Transcript Measures of effect in 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
TPA rate
=
7.3
6.3
=
1.16
RELATIVE RISK REDUCTION
SK rate – TPA rate
SK rate
=
[also calculated as 1 – (1/rate ratio)]
7.3 – 6.3
7.3
= 14%
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
SK rate – TPA rate
=
1
.01
= 100
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 75year 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 2stage 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 2stage 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?
SCREENING AND ENROLLMENT
Screened for delirium
(n = 1855)
Prevalent delirium
(n=243)
Prevalence
rate = 13%
Total delirium
(n=299)
No prevalent delirium
(n=1612)
Incident delirium
(n=56)
Incidence rate = 3%
Refused
(n=72)
Randomized
(n=227)
Intervention
(n=113)
No incident delirium
(n=56)
Control
(n=114)
8 weeks post-discharge
follow-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
Refused follow-up
Completed follow-up
4%
5%
56%
9%
7%
61%
PRIMARY OUTCOME
MEASURE
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 OUTCOME
MEASURE (continued)
Time to improvement in hospital
 Improvement = MMSE score
persistently at least 2 points higher
than initial score
Kaplan-Meier survival curves of
percent with improved MMSE score
% improved
70
60
50
40
30
Intervention (n=109)
Control (n=109)
20
10
0
0
5
10
15
20
25
Days from enrollment
30
35
40
Kaplan-Meier survival curves of percent
with improved MMSE score
stratified by dementia
% improved
70
60
50
40
30
Intervention, no dementia (33)
Control, no dementia (n=36)
Intervention, with dementia (n=67
Control, with dementia (n=64)
20
10
0
0
5
10
15
20
25
Days from enrollment
30
35
40
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?