Use of NONMEM With The Standard Two-Stage Estimation Method

Nick Holford was quick to try out the two-stage business described in recent memos over the past few days. Good thing! He noticed that the syntax FOCE is used in the control stream, whereas it should be METH=COND. Please note this regrettable error. Some of you may wonder (as did Nick) about the form of the equation for Y with an exponential type residual error model. The usual exponential type model is Y = F*EXP(ERR(1)). (A) With an EXP(ETA(3)) term for the sd of ERR(1), the model looks like Y = F*EXP(EXP(ETA(3))*ERR(1)) (B) Of course, because NM-TRAN Version II has certain restrictions on nested parentheses (removed with NM-TRAN Version III), we may need to write this as SD=EXP(ETA(3)) Y = F*EXP(SD)*ERR(1)) (C) However, whether we use (B) or the constant cv type model that Steve Shafer and I wrote, viz. Y = F + F*EXP(ETA(3))*ERR(1), (D) the results will be the same since a first-order approximation to Y in epsilon (being represented by ERR(1)) about epsilon=0 is always used by the NONMEM program. Lastly, Nick reminds us that at the second stage, the CL values, say, are "single-subject" type data, that therefore, only one level of random effects is used to explain the random variability in these data, and that consequently, only a $OMEGA record is to be used. A $SIGMA record is not to be used.