1、应用实例分析应用实例分析 临床流行病学研究临床流行病学研究 胎源性疾病胎源性疾病 DOHAD学习目标学习目标n通过应用实例分析通过应用实例分析，加深对流行病学重要基本概念的理解加深对流行病学重要基本概念的理解n通过应用实例分析通过应用实例分析，提高对流行病学研究重要方法的应用能力提高对流行病学研究重要方法的应用能力内容内容n实例分析实例分析 一个经典的有关胎源性疾病的临床流行病学研究报告一个经典的有关胎源性疾病的临床流行病学研究报告n实例分析实例分析 -设计一个有关胎源性疾病的临床流行病学研究项目设计一个有关胎源性疾病的临床流行病学研究项目胎源性疾病胎源性疾病 /发育源性疾病发育源性疾病(DO
2、HAD)nThe suscepatible ity to many chronic diseases in adulthood can be traced back to exposures during early life(during fetal and early postnatal life)成年期的许多慢性疾病的易感性可以追溯成年期的许多慢性疾病的易感性可以追溯到生命早期的暴露因素（胎儿期和出生后早期）到生命早期的暴露因素（胎儿期和出生后早期）n无致病基因突变无致病基因突变流行病学流行病学 -重要作用之一重要作用之一 发现新联系发现新联系 （DOHAD）*Odds ratio fo
3、r two hour glucose concentration of 7.8 mmol/l adjusted for current body mass index.(X2 for trend=15.4;p7.8 mmol/l adjusted for current body mass index.出生体重（出生体重（lb)糖耐量异常糖耐量异常 n/N（%）Adjusted*ORCrude ORCrudeRR低于 5.5 lb(2.5kg)8/20(40%)6.6?5.5-6.4 (2.9 kg)16/47(34%)4.8?6.5-7.4 (3.4 kg)32/104(31%)4.6?7.
4、5-8.4 (3.9 kg)26/117(22%)2.6?8.5-9.4 (4.2 kg)7/54(13%)1.4?9.5+lb (4.3 kg+)4/28(14%)1.01.01.0Answers to Questions（1）What is the study design 研究设计是？研究设计是？Retrospective cohort study 回顾性队列研究回顾性队列研究Why OR?why not RR?Either good for reasoning,the latter is more accurate in defining the relative risk dispa
5、rity.为什么用比值比（为什么用比值比（OR）？而不是相对风险度）？而不是相对风险度（RR？推理任一均可，推理任一均可，RR在定义相对风险差在定义相对风险差距更准确。距更准确。Can we have crude OR and crude RR?Yes,in cohort studies or RCT,you can calculate RR.我们可我们可以计算粗以计算粗OR（未调整比值比）（未调整比值比）,粗粗RR（未调整相对风险度（未调整相对风险度）吗？）吗？是的，在队列研究或试验，可以计算出是的，在队列研究或试验，可以计算出RR。Why adjusted OR?Why not adjus
6、ted RR?Either is good for reasoning,it is easier to calculate the adjusted OR.为什么是调整为什么是调整OR？而不是调整而不是调整RR？推理任一均可，调整？推理任一均可，调整OR更容易计算更容易计算.For cohort study data,you can use log binomial model,to obtain the adjusted RR.队列研究的数据，您可以使用 log 二项式模型，得到调整后的RR。How to calculate adjusted RR,in this study?在本研究中，在
7、本研究中，如何计算调整后的如何计算调整后的RR？Answers to Questions（2）Do we need adjustments in OR or RR?Most times,yes.我们需要调整吗？大多数时候，是的。我们需要调整吗？大多数时候，是的。Is adjustments always necessary?No,sometimes unnecessary.调整是必要的吗？不，有时不必要。调整是必要的吗？不，有时不必要。What the difference Between OR and RR?OR does not always represent RR.OR can be
8、calculated in any study designs,RRs can not be calculated directly in case control studies.OR和和RR有什么区别？有什么区别？OR 有时不能代表有时不能代表RR。可以在任何临床流行病学研究设计中计算。可以在任何临床流行病学研究设计中计算OR。在病例对照研究不能直接计算。在病例对照研究不能直接计算RR。Whats the difference between Crude OR vs.Adjusted OR?The adjusted OR more often(but not always)represen
9、ts the true association。未调整。未调整OR或与调整或与调整OR区别是什么？调整区别是什么？调整OR更经常（但并不更经常（但并不总是）代表真正的联系。总是）代表真正的联系。Whats the difference between Crude RR vs.Adjusted RR?调整调整RR更经常（但并不总是）代表真正的更经常（但并不总是）代表真正的联系。联系。真理？假象？真理？假象？Causal Inference Considerations 因果推理思考因果推理思考Information bias?信息偏倚信息偏倚 less likelyConfounding fac
10、tors？混杂因素？混杂因素 possiblyConsistency of association?联系的一致性联系的一致性 yesStrength of association?关联强度关联强度 OKDose-response relationship?剂量剂量-反应关系反应关系 yesTemporally order consistent?时间一致性时间一致性 yesDeterministic/probabilistic?决定性决定性 noNecessary?必要性必要性 noSufficient?充分充分 noSpecificity?特异性特异性 noBiological plausib
11、ility?生物合理性生物合理性 yesSurrogate risk factor?替代风险因素替代风险因素 may beAnimal model experiment?实验动物模型实验动物模型 yes Birth weight 出生体重出生体重CrudeORAdjusted*OR Crude ORsIs Current BMI a confounder?*adjusted for current body mass index.Confounder or Effect Mediator?混杂因素混杂因素,或影响介质或影响介质?Glucose tolerance 糖耐量 Blood press
12、ure 血压 Current BMI现体重指数现体重指数Birth weight 出生体重 Confounders 混杂因素 (e.g.ethnicity 如种族)When you inappropriate adjust for a factor in the causal pathway,you could produce a false association,or exaggerated association 当你不适当的调整一个在因果通路途径上的因素，你可能会产生一个虚假的关联，或夸张的关联。It may be inappropriate to adjust for current
13、 BMI in estimating the effect of birth weight on current glucose tolerance or blood pressure.调整现在的体重指数以估计出生体重对目前的糖耐量或血压的影响可能是不合适的。Reversal paradox 逆转谜题逆转谜题 Why evidence for the fetal origins of adult disease might be a statistical artifact:the reversal paradox for the relation between birth weight a
14、nd blood pressure in later life.Tu YK,West R,Ellison GT,Gilthorpe MS.Am J Epidemiol;161(1):27-32.Some researchers have recently questioned the validity of associations between birth weight and health in later life.They argue that these associations might be due in part to inappropriate statistical a
15、djustment for variables on the causal pathway(such as current body size),which creates an artifactual statistical effect known as the reversal paradox.Computer simulations were conducted for three hypothetical relations between birth weight and adult blood pressure.The authors examined the effect of
16、 statistically adjusting for different correlations between current weight and birth weight and between current weight and adult blood pressure to assess their impact on associations between birth weight and blood pressure.When there was no genuine relation between birth weight and blood pressure,ad
17、justment for current weight created an inverse association whose size depended on the magnitude of the positive correlations between current weight and birth weight and between current weight and blood pressure.When there was a genuine inverse relation between birth weight and blood pressure,the ass
18、ociation was exaggerated following adjustment for current weight,whereas a positive relation between birth weight and blood pressure could be reversed after adjusting for current weight.Thus,researchers must consider the reversal paradox when adjusting for variables that lie within causal pathways.S
19、urrogate risk factors 替代风险因素替代风险因素?Glucose tolerance糖耐量糖耐量 Birth weight 出生体重出生体重 Surrogate risk factors 替代风险因素 Shared genetic variants cause both LBW and impaired glucose tolerance?Glucose tolerance糖耐量糖耐量 Birth weight 出生体重出生体重 Genetic variants遗传变异遗传变异Causal Mechanisms/pathways?epienetic changes，etc.
20、Glucose tolerance糖耐量糖耐量 Birth weight 出生体重出生体重 Epigenetic changes,etc.表观遗传改变，等表观遗传改变，等.Intrauterine environmentGlucocorticoids,hormones，etc糖皮质激素糖皮质激素,激素激素 等等Unknown confounders未知的混杂因素未知的混杂因素Hales CN,Barker DJ.The thrifty phenotype hypothesis.Br Med Bull.2001;60:5-20 The thrifty phenotype hypothesis p
21、roposes that the epidemiological associations between poor fetal and infant growth and the subsequent development of type 2 diabetes and the metabolic syndrome result from the effects of poor nutrition in early life,which produces permanent changes in glucose-insulin metabolism.These changes include
22、 reduced capacity for insulin secretion and insulin resistance which,combined with effects of obesity,ageing and physical inactivity,are the most important factors in determining type 2 diabetes.Since the hypothesis was proposed,many studies world-wide have confirmed the initial epidemiological evid
23、ence,although the strength of the relationships has varied from one study to another.The relationship with insulin resistance is clear at all ages studied.Less clear is the relationship with insulin secretion.The relative contribution of genes and environment to these relationships remains a matter
24、of debate.The contributions of maternal hyperglycaemia and the trajectory of postnatal growth need to be clarified.Project-Maternal glucose tolerance,oxidative stress,and programming of the Metabolic,CIHR Funded 2006-2010 Follow-up of Women/Infants at Delivery(n=308)Follow-up of infants at 1 year of
25、 age(n=242)Biomarker AssaysFollow-up of infants at 3 months of age(n=281)Follow-up of women at 32-35 weeks of gestation(n=320)Recruitment-Women bearing a singleton fetusat 24-28 weeks of gestation (n=339)(Montreal)Data Analyses and ReportsLuo et al.Diabetes Care 2010 Maternal Glucose Tolerance in Pr
26、egnancy Affects Fetal Insulin SensitivityLuo et al.Diabetes Care 2010 Maternal BMI was also inversely correlated Fetal Insulin Sensitivity,but less strongly so IGF-1(but not IGF-2)levels in maternal and fetal circulations were elevated in gestational diabetes Luo ZC,et al.J Clinical Endocrinology Me
27、tabolism 2012 Higher maternal IGF-1(not IGF-2)levels predict increased risk of LGA/macrosomia Luo ZC,et al.J Cinical Endocrinology and Metabolism 2012 Leptin and adiponectin levelswere positively correlated in maternal versus fetal circulations Luo ZC,et al.Obesity 2013 Fetal insulin sensitivity was
28、 negatively associated with cord blood leptin(p0.4)levels.Luo ZC,et al.Obesity 2013 Summary 总结总结(1)OR can be calculated in any clinical epidemiologic studies(cross-sectional,case control,cohort),but OR may“overstate”the effect size when the outcome is common.OR可以在任何临床流行病学研究在计算（横截面，病例对照，队列研究，临床试验），OR或许“夸大”效应时，如果结果是常见的。Adjusted OR sometimes may distort the true association,if the adjusted“confounding factor”is not a true confounding factor,but an effect mediator in the causal pathway。调整有时可能会扭曲真正的关联，如果调整后的“混杂因素”不是真正的混杂因素，而是一个在因果通路上的中介因素。
