應(yīng)用實例分析臨床流行病學(xué)研究胎源性疾病dohad

1、應(yīng)用實例分析 - 臨床流行病學(xué)研究 胎源性疾病 （DOHAD),駱忠誠上海交通大學(xué)附屬新華醫(yī)院,,學(xué)習(xí)目標(biāo),通過應(yīng)用實例分析 ， 加深對流行病學(xué)重要基本概念的理解通過應(yīng)用實例分析 ， 提高對流行病學(xué)研究重要方法的應(yīng)用能力,內(nèi)容,實例分析 一個經(jīng)典的有關(guān)胎源性疾病的臨床流行病學(xué)研究報告實例分析 - 設(shè)計一個有關(guān)胎源性疾病的臨床流行病學(xué)研究項目,胎源性疾病 / 發(fā)育源性疾病 (DOHAD),The suscepat

2、ible ity to many chronic diseases in adulthood can be traced back to exposures during early life (during fetal and early postnatal life) 成年期的許多慢性疾病的易感性可以追溯到生命早期的暴露因素（胎兒期和出生后早期）無致病基因突變,流行病學(xué) - 重要作用之一 發(fā)現(xiàn)新聯(lián)系 （DOHAD）,*O

3、dds ratio for two hour glucose concentration of >7.8 mmol/l adjusted for current body mass index. (X2 for trend= 15.4; p<0.001).Reduced growth in early life is strongly linked with impaired glucose tolerance and

4、 non-insulin dependent diabetes (T2DM). 生命早期生長降低與成年期（64歲）糖耐量受損和非胰島素依賴型糖尿病密切相關(guān)。研究樣本· 466 男性·（59-70 歲·， 平均 64 歲） Hales CN, Barker DJ, et al. BMJ 1991;303:1019-22.,OBJECTIVE: To discover whether reduced fe

5、tal and infant growth is associated with non-insulin dependent diabetes and impaired glucose tolerance in adult life.DESIGN: Follow up study of men born during 1920-30 whose birth weights and weights at 1 year were know

6、n.SETTING: Hertfordshire, England.SUBJECTS: 468 men born in east Hertfordshire and still living there. Men known to have diabetes were excluded.MAIN OUTCOME MEASURES: Fasting plasma glucose, insulin, proinsulin, and

7、32-33 split pro-insulin concentrations and plasma glucose and insulin concentrations 30 and 120 minutes after a 75 g glucose drink.,Hales CN, Barker DJ, Clark PM, Cox LJ, Fall C, Osmond C, Winter PD. Fetal and infant gr

8、owth and impaired glucose tolerance at age 64. BMJ 1991;303:1019-22,RESULTS: 93 men had impaired glucose tolerance or hitherto undiagnosed diabetes. They had had a lower mean birth weight and a lower weight at 1 year. Th

9、e proportion of men with impaired glucose tolerance fell progressively from 26% (6/23) among those who had weighted 18 lb (8.16 kg) or less at 1 year to 13% (3/24) among those who had weighed 27 lb (12.25 kg) or more. Co

10、rresponding figures for diabetes were 17% (4/23) and nil (0/24). Plasma glucose concentrations at 30 and 120 minutes fell with increasing birth weight and weight at 1 year. Plasma 32-33 split proinsulin concentration fel

11、l with increasing weight at 1 year. All these trends were significant and independent of current body mass. Blood pressure was inversely related to birth weight and strongly related to plasma glucose and 32-33 split proi

12、nsulin concentrations.CONCLUSIONS: Reduced growth in early life is strongly linked with impaired glucose tolerance and non-insulin dependent diabetes. Reduced early growth is also related to a raised plasma concentratio

13、n of 32-33 split proinsulin, which is interpreted as a sign of beta cell dysfunction. Reduced intrauterine growth is linked with high blood pressure, which may explain the association between hypertension and impaired gl

14、ucose tolerance.,Questions 問題 (1),What is the study design？本研究設(shè)計是？Why OR? why not RR? 為什么用比值比（OR）？而不是相對風(fēng)險度 （RR） ？Can we have crude OR and crude RR? 我們可以計算粗OR （未調(diào)整比值比）, 粗RR （未調(diào)整相對風(fēng)險度 ）嗎？Why adjusted OR? Why not adjuste

15、d RR ? 為什么用調(diào)整OR？為什么不用調(diào)整RR？Do we need adjustments ? Always necessary? 需要調(diào)整嗎？調(diào)整總是必要嗎？,Questions 問題 (2),What the difference Between OR and RR? 比值比與相對危險度有什么區(qū)別？What’s the difference between Crude OR vs. Adjusted OR ?粗

16、OR與調(diào)整OR有什么區(qū)別？What’s the difference between Crude RR vs. Adjusted RR ? 粗RR和調(diào)整RR之間的區(qū)別是什么Is current BMI a confounding factor? 現(xiàn)在的體重指數(shù)是一個混雜因素嗎？,*Odds ratio for two hour glucose concentration of >7.8 mmol/l adjusted for

17、current body mass index.,Answers to Questions （1）,What is the study design 研究設(shè)計是？Retrospective cohort study 回顧性隊列研究Why OR? why not RR? Either good for reasoning, the latter is more accurate in defining the relative risk

18、 disparity. 為什么用比值比（OR）？而不是相對風(fēng)險度 （RR？ 推理任一均可， RR在定義相對風(fēng)險差距更準(zhǔn)確。Can we have crude OR and crude RR? Yes, in cohort studies or RCT, you can calculate RR. 我們可以計算粗OR （未調(diào)整比值比）, 粗RR （未調(diào)整相對風(fēng)險度 ）嗎？ 是的，在隊列研究或試驗，可以計算出RR。Why adjuste

19、d OR? Why not adjusted RR ? Either is good for reasoning, it is easier to calculate the adjusted OR. 為什么是調(diào)整OR？ 而不是調(diào)整RR？推理任一均可，調(diào)整OR更容易計算.,For cohort study data, you can use log binomial model, to obtain the adjusted RR.

20、隊列研究的數(shù)據(jù)，您可以使用 log 二項式模型，得到調(diào)整后的RR。,How to calculate adjusted RR, in this study ?在本研究中， 如何計算調(diào)整后的RR？,Answers to Questions （2）,Do we need adjustments in OR or RR? Most times, yes. 我們需要調(diào)整嗎？大多數(shù)時候，是的。Is adjustments always nec

21、essary? No, sometimes unnecessary.調(diào)整是必要的嗎？不，有時不必要。What the difference Between OR and RR? OR does not always represent RR. OR can be calculated in any study designs, RRs can not be calculated directly in case control

22、studies. OR和RR有什么區(qū)別？OR 有時不能代表RR?？梢栽谌魏闻R床流行病學(xué)研究設(shè)計中計算OR。在病例對照研究不能直接計算RR。What’s the difference between Crude OR vs. Adjusted OR ? The adjusted OR more often (but not always) represents the true association。未調(diào)整OR或與調(diào)整OR區(qū)別是什

23、么？調(diào)整OR更經(jīng)常（但并不總是）代表真正的聯(lián)系。What’s the difference between Crude RR vs. Adjusted RR ? 調(diào)整RR更經(jīng)常（但并不總是）代表真正的聯(lián)系。,真理？假象？,Causal Inference Considerations 因果推理思考Information bias? 信息偏倚 less likelyConfounding factors？混雜因素 possibl

24、yConsistency of association ? 聯(lián)系的一致性 yesStrength of association? 關(guān)聯(lián)強(qiáng)度 OKDose-response relationship? 劑量-反應(yīng)關(guān)系 yesTemporally order consistent? 時間一致性 yesDeterministic / probabilistic? 決定性 noNecessary? 必要性 noSuffi

25、cient? 充分 noSpecificity? 特異性 noBiological plausibility? 生物合理性 yesSurrogate risk factor? 替代風(fēng)險因素 may beAnimal model experiment? 實驗動物模型 yes,ORs for impaired glucose toleranceAdjusted ORs > Crude ORsIs Current BM

26、I a confounder?,*adjusted for current body mass index.,Confounder or Effect Mediator?混雜因素, 或影響介質(zhì)?,Glucose tolerance 糖耐量 ? Blood pressure 血壓 ?,,,,Current BMI現(xiàn)體重指數(shù),Birth weight 出生體重 ?,Confounders 混雜因素 (

27、e.g. ethnicity 如種族 ),,,When you inappropriate adjust for a factor in the causal pathway, you could produce a false association, or exaggerated association 當(dāng)你不適當(dāng)?shù)恼{(diào)整一個在因果通路途徑上的因素，你可能會產(chǎn)生一個虛假的關(guān)聯(lián)，或夸張的關(guān)聯(lián)。It may be inappropria

28、te to adjust for current BMI in estimating the effect of birth weight on current glucose tolerance or blood pressure. 調(diào)整現(xiàn)在的體重指數(shù)以估計出生體重對目前的糖耐量或血壓的影響可能是不合適的。,Reversal paradox 逆轉(zhuǎn)謎題,Why evidence for the fetal origins of adul

29、t 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.,So

30、me 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 vari

31、ables 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 bet

32、ween 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 pressur

33、e 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 w

34、hose 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 b

35、lood 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, rese

36、archers must consider the reversal paradox when adjusting for variables that lie within causal pathways.,Surrogate risk factors 替代風(fēng)險因素 ?,Glucose tolerance糖耐量 ?,,Birth weight 出生體重 ?,Surrogate risk factors 替代風(fēng)險因素,,,Sh

37、ared genetic variants cause both LBW and impaired glucose tolerance ?,Glucose tolerance糖耐量 ?,,Birth weight 出生體重 ?,Genetic variants遺傳變異,,,Causal Mechanisms /pathways? epienetic changes， etc.,Glucose tolerance糖耐量 ?,

38、,Birth weight 出生體重 ?,Epigenetic changes, etc.表觀遺傳改變，等.,,Intrauterine environmentGlucocorticoids, hormones， etc糖皮質(zhì)激素,激素 等,,,Unknown confounders未知的混雜因素,,,Hales CN, Barker DJ. The thrifty phenotype hypothesis. Br Me

39、d Bull. 2001;60:5-20,The thrifty phenotype hypothesis proposes that the epidemiological associations between poor fetal and infant growth and the subsequent development of type 2 diabetes and the metabolic syndrome resul

40、t from the effects of poor nutrition in early life, which produces permanent changes in glucose-insulin metabolism. These changes include reduced capacity for insulin secretion and insulin resistance which, combined with

41、 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 ev

42、idence, 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 r

43、elative contribution of genes and environment to these relationships remains a matter of debate. The contributions of maternal hyperglycaemia and the trajectory of postnatal growth need to be clarified.,Project - Matern

44、al glucose tolerance, oxidative stress, and programming of the Metabolic, CIHR Funded 2006-2010,Luo et al. Diabetes Care 2010,,,Maternal Glucose Tolerance in Pregnancy Affects Fetal Insulin Sensitivity,Luo et al. Diabete

45、s 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

46、. J Clinical Endocrinology Metabolism 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 levelswe

47、re positively correlated in maternal versus fetal circulations,Luo ZC, et al. Obesity 2013,Fetal insulin sensitivity was negatively associated with cord blood leptin (p0.4) levels.,Luo ZC, et al. Obesity 2013,Summary 總結(jié)

48、 (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可以在任何臨床流行病學(xué)研究在計算（橫截面，病例對照，隊列研究，臨床試驗），OR或許“

49、夸大”效應(yīng)時，如果結(jié)果是常見的。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。調(diào)整有時可能會扭曲真正的關(guān)聯(lián)，如果調(diào)整后的“混雜因素”不是真正

50、的混雜因素，而是一個在因果通路上的中介因素。,Summary總結(jié)(2),Be careful with the adjustment factors in regression models; some factors should not be included in the adjustments. 在回歸模型中，要注意小心調(diào)整因素。有些因素不應(yīng)包括在調(diào)整模型中。RR is a better measure of relative

51、 risk disparity, and can be calculated in any cohort studies or RCTs. RR是一個更好的衡量相對風(fēng)險差異指標(biāo)，可以在任何隊列研究或隨機(jī)對照試驗中計算。It is important to know what’s key aspect is not known and needs to be known in the study area in designing y