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Back to the forum  2018-07-16 07:08 CEST (UTC+2h)
Obinoscopy
Junior

Nigeria,
2018-06-25 19:48

Posting: # 18961
Views: 369
 

 ANOVA Model: Carry Over Factor vs Sequence Factor [General Sta­tis­tics]

Hi guys,

Was reading the textbook: Design and Analysis of Bioavailability and Bioequivalence Studies by Shein-Chung Chow and Jen-pei Liu. A nice book for a beginner like me (although I'm still looking for a much more simplified book).

However I noticed they only considered carryover factor, formulation factor and the period factor in the ANOVA model. I don't get to see the sequence factor as stipulated in the WHO guidelines.

Could it be that the Carryover factor is one and same as the Sequence factor? I'd appreciate is someone could explain this to me as if I were a kindergarten pupil ;-).

Regards,

Scopy
Helmut
Hero
avatar
Homepage
Vienna, Austria,
2018-06-26 12:38

@ Obinoscopy
Posting: # 18966
Views: 276
 

 ANOVA Model: Factors

Hi Scopy,

» […] (although I'm still looking for a much more simplified book).

Maybe Hauschke et al.1

» However I noticed they only considered carryover factor, formulation factor and the period factor in the ANOVA model. I don't get to see the sequence factor as stipulated in the WHO guidelines.
» Could it be that the Carryover factor is one and same as the Sequence factor?

Exactly. They are synonyms. An equal carryover does not hurt (will not bias the treatment effect). However, an unequal one will.

» I'd appreciate is someone could explain this to me as if I were a kindergarten pupil ;-).

I’ll try. Which factors do we have in a 2×2 crossover? Subjects2 (1–n), treatments (T and R), periods (1 and 2), and sequences (RT and TR). Actually we have two groups of subjects, one is treated in the order RT and the other in the order TR. Hence, in the statistical literature (not about BE) sometimes you find ‘group’ instead of ‘sequence’… Let’s explore which effects will influence the treatment effect. Simple example: Untransformed data, true values of the reference 100 and of the test 95, balanced sequences. Therefore, we can work with unadjusted means.
  • Period effect: 0%
    Sequence (carryover) effects: RT 0%, TR 0%
                           period     sequence
      sequence            1      2      means
         RT             100     95       97.5
         TR              95    100       97.5
    period means         97.5   97.5     97.5
    treatment means  R  100
                     T   95

                   T/R   95.00%

    Unbiased treatment effect in the absence of a period effect.
    Unbiased treatment effect in the presence of equal carryover effects.

  • Period effect: +20%
    Sequence (carryover) effects: RT 0%, TR 0%
                           period     sequence
      sequence            1      2      means
         RT             100    114      107
         TR              95    120      107.5
    period means         97.5  117      107.25
    treatment means  R  110
                     T  104.5

                   T/R   95.00%

    Unbiased treatment effect in the presence of a period effect..
    Unbiased treatment effect in the presence of equal carryover effects.

  • Period effect: +20%
    Sequence (carryover) effects: RT +20%, TR +20%
                           period     sequence
      sequence            1      2      means
         RT             100    133      116.5
         TR              95    140      117.5
    period means         97.5  136.5    117
    treatment means  R  120
                     T  114

                   T/R   95.00%

    Unbiased treatment effect in the presence of a period effect.
    Unbiased treatment effect in the presence of equal carryover effects.

  • Period effect: 0%
    Sequence (carryover) effects: RT +10%, TR +20%
                           period     sequence
      sequence            1      2      means
         RT             100    104.5    102.25
         TR              95    120      107.5
    period means         97.5  112.25   104.875
    treatment means  R  110
                     T   99.75

                   T/R   90.68%

    Biased treatment effect in the presence of unequal carryover effects.
Problems:
  • No method exists to correct the bias if there is a true unequal carryover.
  • A test for unequal carryover has low sensitivity (you may be hit by false positives).
Likely unequal carryover doesn’t exist in a properly designed study (sufficiently long washout). The test should go to the statistical waste bin and is of historic interest only (EMA GL: “A test for carry-over is not considered relevant and no decisions regarding the analysis (e.g. analysis of the first period only) should be made on the basis of such a test.”).


  1. Hauschke D, Steinijans VW, Pigeot I. Bioequivalence Studies in Drug Development: Methods and Applications. New York: Wiley; 2007.
  2. [image]Since subjects are uniquely coded, stating ‘subject(sequence)’ in the model is superfluous. Say subject 1 is in the sequence RT. There is no subject 1 in the sequence TR, right? Using ‘subject(sequence)’ instead of simply ‘subject’ drives ElMaestro’s Silly-O-Meter as far as it will go.
    Try the simple model instead. You will get exactly the same PE and residual error and therefore, the CI as in the model stated in the guidelines. The only difference is that you get rid of the many lines in the software’s output stating just “not estimable” (Phoenix/WinNonlin) or “.” (SAS).

Cheers,
Helmut Schütz
[image]

The quality of responses received is directly proportional to the quality of the question asked. ☼
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Obinoscopy
Junior

Nigeria,
2018-07-01 02:20

@ Helmut
Posting: # 19004
Views: 179
 

 ANOVA Model: Factors

Wow, thanks. You actually made it look as easy as ABC and 123....just like Kindergarten class :-)

I love those examples/illustrations. If only we can have Textbooks on different BE topics with examples/illustrations (both practical examples and hypothetical examples), there will be less than 5% of Type 1 Errors in all BE Studies.

Hope you are coming out with books on BE? I am already on the waiting list.

Scopy
Helmut
Hero
avatar
Homepage
Vienna, Austria,
2018-07-01 12:14

@ Obinoscopy
Posting: # 19005
Views: 171
 

 ANOVA Model: Factors

Hi Scopy,

» I love those examples/illustrations.

THX for the flowers! Two others in this post.

» If only we can have Textbooks on different BE topics with examples/illustrations (both practical examples and hypothetical examples), there will be less than 5% of Type 1 Errors in all BE Studies.

Well, most of the studies I receive for review failed by design. One can’t get the right answer for a wrong question…

» Hope you are coming out with books on BE? I am already on the waiting list.

Sorry (see there).

Cheers,
Helmut Schütz
[image]

The quality of responses received is directly proportional to the quality of the question asked. ☼
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