应用实例分析--临床流行病学研究-胎源性疾病-DOHAD课件

应用用实例分析例分析 临床流行病学研究床流行病学研究 胎源性疾病胎源性疾病 DOHAD应用实例分析 临床流行病学研究 胎源性疾病 DOHAD应用1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学习目标通过应用实例分析，加深对流行病学重要基本概念的理2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内容实例分析 一个经典的有关胎源性疾病的临床流行病学研究报告3胎源性疾病胎源性疾病/发育源性疾病发育源性疾病(DOHAD)nThesuscepatibleitytomanychronicdiseasesinadulthoodcanbetracedbacktoexposuresduringearlylife(duringfetalandearlypostnatallife)成年期的许多慢性疾病的易感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）性可以追溯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胎源性疾病 /发育源性疾病(DOHAD)The su4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 for 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*ORCrudeORCrudeRR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?7.5-8.4 (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%)1.01.01.0*Odds ratio for two hour gluco10应用实例分析-临床流行病学研究-胎源性疾病-DOHAD课件11AnswerstoQuestions（1）Whatisthestudydesign研究设计是？研究设计是？Retrospectivecohortstudy回顾性队列研究回顾性队列研究WhyOR?whynotRR?Eithergoodforreasoning,thelatterismoreaccurateindefiningtherelativeriskdisparity.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。CanwehavecrudeORandcrudeRR?Yes,incohortstudiesorRCT,youcancalculateRR.我们可以我们可以计算粗计算粗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。WhyadjustedOR?WhynotadjustedRR?Eitherisgoodforreasoning,itiseasiertocalculatetheadjustedOR.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.What is the study design 研究设计是12Forcohortstudydata,youcanuselogbinomialmodel,toobtaintheadjustedRR.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。HowtocalculateadjustedRR,inthisstudy?在本研究中，在本研究中，如何计算调整后的如何计算调整后的RR？For cohort study data,you can13AnswerstoQuestions（2）DoweneedadjustmentsinORorRR?Mosttimes,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。Isadjustmentsalwaysnecessary?No,sometimesunnecessary.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。WhatthedifferenceBetweenORandRR?ORdoesnotalwaysrepresentRR.ORcanbecalculatedinanystudydesigns,RRscannotbecalculateddirectlyincasecontrolstudies.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。WhatsthedifferencebetweenCrudeORvs.AdjustedOR?TheadjustedORmoreoften(butnotalways)representsthetrueassociation。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（但并不总更经常（但并不总是）代表真正的联系。是）代表真正的联系。WhatsthedifferencebetweenCrudeRRvs.AdjustedRR?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。Do we need adjustments in OR o14真理？假象？真理？假象？CausalInferenceConsiderations因果推理思考因果推理思考Informationbias?信息偏倚信息偏倚lesslikelyConfoundingfactors？混杂因素？混杂因素possiblyConsistencyofassociation?联系的一致性联系的一致性yesStrengthofassociation?关联强度关联强度OKDose-responserelationship?剂量剂量-反应关系反应关系yesTemporallyorderconsistent?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noBiologicalplausibility?生物合理性生物合理性yesSurrogateriskfactor?替代风险因素替代风险因素maybeAnimalmodelexperiment?实验动物模型实验动物模型yesCausal Inference Consideration15Birthweight出生体重出生体重CrudeORAdjusted*OR Crude ORsIs Current BMI a confounder?*adjusted for current body mass index.Birth weight 出生体重CrudeAdjusted16ConfounderorEffectMediator?混杂因素混杂因素,或影响介质或影响介质?Glucose tolerance 糖耐量 Blood pressure 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)Confounder or Effect Mediator?17When 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 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。Reversalparadox逆转谜题逆转谜题When you inappropriate adjust 18Why evidence for the fetal origins of adult disease might be a statistical artifact:the reversal paradox for the relation between birth weight and 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 adjustment 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 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,adjustment 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 association 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.Why evidence for the fetal ori19Surrogate risk factors 替代风险因素替代风险因素?Glucosetolerance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 Surrogate risk factors 替代风险因素20Shared genetic variants cause both LBW and impaired glucose tolerance?Glucosetolerance糖耐量糖耐量 Birth weight 出生体重出生体重 Geneticvariants遗传变异遗传变异Shared genetic variants cause21Causal Mechanisms/pathways?epienetic changes，etc.Glucosetolerance糖耐量糖耐量 Birth weight 出生体重出生体重 Epigeneticchanges,etc.表观遗传改变，等表观遗传改变，等.IntrauterineenvironmentGlucocorticoids,hormones，etc糖皮质激素糖皮质激素,激素激素等等Unknownconfounders未知的混杂因素未知的混杂因素Causal Mechanisms/pathways22HalesCN,BarkerDJ.Thethriftyphenotypehypothesis.Br Med Bull.2001;60:5-20 Thethriftyphenotypehypothesisproposesthattheepidemiologicalassociationsbetweenpoorfetalandinfantgrowthandthesubsequentdevelopmentoftype2diabetesandthemetabolicsyndromeresultfromtheeffectsofpoornutritioninearlylife,whichproducespermanentchangesinglucose-insulinmetabolism.Thesechangesincludereducedcapacityforinsulinsecretionandinsulinresistancewhich,combinedwitheffectsofobesity,ageingandphysicalinactivity,arethemostimportantfactorsindeterminingtype2diabetes.Sincethehypothesiswasproposed,manystudiesworld-widehaveconfirmedtheinitialepidemiologicalevidence,althoughthestrengthoftherelationshipshasvariedfromonestudytoanother.Therelationshipwithinsulinresistanceisclearatallagesstudied.Lessclearistherelationshipwithinsulinsecretion.Therelativecontributionofgenesandenvironmenttotheserelationshipsremainsamatterofdebate.Thecontributionsofmaternalhyperglycaemiaandthetrajectoryofpostnatalgrowthneedtobeclarified.Hales CN,Barker DJ.The thrif23Project-Maternalglucosetolerance,oxidativestress,andprogrammingoftheMetabolic,CIHRFunded2006-2010Follow-up of Women/Infants at Delivery(n=308)Follow-up of infants at 1 year of age(n=242)Biomarker AssaysFollow-up of infants at 3 months of age(n=281)Follow-up of women at32-35weeksofgestation(n=320)Recruitment-Women bearing a singleton fetusat 24-28 weeks of gestation (n=339)(Montreal)Data Analyses and ReportsProject-Maternal glucose to24Luoetal.Diabetes Care2010MaternalGlucoseToleranceinPregnancyAffectsFetalInsulinSensitivityLuo et al.Diabetes Care 2010 25Luoetal.Diabetes Care2010MaternalBMIwasalsoinverselycorrelated FetalInsulinSensitivity,butlessstronglysoLuo et al.Diabetes Care 2010 26IGF-1(but not IGF-2)levels in maternal and fetal circulations were elevated in gestational diabetes Luo ZC,et al.J Clinical Endocrinology Metabolism 2012 IGF-1(but not IGF-2)levels i27Higher maternal IGF-1(not IGF-2)levels predict increased risk of LGA/macrosomia Luo ZC,et al.J Cinical Endocrinology and Metabolism 2012 Higher maternal IGF-1(not IGF28Leptin and adiponectin levelswere positively correlated in maternal versus fetal circulations Luo ZC,et al.Obesity 2013 Leptin and adiponectin levels29Fetal insulin sensitivity was negatively associated with cord blood leptin(p0.4)levels.Luo ZC,et al.Obesity 2013 Fetal insulin sensitivity was 30Summary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。Summary 总结(1)OR can be calcul31谢谢观赏谢谢观赏谢谢观赏32