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The SEQTEST Procedure

Example 78.5 Comparing Two Proportions with a Log Odds Ratio Test

This example compares two binomial proportions by using a log odds ratio statistic in a five-stage group sequential test. A clinic is studying the effect of vitamin C supplements in treating flu symptoms. The study consists of patients in the clinic who exhibit the first sign of flu symptoms within the last 24 hours. These patients are randomly assigned to either the control group (which receives placebo pills) or the treatment group (which receives large doses of vitamin C supplements). At the end of a five-day period, the flu symptoms of each patient are recorded.

Suppose that you know from past experience that flu symptoms disappear in five days for of patients who experience flu symptoms. The clinic would like to detect a symptom disappearance with a high probability. A test that compares the proportions directly specifies the null hypothesis with a one-sided alternative and a power of at , where and are the proportions of symptom disappearance in the treatment group and control group, respectively. An alternative trial tests an equivalent hypothesis by using the log odds ratio statistics:

Then the null hypothesis is and the alternative hypothesis is

The following statements invoke the SEQDESIGN procedure and request a five-stage group sequential design by using an error spending function method for normally distributed statistics. The design uses a two-sided alternative hypothesis with early stopping to reject the null hypothesis .

   ods graphics on;
   proc seqdesign altref=0.441833
                  boundaryscale=mle
                  ;
      OneSidedErrorSpending: design method=errfuncpow
                                    nstages=5
                                    alt=upper
                                    stop=accept
                                    alpha=0.025;
      samplesize model=twosamplefreq( nullprop=0.6 test=logor);
   ods output Boundary=Bnd_CSup;
   run;
   ods graphics off;

The ODS OUTPUT statement with the BOUNDARY=BND_CSUP option creates an output data set named BND_CSUP which contains the resulting boundary information for the subsequent sequential tests.

The "Design Information" table in Output 78.5.1 displays design specifications and derived statistics. With the specified alternative reference, the maximum information is derived.

Output 78.5.1 Design Information

The SEQDESIGN Procedure

Design: OneSidedErrorSpending

Design Information
Statistic Distribution	Normal
Boundary Scale	MLE
Alternative Hypothesis	Upper
Early Stop	Accept Null
Method	Error Spending
Boundary Key	Both
Alternative Reference	0.441833
Number of Stages	5
Alpha	0.025
Beta	0.1
Power	0.9
Max Information (Percent of Fixed Sample)	104.6166
Max Information	56.30934
Null Ref ASN (Percent of Fixed Sample)	57.21399
Alt Ref ASN (Percent of Fixed Sample)	102.1058

The "Boundary Information" table in Output 78.5.2 displays information level, alternative reference, and boundary values at each stage. With the specified BOUNDARYSCALE=MLE option, the procedure displays the output boundaries in terms of the MLE scale.

With the specified ODS GRAPHICS ON statement, a detailed boundary plot with the rejection and acceptance regions is displayed by default, as shown in Output 78.5.3.

Output 78.5.3 Boundary Plot

With the SAMPLESIZE statement, the "Sample Size Summary" table in Output 78.5.4 displays the parameters for the sample size computation.

The "Sample Sizes" table in Output 78.5.5 displays the required sample sizes for the group sequential clinical trial.

Thus, new patients are needed in each group at stages , , and , and new patients are needed in each group at stages and . Suppose that patients are available in each group at stage . Output 78.5.6 lists the observations in the data set count_1.

The TrtGrp variable is a grouping variable with the value Control for a patient in the placebo control group and the value C_Sup for a patient in the treatment group who receives vitamin C supplements. The Resp variable is an indicator variable with the value for a patient without flu symptoms after five days and the value for a patient with flu symptoms after five days.

The following statements use the LOGISTIC procedure to compute the log odds ratio statistic and its associated standard error at stage :

   proc logistic data=CSup_1 descending;
      class TrtGrp / param=ref;
      model Resp= TrtGrp;
      ods output ParameterEstimates=Parms_CSup1;
   run;

The DESCENDING option is used to reverse the order for the response levels, so the LOGISTIC procedure is modeling the probability that Resp = .

The following statements create and display (in Output 78.5.7) the data set for the log odds ratio statistic and its associated standard error:

   data Parms_CSup1;
      set Parms_CSup1;
      if Variable='TrtGrp' and ClassVal0='C_Sup';
      _Scale_='MLE';
      _Stage_= 1;
      keep _Scale_ _Stage_ Variable Estimate StdErr;
   run;
   
   proc print data=Parms_CSup1;
      title 'Statistics Computed at Stage 1';
   run;

The following statements invoke the SEQTEST procedure to test for early stopping at stage :

   ods graphics on;
   proc seqtest Boundary=Bnd_CSup
                Parms(Testvar=TrtGrp)=Parms_CSup1
                boundaryadj=errfuncpow
                boundarykey=both
                boundaryscale=mle
                ;
   ods output test=Test_CSup1; run; 
   ods graphics off; 

The BOUNDARY= option specifies the input data set that provides the boundary information for the trial at stage , which was generated in the SEQDESIGN procedure. The PARMS=PARMS_CSUP1 option specifies the input data set PARMS_CSUP1 that contains the test statistic and its associated standard error at stage , and the TESTVAR=TRTGRP option identifies the test variable TRTGRP in the data set.

The ODS OUTPUT statement with the TEST=TEST_CSUP1 option creates an output data set named TEST_CSUP1 which contains the updated boundary information for the test at stage . The data set also provides the boundary information that is needed for the group sequential test at the next stage.

The "Design Information" table in Output 78.5.8 displays design specifications. With the specified BOUNDARYKEY=BOTH option, the information levels and boundary values at future stages are modified to maintain both the and levels.

The "Test Information" table in Output 78.5.9 displays the boundary values for the test statistic with the specified MLE scale. Since the information level at stage is derived from the PARMS= data set and other information levels are not specified, equal increments are used at remaining stages. At stage , the MLE statistic is greater than the corresponding upper boundary value , so the sequential test continues to the next stage.

With the specified ODS GRAPHICS ON statement, a boundary plot with the boundary values and test statistics is displayed, as shown in Output 78.5.10. As expected, the test statistic is in the continuation region.

Output 78.5.10 Sequential Test Plot

The following statements use the LOGISTIC procedure to compute the log odds ratio statistic and its associated standard error at stage :

   proc logistic data=CSup_2 descending;
      class TrtGrp / param=ref;
      model Resp= TrtGrp;
      ods output ParameterEstimates=Parms_CSup2;
   run;

The following statements create and display (in Output 78.5.11) the data set for the mean positive response and its associated standard error at stage :

   data Parms_CSup2;
      set Parms_CSup2;
      if Variable='TrtGrp' and ClassVal0='C_Sup';
      _Scale_='MLE';
      _Stage_= 2;
      keep _Scale_ _Stage_ Variable Estimate StdErr;
   run;
   proc print data=Parms_CSup2;
      title 'Statistics Computed at Stage 2';
   run;

The following statements invoke the SEQTEST procedure to test for early stopping at stage :

   proc seqtest Boundary=Test_CSup1
                Parms( testvar=TrtGrp)=Parms_CSup2
                boundaryadj=errfuncpow
                boundarykey=both
                boundaryscale=mle
                ;
   ods output Test=Test_CSup2;
   run;

The BOUNDARY= option specifies the input data set that provides the boundary information for the trial at stage , which was generated by the SEQTEST procedure at the previous stage. The PARMS= option specifies the input data set that contains the test statistic and its associated standard error at stage , and the TESTVAR= option identifies the test variable in the data set.

The ODS OUTPUT statement with the TEST=CSUP_LDL2 option creates an output data set named CSUP_LDL2 which contains the updated boundary information for the test at stage . The data set also provides the boundary information that is needed for the group sequential test at the next stage.

The "Test Information" table in Output 78.5.12 displays the boundary values for the test statistic with the specified MLE scale. The test statistic is greater than the corresponding upper boundary value , so the sequential test continues to the next stage.

Similar results are found at stages and stage , so the trial continues to the final stage. The following statements use the LOGISTIC procedure to compute the log odds ratio statistic and its associated standard error at stage :

   proc logistic data=CSup_5 descending;
      class TrtGrp / param=ref;
      model Resp= TrtGrp;
      ods output ParameterEstimates=Parms_CSup5;
   run;

The following statements create and display (in Output 78.5.13) the data set for the log odds ratio statistic and its associated standard error at stage :

   data Parms_CSup5;
      set Parms_CSup5;
      if Variable='TrtGrp' and ClassVal0='C_Sup';
      _Scale_='MLE';
      _Stage_= 5;
      keep _Scale_ _Stage_ Variable Estimate StdErr;
   run;
   
   proc print data=Parms_CSup5;
      title 'Statistics Computed at Stage 5';
   run;

The following statements invoke the SEQTEST procedure to test for the hypothesis at stage :

   ods graphics on;
   proc seqtest Boundary=Test_CSup4
                Parms( testvar=TrtGrp)=Parms_CSup5
                boundaryadj=errfuncpow
                boundaryscale=mle
                cialpha=.025
                rci
                plots=rci
                ;
   run;
   ods graphics off;

The BOUNDARY= option specifies the input data set that provides the boundary information for the trial at stage , which was generated by the SEQTEST procedure at the previous stage. The PARMS= option specifies the input data set that contains the test statistic and its associated standard error at stage , and the TESTVAR= option identifies the test variable in the data set. With the default BOUNDARYKEY=ALPHA option, the boundary value at stage is derived to maintain the level.

The "Test Information" table in Output 78.5.14 displays the boundary values for the test statistic with the specified MLE scale. The test statistic is less than the corresponding upper boundary , so the sequential test stops to accept the null hypothesis. That is, there is no reduction in duration of symptoms for the group receiving vitamin C supplements.

The "Test Plot" displays boundary values of the design and the test statistics, as shown in Output 78.5.15. It also shows that the test statistic is in the "Acceptance Region" at the final stage.

Output 78.5.15 Sequential Test Plot

After a trial is stopped, the "Parameter Estimates" table in Output 78.5.16 displays the stopping stage, parameter estimate, unbiased median estimate, confidence limits, and the -value under the null hypothesis . As expected, the -value is not significant at level and the lower confidence limit is less than the value . The -value, unbiased median estimate, and confidence limits depend on the ordering of the sample space , where is the stage number and is the standardized statistic.

Since the test is accepted at stage , the -value computed by using the default stagewise ordering can be expressed as

where is the test statistic at stage , is a standardized normal variate at stage , and is the upper boundary value in the standardized scale at stage .

With the RCI option, the "Repeated Confidence Intervals" table in Output 78.5.17 displays repeated confidence intervals for the parameter. For a one-sided test with an upper alternative hypothesis, since the upper acceptance repeated confidence limit at the final stage is less than the alternative reference , the null hypothesis is accepted.

With the PLOTS=RCI option, the "Repeated Confidence Intervals Plot" displays repeated confidence intervals for the parameter, as shown in Output 78.5.18. It shows that the upper acceptance repeated confidence limit at the final stage is less than the alternative reference . This implies that the study accepts the null hypothesis at the final stage.

Output 78.5.18 Repeated Confidence Intervals Plot

Copyright © 2009 by SAS Institute Inc., Cary, NC, USA. All rights reserved.