Intervention and clinical

epidemiological studies

Including slides from:Barrie M. Margetts

Ian L. Rouse

Mathew J. Reeves,PhD

Dona Schneider

Tage S. Kristensen

Victor J. Schoenbach

Experimental / intervention studies• Experimental studies differ from observational studies described

/reported rather than simply to observe, the exposure of interest.

• There are many different approaches used in experimental studies,

from very tightly controlled laboratory experiments to large scale

community intervention.

• Experimental studies either focus on assessing change at the level of

the individual or the group.

• The most important aspect of experimental studies, no matter what

study group is used., is to ensure that the allocation of the study group

to the different treatments/ interventions / exposures under

investigation is done randomly.

• The development of the research protocol will then focus primarily on

how to measure the effect of an exposure on an outcome with

consideration of the effects of other factors (potential confounders as

well as factors related to the efficacy of the delivery of the intervention)

Intervention

is not always

successful

– see

following

examples

carefully!

Effect of psychosocial treatment on

survival of breast cancer patients

Intervention: Group sessions of 90 min. once a week for one

year.

Spiegel et al. Lancet 1989;II:888-91.

0 20 40 60 80 100 120 140

Months from study entry to

death

Probability of survival

0.2

0.4

0.6

0.8

1

0

Holding handsA randomized trial among women giving birth

Support No support

(249) (168)

Perinatal problems 27 % 59 %

Caesarean section 7 % 17 %

Duration of labor 7.7 h 15.5 h

Transferred to neonatal

intensive care2 % 7 %

Support was a ”doula” who stayed with the women during labor and birth.

Klaus et al. BMJ 1986;293:585-7.

Effect of treatment for high blood pressure and

high cholesterol – A randomized trial

Five-year intervention study of 1222 Finnish businessmen

0

10

20

30

40

0 2 4 6 8 10 12 14 16

Years from

randomizationStrandberg et al. JAMA 1991;266:1225-9.

Effects of debriefing after traffic accidents

A randomized trial

Intervention

group *Control group

Median no of days in hospital 7.7 3.7

Emotional distress score 0.50 0.42

Emotional distress after 4 months 0.62 0.38

Mean impact score 15.13 15.30

Mean impact score after 4 months 15.97 12.87

Proportion with distressing memories 21 % 10 %

Number 51 52

* Debriefing for one hour and an information leaflet.

Hobbs et al. BMJ 1996;313:1438-9.

Effect of debriefing ?A study of policemen involved in the Bijlmermeer plane crash disaster

Debriefed Non-debriefed

(N=46) (N=59)

PTSD symptoms, 8 months after 25 % 27 %

Arousal symptoms, 8 months after 6 % 2 %

PTSD symptoms, 18 months after 24 % 17 %

Arousal symptoms, 18 months after 7 % * 0 %

* P < 0.05

Carlier et al. Stress Med 1998;14:143-8.

Relative risk of IHD of workers exposed to

CS2 compared to controls

R

R

Intervention was started in 1972

Nurminen & Hernberg. Br J Industr Med 1985;42:32-5

0

1

2

3

4

5

6

7

8

1967 1972 1977 1982 Calendar year

Follow-up year0 5 10

15

•

•

• •• •

Intervention in details - exampleQ: Does a course in lifting techniques reduce the

occurrence of low back pain ?

1. Did the participants attend the course ?

2. Did the participants learn anything ?

3. Did the participants learn how to do the lifting ?

4. Were the participants able to use the techniques in practice afterwards ?

5. Did the participants use the techniques in practice ?

6. For how long ?

7. Did the use of the new techniques reduce low back pain among those who already had low back pain ?

8. Did the use of the new techniques reduce the incidence of new cases of low back pain ?

Types of Intervention Studies• All trials test the efficacy of an intervention and assess safety

• Prophylactic vs Treatment– evaluate efficacy of intervention designed to preventdisease, e.g., vaccine, vitamin supplement, patient education

– evaluate efficacy of curative drug or intervention or a drug designed to manage signs and symptoms of a disease (e.g., arthritis, hypertension)

• RCT vs Community Trials– individuals, tightly controlled, narrowly focussed, highly select groups, short or long duration

– Cities/regions, less rigidly controlled, long duration, usually primary prevention

Example of a therapeutic trial

The β-Blocker

Heart Attack

Trial (B-HAT)

The β-Blocker Heart Attack trial.

JAMA, Nov. 6, 1981;246(18):2073

Example of a prevention trial

Perinatal

transmission

of HIV

(ACTG 076)

NEJM 11/3/1994;

331(18):1173-1180

• Experimental studies in whole populations (communities) are usually referred to as community trials or community intervention studies.

• Community trials focuses on mass education campaigns aimed at changing people’s knowledge and attitudes.

• Community intervention studies, the exposure is usually given to subjects (for example, by vector control to reduce malaria, pit latrines for clean water), or to reduce work load and/or to increase disposable income.

• These community intervention studies can be characterized as:

(1) explicitly nutritional

(a) nutrition oriented food programs (b) feeding programs

(c) weaning foods (d) fortification (e) nutrition education;

(2) non- or implicitly nutritional

(a) health related, e.g. immunization, sanitation;

(b) economic, e.g. income generation or substitution;

(c) labor-saving, e.g. cereal mills;

(3) integrated

Community trials

Individual trials

• Individual-based experimental studies are sometimes sub-

divided on the basis of the level of the outcome as clinical

trials (or therapeutic, secondary, or tertiary prevention trials),

and field trials (primary prevention trials) where the subjects

do not have any defined level of outcome which may be

classified as disease.

• In addition, a third group of individual-based studies are called

intervention studies, where the individuals who have the

outcome of interest above a certain level at baseline are

excluded. (in a trial of vitamin A supplementation children

with xerophthalmia are excluded).

Types of individual trials

Blinded Not blinded

Randomised Not randomised

Controlled Not controlled

Trial

Why is randomized assignment

of intervention so important?

1. Best assurance that control group (unexposed)

is a valid substitute population

2. Only way to control for unknown factors

3. Facilitates masking of exposure status

4. Avoids ambiguity of time order of exposure

and outcome (most intervention studies

achieve this)

5. Provides foundation for statistical tests –valid quantification of uncertainty

Randomization methods

• Coin toss: subject to bias

• Random number tables or computer program– Computer-generated less subject to bias.

• Should be done by a third party

• For procedure trials where physician not blinded, assignment either done in central call-in center or put in opaque envelopes and revealed to investigator at last possible time.– Prevents investigator from gaming assignment.

Randomised clinical trials

20

Single vs. double vs. triple blind?

• Much confusion in use of the terms single, double, and triple blind, hence the study should describe exactly who was blinded.

• Ideally, blinding should occur at all of the following levels:• Patients

• Caregivers

• Data collectors

• Adjudicators of outcomes

• Statisticians

Double blind trials

Agree to screening? - Yes Agree to screening? - No

Meet inclusion criteria? - Yes

Wish to continue? - Yes Wish to continue? - No

Agree to randomization? - Yes Agree to randomization? - No

Experimental Population

Validity in experimental trials

Respond to letter? - Yes Respond to letter? - No

Meet inclusion criteria? - No

Are they

similar?

Reference Population

Special forms I.

Crossover Studies

• Subjects begin the study on Treatment A and

later switch to Treatment B

• Patients serve as their own control

• Variation between individuals remains constant

• Washout period between treatments reduces

residual carryover

Design of a Planned Crossover Trial

Randomized

Treatment A

Group 1

Group 1

Group 2

Treatment B

Group 2

Group 2

Group 1

Special forms II.

Factorial Design

• Use the same study population to test

Drug A & Drug B

• Assume:

– The outcomes for each drug are different

– Modes of action are independent

• If you need to terminate the study of Drug

A, you can continue the study to determine

the effects of Drug B instead of beginning

an entirely new study.

Factorial Design for Studying

Effects of Two Treatments

Both A and B

(a)

A only

(b)

B only

(c)

Neither

A nor B

(d)

Treatment B

+ -

+Treatment A

-

Summary of RCTs

• Advantages

– High internal validity

– Able to control selection, confounding and measurement

biases

– True measure of treatment efficacy (cause and effect)

• Disadvantages

– Low external validity (generalizability)

– Strict enrollment criteria creates a unique, highly selected

study population

– Complicated, expensive, time consuming

– Ethical and practical limitations