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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:

[This e-mail message may contain privileged, confidential and/or proprietary information of Eisai. If you believe that it has been sent to you in error, please contact the sender immediately and delete the message including any attachments, without copying, using, or distributing any of the information contained therein. This e-mail message should not be interpreted to include a digital or electronic signature that can be used to authenticate an agreement, contract or other legal document, nor to reflect an intention to be bound to any legally-binding agreement or contract.]

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

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:

[This e-mail message may contain privileged, confidential and/or proprietary information of Eisai. If you believe that it has been sent to you in error, please contact the sender immediately and delete the message including any attachments, without copying, using, or distributing any of the information contained therein. This e-mail message should not be interpreted to include a digital or electronic signature that can be used to authenticate an agreement, contract or other legal document, nor to reflect an intention to be bound to any legally-binding agreement or contract.]

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