Second opinion (PHX 6.3) [RSABE / ABEL]

posted by Helmut Homepage – Vienna, Austria, 2013-05-01 18:21 (3984 d 08:55 ago) – Posting: # 10517
Views: 21,829

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)?

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