From: Leonid Gibiansky <*LGibiansky*>

Date: Tue, 04 Aug 2009 18:01:32 -0400

the model is sensitive to initial values. Try to guess B1, B2, B3 (or at

least B1) based on the observed data. Try B1=-1, B2=1, B3=1,

Also, try to add random effect to B1.

--------------------------------------

Leonid Gibiansky, Ph.D.

President, QuantPharm LLC

web: www.quantpharm.com

e-mail: LGibiansky at quantpharm.com

tel: (301) 767 5566

wangx826

*> Leonid,
*

*> Thanks for your suggestion. I totally agree the part you indicated was
*

*> incorrect in my original control stream. But after I revised it, NONMEM
*

*> still stopped running and gave the same error message like " CONDITIONAL
*

*> LIKELIHOOD SET TO NEGATIVE VALUE WITH INDIVIDUAL 2 (IN INDIVIDUAL RECORD
*

*> ORDERING), DATA RECORD 13". Is there anything else wrong in my coding? I
*

*> would appreciate pretty much if you or some one else could point it out
*

*> for me.
*

*>
*

*> Thanks again,
*

*> Tianli
*

*>
*

*> On Aug 4 2009, Leonid Gibiansky wrote:
*

*>
*

*>> something is incorrect here, either model or comments:
*

*>> P0 = C0/(1+C0) ; Probability of Score=>0
*

*>> P1 = C1/(1+C1) ; Probability of Score=>1
*

*>> P2 = C2/(1+C2) ; Probability of Score=>2
*

*>>
*

*>> Probability of Score=>0 is always 1 (because score is 0 or positive
*

*>> number as I can see).
*

*>>
*

*>> My guess is that the model is incorrect, it should be (assuming that
*

*>> the drug increases probability of higher scores while natural state
*

*>> favors score 0)
*

*>>
*

*>> > A1 = B1 + DRUG
*

*>> > A2 = B1 - B2 + DRUG
*

*>> > A3 = B1 - B2 - B3 + DRUG
*

*>>
*

*>> > C1 = EXP(A1)
*

*>> > C2 = EXP(A2)
*

*>> > C3 = EXP(A3)
*

*>> > P1 = C1/(1+C1) ; Probability of Score=>1
*

*>> > P2 = C2/(1+C2) ; Probability of Score=>2
*

*>> > P3 = C3/(1+C3) ; Probability of Score=>3
*

*>> >
*

*>> > PR0 = 1-P1 ; Probability of Score=0
*

*>> > PR1 = P1-P2 ; Probability of Score=1
*

*>> > PR2 = P2-P3 ; Probability of Score=2
*

*>> > PR3 = P3 ; Probability of Score=3
*

*>>
*

*>> > IF (DV.EQ.0) Y=PR0
*

*>> > IF (DV.EQ.1) Y=PR1
*

*>> > IF (DV.EQ.2) Y=PR2
*

*>> > IF (DV.EQ.3) Y=PR3
*

*>>
*

*>> B2 and B3 should be positive
*

*>>
*

*>> --------------------------------------
*

*>> Leonid Gibiansky, Ph.D.
*

*>> President, QuantPharm LLC
*

*>> web: www.quantpharm.com
*

*>> e-mail: LGibiansky at quantpharm.com
*

*>> tel: (301) 767 5566
*

*>>
*

*>>
*

*>>
*

*>>
*

*>> wangx826 *

*>>> Hi Samer,
*

*>>> Thanks for your quick reply. Here is my control stream:
*

*>>>
*

*>>> $SUBS ADVAN6 TOL=6
*

*>>> $MODEL
*

*>>> COMP=(ABSO)
*

*>>> COMP=(CENT)
*

*>>> COMP=(PERI)
*

*>>> COMP=(EFFECT)
*

*>>> $PK
*

*>>> CL =ICL*24
*

*>>> V2 = IVC
*

*>>> Q=...
*

*>>> K23=Q/V2
*

*>>> V3=
*

*>>> K32=Q/V3
*

*>>> K=CL/V2
*

*>>> KA=...
*

*>>> KE0 = THETA(6)
*

*>>> B1 = THETA(1)
*

*>>> B2 = THETA(2)
*

*>>> B3 = THETA(3)
*

*>>> EMAX = THETA(4)
*

*>>> EC50 = THETA(5)*EXP(ETA(1))
*

*>>>
*

*>>> $DES
*

*>>> DADT(1)=-A(1)*KA
*

*>>> DADT(2)=A(1)*KA-A(2)*K23+A(3)*K32-A(2)*K
*

*>>> DADT(3)=A(2)*K23-A(3)*K32
*

*>>> DADT(4)=KE0*(A(2)/V2-A(4))
*

*>>>
*

*>>> $ERROR
*

*>>> CE=A(4)
*

*>>> DRUG = EMAX*CE/(EC50+CE)
*

*>>> A0 = B1 + DRUG
*

*>>> A1 = B1 + B2 + DRUG
*

*>>> A2 = B1 + B2 + B3 + DRUG
*

*>>> C0 = EXP(A0)
*

*>>> C1 = EXP(A1)
*

*>>> C2 = EXP(A2)
*

*>>> P0 = C0/(1+C0) ; Probability of Score=>0
*

*>>> P1 = C1/(1+C1) ; Probability of Score=>1
*

*>>> P2 = C2/(1+C2) ; Probability of Score=>2
*

*>>>
*

*>>> PR0 = P0 ; Probability of Score=0
*

*>>> PR1 = P1-P0 ; Probability of Score=1
*

*>>> PR2 = P2-P1 ; Probability of Score=2
*

*>>> PR3 = 1-P2 ; Probability of Score=3
*

*>>> IF (DV.EQ.0) Y=PR0
*

*>>> IF (DV.EQ.1) Y=PR1
*

*>>> IF (DV.EQ.2) Y=PR2
*

*>>> IF (DV.EQ.3) Y=PR3
*

*>>>
*

*>>> $THETA (-20 -6.3) ; THETA1 B1
*

*>>> $THETA (-10 -0.3) ; THETA2 B2
*

*>>> $THETA (-10 2) ; THETA3 B3
*

*>>> $THETA (0 5) ; THETA4 EMAX
*

*>>> $THETA (0 50) ; THETA5 EC50
*

*>>> $THETA (0 1) ; THETA6 KEO
*

*>>>
*

*>>> $OMEGA 2
*

*>>>
*

*>>> $ESTIMATION MAXEVAL=9999 PRINT=5 METHOD=COND LAPLACIAN LIKELIHOOD
*

*>>> NOABORT MSFO=MSF1
*

*>>> Here I include the dataset for first two subjects. Since it is a
*

*>>> simultaneous PKPD link model, DV in the data set as follows is
*

*>>> categorical PD data. The dose was given daily and DV was recorded
*

*>>> daily as well.
*

*>>> #SUBJ TIME AMT EVID II ADDL PD KA CL V2
*

*>>> MDV
*

*>>> 1 0 . 0 . . 0 9.96 4.12 63.57 0
*

*>>> 1 0 1 1 1 20 . 9.96 4.12 63.57 1
*

*>>> 1 1 . 0 . . 0 9.96 4.12 63.57 0
*

*>>> 1 2 . 0 . . 0 9.96 4.12 63.57 0
*

*>>> 1 3 . 0 . . 0 9.96 4.12 63.57 0
*

*>>> 1 4 . 0 . . 0 9.96 4.12 63.57 0
*

*>>> 1 5 . 0 . . 0 9.96 4.12 63.57 0
*

*>>> 1 6 . 0 . . 0 9.96 4.12 63.57 0
*

*>>> 1 7 . 0 . . 0 9.96 4.12 63.57 0
*

*>>> 1 8 . 0 . . 0 9.96 4.12 63.57 0
*

*>>> 1 9 . 0 . . 0 9.96 4.12 63.57 0
*

*>>> 1 10 . 0 . . 0 9.96 4.12 63.57 0
*

*>>> 1 11 . 0 . . 0 9.96 4.12 63.57 0
*

*>>> 1 12 . 0 . . 0 9.96 4.12 63.57 0
*

*>>> 1 13 . 0 . . 0 9.96 4.12 63.57 0
*

*>>> 1 14 . 0 . . 0 9.96 4.12 63.57 0
*

*>>> 1 15 . 0 . . 0 9.96 4.12 63.57 0
*

*>>> 1 16 . 0 . . 0 9.96 4.12 63.57 0
*

*>>> 1 17 . 0 . . 0 9.96 4.12 63.57 0
*

*>>> 1 18 . 0 . . 0 9.96 4.12 63.57 0
*

*>>> 1 19 . 0 . . 0 9.96 4.12 63.57 0
*

*>>> 1 20 . 0 . . 0 9.96 4.12 63.57 0
*

*>>> 1 21 . 0 . . 0 9.96 4.12 63.57 0
*

*>>> 1 22 . 0 . . 0 9.96 4.12 63.57 0
*

*>>> 1 23 . 0 . . 0 9.96 4.12 63.57 0
*

*>>> 1 24 . 0 . . 0 9.96 4.12 63.57 0
*

*>>> 1 25 . 0 . . 0 9.96 4.12 63.57 0
*

*>>> 1 26 . 0 . . 0 9.96 4.12 63.57 0
*

*>>> 1 27 . 0 . . 0 9.96 4.12 63.57 0
*

*>>> 2 0 . 0 . . 0 1.52 4.68 66.91 0
*

*>>> 2 0 2 1 1 20 . 1.52 4.68 66.91 1
*

*>>> 2 1 . 0 . . 0 1.52 4.68 66.91 0
*

*>>> 2 2 . 0 . . 0 1.52 4.68 66.91 0
*

*>>> 2 3 . 0 . . 0 1.52 4.68 66.91 0
*

*>>> 2 4 . 0 . . 0 1.52 4.68 66.91 0
*

*>>> 2 5 . 0 . . 0 1.52 4.68 66.91 0
*

*>>> 2 6 . 0 . . 0 1.52 4.68 66.91 0
*

*>>> 2 7 . 0 . . 0 1.52 4.68 66.91 0
*

*>>> 2 8 . 0 . . 0 1.52 4.68 66.91 0
*

*>>> 2 9 . 0 . . 0 1.52 4.68 66.91 0
*

*>>> 2 10 . 0 . . 0 1.52 4.68 66.91 0
*

*>>> 2 11 . 0 . . 0 1.52 4.68 66.91 0
*

*>>> 2 12 . 0 . . 1 1.52 4.68 66.91 0
*

*>>> 2 13 . 0 . . 1 1.52 4.68 66.91 0
*

*>>> 2 14 . 0 . . 1 1.52 4.68 66.91 0
*

*>>> 2 15 . 0 . . 1 1.52 4.68 66.91 0
*

*>>> 2 16 . 0 . . 1 1.52 4.68 66.91 0
*

*>>> 2 17 . 0 . . 1 1.52 4.68 66.91 0
*

*>>> 2 18 . 0 . . 1 1.52 4.68 66.91 0
*

*>>> 2 19 . 0 . . 1 1.52 4.68 66.91 0
*

*>>> 2 20 . 0 . . 1 1.52 4.68 66.91 0
*

*>>> 2 21 . 0 . . 3 1.52 4.68 66.91 0
*

*>>> 2 22 . 0 . . 3 1.52 4.68 66.91 0
*

*>>> 2 23 . 0 . . 3 1.52 4.68 66.91 0
*

*>>> 2 24 . 0 . . 3 1.52 4.68 66.91 0
*

*>>> 2 25 . 0 . . 3 1.52 4.68 66.91 0
*

*>>> 2 26 . 0 . . 3 1.52 4.68 66.91 0
*

*>>> 2 27 . 0 . . 3 1.52 4.68 66.91 0
*

*>>> 2 28 . 0 . . 2 1.52 4.68 66.91 0
*

*>>>
*

*>>> Thanks,
*

*>>> Tianli
*

*>>>
*

*>>>
*

*>>> ******************************************************************************
*

*>>>
*

*>>>
*

*>>> Tianli Wang
*

*>>> University of Minnesota,
*

*>>> Department of Pharmaceutics
*

*>>>
*

*>>> On Aug 4 2009, Samer Mouksassi wrote:
*

*>>>
*

*>>>> Can you include your control (or at least your $EST bloc)
*

*>>>> And the proportional odds PD data. The likelihood may go wild if some
*

*>>>> categories are very rare or non esistent. You need to gard against over
*

*>>>> or underflow.
*

*>>>>
*

*>>>> -----Original Message-----
*

*>>>> From: owner-nmusers *

*>>>> [mailto:owner-nmusers *

*>>>> On Behalf Of wangx826 *

*>>>> Sent: 2009-08-04 13:38
*

*>>>> To: NMUSERS
*

*>>>> Subject: [NMusers] COND LAPLACE LIKELIHOOD
*

*>>>>
*

*>>>> Dear nmusers,
*

*>>>>
*

*>>>> Has anybody seen the following error message from NONMEM:
*

*>>>> "CONDITIONAL LIKELIHOOD SET TO NEGATIVE VALUE
*

*>>>> WITH INDIVIDUAL 2 (IN INDIVIDUAL RECORD ORDERING), DATA RECORD 13"?
*

*>>>> What does it mean?
*

*>>>>
*

*>>>> I am trying to use conditional lapalacian likelihood method to generate
*

*>>>> a proportional odds model dealing with categorical PD data. Here is a
*

*>>>> little piece of my data set:
*

*>>>> SUBJ TIME AMT EVID II ADDL DV CL V
*

*>>>> MDV
*

*>>>> 2 0 . 0 . . 0 4.12 63
*

*>>>> 0
*

*>>>> 2 0 1 1 1 20 . 4.12 63
*

*>>>> 1
*

*>>>> 2 0.005 . 2 . . . 4.12 63
*

*>>>> 1
*

*>>>> 2 0.01 . 2 . . . 4.12 63
*

*>>>> 1
*

*>>>> .
*

*>>>> .
*

*>>>> .
*

*>>>> 2 12 . 0 . . 0 4.12 63
*

*>>>> 0
*

*>>>> 2 13 . 0 . . 1 4.12 63
*

*>>>> 0
*

*>>>> .
*

*>>>> .
*

*>>>> .
*

*>>>> But I don't think the problem exists in the data set because I tried
*

*>>>> deleting the rows indicated in the error message, but the exactly
*

*>>>> same message still came out and NONMEM stopped running. I have no
*

*>>>> idea what's
*

*>>>>
*

*>>>> the problem for my model.
*

*>>>>
*

*>>>> Thanks in advance,
*

*>>>>
*

*>>>> Tianli
*

*>>>>
*

*>>>
*

*>>>
*

*>>
*

*> *

Received on Tue Aug 04 2009 - 18:01:32 EDT

Date: Tue, 04 Aug 2009 18:01:32 -0400

the model is sensitive to initial values. Try to guess B1, B2, B3 (or at

least B1) based on the observed data. Try B1=-1, B2=1, B3=1,

Also, try to add random effect to B1.

--------------------------------------

Leonid Gibiansky, Ph.D.

President, QuantPharm LLC

web: www.quantpharm.com

e-mail: LGibiansky at quantpharm.com

tel: (301) 767 5566

wangx826

Received on Tue Aug 04 2009 - 18:01:32 EDT