No convergence in JMP and Phoenix WinNonlin [Regulatives / Guidelines]
❝ ❝ 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 was right about failing in JMP and Phoenix WinNonlin.

Sorry I can’t disclose the data set. Naïve pooling was performed. Deficiency letter by the MHRA in summer 2016:
The applicant should present estimates and 95% confidence interval for the difference between the Test and the Reference product on a ratio scale from ANOVA model, that reflects the design of the study, with terms for Group, Sequence, Sequence * Group, Subject (Sequence * Group), Period (Group), Treatment as fixed effects.
Note that this is the FDA’s model 2 with fixed effects. Why the 95% CI instead of the 90% CI was required is another story. The data set (subjects fixed) did not converge in JMP. Switched to random and all was good. Was accepted by the MHRA’s assessor.Phoenix showed me the finger with the fixed effect
Subject(Sequence*Group)
in Model 1In model 2 I got the same warning as above but these results:
Partial Sum of Squares
Hypothesis DF SS MS F_stat P_value
---------------------------------------------------------------------------
Group 2 0.0758837 0.0379418 3.48232 0.0381
Sequence 1 0.0708455 0.0708455 6.50224 0.0138
Group*Sequence 2 0.145263 0.0726313 6.66614 0.0026
Sequence*Group*Subject 50 7.67886 0.153577 14.0954 0.0000
Group*Period 3 0.0111135 0.0037045 0.340001 0.7965
Treatment 1 0.144129 0.144129 13.2283 0.0006
Error 52 0.566569 0.0108956
Partial Tests of Model Effects
Hypothesis Numer_DF Denom_DF F_stat P_value
--------------------------------------------------------------
Group 2 52 3.48232 0.0381
Sequence 1 52 6.50224 0.0138
Group*Sequence 2 52 6.66614 0.0026
Sequence*Group*Subject 50 52 14.0954 0.0000
Group*Period 3 52 0.340001 0.7965
Treatment 1 52 13.2283 0.0006
No problems in R.
Model 1:
Analysis of Variance Table
Response: log(Cmax)
Df Sum Sq Mean Sq F value Pr(>F)
group 2 0.078270 0.03913490 3.54171 0.03643331 *
sequence 1 0.073106 0.07310604 6.61611 0.01312377 *
treatment 1 0.141465 0.14146461 12.80257 0.00078035 ***
group:period 3 0.011114 0.00370450 0.33526 0.79988452
group:sequence 2 0.145263 0.07263128 6.57314 0.00292116 **
group:treatment 2 0.014083 0.00704174 0.63728 0.53296911
group:sequence:subject 50 7.678856 0.15357712 13.89875 < 2.22e-16 ***
Residuals 50 0.552485 0.01104970
Model 2:Analysis of Variance Table
Response: log(Cmax)
Df Sum Sq Mean Sq F value Pr(>F)
group 2 0.078270 0.03913490 3.59182 0.03458136 *
sequence 1 0.073106 0.07310604 6.70971 0.01241215 *
treatment 1 0.141465 0.14146461 12.98370 0.00070289 ***
group:period 3 0.011114 0.00370450 0.34000 0.79647341
group:sequence 2 0.145263 0.07263128 6.66614 0.00264706 **
group:sequence:subject 50 7.678856 0.15357712 14.09540 < 2.22e-16 ***
Residuals 52 0.566569 0.01089555
![[image]](img/uploaded/image4.gif)
Bioequivalence
module, which sits on top of Linear Mixed Effects
. When I send the data directly to Linear Mixed Effects
(all fixed) no error, no warning, nada. CI identical to the one from R to 12 significant digits.Conclusion: Bug in Phoenix WinNonlin’s
Bioequivalence
module.![[image]](img/uploaded/image75.png)
Bioequivalence
takes more than ten hours and sucks up almost my entire 16 GB RAM (memory leak?). Direct execution in Linear Mixed Effects
takes five minutes (max. RAM consumption 175 MB).Much slower than R, which takes five seconds for model 1, model 2, model 3 (for each group), and model 3 (pooled).
I was wrong. Has nothing to do with unbalanced sequences and/or unequal group sizes.
Dif-tor heh smusma 🖖🏼 Довге життя Україна!
![[image]](https://static.bebac.at/pics/Blue_and_yellow_ribbon_UA.png)
Helmut Schütz
![[image]](https://static.bebac.at/img/CC by.png)
The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
Complete thread:
- Russian «Экспертами» and their hobby Helmut 2017-04-29 00:46 [Regulatives / Guidelines]
- 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 answers Helmut 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
- loosing specificity due to low sensitivity mittyri 2017-05-08 23:28
- 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
- IMP handling mittyri 2017-05-08 23:40
- Loss in power Helmut 2017-05-14 17:22
- Simulations Helmut 2017-05-05 14:38
- Some answers ElMaestro 2017-05-02 09:04
- No convergence in JMP and Phoenix WinNonlinHelmut 2017-05-25 15:26
- Ouch?!??? ElMaestro 2017-05-25 16:24
- Some answers Helmut 2017-05-02 01:10
- Let’s forget the Group-by-Treatment interaction, please! ElMaestro 2017-05-01 16:19
- Let’s forget the Group-by-Treatment interaction, please! Helmut 2017-04-30 13:54
- 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
- be careful with mixed models mittyri 2017-05-02 17:53
- 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
- regulators convinced by science? Beholder 2018-01-10 17:14
- help us to stop it, please... Astea 2018-01-10 12:09
- Trying your model for EEU Helmut 2018-01-05 00:06
- Belarus = member of the EEU Helmut 2018-01-04 13:08
- Russian «Экспертами» following the EEU GLs Beholder 2017-05-24 22:37
- Low power of Group-by-Treatment interaction mittyri 2017-04-29 22:57