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Using SAS for the self-controlled case series method.

The SAS macros are written to run under SAS v8.0 or above.

The macros

There are two main macros for fitting the self-controlled case series method (both parametric and semi-parametric) in SAS:

• Sccs.sas: This macro creates the dataset for case series analysis

• Poisreg.sas: This macro fits a Poisson (case series) regression model with the possibility to eliminate a factor from the model, to reduce the computation time (similar to ELIMINATE in GLIM or the GROUPS option to MODEL in GENSTAT). Estimation is done using Newton-Raphson.

A third macro (element.sas) is a small macro to create macro variables in SAS from a list of variable names. This macro is used in the above main macros.

These macros can be read into SAS using the %INCLUDE statement (change the directory according to the location of the macros):

%INCLUDE “c:\temp\sccs\sccs.sas”;

%INCLUDE “c:\temp\sccs\poisreg.sas”;

%INCLUDE “c:\temp\sccs\element.sas”;

The following global parameters should be specified before calling the macros sccs.sas or poisreg.sas:

• agerange: e.g., 0 730 (from 0 to 730 days of age). The observation period for a subject will be determined from agerange and the variables startst and endst, specified in sccs.sas

• risk: risk periods after vaccination, e.g., 0 6 7 14 (first period from 0 to 6 days and a second period from 7 to 14 days)

• age: age cutpoints for age covariates in model,e.g., 90 180 270 360. Leave empty if no age categories are used. This global macrovariable will not be used in a semiparametric model

• season: season cutpoints for season covariates in model,e.g., 31MAR 30JUN 30SEP 31DEC. Leave empty if no season categories are used

• semi: put this parameter equal to Y if a semiparametric analysis needs to be fitted. In this case, the global macrovariable age will not be used. Further, the output dataset wk_sccs will not contain the variables start, offset and l_off because these are irrelevant

The macro sccs.sas has the following parameters:

Note that dates can be specified on the age scale (i.e., number of days since birth) or on the calendar scale (i.e., SAS numeric date value: number of days since 01JAN1960)

• data: Input dataset which contains the variables used in the analysis in cross-sectional format (i.e., only one row per subject)

• pid: variable in dataset data that contains the subject ID number

• dob_raw: variable (numeric) in dataset data that contains the date of birth (on the calendar scale). Leave this parameter empty if the dates of events and vaccinations are specified on the age scale

• events: variables (numeric) in dataset data that contain the dates (on age or calendar scale) for the different events. If events are specified on calendar scale, dob_raw should be specified

• vacc: variables (numeric) in dataset data that contain the dates (on age or calendar scale) for the different vaccinations. If vaccinations are specified on calendar scale, dob_raw should be specified

• startst: variable (numeric) in dataset data that contains the study start for each individual (on age or calendar scale)

• endst: variable (numeric) in dataset data that contains the study end for each individual (on age or calendar scale)

• covars: covariates in dataset data that should be put in the output dataset such that they can be used in the analysis

• overlap: Indicator variable to allow overlapping risk intervals (Default=N)

• outdata: Output dataset (Default=wk_sccs)

The macro sccs.sas outputs a dataset (default name=wk_sccs) which contains several rows per subject (one for each interval) and the following parameters:

• Variable containing subject ID number (same as in pid)

• Variable containing date of birth (same as in dob_raw)

• start: beginning of each interval (on age scale). Not available when a semi-parametric model is used

• stop: end of each interval (on age scale). If a semi-parametric model is used, this variable contains the timings at which events occurred

• offset: difference between start and stop. Not available when a semi-parametric model is used

• l_off: natural log of offset. Not available when a semi-parametric model is used

• nevt: number of events per interval

• age: class variable which contains the age category for each interval (specified in global macrovariable age)

• season: class variable which contains the season category for each interval (specified in global macrovariable season)

• Several indicator variables for the risk periods

• Risk = 1 if the interval lies in a risk period (over all doses and all risk periods)

• RiskVi = 1 if the interval lies in a risk period after dose i

• RiskRj = 1 if the interval lies in a jth risk period (over all doses)

• Riskk = 1 if the interval lies in the kth risk period (each risk period after each dose has a separate indicator variable)

• When overlap=Y, overlapping intervals are possible and these variables should be used with caution

• int: intercept (equal to 1)

• Different covariates specified in covars

The macro poisreg.sas has the following parameters:

• data: input dataset (e.g., wk_sccs from macro sccs.sas)

• y: Response variable for the Poisson regression (e.g., nevt)

• covar: Covariates in the model that are not in class or elim

• class: Class variables in model (e.g., age)

• elim: Variable that should be eliminated from the model. This variable is in the model but is not estimated (e.g., pid)

• offset: Offset variable (Leave empty when using a semiparametric model)

• beta0: Starting values. If empty, all parameters are put equal to 0

• outdata: dataset with parameter estimates (DEFAULT =out)

• eps: convergence criteria (DEFAULT=1e-08), the maximum of the absolute value of the first derivative is calculated, if smaller than eps, the algorithm stops

• alpha: significance level for confidence interval (DEFAULT=0.05)

• prntyn: print results (DEFAULT=Y)

• covb: if Y, print variance-covariance matrix and save into SAS dataset _covb (DEFAULT=N)

The following examples show how the macros can be used for fitting the self-controlled case series analysis in SAS.

In each of the examples, three global macro variables are defined which contain the following directories:

• the directory containing the macros (macdir)

• the directory where the output will be stored (outdir)

• and the directory with the input datasets (indir)

These directories are only used in the different batches and not in the macros for analysis.

MMR and meningitis in Oxford example

The SAS batch oxford.sas contains the case series analysis of the Oxford dataset from Miller et al. (The Lancet, 1993;341:979-982). The results can be found in oxford.lst.

Additional details and comments are given in the SAS program itself.

Both the original analysis as well as the semi-parametric analysis are illustrated.

oxford_cov.sas contains the case series analysis of the Oxford dataset, displaying the variance-covariance matrix. The option COVB in PROC GENMOD to has also been included to compare the output. The covariance matrix is saved in a matrix _covb and printed when parameter covb=Y.

MMR and ITP examples

The SAS batch ITP and MMR.sas contains the case series analysis of the ITP and MMR dataset from Miller et al. (Archives of Disease in Childhood 2001;84:227-229). The results can be found in ITP and MMR.lst.

The data is imported from itp.dat using the INFILE statement.

The SAS program contains

• the analyses on all events (multiple events per subject),

• the analysis using the first event for each subject only and

• the semi-parametric analysis

OPV and IS examples

The SAS batch IS and OPV.sas contains the case series analysis of the IS and OPV dataset from Andrews et al. (European Journal of Epidemiology 2001; 17:701-706). The results can be found in IS and OPV.lst.

The data is imported from intus.dat using the INFILE statement.

The SAS program contains the different analyses that are performed in the tutorial:

• Analysis 1: Standard analysis, including only Dose 3 (with and without gender interaction)

• Analysis 2: Observation period starts at Dose 3

• Analysis 3: pre-Dose 3 period

• Analysis 4: All doses with no dose effect

• Analysis 5: All doses with dose effect

In addition, the semi-parametric analysis of the Analysis 1 is also shown.