EXERCISE: SELF CONTROLLED CASE SERIES

ANALYSIS

• Caitlin Dodd Cincinnati Children’s Hospital

• Hector S Izurieta U.S. FDA

self-controlled case series method

• Methodology for epidemiological studies

• Based on cases only

• Provides consistent estimates of relative incidence

• Controls for fixed confounders

• Allows age and temporal variation in baseline

• Highly efficient

Simple Example Subject vaccinated at day 10 of observation 1 risk period: - Days 0 to 2 following vaccination - Seizure at day 11 of observation, day 1 following vaccination

Days: 1 10 11 12 15 22 60

Febrile Seizure

Risk Period

Vaccination

ID START DAY OF VACCINATION DAY OF ADVERSE EVENT END

0 1 10 11 60

Expansion of Simple Example Days: 1 10 11 12 30 60

Febrile Seizure

Risk Period

Vaccination

ID START OF

WINDOW (START)

END OF

WINDOW

(STOP)

# OF

EVENTS IN

WINDOW

(NEVENT)

# OF DAYS

IN

WINDOW

(OFFSET)

AT RISK?

YES/NO (RISK)

IN RISK PERIOD 1?

(RISKR1)

IN RISK

PERIOD 2?

(RISKR2)

X 1 9 0 9 NO NO NO

X 10 12 1 3 YES YES NO

X 13 60 0 48 NO NO NO

Simple Example 2 Subject vaccinated at day 10 of observation 2 risk periods: - Days 0 to 2 following vaccination - Days 5 to 12 following vaccination - Seizure at day 11 of observation, day 1 following vaccination

Days: 1 10 11 12 15 22 60

Febrile Seizure

Risk Period

Vaccination

ID START DAY OF VACCINATION DAY OF ADVERSE EVENT END

0 1 10 11 60

Expansion of Simple Example Days: 1 10 11 12 15 22 60

Febrile Seizure

Risk Period

Vaccination

ID START OF

WINDOW (START)

END OF

WINDOW

(STOP)

# OF

EVENTS IN

WINDOW

(NEVENT)

# OF DAYS

IN

WINDOW

(OFFSET)

AT RISK?

YES/NO (RISK)

IN RISK PERIOD 1?

(RISKR1)

IN RISK

PERIOD 2?

(RISKR2)

X 1 9 0 9 NO NO NO

X 10 12 1 3 YES YES NO

X 13 14 0 2 NO NO NO

X 15 22 0 8 YES NO YES

X 23 60 0 38 NO NO NO

Exercise For the exercise:

The observation period is from day 1 to day 60 inclusive. Risk periods are days 0 to 2 and 5 to 12 following vaccination.

The observation period covers approximately 2 months and all data is on the observation period scale, meaning subject 2 received the first dose six

days after the start of the observation period. Expand data for subjects two and three.

ID START END DAY OF OBSERVATION AT EVENT

DOSE 1 DOSE 2 DOSE 3

2 0 60 44 6 40 .

3 0 60 23 47 . .

Check Your Work

ID START OF

WINDOW

(START)

END OF

WINDOW

(STOP)

# OF EVENTS

IN WINDOW

(NEVENT)

# OF DAYS

IN WINDOW

(OFFSET)

AT RISK?

YES/NO

(RISK)

IN RISK

PERIOD 1?

(RISKR1)

IN RISK

PERIOD 2?

(RISKR2)

2 1 5 0 5 0 0 0

2 6 8 0 3 1 1 0

2 9 10 0 2 0 0 0

2 11 18 0 8 1 0 1

2 19 39 0 21 0 0 0

2 40 42 0 3 1 1 0

2 43 44 1 2 0 0 0

2 45 52 0 8 1 0 1

2 53 60 0 8 0 0 0

3 1 46 1 46 0 0 0

3 47 49 0 3 1 1 0

3 50 51 0 2 0 0 0

3 52 59 0 8 1 0 1

3 60 60 0 2 0 0 0

Exercise - SAS For the exercise:

The observation period is from day 1 to day 60 inclusive. Risk periods are days 0 to 2 and 5 to 12 following vaccination. Subjects may

experience more than one event.

The observation period covers approximately 2 months and all data is on the observation period scale, meaning subject 1 received the first dose 50

days before the start of the observation period.

ID START END DAY OF OBSERVATION AT EVENT1

DAY OF OBSERVATION AT EVENT 2

DOSE 1 DOSE 2 DOSE 3

1 0 60 17 . -50 -7 32

2 0 60 44 . 6 40 .

3 0 60 23 . 47 .

4 0 60 7 31 6 30 .

SAS Code

/* Define macro directory*/

%LET macdir = c:\sccs\macro;

/* Read in macros */

%INCLUDE "&macdir\sccs.sas";

%INCLUDE "&macdir\poisreg.sas";

%INCLUDE "&macdir\element.sas";

/***********************************************

* Creating the data set used in the worksheet

* Adding 4th subject with two events

************************************************/

data simple;

input pid start end seizure1 seizure2 dose1 dose2 dose3;

cards;

1 0 60 17 . -50 -7 32

2 0 60 44 . 6 40 .

3 0 60 23 . 47 . .

4 0 60 7 31 6 30 .

;

run;

SAS Code

/* Agerange defines the age range for each subject

In this example, the observation period goes from 0 (exclusive) to 60 (inclusive) days */

%LET agerange=1 60;

/* Define risk periods */

%LET risk=0 2 5 12;

/* Define age categories - NO AGE CATEGORIES FOR THIS EXAMPLE */

%LET age=;

/* No adjustment for seasonality is used in this example */

%LET season=;

/* No semiparametric analysis is done */

%LET semi=N;

SAS Code to format the data set

/* ********** */

/* ALL DOSES */

/* ********** */

/*Create dataset for use with case series analysis*/

%sccs(data=simple, pid=pid, events=seizure1 seizure2, vacc=dose1 dose2 dose3,

startst=start, endst=end);

SAS data set pid _dob start stop nevt offset age season risk riskR1 riskR2 riskV1 riskV2 riskV3 risk1 risk2 risk3 risk4 risk5 risk6 l_off int

1 0 0 5 0 5 1 0 1 0 1 0 1 0 0 0 0 1 0 0 1.60944 1

1 0 5 31 1 26 1 0 0 0 0 0 0 0 0 0 0 0 0 0 3.2581 1

1 0 31 34 0 3 1 0 1 1 0 0 0 1 0 0 0 0 1 0 1.09861 1

1 0 34 36 0 2 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0.69315 1

1 0 36 44 0 8 1 0 1 0 1 0 0 1 0 0 0 0 0 1 2.07944 1

1 0 44 60 0 16 1 0 0 0 0 0 0 0 0 0 0 0 0 0 2.77259 1

2 0 0 5 0 5 1 0 0 0 0 0 0 0 0 0 0 0 0 0 1.60944 1

2 0 5 8 0 3 1 0 1 1 0 1 0 0 1 0 0 0 0 0 1.09861 1

2 0 8 10 0 2 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0.69315 1

2 0 10 18 0 8 1 0 1 0 1 1 0 0 0 1 0 0 0 0 2.07944 1

2 0 18 39 0 21 1 0 0 0 0 0 0 0 0 0 0 0 0 0 3.04452 1

2 0 39 42 0 3 1 0 1 1 0 0 1 0 0 0 1 0 0 0 1.09861 1

2 0 42 44 1 2 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0.69315 1

2 0 44 52 0 8 1 0 1 0 1 0 1 0 0 0 0 1 0 0 2.07944 1

2 0 52 60 0 8 1 0 0 0 0 0 0 0 0 0 0 0 0 0 2.07944 1

3 0 0 46 1 46 1 0 0 0 0 0 0 0 0 0 0 0 0 0 3.82864 1

3 0 46 49 0 3 1 0 1 1 0 1 0 0 1 0 0 0 0 0 1.09861 1

3 0 49 51 0 2 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0.69315 1

3 0 51 59 0 8 1 0 1 0 1 1 0 0 0 1 0 0 0 0 2.07944 1

3 0 59 60 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1

4 0 0 5 0 5 1 0 0 0 0 0 0 0 0 0 0 0 0 0 1.60944 1

4 0 5 8 1 3 1 0 1 1 0 1 0 0 1 0 0 0 0 0 1.09861 1

4 0 8 10 0 2 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0.69315 1

4 0 10 18 0 8 1 0 1 0 1 1 0 0 0 1 0 0 0 0 2.07944 1

4 0 18 29 0 11 1 0 0 0 0 0 0 0 0 0 0 0 0 0 2.3979 1

4 0 29 32 1 3 1 0 1 1 0 0 1 0 0 0 1 0 0 0 1.09861 1

4 0 32 34 0 2 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0.69315 1

4 0 34 42 0 8 1 0 1 0 1 0 1 0 0 0 0 1 0 0 2.07944 1

4 0 42 60 0 18 1 0 0 0 0 0 0 0 0 0 0 0 0 0 2.89037 1

Sas Code to Run the Analysis

/* Perform the case series analysis */

%poisreg(data=wk_sccs,y=nevt,covar=int riskr1

riskr2, offset=offset

,elim=pid,prntyn=Y,title="Seizure and DTP -

All events");

SAS Output

Seizure and MMR - All events

Wald 95% Confidence Limits

Exp 95% Confidence Limits

Parameter Estimate Standard Error Lower Upper Chi-square Pr>ChiSq

Exp Estimate Lower Upper

INT -3.6 0.8 -5.2 -2.0 18.5 <.0001 0.0 0.0 0.1

RISKR1 1.8 0.9 -0.1 3.6 3.6 0.1 5.9 0.9 36.8

RISKR2 -19.0 8182.6 -16056.7 16018.7 0.0 1.0 0.0 0.0 .