Choice of baseline period using the selfcontrolled case series study
Ian Douglas
Non-Communicable Disease Epidemiology Dept
London School of Hygiene & Tropical Medicine
With thanks to Paddy Farrington, Richard Hubbard, Liam Smeeth,
Heather Whitaker
Funded by Medical Research Council Methodology Fellowship
Improving health worldwide
www.lshtm.ac.uk
Outline
• Thinking around the basic design for SCCS – what is baseline?
• Modifying the approach to suit the question
Self-controlled case-series method – simplest
form
Exposure
Baseline time
Other periods of interest
Event
Rate in period of interest = Rate Ratio
Rate in baseline period
Farrington CP. Biometrics 1995;51:228-235
Self-controlled case-series method – simplest
form
Start observation
Exposure
Baseline time
Other periods of interest
End observation
Other possible approaches to
baseline time
• Pre-exposure time
• Post exposure time
• Post-death observation time
Pre-exposure time – the theory
• Prescribing and vaccination decisions depend on a patient’s
underlying health
• Some health states might make it less or more likely a treatment will
be given
• The risk of an event in the pre-exposure period may differ from other
baseline times
• If so, remove it from baseline time to avoid bias
SCCS – pre-exposure period
Start observation
Baseline time
Other periods of interest
End observation
SCCS – pre-exposure period
Start observation
Baseline time
Other periods of interest
End observation
Pre-exposure time
Example – orlistat and liver
injury
• Weight loss drug
• Linked with possible liver injury
• SCCS using UK primary care data from the Clinical Practice Research
Datalink and Hospital Episode Statistics.
• 988 cases of possible liver injury
• Douglas et al, BMJ 2013;346:f1936
Start of
observation
First orlistat
prescription
End of
orlistat
Baseline period (no orlistat exposure)
90 day period before 1st orlistat
Days 1-30 of 1st orlistat
Days 31-60 of 1st orlistat
Days 61-90 of 1st orlistat
>90 days orlistat
Results
DEFINITE + PROBABLE CASES
(n=988)
Patient years Number of
events
Age Adjusted
Rate Ratio
8,872
852
(95% CI)
-
Pre-exposed (90 days)
241
42
1.50 (1.10-2.06)
Exposed 1-30 days
81
21
2.21 (1.43-3.42)
Exposed 31-60 days
80
10
1.06 (0.57-1.99)
Exposed 61-90 days
78
12
1.32 (0.75-2.34)
Exposed>90 days
986
51
0.78 (0.58-1.05)
Unexposed
Results
DEFINITE + PROBABLE CASES
(n=988)
Patient years Number of
events
Age Adjusted
Rate Ratio
8,872
852
(95% CI)
-
Pre-exposed (90 days)
241
42
1.50 (1.10-2.06)
Exposed 1-30 days
81
21
2.21 (1.43-3.42)
Exposed 31-60 days
80
10
1.06 (0.57-1.99)
Exposed 61-90 days
78
12
1.32 (0.75-2.34)
Exposed>90 days
986
51
0.78 (0.58-1.05)
Unexposed
Results
DEFINITE + PROBABLE CASES
(n=988)
Patient years Number of
events
Age Adjusted
Rate Ratio
8,872
852
(95% CI)
-
Pre-exposed (90 days)
241
42
1.50 (1.10-2.06)
Exposed 1-30 days
81
21
2.21 (1.43-3.42)
Exposed 31-60 days
80
10
1.06 (0.57-1.99)
Exposed 61-90 days
78
12
1.32 (0.75-2.34)
Exposed>90 days
986
51
0.78 (0.58-1.05)
Unexposed
Results
DEFINITE + PROBABLE CASES
(n=988)
Patient years Number of
events
Age Adjusted
Rate Ratio
8,872
852
(95% CI)
-
Pre-exposed (90 days)
241
42
1.50 (1.10-2.06)
Exposed 1-30 days
81
21
2.21 (1.43-3.42)
Exposed 31-60 days
80
10
1.06 (0.57-1.99)
Exposed 61-90 days
78
12
1.32 (0.75-2.34)
Exposed>90 days
986
51
0.78 (0.58-1.05)
Pre-exposed 30 days
81
19
-
Exposed 1-30 days
81
21
1.11 (0.59-2.06)
Unexposed
Orlistat Conclusions
• Initiation of orlistat temporally associated with increased risk of liver
injury
• Period prior to initiation also associated with similar increased risk of
liver injury
• Treatment initiation does not change the incidence of liver injury
• Choice of baseline period impacts results and interpretation
Post-exposure – the theory
• Time between exposures or after exposure normally considered as
baseline
• What about medications we expect to be taken continuously?
• What do gaps mean?
SCCS – post-exposure, chronic treatments
Start observation
End observation
Exposure
Baseline time
Are we sure there are breaks here?
Other periods of interest
Post-exposure example –
glitazones and fracture
• Glitazone antidiabetics associated with fractures in trials
• Details unclear
• Chronic treatment, but prescribing pattern suggested gaps in
minority of patients
• Are gaps real or ascertainment errors?
• Douglas et al (2009) PLoS Med 6(9): e1000154.
doi:10.1371/journal.pmed.1000154
Start of
observation period
First glitazone
prescription
Baseline period
Risk period during exposure
End of
observation period
Glitazones and fractures
Fractures
during
treatment
Age adj
Rate ratio
95% CI
720
1.43
1.25-1.62
0-1 year
235
1.26
1.07-1.47
1-2 years
179
1.49
1.24-1.79
2-3 years
127
1.70
1.37-2.12
3-4 years
104
2.31
1.80-2.97
4-7 years
75
2.00
1.48-2.70
Any glitazone, all fractures
Overall
Glitazone duration
Glitazones and fractures
• Baseline always earlier than exposure
• Is age adjusted well enough?
• Use a comparator
Sulphonylureas and fractures
Fractures
during
treatment
Age adj
Rate ratio
95% CI
348
0.84
0.66-1.08
0-1 year
102
0.89
0.69-1.16
1-2 years
61
0.77
0.56-1.05
2-3 years
53
0.94
0.67-1.31
3-4 years
43
1.09
0.76-1.59
4-7 years
62
1.01
0.71-1.43
Any sulph, any fracture
Overall
Sulphonylurea duration
Pre-exposure conclusions
• Treatment uncertainty led to exclusion of post-treatment period
• Possibility of seeing attenuated effect if gaps are actually treated
periods
• Censor post-exposure
• Have a control analysis to reassure
Post-death – the theory
•
•
•
•
•
•
Observation normally ends at death
Surely we can’t observe exposure post-death?
We can (and should!) in some special cases...
Unique, predictable and short exposures only
Baseline can’t be pre-exposure – need to be alive to get exposed
Baseline must come later, even for people who die
Post-death example – bupropion
and sudden death
•
•
•
•
•
Smoking cessation treatment
Taken for 28 days only as single exposure
Reports of sudden death emerged, unclear if related to treatment
Can SCCS be used to look at this?
Hubbard et al, 2005; Thorax, 60:848-850
SCCS – outcome = death
Start observation
Exposure
Baseline time
Other periods of interest
End observation
SCCS – outcome = death
June 2000
Exposure
Baseline time
Other periods of interest
Nov 2003
SCCS – outcome = death
Observation period
June 2000
Exposure
Baseline time
Buproprion exposure (28 days)
Nov 2003
Results
Number of Age Adjusted Rate
events
Ratio
unexposed
119
(95% CI)
1.00
bupropion
2
0.50 (0.12-2.05)
Post-death - conclusions
•
•
•
•
•
SCCS can look at fatal outcomes in special circumstances
Relatively short observation period
Observation begins with exposure
Exposure length predictable and short
Later periods always unexposed
Baseline period conclusions
• Suitable baseline varies
• Need to consider:
– Outcome – how well recorded, how detected
– Type of exposure – predictable, short, chronic
Any questions?