Download - Lecture 9: Analysis of intervention studies
Lecture 9: Analysis of intervention studies
• Randomized trial - categorical outcome
• Measures of risk:– incidence rate of an adverse event (death, etc)
• It = incidence rate in treatment group
• Ic = incidence rate in control group
• Example (mammography and mortality):• It = 2/10,000/year
• Ic = 4/10,000/year
Risk difference and ratio
Risk difference = Ic - It/units
– usually easier to express as risk reduction
– 4 - 2/10,000/year = 1/10,000/year
Risk ratio (relative risk) = Ic = 4/2 = 2.0
It
Alternatively: = It = 2/4 = 0.50
Ic
Relative risk reduction
• Analogous to attributable risk percent
• Sometimes called percent effectiveness
= risk difference = Ic - It
risk in control group Ic
= 2/4 = 50%
• Can be computed from the risk ratio: 1 - 1
RR
= 1 -1/2
Example from GUSTO trial
• tissue plasminogen activator (TPA) vs streptokinase (SK) as thrombolytic strategy in treatment of AMI.
30-day mortality in TPA group = 6.3%
• 30-day mortality in SK group = 7.3%
Measures of effect
RATE/RISK RATIO
SK rate = 7.3 = 1.16
TPA rate 6.3
RELATIVE RISK REDUCTION
SK rate – TPA rate = 7.3 – 6.3 = 14%
SK rate 7.3
[also calculated as 1 – (1/rate ratio)]
Measures of effect (cont)
ABSOLUTE RISK REDUCTION (rate/risk difference; attributable risk)
SK rate – TPA rate = 7.3% – 6.3% = 1.0%
NUMBER NEEDED TO TREAT (NNT)(Reciprocal of risk difference)
1 = 1 = 100
SK rate – TPA rate .01
SELECTION OF EFFECT MEASURES
Ratio measures assess strength of effect - how effective is the treatment?
Difference measures take into account frequency of the outcome – can assess whether it is worthwhile (allocation of time and $$)
Both ratio and difference measures are needed
All these measures are estimates and are subject to sampling error – need confidence intervals to determine their precision
All the measures are limited by the study(ies) that generated them – they may vary by patient characteristics, adherence to treatment, duration of follow-up, etc)
Measures consider only beneficial and not adverse effects of treatment.
Aspirin in prevention of MI among male smokers
(data from Physicians’ Health Study)
5-year incidence of MI:
aspirin group = 1.2%
placebo group = 2.2%
Risk ratio = 1.8
Relative risk reduction = 45%
Absolute risk reduction = 1.0% in 5 years
NNT = 100 for 5 years (to prevent 1 MI)
Antihypertensive treatment in 75-year old women with BP of 170/80
(data from SHEP study)
• 5-year incidence of stroke:
treatment group = 5.2%
placebo group = 8.2%– Risk ratio = 1.6– Relative risk reduction = 37%– Absolute risk reduction = 3.0% in 5 years– NNT = 33 / 5 years (to prevent 1 stroke)
Measures of effect in RCTs: continuous outcomes
• Example: RCT of antidepressant vs placebo:
• Measures on depression scale at baseline and at follow-up
• Possible measures:– Difference in mean scores at follow-up – Difference in change scores from baseline to
follow-up
Measures of effect in RCT: adjustment for covariates
• Is it necessary?
• Compare characteristics of study groups at baseline (statistical testing not appropriate but may be requested!)
• Regression models:
– time to event: Cox proportional hazards
– categorical outcome at point in time: multiple logistic regression
– continuous outcome (at point in time or change score): multiple linear regression
Measures of effect in observational studies
• Cohort studies:
– can use same measures as in RCTs but control of confounding is essential
• Case-control studies:
– odds ratio may be used to estimate relative risk under certain assumptions
– relative risk reduction can be computed as:
1 - 1/OR
– risk difference and NNT cannot normally be computed from case-control studies
Example: a quasi-randomized trial of a 2-stage ED intervention for seniors
• 2-stage intervention:– screening with ISAR screening tool
– (if ISAR 2+): brief, standardized nurse assessment
– referrals to primary MD, CLSC, etc, as needed
• Patients randomized by day of visit to:– intervention
– usual care
• Outcomes (4 months after ED visit):– Functional decline
Example: a quasi-randomized trial of a 2-stage ED intervention for seniors
• Outcomes (4 months after ED visit):– Functional decline
– Change in depresssive symptoms
– Caregiver physical and mental health
– Patient and caregiver satisfaction with care
• Which method of analysis?
Example: Systematic detection and multidisciplinary care of delirium in older
medical inpatients Cole et al, CMAJ 2002; 167:753-9
• Intervention group:– Consultation by geriatrician or psychogeriatrician
– Identification of associated factors - recommendations
– Nurse daily visits
• Control group:– Usual care
– Limitations?
Screened for delirium(n = 1855)
Prevalent delirium(n=243)
No prevalent delirium(n=1612)
Total delirium(n=299)
Incident delirium(n=56)
No incident delirium(n=56)
Refused(n=72)
Randomized(n=227)
Intervention(n=113)
Control(n=114)
Incidence rate = 3%
Prevalence rate = 13%
SCREENING AND ENROLLMENT
8 weeks post-discharge8 weeks post-dischargefollow-upfollow-up
Intervention(n=113)
Control(n=114)
In-hospital death 25% 22%
Withdrew before discharge 7% 2%
Still in hospital at 8 weeks 16% 13%
Discharged before 8 weeks 65% 77%
Died after discharge 4% 9%Refused follow-up 5% 7%Completed follow-up 56% 61%
PRIMARY OUTCOMEPRIMARY OUTCOME
MEASUREMEASURE Mini-Mental State Exam (MMSE):
Every 2-3 days during 1st week, then weekly until discharge
If discharged before 8 weeks: 8-week post discharge home assessment
PRIMARY OUTCOMEPRIMARY OUTCOME
MEASURE MEASURE (continued)(continued)
Time to improvement in hospital Improvement = MMSE score
persistently at least 2 points higher than initial score
Kaplan-Meier survival curves ofKaplan-Meier survival curves ofpercent with improved MMSE scorepercent with improved MMSE score
0
10
20
30
40
50
60
70
0 5 10 15 20 25 30 35 40
Days from enrollment
% improved
Intervention (n=109)
Control (n=109)
Kaplan-Meier survival curves of percent Kaplan-Meier survival curves of percent with improved MMSE scorewith improved MMSE score
stratified by dementiastratified by dementia
0
10
20
30
40
50
60
70
0 5 10 15 20 25 30 35 40
Days from enrollment
% improved
Intervention, no dementia (33)Control, no dementia (n=36)Intervention, with dementia (n=67Control, with dementia (n=64)
Measure of effect
• Hazard ratio (HR) for shorter time to improvement = 1.10 (95% CI: 0.74, 1.63)
• Pre-specified sub-group analyses:– no dementia: HR 1.54 (0.80, 2.97)– less comorbidity HR 1.36 (0.75, 2.46)
• Conclusion?