter 4: Melanoma and pigmented lesions 4.1 Introduction Pag. 57 4.2 Materials and Methods 4.2.1 Data sources and search strategy Pag. 60 4.2.2 Selection of studies Pag. 61 4.2.3 Extraction and unification of the data Pag. 62 4.2.4 Data analysis strategy Pag. 65 4.3 Results 4.3.1 Literature search and selection Pag. 66 4.3.2 Studies characteristics Pag. 67 4.3.3 Pooled RR estimates Pag. 68 4.3.4 Heterogeneity analysis Pag. 69 4.3.5 Sensitivity Analysis Pag. 72 4.3.6 Publication bias Pag. 74 4.4 Discussion Pag. 75 4.5 Appendix: Reasons for exclusion Pag. 79 4.6 Tables Pag. 82 4.7 Figures Pag. 88 VI Chapter 5: Melanoma and the other risk factors 5.1 Introduction Pag. 94 5.2 Methods Pag. 97 5.3 Ultraviolet radiations exposure: Introduction Pag. 99 5.3.1 Extraction and homogenisation of the data on sun exposure Pag.103 5.3.2 Total sun exposure 5.3.2.1 Materials and methods Pag. 105 5.3.2.2 Results Pag. 106 5.3.2.3 Heterogeneity analysis Pag. 106 5.3.2.4 Sensitivity analysis Pag. 108 5.3.3 Intermittent sun exposure 5.3.3.1 Materials and methods Pag. 109 5.3.3.2 Results Pag. 111 5.3.3.3 Heterogeneity analysis Pag. 111 5.3.3.4 Sensitivity analysis Pag. 113 5.3.4 Chronic sun exposure 5.3.4.1 Materials and methods Pag. 114 5.3.4.2 Results Pag. 115 5.3.4.3 Heterogeneity analysis Pag. 115 5.3.4.4 Sensitivity analysis Pag. 119 5.3.5 Discussion on intermittent and chronic sun exposure Pag. 120 5.3.6 Sunburns history: Introduction Pag. 124 5.3.7 Sunburn in childhood 5.3.7.1 Materials and methods Pag. 126 5.3.7.2 Results Pag. 127 5.3.7.3 Heterogeneity analysis Pag. 127 5.3.7.4 Sensitivity analysis Pag. 128 5.3.8 Sunburn in adulthood 5.3.8.1 Materials and methods Pag. 129 5.3.8.2 Results Pag. 131 5.3.8.3 Heterogeneity analysis Pag. 131 VII 5.3.8.4 Sensitivity analysis Pag. 134 5.3.9 Discussion on sunburns Pag. 135 5.3.10 Conclusions on sunburns and sun exposure Pag. 138 5.4 Family history of melanoma 5.4.1 Introduction Pag. 139 5.4.2 Materials and methods Pag. 140 5.4.3 Results Pag. 140 5.4.4 Sensitivity analysis Pag. 141 5.4.5 Discussion on family history Pag. 141 5.5 Indicators of actinic damage 5.5.1 Introduction Pag. 142 5.5.2 Materials and methods Pag. 143 5.5.3 Results Pag. 144 5.5.6 Heterogeneity analysis Pag. 144 5.5.5 Sensitivity analysis Pag. 146 5.5.6 Discussion on indicators of photodamage Pag. 146 5.6 Host factors 5.6.1 Freckles 5.6.1.1 Materials and methods Pag. 147 5.6.1.2 Results Pag. 148 5.6.1.3 Heterogeneity analysis Pag. 149 5.6.1.4 Sensitivity analysis Pag. 151 5.6.2 Eye colour 5.6.2.1 Materials and methods Pag. 152 5.6.2.2 Results Pag. 153 5.6.2.3 Heterogeneity analysis Pag. 154 5.6.2.4 Sensitivity analysis Pag. 154 5.6.3 Hair colour 5.6.3.1 Materials and methods Pag. 156 5.6.3.2 Results Pag. 157 5.6.3.3 Heterogeneity analysis Pag. 157 VIII 5.6.3.4 Sensitivity analysis Pag. 159 5.6.4 Skin colour 5.6.4.1 Materials and methods Pag. 160 5.6.4.2 Results Pag. 161 5.6.4.3 Heterogeneity analysis Pag. 161 5.6.4.4 Sensitivity analysis Pag. 161 5.6.5 Skin phototype 5.6.5.1 Materials and methods Pag.