RE: RE: re: bug in NONMEM VI?

> From: Bonate, Peter [mailto:[EMAIL PROTECTED] > Sent: Wed 1/2/2008 10:03 PM > To: Bill Bachman; John Lukas; [email protected] > Subject: RE: [NMusers] RE: re: bug in NONMEM VI? > > > I'd also like to see how correlated COV3 and COV4 are. This may be a > collinearity issue. > > pete bonate > > Peter L. Bonate, PhD, FCP > Genzyme Corporation > Senior Director > Clinical Pharmacology and Pharmacokinetics > 4545 Horizon Hill Blvd > San Antonio, TX 78229 USA > [EMAIL PROTECTED] > phone: 210-949-8662 > fax: 210-949-8219 > crackberry: 210-315-2713 > > > ________________________________ > > From: [EMAIL PROTECTED] [mailto:[EMAIL PROTECTED] > On Behalf Of Bill Bachman > Sent: Wednesday, January 02, 2008 2:38 PM > To: 'John Lukas'; [email protected] > Subject: RE: [NMusers] RE: re: bug in NONMEM VI? > > > > Have you tried both of these runs using the SLOW option on the estimation > record? > > > > ________________________________ > > From: [EMAIL PROTECTED] [mailto:[EMAIL PROTECTED] > On Behalf Of John Lukas > Sent: Wednesday, January 02, 2008 2:36 PM > To: [email protected] > Subject: [NMusers] RE: re: bug in NONMEM VI? > > > > > > > > ________________________________ > > From: John Lukas > Sent: Mon 12/17/2007 11:51 PM > To: [email protected] > Subject: re: bug in NONMEM VI? > > Dear Nmusers, > > > > A simple LME model run using NM version VI, FO method, with 4 covariates > (5 THETA's) as, > > . > > . > > $PRED > > > > SUM1=THETA(2)*COV1+THETA(3)*COV2 > > SUM2=THETA(4)*COV4+THETA(5)*COV3 > > > > TLAU=THETA(1)+SUM1+SUM2 > > F=TLAU+ETA(1) > > > > Y=F+EPS(1) > > > > $THETA 4 .1 .1 .1 .1 > > $OMEGA .1 > > $SIGMA .1 > > > > $ESTIMATION MAXEVALS=1900 PRINT=5 METHOD=0 > > > > (let's call this FIT A) gave a different fit from another (FIT B) where > only the order of THETA( 4) and 5 was reversed, all else kept the same, > as, > > . > > . > > SUM2=THETA(5)*COV4+THETA(4)*COV3 > > . > > . > > (even more strange, FIT B, the reversed order run, proved to be the good > run!) > > > > NONMEM version V had the same result for both FITS A and B, as expected > (and same as FIT B from version 6). FOCE gave good answers always in > both NONMEM version V and version VI. But, the question remains about > that dependence on ordering of the THETAs with the FO method for version > VI. > > > > Any comments? Has there been discussion on this earlier that I missed? > Thanks in advance. > > > > John > > PS I am aware of other *important* incosistencies between version VI and > V from university colleagues working on a PK problem with FOCE... > > > > > > John C Lukas > > Strategic Consulting Services > > Pharsight Corp. > > > > line: + 33 492 726 495 > > cell: + 33 626 496 777 > > > > > -- Alison Boeckmann [EMAIL PROTECTED] I was concerned about this issue, and John was kind enough to send me a control stream and data set. I cannot reproduce his results on my Sun workstation, but I do see a difference between NONMEM V and NONMEM VI minimum as NONMEM V. Surprisingly, the minimum value of the objective function is higher with VI than with V. According to Tom Ludden, "it is more common, when results differ between V and VI using a conditional estimation method, that the NONMEM VI results (without SLOW) are associated with a lower objective function value rather than a higher value. At least that has been our experience." My NONMEM V runs are consistent (model A vs. model B). My NONMEM VI runs are consistent (model A vs. model B). NONMEM VI reaches a different minimum than does NONMEM V unless the SLOW option of $ESTIM is used, in which case it reaches the same minimum as NONMEM V. There are 130 subjects with ages from <1 to 96. Of these, 31 are under the age of 21. Age and WT are clearly correlated till roughly that age, after that there is no strong correlation. (I looked a simple NONMEM scatter of AGE vs. WT). I cannot explain why NONMEM VI results differs from NONMEM V, but in my runs it has nothing to do with the order of thetas (model A vs. model B.) It is always disturbing when NONMEM VI gets a different result than NONMEM V, but this is a known problem and I cannot see that this particular case is evidence for a bug in VI. Legend for results: "VI" is NONMEM VI 1.0 "V" is NONMEM V 1.0 "A" uses the model COV2=THETA(4)*(AGE-36)+THETA(5)*(WT-65) "B" uses the model COV2=THETA(5)*(AGE-36)+THETA(4)*(WT-65) "s" is SLOW "n" is SLOW option omitted (default). Minimum value of the objective function: VInA: mm 45.414 VInB: mm 45.413 VIsA: mm 33.771 VIsB: mm 33.771 V__A: mm 33.771 V__B: mm 33.771 Final values of THETA: VInA: tf -3.27E-01 -2.85E-02 2.88E-04 -1.04E-03 1.44E-02 VInB: tf -3.27E-01 -2.85E-02 2.88E-04 1.44E-02 -1.05E-03 VIsA: tf -3.13E-01 -2.65E-02 2.87E-04 -1.40E-03 1.45E-02 VIsB: tf -3.13E-01 -2.65E-02 2.87E-04 1.45E-02 -1.40E-03 V__A: tf -3.13E-01 -2.65E-02 2.86E-04 -1.40E-03 1.45E-02 V__B: tf -3.14E-01 -2.65E-02 2.87E-04 1.45E-02 -1.38E-03 Final value of OMEGA: VInA: of 1.57E-02 VInB: of 1.57E-02 VIsA: of 2.49E-01 VIsB: of 2.49E-01 V__A: of 2.49E-01 V__B: of 2.50E-01 Final value of SIGMA: VInA: sf 4.51E-01 VInB: sf 4.51E-01 VIsA: sf 2.42E-01 VIsB: sf 2.42E-01 V__A: sf 2.43E-01 V__B: sf 2.42E-01 I use a Sun Solaris 2 workstation, using f90 (Forte Developer 7 Fortran 95 7.0 Patch 111714-04 2002/12/17)