病例对照研究中对照的选择Selection of controls in a case-control or case-

base study

Robert E. Fontaine, MD, MSc

Bao-Ping Zhu, MD, MS

US Expert Advisors to Chinese FETP

选择对照的原则 Rules of control selection

病例和对照来自于同一人群或人群组 Cases and controls

come from the same base (population or population subset)

病例和对照间除了要研究的暴露因素外其他越相似越好 Selection designed to increase similarity with cases for all

characteristics except the exposures under investigation

如果对照发生了疾病，那么也会变成病例的一部分 If

controls had developed illness, they would have been detected

as a case

在工厂、学校、小村庄中选择对照 Selection of controls: factories, schools, institutions, small villages

• 常常有各群组的名单 Lists are available by groups

• 用单纯随机、系统抽样或其他方法来抽样 Random, systematic or other probability selection from lists.

• 若各群组罹患率不同，应使病例和对照中各组人数平衡 If attack rates differ by group then balance cases to controls by group.

某工厂疾病在各群组中的分布情况。如何选择对照？ A disease in a factory. How do you choose controls?

Group Cases People

A 6 35

B 12 80

C 10 55

D 13 90

E 14 95

F 18 125

G 9 50

H 10 65

Group Cases People

A 0 35

B 28 80

C 0 55

D 3 90

E 24 95

F 34 125

G 2 50

H 1 65

某工厂疾病在各群组中的分布情况。如何选择对照？ A disease in a factory. How do you choose controls?

在“开放”人群中选择对照 Control selection in an “open” population

没有有用的名单 No useful list

例：o 大单位或工厂 Large institutions or factorieso 城镇 Townso 城市 Citieso 县 Countieso 省 Provinces,o 国家 Countries

根据入选标准，从范围较小的人群中选择 We select from a more limited population defined by eligibility criteria

将人群根据以下特征进行定义 Population + collection of persons defined by:o 时间 Timeo 地点 Placeo 人群 Person

用入选标准，从这一假定人群中选择对照 Use eligibility criteria to select from this hypothetical population

病例和对照应该用同样的入选标准 Eligibility criteria should be applied equally to cases and controls.

例：在一个 1,110,000 人的城市中有 150 个病例。需要随机选择对照 You have 150 cases in a city of 1,110,000 you select controls at random

如何选择对照？ How do you select

controls?

要考虑哪些问题？ What must you think

about?

假定我们随机选择了 150 名对照 Let’s take a

random selection of 150

但是，分析时却发现病例和对照的分布如下 But you find in analysis the following distribution of cases and controls

Group Cases Controls

流动人口 A Mobile A 50 2

流动人口 B Mobile B 50 15

当地固定人口 Local 50 133

合计 All 150 150

为什么会发生这样的问题？ Why??

因为大多数暴露都发生在较小的人群组内 Much of the exposure was in a limited population.

Group Cases People Controls

流动人口 A Mobile A 50 10000 2

流动人口 B Mobile B 50 100000 15

当地固定人口 Local 50 1000000 133

合计 All 150 1110000 150

所面临的问题与前面“封闭”人群中的情况相似 You will risk the same problem as in the earlier example in a closed population.

假设病例的年龄分布不均衡 Imagine that the case have a limited age distribution.

Group Cases People

0-9 5 11000

10-19 35 10000

20-29 87 8000

30-39 15 7000

40-49 1 5000

50-59 1 4000

对人群中进行随机抽样作为对照组 A probability survey can be a control group

优点 Strength o 较少偏倚 Less subject to biases

o 抽样比例已知，因此可以计算率 Sampling fraction known – one can estimate risk

缺点 Weaknesso 代价昂贵 Expensive

o 需要处理复杂抽样的分析问题 Need to handle complex survey analysis

家庭内的对照效率很高 Household controls are very efficient

对照与病例在许多因素上很类似 Similar to cases in many factors besides the disease

病例和对照的暴露机会机会完全均等 Exposure opportunity nearly identical to cases

每一个家庭可以看出是一个小的队列 Each household and be a small cohort

实施较容易，常常配合良好 Logistics and cooperation are easy

可以研究家庭外的暴露因素 Evaluates exposures outside the home

缺点：可选择的人数有限，尤其是要对年龄或性别进行匹配时 Limited in numbers -- age or sex

朋友、同学、同事对照很方便 Friends, schoolmates, and workmates are very convenient controls

优点 Strength

病例与对照间许多因素类似 Similar to cases in many factors besides the disease

实施较容易，常常配合良好 Logistics and cooperation are easy

缺点 Weakness

o被人提名作为对照，常常与暴露有关 Being named may be related to exposure

o病例影响对照的选择 Case influences control selection

o重复：同一个人可能被两个病例所提名 Overlap – same person named by ≥ 2 cases

邻居对照：可以减少可能的地区偏倚 Selection of neighbors handles potential geographic biases

比抽样较容易实施 Logistics more simple than surveys

若入户调查病例家庭，这一方法很好 Good if visits to case-household are done

邻居对照有很高的暴露机会 High probability of exposure opportunity

在对照家庭内随机抽取对照 Best to use a random selection rule inside the neighborhood

需要进行多次家访 Will require revisits

医院或诊所病人作为对照 Persons coming to the same hospital and clinic as a case are possible controls.

易得到、易面访 Easy to obtain and interview

如果对照也发病，比较容易发现 If they develop the disease the probability is high that they would be detected

对照与病例之间暴露机会可能不同 Can have different exposures than study base

可能会有其他的暴露、或因治疗而受到保护 Can have other exposures and protective effects from treatment and management

某特殊危险因素在病例和对照间的分布可能迥异 The control can differ from the base population by special risk factors

Risk Factor

Hospital control

Study Base

OR

+ 80 50 4.0

- 20 50

对照可能是人群中一个特殊群组。这种选择性对研究的影响无法预料 These controls are a very special subgroup of the study base. Their effect is not predictable

其他“与疾病有关”的对照也有同样问题 Other “disease dependent” control selection have similar problems

阴性实验室结果 Negative laboratory tests

监测系统中的其他疾病病例 Other diseases detected in surveillance

时间上的可比性：举例 Time comparability: Example

病例对照研究，调查医院中败血症的危险因素 Case-control study examining risk factors for septicaemia in a hospital

o怀疑中心静脉导管是危险因素 Central venous line is a suspected risk factor

o若某位被感染的医护人员是感染来源，则暴露会根据该医护人员是否上班发生时间变异 If an infected health care worker is a source of infection, the effect of exposure (central line) will vary over time (presence of the health care worker)

餐次 Meal Cases Controls OR

早餐 B 1/10 50% 55% 0.81

午餐 L 1/10 85% 40% 8.5

晚餐 D 1/10 60% 45% 1.8

早餐 B 2/10 35% 45% 0.66

午餐 L 2/10 50% 50% 1.0

晚餐 D 2/10 60% 55% 1.2

食源性爆发常常发生如下情况 The following situation often arises from foodborne outbreaks

若用同一组病例和对照对 10 月 1 日午餐进行研究，会发生什么情况？ What if you use the same cases and controls for a food for lunch on 1/10?

午餐 L 1/10

Cases Controls

+ 85 40

- 15 60

合计 Total 100 100• 这样，午餐中每一种食物，都有 15% 的病例和 60% 的对照

没有吃过 For any individual food that I evaluate 15% of cases and 60% of controls were not present to eat it.

• 他们没有暴露机会！ There was no exposure opportunity!

对 1 月 10日午餐B 食物进行病例对照研究 Case-control study on Food B at lunch on 1/10

1 月 10日午餐 L 1/10+

Cases Controls OR

吃了 B食物 34 16 1.0

未吃 B食物 51 24

没吃 1 月 10日午餐Did not eat L 1/10

15 60

没有吃 B食物总数 66 84 3.5

If I include these unexposed cases and controls, the OR will be incorrect and highIf I exclude them, I may not have enough controls.

Food B

如果不小心，可能发生如下情况 This is what happens if one does not take care

1 月 10日午餐 L 1/10+

Cases Controls OR

吃了 B食物 34 16 1.0

未吃 B食物 51 24

没吃 1 月 10日午餐Did not eat L 1/10

15 60

没有吃 B食物总数 66 84 3.5

If I include these unexposed cases and controls, the OR will be incorrect and highIf I exclude them, I may not have enough controls.

Food B

如果不小心，可能发生如下情况 This is what happens if one does not take care

1 月 10日午餐 L 1/10+

Cases Controls OR

吃了 B食物 34 16 1.0

未吃 B食物 51 24

没吃 1 月 10日午餐Did not eat L 1/10

15 60

没有吃 B食物总数 66 84

If I include these unexposed cases and controls, the OR will be incorrect and highIf I exclude them, I may not have enough controls.

Food B

如果不小心，可能发生如下情况 This is what happens if one does not take care

1 月 10日午餐 L 1/10+

Cases Controls OR

吃了 B食物 34 16 1.0

未吃 B食物 51 24

没吃 1 月 10日午餐Did not eat L 1/10

15 60

没有吃 B食物总数 66 84

• 若把没有暴露机会（未吃 1/10午餐）者加进去，可能高估 OR If we include these unexposed cases and controls, the OR will be incorrect and high

• 若把他们去掉，对照数目可能不够 If we exclude them, I may not have enough controls.

Food B 3.5

对左旋色氨酸进行序列研究 Sequential studies in assessment of L-tryptophan in the United States

嗜酸性粒细胞增多 -肌痛综合征 ， 1989 Eosinophilia-myalgia

syndrome, USA, 1989

问题 Question: 原因是什么？ Cause of syndrome?

研究人群 Study base: 全人群，分年龄 - 性别 Age-sex band of

population

问题 Question: 所有品牌都有危险？ All brands of tryptophan?

研究人群 Study base:左旋色氨酸使用者 Tryptophan users

问题 Question: X品牌所有批次都有问题？ All lots of brand X?

研究人群 Study base:使用 X品牌者 Brand X tryptophan users

需要为每名病例选择 >1 名对照吗？ Should you select > 1 control per case

病例数比对照数重要 Case numbers are more important

为每名病例选择≥ 1 名对照可以增加统计效力 ≥ 1 control per case can increase statistical power

≥ 4 名对照时，统计效力增加得很有限 ≥ 4 does not improve power

5-6 名对照在病例数很少时可能有帮助 5 to 6 helps with very low (≤ 10) case numbers

≥2 个对照组常常不好 ≥ 2 control groups to test the same hypothesis is usually a poor idea.

可以考虑采用序列假设Testing sequential hypotheses is better

某病在一所学校爆发，研究者决定选择临近一所学校学生作对照。 For a disease in a school, students from a nearby, similar school are used for controls.

这种方法选择对照如何？ Is this a good choice for a control group?

应该如何选择？ What is the proper choice?

如果这所学校所有学生都暴露怎么办？ Suppose every student was exposed? What do you do?

猪链球菌感染病人的病例定义如下。如何选择对照？ Streptococcus suis case definition, what is your control group?

临床诊断病人 +接触病猪或死猪 Clinical disease + exposure to a sick or dying pig

研究问题：接触病猪或死猪的 RR 或 OR 是多少？ Question: What is the relative risk (OR) of disease for contact with a sick or dying pig?

这种情况下的 2X2表 Here is what your 2X2 table will look like

Pig

exposure

Cases Controls

+ 100% 100%

- 0 0

临床诊断病人 +接触病猪或死猪 Clinical disease + exposure to a sick or dying pig

研究问题：何种暴露是危险因素？ Question: What type of exposure is a risk factor for infection?

猪链球菌感染病人的病例定义如下。如何选择对照？ Streptococcus suis case definition, what is your control group?

病例和对照的暴露时间相同 Cases and controls are examined for the same referent exposure period

病例在某一时间段内暴露 Cases were exposed during the referent exposure period

病例和对照的暴露时间段必须相同 Referent exposure period must be identical for cases and controls

时间长短相同 Same duration

时间段相同 Same time frame

END

Extra Slides

A disease in a school 40/class. How do you choose controls?

Cases Classes

0 10

1 8

2 6

3 5

4 2

5 3

6 1

8 1

72 36

Mean = 2 cases/class

Expected cases under random (Poisson) distribution per class – mean = 2/class

Cases Classes Expected

0 10 4.8

1 8 9.7

2 6 9.7

3 5 6.5

4 2 3.2

5 3 1.3

6 1 0.43

8 1 0.031

72 36