intervention research. contents definition of intervention research characteristics of intervention...
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Intervention research
Contents
• Definition of intervention research• Characteristics of intervention research• Analyses• Exercise• Reporting• Summary
Intervention research
Quantitative measurement of effects of therapy or preventive measures
Experimental: investigator determines who is treated, not the treating physician
Example: Sehat®
Sehat®: new blood pressure drug
1st experiment Ny. Ani with high blood pressure
Intervention: 6 weeks sehat®
Outcome: blood pressure
Weekly measured systolic blood pressure of Ny. Ani using Sehat®
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140
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170
Learn from single observation or ‘experience’
“For certain patients the blood pressure will decrease after using the drug”
What reasons can you think of that explain Ny. Ani’s decrease in blood pressure?
Learn from single observation or ‘experience’
Explanations for the observed effect:
- Regression to the mean
- Natural course / prognosis of disease
- External effects
- Measurement error
- True effect drug
Regression to the mean
Quartiles systolic blood pressure
1st measurement
2nd measurement
• Centripetal movement of data in successive measurements
• Effect of variability
• “the Doctor’s friend”
Solutions:
• measure more often
• control group
Natural course / prognosis of disease
Independent of treatment, blood pressure can change over time and this change can differ between people
External effects
Only interest: effect of Sehat®
Effects of other factors can influence the measurement of the effect of Sehat® in two ways:
-“placebo” effects
- induced effects
Induced external effects
Behavioral changes as effect of treatment of high blood pressure with Sehat®, e.g. eating and drinking pattern, physical activity, etc.
Observation errors (“information bias”)
Observer effects
• Patients, treating physicians, manufacturer can have expectations for the effect of Sehat®
• These expectations can influence, for example the reporting of patients or the measurements made by treating physicians
Result: measurement error
Learn from single observation or ‘experience’
Quantitative measurement of the effect of Sehat® can be distorted (confounded) because of :
• Natural course / regression to the mean (NC)• External effects (EE)• Observation errors (Information Bias) (IB)
Weekly measured systolic blood pressure of Ny. Ani using Sehat®
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140
150
160
170
Observed effect
Components of the observed effect
• Observed effect (OE) =
Drug effect (Rx) +
Natural course (NC) +
External effects (EE) +
Observation errors (Information Bias) (IB)
General: only interest in Rx
How do we distinguish RX effects from confounding effects?
We ‘control’ the experiment
Comparison:
Ny. Ani (green) with Sehat®,
Ny. Sri (pink) without Sehat®
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RX?
Controlled study
Index (drug treatment):
OEi = Rx + NCi + EEi + IBi
Reference group (no treatment):
OEr = NCr + EEr + IBr
Therapeutic drug effect
• OEi - OEr =
Rx + (NCi - NCr) + (EEi - EEr) + (IBi - IBr)
• So, OEi - OEr = Rx
• If, NCi = NCr and EEi = EEr and IBi = IBr
Validity
Essence: validity in experimental research is assessed through comparability of groups
The basis of an experiment’s design is the prevention of non-comparibility
Comparability of natural course
= comparability populations = comparability prognosis
What could we do to assure comparability of the natural course?
Sleepy?
How about some coffee?
Clinical trial:
“The effect of coffee to daytime drowsiness”
Now open your envelope!
coffee no coffee
male 25 19
Live with parents 21 17
First child 16 19
High school in Jakarta 22 19
Comparability of natural course
Options:
- Selection or matching
- Measure prognostic variables at baseline and control for these during analysis
- Randomisation - paradigm for comparative research since 1948
Aim of randomization
To ensure that the groups to be compared have the same average baseline probability of change in blood pressure (prognosis, natural course)
To make the index and reference groups comparable for all known and unknown factors that may influence blood pressure
Randomized trial Table 1. Baseline characteristics at randomization
Sehat®
YES
Ny. Ani
NO
Ny. Sri
Age (years) 41 57
BMI (kg/m2) 24,6 32,3
SBP (mmHg) 160 160
Randomized trial:
Ny. Ani (green) with Sehat®,
Ny. Sri (pink) without Sehat®
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140
150
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RX?
Randomized trial Table 1. Baseline characteristics at randomization
Sehat®
YES
N = 5,000
NO
N = 5,000
Age (years) 52,3 52,4
BMI (kg/m2) 25,7 25,6
SBP (mmHg) 160 160
Randomized trial:
5000 women (green) with Sehat®,
5000 women (pink) without Sehat®
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140
150
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RX?
Comparability of external effects (EEi=EEr)
What could we do to assure comparability of external effects?
Comparability of external effects (EEi=EEr)
Options:
- Randomize
- Placebo or simulated treatment in the reference group
- Blinding
Comparability of observations (IBi = IBr)
What could we do to assure comparability for the observations (=no observation errors)?
Comparability observation (IBi = IBr)
Options:- Use protocols, systematics- Placebo
- Blinding (single, double, triple)
Comparability observation (IBi = IBr)
Need to blind depends on the interpretability of the studied endpoint:
- death- myocardial infarction- angina pectoris- blood glucose- quality of life
Measurement Bias -minimizing differential error
• Blinding – Who?– Participants?– Investigators?– Outcome assessors?– Analysts?
• Most important to use "blinded" outcome assessors when outcome is not objective!
• Papers should report WHO was blinded and HOW it was done
•Schulz and Grimes. Lancet, 2002
Placebo effectTrial in patients with chronic severe itching
0
10
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Itching score•Cyproheptadine• HCL
•Trimeprazine• tartrate
•No treatment
•Treatment vs no treatment for itching
Placebo effectTrial in patients with chronic severe itching
0
10
20
30
40
50
60
Itching score•Cyproheptadine• HCL
•Trimeprazine• tartrate
•Placebo
•No treatment
•Treatment vs no treatment vs placebo for itching•Placebo effect - attributable to the expectation that
•the treatment will have an effect
Randomized triple blind placebo controlled trial Table 1. Baseline characteristics at randomization
Sehat®
BUGAR®
N = 5,000
PLACEBO
N = 5,000
Age (years) 52,3 52,4
BMI (kg/m2) 25,7 25,6
SBP (mmHg) 160 160
Randomized triple blind placebo controlled trial: 5000 women (green) Sehat BUGAR®,
5000 women (pink) Sehat PLACEBO®
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RX?
Need of comparability
Natural course/prognosis: always
External effects: depends on aim research: “explanatory” vs. pragmatic
Observation errors: depends on endpoint
Randomize Blind Placebo NC + EE + + (patient) + IB + (investigator) +
Randomized double blind controlled trial
Intervention: and then
• Different aims: explanatory vs pragmatic• Analysis• Loss-to follow-up• Choice of study endpoints• Disadvantages• Alternatives for experimental research• Size of trials• Reporting
Aims of intervention
Explanatory
Interest in a single aspect of high blood pressure treatment, by Sehat®
Pragmatic
Interest in strategy (procedure with all that belongs to it) of high blood pressure treatment, e.g. combination of drugs with living rules and weight loss, including induced effects
Analysis randomized research
Randomisation is a powerful way to solve the problem of differences in the natural course:
This principle should not be undone in the analysis!
“Intention to treat” analysis
Once a member of the cohort, always a member of the cohort
contrary to
Analysis of only those patients who really received the treatment (‘per treatment’ or ‘per protocol’ analysis).
Problem: loss to follow-up
Loss to follow-up: what is the problem?
People stop treatment for a reason– Treatment does work or does not– People are ill or are not
Reasons can be related to the occurrence relation: drug and outcome
Problem: we do not know why people stop
Result: bias?
Outcomes and endpoints
• Intuitive preference for “hard” clinical measures, but:Growing realization of importance of patient preference in assessment of choices
• Often unclear choice of endpoints• Often unclear validity of chosen endpoints
Exercise intervention(open your exercise book!)
Question 1
Do children of mothers from high risk-families (patient/domain) have a lower 2-year risk of atopic diseases (outcome) if they are exposed, before and after the pregnancy, to probiotics (intervention/determinant) than to placebo (comparison)?
Question 2
Somewhat more atopy and smoking in placebo families, a somewhat more higher incidence of pets and detectable IgE in Lactobacillus, but as a whole reasonably comparable
Question 3 and 4
2-year risk of atopy in Lactobacillus group
15 / 64 = 23%
2-year risk of atopy in placebo group
31 / 68 = 46%
Question 5
RR = = 0.5115 / 64
31 / 68
Question 6
Eln0.51 ± 1.96√[49/15*64 + 37/31*68]
95% CI = 0.31 to 0.85
Question 7
Confidence interval tells something about the precision of the effect estimate
Question 8
Fairly strong protective effect of Lactobacillus treatment against developing atopy
Complete explanation of effect by baseline differences or differential loss to follow-up very unlikely
Question 9
Pre- and postnatal use of Lactobacillus in high risk children seems to prevent the development of early atopy
Disadvantages of trials
Limits to generalisability
Selection of the study population
Budget
RCT is expensive
Takes long
RCT is prospective
Number of patients
Ethical dilemma’s (a.o. equipoise)
Alternative: comparative non-experimental research
• Cohort studies / Case control studies• Not inherently less valid, but much more difficult
to design and conduct and therefore much more sensitive to bias
• In comparative non-experimental research exists a large probability of non-comparibility of especially those three components that are solved so well in an RCT
Confounding by indication
The prognosis influences the probability to be assigned a certain intervention
E.g. -observational studies on the effectivity of vaccinations
- observational study on the effect ofantihypertensives
Confounding by indication
Confounding by indication: research on the effect of anti-hypertensives among 793 Dutch hypertensive women, who were followed for over 10 years
Crude and adjusted rate ratios for fatal cardiovascular diseases in treated women compared with non-treated women
Confounding by indication
RR cardio-vascular mortality 95% CI
Crude 1.0 0.6 TO 1.5
Adjusted* 0.6 0.3 TO 0.9
* For age, Quetelet index, hart frequency, smoking habits, serum cholesterol, diabetes, previous myocardial infarction or stroke
Reporting randomized trials
• Table 1: prognostic factors in index and reference group (see exercise)– Show whether randomization succeeded
• Table 2: shows intervention effects– Difference in group averages, difference in
group proportions– Relative risk (reduction), risk difference,
NNT
Reporting: flow-chart
Conclusions
• To evaluate the effects of therapy a comparison is necessary
• In trials, very effective methods have been developed to enhance the comparability of the natural course, external effects and information
randomisation, blinding and placebo• The concepts and principles of a trial are a model
for non-experimental research
Thank you