Download 应用实例分析- 临床流行病学研究胎源性疾病

应用实例分析 临床流行病学研究 胎源性疾病 （DOHAD)
骆忠诚
上海交通大学附属新华医院
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解
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
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
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
胎源性疾病 / 发育源性疾病 (DOHAD)
The 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
可以追溯到生命早期的暴露因素（胎儿期和出生后早期）
无致病基因突变
流行病学 - 重要作用之一
发现新联系 （DOHAD）
出生体重（lb)
糖耐量异常
n/N（%）
调整比值比 (95% 可信区间)
Adjusted OR （95% CI）*
低于 5.5 lb (2.5kg)
8/20 (40)
6.6 (1.5-28.0)
5.5-6.4
(2.9 kg)
16/47 (34)
4.8 (1.3-17.0)
6.5-7.4
(3.4 kg)
32/104 (31)
4.6 (1.4-16.0)
7.5-8.4
(3.9 kg)
26/117 (22)
2.6 (0.8-8.9)
8.5-9.4
(4.2 kg)
7/54 (13)
1.4 (0.3-5.6)
9.5+ lb (4.3 kg +)
4/28 (14)
1.0 (参照组)
*Odds 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 non-insulin dependent diabetes (T2DM). 生命早期生长降低
与成年期（64岁）糖耐量受损和非胰岛素依赖型糖尿病密切相关。
研究样本· 466 男性·（59-70 岁·， 平均 64 岁）
– Hales CN, Barker DJ, et al. BMJ 1991;303:1019-22.
Hales CN, Barker DJ, Clark PM, Cox LJ, Fall C, Osmond C, Winter
PD. Fetal and infant growth and impaired glucose tolerance at
age 64. BMJ 1991;303:1019-22
 OBJECTIVE: To discover whether reduced fetal 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 known.
 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 32-33 split pro-insulin concentrations
and plasma glucose and insulin concentrations 30 and 120
minutes after a 75 g glucose drink.
•
•
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. The 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. Corresponding 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 fell 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 proinsulin 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 concentration 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 glucose
tolerance.
Questions 问题 (1)
• What is the study design？本研究设计是？
• Why OR? why not RR? 为什么用比值比（OR）？
而不是相对风险度 （RR） ？
• Can we have crude OR and crude RR? 我们可
以计算粗OR （未调整比值比）, 粗RR （未调整
相对风险度 ）吗？
• Why adjusted OR? Why not adjusted RR ? 为
什么用调整OR？为什么不用调整RR？
• Do we need adjustments ? Always necessary?
需要调整吗？调整总是必要吗？
Questions 问题 (2)
• What the difference Between OR and RR?
比值比与相对危险度有什么区别？
• What’s the difference between Crude OR vs.
Adjusted OR ?粗OR与调整OR有什么区别？
• What’s the difference between Crude RR vs.
Adjusted RR ? 粗RR和调整RR之间的区别是什
么
• Is current BMI a confounding factor? 现在的体
重指数是一个混杂因素吗？
出生体重（lb)
糖耐量异常
n/N（%）
Adjusted *
OR
Crude
OR
Crude
RR
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%)
1.0
1.0
1.0
*Odds ratio for two hour glucose concentration of >7.8 mmol/l adjusted for
current body mass index.
Calculation of Crude OR and RR for impaired glucose tolerance from published data
(based on Table 2 in Hales and Barker, BMJ 1991 paper)
Exposure Group
No-exposure group
Birth weight
(Birth weight >=9.5 lb)
Crude OR Crude RR Adjusted OR
Event Total n1-a Rate1 Event Total n0-c Rate0 (a/b)/(c/d) (a/n1)/(c/n0) *
a n1 b a/n1 c
n0
d c/n0 ad/bc an0/cn1
<5.5 lb
8 20 12 40% 4
28
24 14% 4.0
2.8
6.6
5.5-6.4 lb 16 47 31 34% 4
28
24 14% 3.1
2.4
4.8
6.5-7.4 lb 32 104 72 31% 4
28
24 14% 2.7
2.2
4.6
7.5-8.4 lb 26 117 91 22% 4
28
24 14% 1.7
1.6
2.6
8.5-9.4 lb 7 54 47 13% 4
28
24 14% 0.9
0.9
1.4
*adjusted for current body mass index
Answers to Questions （1）
•
•
•
•
What is the study design 研究设计是？Retrospective cohort
study 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 disparity. 为什么用比值
比（OR）？而不是相对风险度 （RR？ 推理任一均可， RR在定义相
对风险差距更准确。
Can we have crude OR and crude RR? Yes, in cohort studies or
RCT, you can calculate RR. 我们可以计算粗OR （未调整比值比）,
粗RR （未调整相对风险度 ）吗？ 是的，在队列研究或试验，可以计
算出RR。
Why adjusted OR? Why not adjusted RR ? Either is good for
reasoning, it is easier to calculate the adjusted OR. 为什么是调整
OR？ 而不是调整RR？推理任一均可，调整OR更容易计算.
How to calculate adjusted RR, in this study ?
在本研究中， 如何计算调整后的RR？
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。
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。
Is adjustments always necessary? No, sometimes unnecessary.
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 calculated in any study designs, RRs
can not be calculated directly in case control studies. OR和RR有
什么区别？OR 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OR。在病例对照研究不能直接计算RR。
What’s the difference between Crude OR vs. Adjusted OR ? The
adjusted OR more often (but not always) represents the true
association。未调整OR或与调整OR区别是什么？调整OR更经常
（但并不总是）代表真正的联系。
What’s the difference between Crude RR vs. Adjusted RR ? 调整
RR更经常（但并不总是）代表真正的联系。
真理？假象？
Causal Inference Considerations 因果推理思考
•Information bias? 信息偏倚 less likely
•Confounding factors？混杂因素 possibly
•Consistency of association ? 联系的一致性 yes
•Strength of association? 关联强度 OK
•Dose-response relationship? 剂量-反应关系 yes
•Temporally order consistent? 时间一致性 yes
•Deterministic / probabilistic? 决定性 no
•Necessary? 必要性 no
•Sufficient? 充分 no
•Specificity? 特异性 no
•Biological plausibility? 生物合理性 yes
•Surrogate risk factor? 替代风险因素 may be
•Animal model experiment? 实验动物模型 yes
ORs for impaired glucose tolerance
Adjusted ORs > Crude ORs
Is Current BMI a confounder?
Crude
OR
Adjusted*
OR
<5.5 lb
4.0
6.6
5.5-6.4 lb
3.1
4.8
6.5-7.4 lb
2.7
4.6
7.5-8.4 lb
1.7
2.6
Birth weight 出生体重
*adjusted for current body mass index.
Confounder or Effect Mediator?
混杂因素, 或影响介质?
Birth weight
出生体重 
Current BMI
现体重指数
Confounders 混杂因素
(e.g. ethnicity 如种族 )
Glucose tolerance 糖耐量 
Blood pressure 血压 
Reversal paradox 逆转谜题
 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 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。
Why 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):2732.
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.
Surrogate risk factors
替代风险因素 ?
Birth weight
出生体重 
Surrogate risk factors
替代风险因素
Glucose tolerance
糖耐量 
Shared genetic variants
cause both LBW and impaired glucose tolerance ?
Birth weight
出生体重 
Genetic variants
遗传变异
Glucose tolerance
糖耐量 
Causal Mechanisms /pathways?
epienetic changes， etc.
Birth weight 出生体重 
Unknown confounders
未知的混杂因素
Epigenetic changes, etc.
表观遗传改变，等.
Glucose tolerance
糖耐量 
Intrauterine environment
Glucocorticoids,
hormones， etc
糖皮质激素,激素 等
Hales CN, Barker DJ. The thrifty phenotype
hypothesis. Br Med 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 result
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 effects of obesity, ageing and physical
inactivity, are the most important factors in determining type 2
diabetes. Since the hypothesis was proposed, many studies worldwide have confirmed the initial epidemiological evidence, 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 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
Recruitment - Women bearing a singleton fetus
at 24-28 weeks of gestation (n=339) (Montreal)
Follow-up of women
at 32-35 weeks of gestation (n=320)
Follow-up of Women/Infants
at Delivery (n=308)
Follow-up of infants at 3 months of age (n=281)
Follow-up of infants at 1 year of age (n=242)
Biomarker Assays
Data Analyses and Reports
Maternal Glucose Tolerance in Pregnancy
Affects Fetal Insulin Sensitivity
Luo et al. Diabetes Care 2010
Maternal BMI was also inversely correlated
Fetal Insulin Sensitivity, but less strongly so
Luo et al. Diabetes Care 2010
IGF-1 (but not IGF-2) levels in maternal and fetal
circulations were elevated in gestational diabetes
GD = gestational diabetic
Plasma IGF-1 (nmol/l)
1000.0
100.0
35.5
45.2
24.3
36.8
10.0
9.6
7.2
1.0
GD
Non-GD
Maternal blood
24-28 weeks
GD
Non-GD
Maternal blood
32-35 weeks
GD
Non-GD
Cord
blood
Luo ZC, et al. 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 levels
were positively correlated
in maternal versus fetal circulations
Luo ZC, et al. Obesity 2013
Fetal insulin sensitivity was negatively
associated with cord blood leptin (p<0.01)
but not adiponectin (p>0.4) levels.
Luo ZC, et al. Obesity 2013
Summary 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(2)
 Be careful with the adjustment factors in regression
models; some factors should not be included in the
adjustments. 在回归模型中，要注意小心调整因素。
有些因素不应包括在调整模型中。
 RR is a better measure of relative risk disparity, and
can be calculated in any cohort studies or RCTs. RR
是一个更好的衡量相对风险差异指标，可以在任何队
列研究或随机对照试验中计算。
 It is important to know what’s key aspect is not known
and needs to be known in the study area in designing
your own clinical epidemiologic study。在设计你自己
的临床流行病学研究项目时， 重要的是要知道在该研
究领域， 什么关键方面有什么未知的需要解决的问题。