Identifying the environmental causes of disease: how should we decide what to believe and when to take action? An Academy of Medical Sciences working group report chaired by Sir Michael Rutter CBE FRS FBA FMedSci November 2007 The Academy of Medical Sciences The Academy of Medical Sciences promotes advances in medical science and campaigns to ensure these are converted into healthcare benefits for society. Our Fellows are the UK’s leading medical scientists from hospitals and general practice, academia, industry and the public service. The Academy plays a pivotal role in determining the future of medical science in the UK, and the benefits that society will enjoy in years to come. We champion the UK’s strengths in medical science, including the unique opportunities for research afforded by the NHS, encourage the implementation of new ideas and solutions – often through novel partnerships, promote careers and capacity building and help to remove barriers to progress. ISBN No: 1-903401-16-X Identifying the environmental causes of disease: how should we decide what to believe and when to take action? An Academy of Medical Sciences working group report chaired by Sir Michael Rutter CBE FRS FBA FMedSci November 2007 IDenTifYinG THE enVirOnmenTAL caUses OF Disease Acknowledgements The Academy of Medical Sciences is most grateful to Professor Sir Michael Rutter CBE FRS FBA FMedSci and the members of the working group for undertaking this study. The Academy wishes to thank the review group, the Academy's Officers, Council and staff, participants at the workshop and all respondents to the consultation for their informative comments and support. The Academy is grateful to the University Hospitals Association for its support. Disclaimer This report is published by the Academy of Medical Sciences and has been endorsed by its Officers and Council. Contributions by the working group and respondents to the call for evidence are made purely in an advisory capacity. The review group added a further ‘peer-review’ stage of quality control to the process of report production. The reviewers were not asked to endorse the report or its findings. The members of the working group and the review group participated in this report in an individual capacity and not as representatives of, or on behalf of, their affiliated hospitals, universities, organisations or associations. Their participation should not be taken as endorsement by these bodies. © Academy of Medical Sciences 2 CONTenTS Contents Summary 7 Recommendations 11 Guidelines 13 Guidelines for researchers 1 Guidelines for editors of science and medical journals 14 Guidelines for science or medical writers and journalists 15 Guidelines for policymakers 16 Guidelines for clinicians and healthcare practitioners 17 Guidelines for funders 18 1. Introduction 19 2. What is a cause? 23 2.1 What is meant by a cause when there are multiple causal elements? 2 2.2 Are environmental influences on human disease likely to be important? 25 3. Types of designs used to identify causes 27 .1 Experiments 27 .2 Randomised controlled trials 27 . Regression discontinuity designs 28 .4 Natural experiments 28 .5 Non-experimental studies 29 .5.1 Cohort studies 29 .5.2 Case-control studies 29 .5. Ecological designs 29 .6 Animal models 0 4. Non-experimental research in medicine 33 5. Identification of the causes of disease 35 5.1 Non-causal explanations of an observed association 5 5.2 Making a causal inference 6 5. Counterfactual reasoning 8 5.4 Dealing with errors and confounders 9 5.4.1 Major sources of bias in non-experimental studies 9 5.4.2 Confounders 40 5.4. Mixed approaches 42 5.4.4 Statistical modelling based on causal graphs 4 5.4.5 Propensity scores 4 5.4.6 Sensitivity analyses 45 5.4.7 Can statistical control for measured confounders be sufficient? 45 5.5 Natural experiments 46 5.5.1 Genetically sensitive designs 46 5.5.2 Other uses of twin and adoption designs 47 IDenTifYinG THE enVirOnmenTAL caUses OF Disease 5.5. Designs to avoid selection bias 49 5.5.4 Within individual change 50 5.5.5 Overview of natural experiments 51 5.6 What is the place of RCTs in research into causes? 51 6. Examples of non-experimental research 55 6.1 Introduction to examples of non-experimental research 55 6.2 Non-experimental research that has led to relatively strong inferences 55 6.2.1 Smoking and lung cancer 55 6.2.2 Lipids and coronary artery disease 55 6.2. Perinatal studies in HIV infection 56 6.2.4 Male circumcision and HIV 57 6.2.5 Blood transfusion and variant Creutzfeldt-Jacob disease (vCJD) 58 6.2.6 Folic acid and neural tube defects 58 6.2.7 Fetal alcohol syndrome 59 6.2.8 Rubella, thalidomide and teratogenic effects 60 6.2.9 Physical and sexual abuse of children 61 6.2.10 Institutional care and disinhibited attachment disorders 61 6.2.11 Lessons from case studies with relatively strong causal claims 62 6.. Non-experimental research with probably valid causal inferences 62 6..1 Hormone replacement therapy and breast and uterine cancer 6 6..2 Social and economic inequality and adverse health outcomes 64 6.. Sleeping position and Sudden Infant Death Syndrome (SIDS) 65 6..4 Gene-environment interactions and psychopathology 66 6..5 Lessons from examples of probably valid causal inferences 66 6.4 Non-experimental research with probably misleading causal claims 67 6.4.1 The Measles Mumps Rubella vaccine 67 6.4.2 Hormone replacement therapy and coronary artery disease 68 6.4. Calcium channel blockers 69 6.4.4 Caffeine in pregnancy 69 6.4.5 Vitamin supplements and mortality 70 6.4.6 Early alcohol use and later alcohol abuse or dependency 70 6.4.7 Lessons from misleading claims 71 7. Identification of causes and implications for policy and practice 73 7.1 How and when to act on identification of causes of disease 7 7.2 Quantifying risk 7 7. Mediation of causal effects 74 7.4 Decision making on research evidence 74 7.5 When should identification of causes of disease lead to policy action? 76 7.6 Governmental attitudes to research 78 8. Communicating the findings from causal research 81 9. Conclusions 85 9.1 When are causal inferences from non-experimental studies justifiable? 85 9.2 Can non-experimental studies give rise to a causal inference? 86 9. Can non-experimental studies be misleading? 87 4 CONTenTS 9.4 Why are there conflicting claims on causes? 87 9.5 Do RCTs constitute the only satisfactory means of establishing causation? 88 9.6 Is there a statistical approach that completely deals with confounding variables? 88 9.7 Recommendations and guidelines 89 9.8 Overall conclusion 91 Appendix I: Statistics 93 Appendix II: Working group and summary of their interests 103 Appendix III: Reviewers 107 Appendix IV: List of consultees and respondents to the call for evidence 109 Appendix V: Glossary 113 Appendix VI: Abbreviations 119 Appendix VII: References 121 5 IDenTifYinG THE enVirOnmenTAL caUses OF Disease 6 SUmmarY Summary 1. Scarcely a day goes by without some new knowledge on the specifics of these report of a study claiming to have discovered a environmental influences, and of the biological new important environmental cause of disease. pathways through which they exert their causal Often these concern serious disorders such as effects, is decidedly limited. We concluded cancer or heart disease and sometimes they that priority needs to be given to high quality implicate factors such as toxins or diet that are research using designs that could help identify readily susceptible to modification. The problem the environmental components of the causal is that few of these findings are confirmed by pathways that lead to disease. subsequent research and, occasionally, new studies even find the opposite. If many of these 5. Sometimes people have wanted research to causal claims turn out to be mistaken, how identify the single basic cause of disease. should we decide what to believe and when to We concluded that this was not the right take action? question. Most common diseases involve the coming together of multiple environmental 2. The challenge for the working party was and multiple genetic causes. Accordingly, the to consider the types of research needed question needed to be: how can we identify to identify environmental causes of disease whether some specific environmental factor when, for practical or ethical reasons, they has a true causal effect that contributed to could not be experimentally investigated. the development of a disease – meaning Inevitably, therefore, our attention had to be that, if it were not present, the rate of that focused on non-experimental studies observing disease would be less? The implication is that associations between specific risk features and knowledge about the causes of disease can different disease outcomes. We considered have an important impact on its treatment, the strengths and limitations of such non- diagnosis or prevention. experimental studies and what steps can be taken to reduce the uncertainties about their 6. We concluded that non-experimental supposed causal effects. methods are fundamental to clinical practice and policymaking. Provided stringent criteria . In order to build the rich evidence base are met, non-experimental research can, that underpins the conclusions of this project and does, give rise to valid inferences on the we issued a call for evidence to which over environmental causes of disease. This has 70 written submissions were received. This important implications for both public policy was buttressed by the findings of a successful and the treatment of individual patients. workshop that brought together a wide range of stakeholders. The evidence obtained from these 7.