Bioequivalence and Bioavailability Forum • Variance components

Variance components – Proc mixed [Software]

posted by Helmut – Vienna, Austria, 2014-02-03 15:14 (4503 d 15:46 ago) – Posting: # 12323
Views: 32,570

Dear all,

❝ This is mindblowing. I can't say that I understand in any way, but it is clear that the unbounded (=unfiddled, native and pure) optimisation analysis results in the same residual as the all-fixed lm/anova.

I followed Yung-jin’s suggestions; comes up with 1.78 mio hits. Amazing this one – especially the “ways out” mentioned on page 130.

❝ An agonising choice indeed.

Yep.

❝ Why care about between-Vars in a 2,2,2-BE?

The only possible reason I can imagine: The cross-over turned out to be not such a good idea and you want to plan the next study in a parallel design. Then you would need the total (pooled) CV for sample size estimation. The common formula

\(CV_p\% = 100\sqrt{e^{(MS_s+MS_e)/2}-1}\)

would “work”, but result in values smaller than CV_intra. Forget it.

           MSe       MSs    CVintra CVinter CVpooled

Cmax    0.0178034 0.0236397  13.40%  5.41%   14.47%

AUCt    0.0332878 0.0211136  18.40%   NA     16.61%

AUCinf  0.0311744 0.0188434  17.79%   NA     15.91%

❝ Why not just do the anova, fetch the residual, calculate a CI on basis of it…

Sure.

❝ …and punch any guy who asks about betweens hard in the face?

That’s Zan’s business.

❝ I wonder how the PK-workgroup at EMA would deal with this.

Not a problem for them, I guess. Doesn’t appear in their mandatory all fixed effects model (PHX) or Proc GLM. For the rest of the world (if running Proc MIXED) I would go with the UNBOUND option (see Detlew’s post). But – hey! – that’s not the code given in FDA’s guidances. ;-)

Reading a lot of stuff it’s evident that the restriction to ≥0 results in biased estimates. With Yung-jin’s data set the resulting CI turned out to be liberal. Keeping patient’s risk in mind that’s not a good idea. Is the unrestricted method (accepting negative variances) always conservative? I think so, but I’m lacking the intellectual horsepower to prove it.

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Helmut Schütz

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Complete thread:

How to calculate intersubject variability in PHX WinNonlin zan 2014-01-29 23:58 [Software]
- Negative variance component Helmut 2014-01-30 01:16
  - Negative variance component zan 2014-01-30 18:11
  - Negative variance component zan 2014-01-31 00:16
    - Negative variance component ElMaestro 2014-01-31 08:20
    - Negative variance component yjlee168 2014-01-31 10:26
      - Example data set Helmut 2014-02-01 16:03
        
        Example data set yjlee168 2014-02-01 17:40
        
        PHX build 6.3.0.395 / 6.4.0.511 Helmut 2014-02-02 02:04
        
        PHX build 6.3.0.395 / 6.4.0.511 yjlee168 2014-02-02 07:54
    - Negative variance component ElMaestro 2014-02-01 16:31
      - Negative variance component yjlee168 2014-02-01 17:47
        
        Just thinking loud ElMaestro 2014-02-01 19:02
        
        All models are wrong… Helmut 2014-02-02 02:31
        
        another book for linear model yjlee168 2014-02-02 08:07
      - References Helmut 2014-02-02 02:19
        
        References ElMaestro 2014-02-02 09:56
    - Negative variance component – Chow/Liu d_labes 2014-02-03 09:02
      - Negative variance component – Chow/Liu ElMaestro 2014-02-03 10:22
        
        Variance components – Proc mixed d_labes 2014-02-03 11:58
        
        Variance components – Proc mixed ElMaestro 2014-02-03 12:58
        
        Variance components – Proc mixed 90% CIs d_labes 2014-02-03 13:16
        Variance components – Proc mixedHelmut 2014-02-03 14:14
        
        FDA code for non-replicate crossover? d_labes 2014-02-03 15:54
        
        Proc GLM rulez Helmut 2014-02-03 16:16
        
        Variance components – Proc mixed yjlee168 2014-02-03 20:43
        
        NOBOUND Helmut 2014-02-03 22:08
      - lm() or lme() for 2x2x2 study design? yjlee168 2014-02-03 20:22
        
        lm() or lme() for 2x2x2 study design? ElMaestro 2014-02-03 22:11
        
        lm() or lme() for 2x2x2 study design? yjlee168 2014-02-04 13:09
        
        bear for 2x2x2 study with negative variance components yjlee168 2014-02-05 19:12