Mediation analysis in life course epidemiology: methodological innovation and application to studies of obesity and cardiometabolic health

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Life course epidemiology is the study of how things that happen during pregnancy, childhood and adulthood influence health and wellbeing. Studying people across their life allows us to examine the dynamic ways in which things change across life and how the pattern of change relates to disease; for example we could ask whether people who become obese as children have the same risk of heart disease as people who are normal weight as children but become obese as adults. A key aim of life course studies is to understand the chain of events leading from cause to effect. For example, we know that people with low income have greater risk of becoming obese and we may want to understand why, e.g. what role does physical activity play? This type of analysis is called mediation. Mediation studies can tell us what might happen if we intervened on the steps linking cause to effect. For example if we could make blood pressure levels more similar in obese and non-obese people, would the link between obesity and heart attacks be reduced? At the moment, most mediation studies carry out the analysis in a way that does not reflect the complexity of real life. For example if we are interested in how obesity is related to the structure and function of the heart and whether any link between them was due to blood pressure, most research so far has used obesity measured at one age, blood pressure measured at one age, and structure and function of the heart measured at one age. All of these things change across life, and ignoring these changes means the research could get the wrong answers. In order to do research on mediation that makes better use of data from across life, we need to develop statistical methods that can do this. I will compare several methods for this type of analysis. As well as comparing the methods, I will use them to answer these questions about obesity, heart disease and diabetes:1. Babies who are born small or who grow very quickly in the first few months of life have a higher risk of diabetes and heart disease as adults. This may be because what happens in early life changes the way the body's metabolic system works. In this case, we would need to change growth before or very soon after birth to reduce the risk of diabetes and heart disease. Alternatively, growth in early life might set people on a path, and only the end of that path that matters; e.g. it could be only obesity in adulthood that causes disease. In this case, we could change body size either in childhood or adulthood and would still be able to reduce the risk of disease. To tell the difference between these two possibilities, I will use information from across the whole life. This research will help us to know what might happen to the risk of diabetes and heart disease if we can prevent or treat obesity at different ages.2. Obesity can lead to many different health problems. Because of this we might want to try and prevent people from becoming obese, but this is not always possible. Therefore it is also important to find ways to stop obese people from becoming ill. It is possible to reduce the link between obesity and heart disease, for example by using drugs to reduce blood pressure or levels of lipids (fats) in the blood. I will use one of the largest available research studies (UK Biobank) to find out how much the link between obesity and heart disease could be reduced if we intervened on different pathways.3. Low income, education and social class are all linked with a higher risk of diabetes and heart disease. We know that smoking, physical activity, diet and alcohol explain some, but not all, of this link. However, most research so far has only used information from one time in life. I will use detailed data from across life to understand how we could reduce these unfair differences in the risk of disease.