From: Gastonguay, Marc <*marcg*>

Date: Fri, 26 Feb 2010 12:34:16 -0500

Vincenzo / Amit:

A quick inspection of your code reveals a typo in the denominator of

your probability expression.

P = EXP(A)/1+EXP(A)

should be:

P = EXP(A)/ (1+EXP(A))

Due to FORTRAN order of operation, you need the parentheses around the

entire term (1+EXP(A)).

Hope this helps.

Marc

Marc R. Gastonguay, Ph.D.

President & CEO, Metrum Research Group LLC < metrumrg.com >

Scientific Director, Metrum Institute < metruminstitute.org >

2 Tunxis Rd, Suite 112, Tariffville, CT 06081 Direct:

+1.860.670.0744 Main: +1.860.735.7043 Fax: +1.860.760.6014

On Feb 26, 2010, at 11:35 AM, Vincenzo Di Iorio wrote:

*>
*

*> On behalf of Amit Taneja:
*

*>
*

*> Dear Nonmem users,
*

*>
*

*> I have been trying to fit a linear logistic model to a set of binary
*

*> response data in nonmem6. However, nonmem terminates and gives the
*

*> following
*

*> message. My dataset has 36 subjects and 5 pd sample points per
*

*> subject. On
*

*> the other hand, a logistic emax model fits the data well and
*

*> consistently. I
*

*> even get the covariance step. One would expect a linear model to fit
*

*> more
*

*> easily than an emax model?
*

*>
*

*> My control stream is provided below as is a sample of the dataset,
*

*> and the
*

*> output file is enclosed. I would appreciate your inputs on resolving
*

*> this
*

*> vexing issue.
*

*>
*

*> Thanks
*

*> Amit Taneja
*

*>
*

*> Pharmacology
*

*> Leiden Amsterdam Center for Drug Research
*

*> Leiden
*

*> Netherlands
*

*>
*

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

*>
*

*> Relevant part of output file (Error message)=
*

*>
*

*> MONITORING OF SEARCH:
*

*>
*

*> 0HESSIAN OF POSTERIOR DENSITY IS NON-POSITIVE-DEFINITE DURING SEARCH
*

*>
*

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

*>
*

*> $PROB
*

*> $INPUT ID TIME PDB=DV PD CAUC MDV EVID DGRP
*

*> $DATA GpdV_od.csv IGNORE= *

*>
*

*> $PRED
*

*> ;in this model we fit a linear model in the logit space
*

*>
*

*> ; Baseline Probabilities
*

*> PLAC = THETA(1)
*

*>
*

*> ; Drug Conc effect Emax model, assuming gamma = 1
*

*> SLOP = THETA(2)
*

*> ;EC50 = THETA(3)
*

*> DRUG = SLOP*CAUC
*

*>
*

*> ; Logit
*

*> A = DRUG + PLAC + ETA(1) ;
*

*>
*

*> ; the term exp(drug+plac+eta) is expressed as A
*

*> P = EXP(A)/1+EXP(A)
*

*>
*

*> ;PB0 = P0/(1+P0) ; Probability of parameter=0 ; e**x/1+e**x; x=logit
*

*> function
*

*> ;PB1 = 1-PB0 ; probability of parameter=1
*

*> ;IF (DV.EQ.0) PB = PB0
*

*> ;IF (DV.EQ.1) PB = PB1
*

*>
*

*> Y = -2*PDB*A-2*LOG(1-P)
*

*>
*

*> $THETA
*

*> (1,157.9) ; PLAC Theta(1)
*

*> (1,10) ; SLOP Theta(2)
*

*> ; EC50 EPER 1 Theta(3)
*

*> ;15.85 ; L0 Theta(4)
*

*>
*

*> $OMEGA
*

*> 1
*

*>
*

*> $ESTIM METHOD=COND LAPLACIAN -2LL
*

*> $COV MAT=R
*

*>
*

*> $TABLE ID TIME P PD CAUC PLAC SLOP MDV EVID DGRP NOPRINT ONEHEADER
*

*> FILE=Gp_lin15.tab
*

*>
*

*>
*

*> # SAMPLE OF THE INPUT DATASET
*

*>
*

*> ID TIME PDB PD CAUC MDV EVID DGRP CONC
*

*> 1 0 0 5.328576 0 0 0 0 0
*

*> 1 1 0 0.499059 0 0 0 0 0
*

*> 1 2 1 22.8096 0 0 0 0 0
*

*> 1 3 0 0.299475 0 0 0 0 0
*

*> 1 4 0 0.333036 0 0 0 0 0
*

*> 8 0 0 2.168496 0 0 0 100 0
*

*> 8 1 1 111.4464 1131.1 0 0 100 359.43
*

*> 8 2 1 54.94748 3638.7 0 0 100 541.01
*

*> 8 3 1 222.75 6887.6 0 0 100 636.91
*

*> 8 4 1 222.75 10529.2 0 0 100 688.48
*

*> 15 0 0 17.21501 0 0 0 100 0
*

*> 15 1 1 65.75828 1131.1 0 0 100 356.33
*

*> 15 2 1 222.75 3638.7 0 0 100 541
*

*>
*

*>
*

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

*> Vincenzo Luca Di Iorio
*

*> Consultant PME User support - GSK R&D Limited
*

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

*>
*

*>
*

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

*> This e-mail was sent by GlaxoSmithKline Services Unlimited
*

*> (registered in England and Wales No. 1047315), which is a
*

*> member of the GlaxoSmithKline group of companies. The
*

*> registered address of GlaxoSmithKline Services Unlimited
*

*> is 980 Great West Road, Brentford, Middlesex TW8 9GS.
*

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

*>
*

Received on Fri Feb 26 2010 - 12:34:16 EST

Date: Fri, 26 Feb 2010 12:34:16 -0500

Vincenzo / Amit:

A quick inspection of your code reveals a typo in the denominator of

your probability expression.

P = EXP(A)/1+EXP(A)

should be:

P = EXP(A)/ (1+EXP(A))

Due to FORTRAN order of operation, you need the parentheses around the

entire term (1+EXP(A)).

Hope this helps.

Marc

Marc R. Gastonguay, Ph.D.

President & CEO, Metrum Research Group LLC < metrumrg.com >

Scientific Director, Metrum Institute < metruminstitute.org >

2 Tunxis Rd, Suite 112, Tariffville, CT 06081 Direct:

+1.860.670.0744 Main: +1.860.735.7043 Fax: +1.860.760.6014

On Feb 26, 2010, at 11:35 AM, Vincenzo Di Iorio wrote:

Received on Fri Feb 26 2010 - 12:34:16 EST