Bioequivalence and Bioavailability Forum • Some answers

Some answers [Regulatives / Guidelines]

posted by Helmut – Vienna, Austria, 2017-05-02 03:10 (2541 d 13:04 ago) – Posting: # 17287
Views: 30,468

Hi ElMaestro,

❝ M: "Is it possible to prove that with sims?" - what is it you want to prove? Can you formulate it plain and simple? Sims are totally possible, I just need to figure out the equations, as well as have a purpose. :-D

Not M but answering anyway.
The idea behind the Group-by-Treatment interaction is that the T/R in one group is different from the other (i.e., we have collinearity with a “hidden” variable). Therefore, simulate a group of subjects with T/R 0.95 and another one with T/R 0.95^–1 (CV ad libitum). Merge them to get a “study”. Run model 1 and check the p-value of the Group-by-Treatment interaction. With the simple model you should expect T/R 1.

❝ H: "It should be noted that in rare cases (e.g., extremely unbalanced sequences) the fixed effects model gives no solution and the mixed effects model has to be used." - a realistic linear model will have a single analytical solution unless you make a specification error. Imbalance would not affect that, please describe where/how you came a cross a fit which failed with the lm.

I had one data set where the fixed effects model in Phoenix/WinNonlin showed me the finger. Same in JMP (“poor man’s SAS”). Have to check again.

❝ M+H: FDA are also fitting subject as fixed even when using the random statement in PROC GLM. Some of them just have not realised it :-)

True.

❝ H: "(...) seemingly ~10% of studies show a significant group-by-treatment interaction. " - this is expected by chance. You apply a 10% significance level. By chance 10% will then be significant.

Exactly. That’s the idea of assessing real studies. If there would be a true Group-by-Treatment interaction (i.e., not random alone) we could expect significant results in >10% of studies. This is what I have so far (I hope that the Canadians will come up with another ~100).

[image]

Min. 1st Qu. Median Mean 3rd Qu. Max. 0.0012 0.2693 0.5573 0.5206 0.7725 0.9925

[image]

Min. 1st Qu. Median Mean 3rd Qu. Max. 0.00376 0.28731 0.47584 0.49187 0.71717 0.98837

86 studies (60 analytes), 85 data sets for AUC and 86 for C_max, sample sizes 15 to 74, two to four groups, median interval between groups three days. Significant Group-by-Treatment interaction in 8.24% (AUC) and 12.79% (C_max) of data sets. Hence, I guess it is a bloody myth.

❝ (and by the way: Which denominator in F did you apply; within or between?)

Numerator DF = Groups – 1
Denominator DF = Subjects – 2 × Groups

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Complete thread:

Russian «Экспертами» and their hobby Helmut 2017-04-29 00:46
- Low power of Group-by-Treatment interaction mittyri 2017-04-29 22:57
  - Let’s forget the Group-by-Treatment interaction, please! Helmut 2017-04-30 13:54
    - Let’s forget the Group-by-Treatment interaction, please! ElMaestro 2017-05-01 16:19
      - Some answersHelmut 2017-05-02 01:10
        
        Some answers ElMaestro 2017-05-02 09:04
        
        Example Helmut 2017-05-02 12:35
        
        Sensitivity of term? mittyri 2017-05-02 18:29
        
        Simulations Helmut 2017-05-05 14:38
        
        loosing specificity due to low sensitivity mittyri 2017-05-08 23:28
        
        loosing specificity due to low sensitivity Helmut 2017-05-09 00:55
        
        Loss in power Helmut 2017-05-06 17:31
        Interval between groups Helmut 2017-05-08 19:02
        
        IMP handling mittyri 2017-05-08 23:40
        
        IMP handling Helmut 2017-05-09 01:08
        
        Loss in power Helmut 2017-05-14 17:22
      - No convergence in JMP and Phoenix WinNonlin Helmut 2017-05-25 15:26
        
        Ouch?!??? ElMaestro 2017-05-25 16:24
- Russian «Экспертами» and their hobby Artem Gusev 2017-05-02 16:13
  - be careful with mixed models mittyri 2017-05-02 17:53
    - be careful with mixed models Artem Gusev 2017-05-03 11:02
  - p-value(s) in model 2 Helmut 2017-05-05 14:48
- Russian «Экспертами» following the EEU GLs Helmut 2017-05-24 20:17
  - Russian «Экспертами» following the EEU GLs Beholder 2017-05-24 22:37
    - Penalty for carelessness mittyri 2017-05-25 08:52
    - Russian «Экспертами» following the EEU GLs Beholder 2017-05-25 10:43
  - Russian «Экспертами» following the EEU GLs Mikalai 2018-01-04 10:43
    - Belarus = member of the EEU Helmut 2018-01-04 13:08
      - Belarus = member of the EEU Mikalai 2018-01-04 19:49
      - Trying your model for EEU mittyri 2018-01-04 22:04
        
        Trying your model for EEU Helmut 2018-01-05 00:06
        
        help us to stop it, please... Astea 2018-01-10 12:09
        
        help us to stop it, please... Beholder 2018-01-10 12:49
        regulators convinced by science? d_labes 2018-01-10 15:15
        
        regulators convinced by science? Beholder 2018-01-10 17:14
        
        Чёрт побери! d_labes 2018-01-10 18:53
        
        regulators convinced by science? Astea 2018-01-10 19:10
        
        Excuse me d_labes 2018-01-10 20:18
        
        Excuse me Astea 2018-01-10 20:38