Second opinion (PHX 6.3) [RSABE / ABEL]

posted by Helmut Homepage – Vienna, Austria, 2013-05-01 14:21 (2976 d 08:07 ago) – Posting: # 10517
Views: 18,326

Hi John,

» For AUCt
» Ratio: 94.7377; 90% CI: 87.4898-102.586

PHX tells me:
Ratio: 94.7377; 90% CI: 87.4898–102.586 [image]
Warning 11091: Newton's algorithm converged with modified Hessian. Output is suspect.
Model may be over-specified. A simpler model could be tried.

PHX after 6 iterations:

Final variance parameter estimates:
           lambda(1,1)_11     0.44268399
           lambda(1,2)_11     0.42362946
           lambda(2,2)_11     0.16237525
Var(Period*Formulation*Subject)_21    0.053010265
Var(Period*Formulation*Subject)_22    0.061648310

» However, Proc Mixed failed to compute the above for ln AUCi

Contrary to SAS PHX ‘succeeded’ for AUCi as well …

Ratio: 95.2967; 90% CI: 88.4014–102.730

… but throws the same warning as above.

» The last output from Proc Mixed on ln AUCi was:
» Covariance Parameter Values At Last Iteration
» Cov Parm   Subject   Group          Estimate
» FA(1,1)    subject                  0.3722
» FA(2,1)    subject                  0.3975
» FA(2,2)    subject                  0.2362
» Residual   subject formulation Ref  0.06248
» Residual   subject formulation Test 0.01460

PHX after 6 iterations:

Final variance parameter estimates:
           lambda(1,1)_11     0.37216022
           lambda(1,2)_11     0.39747315
           lambda(2,2)_11     0.15492894
Var(Period*Formulation*Subject)_21    0.0624828
Var(Period*Formulation*Subject)_22    0.0463781

Except for the subject-by-formulation interaction and s²wT quite similar. We have seen with other data sets that SAS and PHX disagree here. Can you post your variances for AUCt as well? I bet we will see differences.

» Any idea?

Nope. Let’s wait for the SAS-guru Detlew. :-D
IMHO, since a partial replicate according to FDA’s model is always (!) over-specified there is no guarantee that the LME-engine will converge. Don’t blame SAS and PHX; they warn us… Stupid design. If you want to have only three periods maybe it is better to run a fully replicated design (TRT|RTR) in the future.

P.S.: You are not alone. Last week a colleague posted at Pharsight’s Extranet an example where a replicate design failed to converge for Cmax (but not for AUCt and AUC). Pharsight suggested to change the variance structure to Heterogeneous Compound Symmetry (instead of FDA’s Banded No-Diagonal Factor Analytic [f=2]). In my experience this rarely helps…
BTW, does anybody know the rationale behind FDA’s partial replicate? Higher precision of the estimate of CVwR (see this post and followings)?

Dif-tor heh smusma 🖖
Helmut Schütz

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