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

生命过程流行病学是研究怀孕，童年和成年期间发生的事情如何影响健康和福祉的研究。通过研究人们的一生，我们可以研究生活中事物变化的动态方式以及变化模式与疾病的关系;例如，我们可以问，儿童时期肥胖的人是否与儿童时期体重正常但成年后肥胖的人患心脏病的风险相同。生命历程研究的一个关键目标是了解从原因到结果的事件链。例如，我们知道低收入的人有更大的肥胖风险，我们可能想知道为什么，例如，体育活动发挥了什么作用？这种类型的分析被称为调解。中介研究可以告诉我们，如果我们对因果联系的步骤进行干预，可能会发生什么。例如，如果我们可以使肥胖和非肥胖人群的血压水平更加相似，肥胖和心脏病发作之间的联系会减少吗？目前，大多数中介研究进行的分析方式，并没有反映真实的生活的复杂性。例如，如果我们感兴趣的是肥胖与心脏的结构和功能之间的关系，以及它们之间的任何联系是否是由于血压，到目前为止，大多数研究都使用在一个年龄测量的肥胖，在一个年龄测量的血压，以及在一个年龄测量的心脏结构和功能。所有这些事情在生活中都会发生变化，忽视这些变化意味着研究可能会得到错误的答案。为了更好地利用生活中的数据进行调解研究，我们需要开发可以做到这一点的统计方法。我将比较这类分析的几种方法。除了比较这些方法外，我还将用它们来回答有关肥胖、心脏病和糖尿病的问题：1.出生时很小或在生命的最初几个月内生长非常快的婴儿在成年后患糖尿病和心脏病的风险更高。这可能是因为生命早期发生的事情改变了身体代谢系统的工作方式。在这种情况下，我们需要在出生前或出生后不久改变生长，以降低患糖尿病和心脏病的风险。或者，早期的成长可能会让人们走上一条道路，只有这条道路的终点才重要;例如，只有成年后的肥胖才能导致疾病。在这种情况下，我们可以在童年或成年时改变体型，仍然能够降低疾病的风险。为了区分这两种可能性，我将使用整个生活中的信息。这项研究将帮助我们了解如果我们能够预防或治疗不同年龄段的肥胖，糖尿病和心脏病的风险可能会发生什么。2.肥胖会导致许多不同的健康问题。正因为如此，我们可能想尝试防止人们变得肥胖，但这并不总是可能的。因此，找到阻止肥胖者生病的方法也很重要。减少肥胖和心脏病之间的联系是可能的，例如通过使用药物降低血压或血液中的脂质（脂肪）水平。我将使用最大的研究之一（英国生物银行）来找出如果我们在不同的途径上进行干预，肥胖和心脏病之间的联系可以减少多少。低收入、教育和社会阶层都与糖尿病和心脏病的高风险有关。我们知道，吸烟、体育活动、饮食和酒精可以解释这种联系的部分原因，但不是全部。然而，到目前为止，大多数研究都只使用了生命中某个时期的信息。我将使用生活中的详细数据来了解我们如何减少这些不公平的疾病风险差异。

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.