1

서 론

- (Case-crossover design) 1991

Maclure

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본 론

1. 환자-교차 연구 설계의 정의와 개발 배경

(‘A dictionary of epidemiology’4 )

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( )

[2].

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1991 [1],

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- (“The Onset Study”)

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(‘healthy-volunteer bias’)

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(‘healthy-day bias’) .

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환자-교차 연구(Case-Crossover Design)의 이론과 활용

기모란

을지대학교 의과대학 예방의학교실

지상강좌

2

. ,

. , ‘

’( ) ‘ ’(

)

. (

) ( )

-

[3].

2. 환자-교차 연구 설계의 기본 개념

.

(crossover)

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A

Comparison

Physical Activity in Control

Period, One Day Before MI

Physical Activity in HazardPeriod, One Hour Before MI

Hours Prior to MI Onset

25 24 1 Hr 0

MI

B

Comparison

Hours Prior to MI Onset26 1 Hr 0

MI

C

Comparison

MI

Months Prior to MI Onset12 1 Hr 0

Usual Frequency of Exposure During Past Year

Fig.Fig.Fig.Fig. 1.1.1.1. Schematic representation of control selection in case-crossover studies. It is assumed arbitrarily that the physical activity effect on risk of myocardial infarction (MI) lasts 1 hour. A) 1:1 pair-matched interval approach, B) 1:4 pair-matched intervals approach, C) Usual frequency approach

3

- (person-time)

. -

(average incidence rate ratio) .

100 -

100

[1].

- Fig. 1 .

(hazard

period case period) ,

(control period referent

period) , (

) (Fig. 1 A).

-

.

1:M (Fig. 1 B),

1

(Fig. 1 C).

1 2*2

.

1 , 2

,

2 22

.

. 1

1, 0

. (rate ratio) 1/0 2/

22 . 1

22

0/1 2/22 0

(Fig. 2). 2*2

.

. Table 1

1

10 [1].

9

2 .

0:1 ,

(1 730 , 8036

) 730:8036 .

20

1 .

1:0

365:8401 . 10

(Mantel Haenszel estimates)

8401+5116=13517 , 730+36+1820+2920+24

+730+730+365=7355 , 1.8(95% :

Within 1 hour of last physical Activity

Yes No

Myocardial Infarction 1 0

Person - hours 2 22

Rate ratio ∞

n

Within 1 hour of last physical Activity

Myocardial Infarction Yes No

Person - hours 0 1

Rate ratio 2 22

n 0

Fig.Fig.Fig.Fig. 2.2.2.2. Two by two tables of case-crossover studies. Hypothetical data from a patient who reported physical activity 2 hours per day and suffered a myocardial infarction. Up: less than 1 hour after last physical activity, down: more than 1 hour after last physical activity.

4

0.35-9.8) .

3. 환자-교차 연구 설계의 활용

- .

[4], [5],

[6], [7], [8] .

-

[9-13]

30 .

[14-16] .

-

1997 New England Journal of Medicine

(NEJM) Redelmeier Tibshirani

[17].

-

1999 -

[18] [19]

,

[20] 100

.

,

[21].

MMR( , , )

.

MMR

,

.

Urabe

SubjectLast time Usual

Observed Odds*

Expected Odds*

before MI frequency

1 9 hours 2 /day 0:1 730:8,036

2 20 minutes 1 /day 1:0 365:8,401

3 3 hours 3 /month 0:1 36:8,736

4 22 hours 5 /day 0:1 1,820:6,946

5 6 hours 8 /day 0:1 2,920:5,846

6 7 hours 2 /month 0:1 24:8,742

7 12 hours 2 /day 0:1 730:8,036

8 5 hours 2 /day 0:1 730:8,036

9 <1 hour 10 /day 1:0 3,650:5,116

10 24 hours 1 /day 0:1 365:8,401

Mantel-Haenszel estimate

of relative risk

Numerator:

Denominator:

Ratio

13,517

7,355

= 1.8

(95 % confidence interval) (0.35-9.8)

* The observe odds (1:0 or 0:1) are the odds that exposure was less than one hour before onset of myocardial infarction. The expected odds

are the odds that a random event during the past year would have fallen within one hour after an episode of exposure. The effect-period

after the hypothesized trigger is here assumed to be one hour long, with a minimum induction time of zero.

Table Table Table Table 1.1.1.1. Case-crossover study of the Myocardial Infarction (MI) onset data from The Onset Study (1).

5

am 9 Hoshino

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, Urabe am

9 Hoshino

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Fig. 3

2*2 .

,

a . b, c,

d .

a+b . c

d .

( MMR 90%

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Fig. 4 . 1

0-42

, 43-365

. 6

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MMR

12-15 . -

(time trend)

.

MMR

,

Illness or Syndrome

Yes No

Vaccination

Yes a b

No c d

Fig.Fig.Fig.Fig. 3.3.3.3. Two by two table for vaccine adverse events studies.

Comparison

MMR vaccination in controlperiod during past year

MMR vaccination in hazardperiod before Meningitis

Meningitis

365d 42d 0

Duration of time prior toMeningitis onset, day

Fig.Fig.Fig.Fig. 4.4.4.4. Case-crossover study design for MMR vaccination and aseptic meningitis [23].

6

. , (age-depe-

ndent) (time-dependent)

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, .

3

,

.

Farrington

[23].

- MMR

,

2.17(95% : 1.22-3.85) .

Urabe am 9 Hoshino MMR

5.54 (95% : 2.60-11.8)

. Jeryl Lyn Rubini

MMR

0.60 (95% : 0.18-1.97)

.

, 1998 1 3

441 37

.

8.4% .

Urabe am 9

Hoshino MMR

. Jeryl

Lynn MMR .

4. 환자-교차 설계 적용시 고려해야 할 기준

-

( )

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( )

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(Acute hemorrhagic

fever with renal syndrome)

7-34 , 35-60

[24]. MMR

, 1-42

, 42-365

MMR [22].

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1-2

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,

[3].

-

( ) .

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, 3 [22]

MMR

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365 , 366-730

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(case-time-control) [25].

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15 [3].

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(pilot study) .

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[17]. MMR

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5. 환자-교차 설계시 통계 분석

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(concordance pair)

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(overmatching) .

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(

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35% ,

100 40%

[26].

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-

- . 2*2

Fig. 2 -

(aiNoi/Ti) / (biN1i/Ti) .

(subgroup analysis) ,

(homogeneity test)

. (condit-

ional logistic regression analysis) . MMR

(person-years)

[27].

-

.

6. 환자-교차 연구 설계의 제한점

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. 1) .

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(carry-over effect)

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bias) .

(selection bias) . -

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(time trend)

(24 , ),

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[21].

- (bidirectional case-crossover

designs)

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결 론

(case-only study) -

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ai bi

N1i N0i

Ti

Fig.Fig.Fig.Fig. 5.5.5.5. Notations for Mantel-Haenszel estimates in case-crossover studies. Mantel-Haenszel Estimates = (ai Noi/Ti) / (bi N1i/Ti)

9

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참고문헌

1. Maclure M. The case-crossover design: a method

for studying transient effects on the risk of acute

events. Am J Epidemiol 1991;133(2):144-53.

2. Last JM, Spasoff RA, Harris SS, Thuriaux MC,

International Epidemiological Association. A

dictionary of epidemiology. 4th ed. Oxford ; New

York: Oxford University Press; 2001.

3. Maclure M, Mittleman MA. Should we use a

case-crossover design? Annu Rev Public Health

2000;21:193-221.

4. Mittleman MA, Maclure M, Tofler GH, Sherwood

JB, Goldberg RJ, Muller JE. Triggering of acute

myocardial infarction by heavy physical exertion.

Protection against triggering by regular exertion.

Determinants of Myocardial Infarction Onset

Study Investigators. N Engl J Med 1993;329(23)

:1677-83.

5. Mittleman MA, Maclure M, Sherwood JB, Mulry

RP, Tofler GH, Jacobs SC, et al. Triggering of

acute myocardial infarction onset by episodes of

anger. Determinants of Myocardial Infarction

Onset Study Investigators. Circulation 1995;92(7):

1720-5.

6. Muller JE, Mittleman MA, Maclure M, Sherwood

JB, Tofler GH. Triggering myocardial infarction

by sexual activity. Low absolute risk and prev-

ention by regular physical exertion. Determinants

of Myocardial Infarction Onset Study Investig-

ators. Jama 1996;275(18):1405-9.

7. Mittleman MA, Mintzer D, Maclure M, Tofler GH,

Sherwood JB, Muller JE. Triggering of myocardial

infarction by cocaine. Circulation 1999;99(21):

2737-41.

8. Mittleman MA, Lewis RA, Maclure M, Sherwood

JB, Muller JE. Triggering myocardial infarction by

marijuana. Circulation 2001;103(23):2805-9.

9. Vinson DC, Maclure M, Reidinger C, Smith GS.

A population-based case-crossover and case-control

study of alcohol and the risk of injury. J Stud

Alcohol 2003;64(3):358-66.

10. Roberts I, Marshall R, Lee-Joe T. The urban traffic

environment and the risk of child pedestrian injury:

a case-crossover approach. Epidemiology 1995;6

(2):169-71.

11. Petridou E, Mittleman MA, Trohanis D, Dessypris

N, Karpathios T, Trichopoulos D. Transient exposures

and the risk of childhood injury: a case-crossover

study in Greece. Epidemiology 1998;9(6):622-5.

12. Cherpitel CJ, Ye Y. Alcohol-attributable fraction

for injury in the U.S. general population: data from

the 2005 National Alcohol Survey. J Stud Alcohol

Drugs 2008;69(4):535-8.

13. Vegso S, Cantley L, Slade M, Taiwo O, Sircar K,

Rabinowitz P, et al. Extended work hours and risk

of acute occupational injury: A case-crossover

study of workers in manufacturing. Am J Ind Med

2007;50(8):597-603.

14. Barbone F, McMahon AD, Davey PG, Morris AD,

Reid IC, McDevitt DG, et al. Association of

road-traffic accidents with benzodiazepine use.

Lancet 1998;352(9137):1331-6.

15. Viboud C, Boelle PY, Kelly J, Auquier A, Schlin-

gmann J, Roujeau JC, et al. Comparison of the

statistical efficiency of case-crossover and case-

control designs: application to severe cutaneous

adverse reactions. J Clin Epidemiol 2001;54(12):

1218-27.

16. Azoulay L, Blais L, Koren G, LeLorier J, Berard

A. Isotretinoin and the risk of depression in

patients with acne vulgaris: a case-crossover study.

J Clin Psychiatry 2008;69(4):526-32.

10

17. Redelmeier DA, Tibshirani RJ. Association between

cellular-telephone calls and motor vehicle collisions.

N Engl J Med 1997;336(7):453-8.

18. Neas LM, Schwartz J, Dockery D. A case-crossover

analysis of air pollution and mortality in Philade-

lphia. Environ Health Perspect 1999;107(8):629-31.

19. Lee JT, Schwartz J. Reanalysis of the effects of

air pollution on daily mortality in Seoul, Korea:

A case-crossover design. Environ Health Perspect

1999;107(8):633-6.

20. Bell ML, O’Neill MS, Ranjit N, Borja-Aburto VH,

Cifuentes LA, Gouveia NC. Vulnerability to heat-

related mortality in Latin America: a case-cros-

sover study in Sao Paulo, Brazil, Santiago, Chile

and Mexico City, Mexico. Int J Epidemiol 2008;

37(4):796-804.

21. Navidi W. Bidirectional case-crossover designs for

exposures with time trends. Biometrics 1998;54(2):

596-605.

22. Ki M, Park T, Yi SG, Oh JK, Choi B. Risk analysis

of aseptic meningitis after measles-mumps-rubella

vaccination in Korean children by using a case-

crossover design. Am J Epidemiol 2003;157(2)

:158-65.

23. Ki M, Park T. Two Authors Reply. Am J Epidemiol

2004;159:716-20.

24. Dixon KE. A comparison of case-crossover and

case-control designs in a study of risk factors for

hemorrhagic fever with renal syndrome. Epide-

miology 1997;8(3):243-6.

25. Suissa S. The case-time-control design. Epidemi-

ology 1995;6(3):248-53.

26. Mittleman MA, Maclure M, Robins JM. Control

sampling strategies for case-crossover studies: an

assessment of relative efficiency. Am J Epidemiol

1995;142(1):91-8.

27. Park T, Ki M, Yi SG. Statistical analysis of MMR

vaccine adverse events on aseptic meningitis using

the case cross-over design. Stat Med 2004;23(12):

1871-83.

11

A case-crossover study design is a method to assess the effect of transient exposures on the risk of onset of acute

events. Which was introduced by Maclure in 1991 for Myocardial Infarction Onset Study. The design has been used

to diverse fields of epidemiology such as injury, drug adverse events, air pollution and so on. The most valuable

advantage of this design is unnecessary of control selection. To estimate relative risk, the exposure frequency during

a window just before outcome onset is compared with exposure frequencies during control times rather than in control

persons. One or more control times are supplied by each of the cases themselves. Self-matching of cases eliminates

the threat of control-selection bias and increases efficiency. To application of the case-crossover design, we need to

make sure several criteria and the possibility of specific bias. This review is designed to help the reader apply a

case-crossover study design to their research fields by understanding general ideas, prior conditions and limitations of

the design.

: case-control studies, crossover design, epidemiologic methods.

Theory and practice of Case-Crossover Study Design

Moran Ki