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The clearance (CL) related parameters were estimated with sufficient accuracy in all study designs and all analysis algorithms: the first order (FO), first order conditional estimation (FOCE) and first order conditional estimation with interaction (FOCE-INTER) methods.
The first order conditional expectation is zero, i.e. E[S 1|S 2=s 2]=E[N 1|S 2=0.
NONMEM's first order conditional estimation method was used.
NONMEM's first order conditional estimation method with interaction was used for model development.
The first order conditional estimation with interaction algorithm was used for parameter estimation.
Moreover, a first order conditional independence metric [ 4] has been proposed to specifically detect direct interactions.
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The subroutine ADVAN 9 and first-order conditional estimation with interaction were used throughout the modeling procedure.
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