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[NMusers] EM methods giving different outcomes at each repeated run

From: <Edgar_Schuck_at_eisai.com>
Date: Mon, 26 Sep 2016 16:33:07 -0400

Hi all,

I am new to the EM methods, but thought I would give it a try since I had
no success in generating confidence intervals with the other more
traditional methods. I am modeling a rich data set for a compound that has
shown to have a second peak between 12 - 24 hours postdose. I have been
able to get good runs with ITS followed by SAEM and IMP. The problem I am
having is that if I repeat a run, with exactly the same settings and
initial estimates, I get different results each time. Not only the
estimates change, but the OFV does too, sometimes up to 10 points. I have
tried multiple alternatives, but I continuously have the same issue.
Parameter estimates are generally fine, diagnostic plots are fine,
residual variability is low, but I cannot to move into covariate analysis
without understanding why is this happening. I remember seeing this before
the first time I tried the EM methods, so my guess is that I am doing
something wrong. The model below is the last one I ran, I would appreciate
your help.

thanks in advance,

Edgar

$INPUT C NMID=ID DOSE AMT MDV EVID TIME DV LNDV=DROP CMT
$DATA XXX.CSV IGNORE=C
$SUBROUTINES ADVAN13 TOL=9

$MODEL
COMP=(1_DOS, DEFDOSE) ; DOSE, 1
COMP=(2_DOS) ; DOSE, 2
COMP=(3_CENT, DEFOBS) ; CENTRAL
COMP=(4_PERI) ; PERIPHERAL
COMP=(5_ABS_2) ; TRANSIT 1
COMP=(6_ABS_3) ; TRANSIT 2
COMP=(7_ABS_3) ; TRANSIT 3

$PK

MU_1=LOG(THETA(1))
CL=EXP(MU_1+ETA(1))

MU_2=LOG(THETA(2))
V3=EXP(MU_2+ETA(2))
 
MU_3=LOG(THETA(3))
Q=EXP(MU_3+ETA(3))
 
MU_4=LOG(THETA(4))
V4=EXP(MU_4+ETA(4))

MU_5=LOG(THETA(5))
KTR=EXP(MU_5+ETA(5))

MU_6=LOG(THETA(6))
KA1=EXP(MU_6+ETA(6)) ; First order rate of absorption for first
absorption path

MU_7=LOG(THETA(7))
KA2=EXP(MU_7+ETA(7)) ; First order rate of absorption for second
absorption path

MU_8=LOG(THETA(8))
FR1=EXP(MU_8+ETA(8))

FR2=1-FR1
 
S3=V3/1000

K23 = KA2
K30 = CL/V3
K34 = Q/V3
K43 = Q/V4
 
$DES
DADT(1) = -KA1*A(1)*FR1
DADT(2) = -KTR*A(2)*FR2
DADT(3) = KA1*FR1*A(1)+K43*A(4)-K34*A(3)-K30*A(3)+KA2*A(7)
DADT(4) = K34*A(3)-K43*A(4)
DADT(5) = KTR*A(2)*FR2 - KTR*A(5)
DADT(6) = KTR*A(5) - KTR*A(6)
DADT(7) = KTR*A(6) - KA2*A(7)

$ERROR
  IPRE=F
  Y=F*(1+ERR(1))

$EST METHOD=ITS INTERACTION NITER=50 NOABORT
$EST METHOD=SAEM INTERACTION NBURN=1000 ISAMPLE=2 NITER=3000 CTYPE=3
PRINT=200 SEED=1556678 NOABORT
$EST METHOD=IMP INTERACTION EONLY=1 ISAMPLE=1000 NITER=20 MAPITER=20
PRINT=1 MSFO=XXX.MSF

$COVARIANCE UNCONDITIONAL SIGL=8 TOL=10
 
$THETA
   (0,13,) ;[CL]
  (0,20) ;[V3]
  (0,60,) ;[Q]
  (0,200,) ;[V4]
  (0,1,) ;[KTR]
  (0,1,) ;[KA1]
  (0,3,) ;[KA2]
  (0,0.2,1) ;[FR1]
 
$OMEGA
  0.3 ;[P] CL
  0.3 ;[P] V3
  0.3 ;[P] Q
  0.3 ;[P] V4
  0.3 ;[P] KTR
  0.3 ;[P] KA1
  0.3 ;[P] KA2
  0.3 ;[P] FR1
 
$SIGMA
  0.1 ;[P] sigma(1,1)

$TABLE ID TIME IPRE CWRES ONEHEADER NOPRINT FILE=XXX.tab

Here is a sample of the dataset:





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Received on Mon Sep 26 2016 - 16:33:07 EDT

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