RE: Coding for missing data values

From: Nick Holford n.holford@auckland.ac.nz Subject: RE: [NMusers] Coding for missing data values Date: Mon, June 28, 2004 7:40 pm Bill, In your first method you propose estimating THETA(1) for CL when TECL is missing and THETA(2) for CL when TECL is equal to the mean TECL. If TECL is missing then wouldn't the simplest thing be to assume that TECL is equal to the mean TECL (e.g. 5.4) in which case THETA(2) is the prediction for CL if TECL is missing? This only requires estimation of one THETA instead of two. If I understand the second method you are proposing correctly then it shouldn't be any worse than method 1 and in general will be better. If observed TECL is used as a DV with DVID.EQ.2 and observed CONC has DVID.EQ.1 then I would suggest the following: $THETA 10 ; POPCL $THETA 5.4 ; POPTCL $THETA 0.1 ; SLOPE $OMEGA 0.25 ; PPV for CL $OMEGA 0.01 ; PPV for POPTCL $SIGMA 1 ; eps(1) $SIGMA 0.01 FIX ; eps(2). Use a plausible value for the measurement error of TECL e.g. SD=0.1 $PK ITCL=THETA(2)*EXP(ETA(2)) ; individual prediction for TECL GRPCL=THETA(1)*EXP((ITCL-5.4)*THETA(3)) ; group prediction for CL CL=GRPCL*EXP(ETA(1)) ; individual CL prediction ... $ERROR IF (DVID.EQ.1) THEN Y=F+EPS(1) ; observed conc ENDIF IF (DVID.EQ.2) THEN Y=POPTCL+EPS(2) ; observed TECL ENDIF If population parameter variability for TECL [OMEGA(2,2)] is fixed to 0 then this becomes essentially the same as your method 1 i.e. it uses the mean observed TECL to centre the TECL covariate. If OMEGA(2,2) is estimated then the value of ITCL will vary from subject to subject. Depending on how small EPS(2) is made the value will be close to the observed value when TECL is not missing. If it is missing then a plausible value will be imputed that reflects the uncertainty in CL for that individual given the particular covariate model using TECL. If I remember correctly this method for imputing missing covariates with NONMEM was first proposed by Karlsson M, Jonsson E, Wiltse C, Wade J. Assumption testing in population pharmacokinetic models: illustrated with an analysis of moxonidine data from congestive heart failure patients. J Pharmacokinet Biopharm 1998;26(2):207-46. Note the empirical covariate model for TECL uses EXP() to avoid predicting negative values of GRPCL. If THETA(3) is 'small' then this model is approximately the same as a linear function of TECL. Nick -- Nick Holford, Dept Pharmacology & Clinical Pharmacology University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand email:n.holford@auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556 http://www.health.auckland.ac.nz/pharmacology/staff/nholford/