Mark, just wondering: Why does it make a difference whether NONMEM runs into an error condition from PRED with ODE's versus any other method of computing the prediction F? There are error messages and error returns from other ADVAN routines. Also, a user $PRED has the option of using the EXIT statement if the values of THETA/ETA are such that it cannot compute the prediction. NONMEM does the same thing in all cases: back away from the problematic THETA/ETA because of the "spike", and search in a different direction for a better THETA/ETA. BTW, if PREDPP cannot return F, then it certainly cannot return the first and second eta derivatives of F, G and H. Sometimes a given error condition is raised in PREDPP not because F cannot be computed, but during the computation of the eta derivatives. There is no distinction made to NONMEM as to which was the problem. With the ODE's, for example, an augmented state vector (A and dA/deta and if appropriate d2A/detadeta) is integrated all together. (With ADVAN5 and 7, the ADVAN does know if the trouble was with a given eta and the text of the message itself indicates this, though nothing is said to NONMEM about it.)
On Mon, 28 May 2007 13:04:22 -0700, "Mark Sale - Next Level Solutions" <[EMAIL PROTECTED]> said: > Alison, Thanks for this, (the answer to my question from 2 years > ago). This will help greatly with some automated > diagnostics/corrections in work on automated model selection, > especially with my favorite error message > > MINIMIZATION TERMINATED DUE TO PROXIMITY OF NEXT ITERATION EST. TO A > VALUE AT WHICH THE OBJ. FUNC. which I never understood how that could > happen (unless you have a proportional error and prediction of 0). > > The "spike", is an interesting solution to be problem (not that I > have a better suggestion, since, in that situation you really can't > calculate a meaningful OBJ). I'd like to ask some of the people out > there who know about numerical method if there are other options for > recovering from a THETA vector for which you cannot the ODE solution, > in estimation. Perhaps an estimate of the OBJ based just on the first > and second derivative (with some penalty, to keep it out of that > range again)? > > > > Mark > > Mark Sale MD Next Level Solutions, LLC www.NextLevelSolns.com > > > > -------- Original Message -------- Subject: Re: [NMusers] NONMEM ODE > > solver From: "Alison Boeckmann" <[EMAIL PROTECTED]> Date: > > Mon, May 28, 2007 1:01 pm To: "Benjamin Ribba" <[EMAIL PROTECTED] > > lyon1.fr>, nmusers@globomaxnm.com > > > > My comments are attached. > > > > > > On Sun, 27 May 2007 18:53:21 +0200, "Benjamin Ribba" <[EMAIL PROTECTED] > > lyon1.fr> said: > > > Dear NMusers, > > > > > > 1. I have some difficulties to find information on the ODE solver > > > implemented in NONMEM. Can anyone tell me about the numerical > > > integrator(s) implemented when using ADVAN6 (recommended for > > > non-stiff) and ADVAN8 (stiff problems)? In particular, is the > > > integrator able to switch automatically between > > stiff > > > and non-stiff resolution techniques? > > > > > > 2. Then, still related to the ODE solver, I was also interested in > > > a message I?ve picked up from the archive (from Mark Sale, > > > posted January > > 2005, see > > > below), for which I couldn?t find any answer from the group. > > Additional > > > information on these items would be greatly appreciated. > > > _______________________________________________________ > > > > > > From: [EMAIL PROTECTED] Subject: [NMusers] questions on ODE > > > solver errors Date: Wed, January 26, 2005 4:40 pm > > > > > > If the NOABORT option is used for the ODE solvers, and the ODE > > > solver has "numerical difficulties", giving the message: > > > > > > NUMERICAL DIFFICULTIES WITH INTEGRATION ROUTINE. MAXIMUM NO. OF > > > EVALUATIONS OF DIFFERENTIAL EQUATIONS, 100000, > > EXCEEDED. > > > 0END OF PRED EXIT CODE MESSAGES FROM THE ESTIMATION STEP > > > > > > But, NONMEM continues to plod along. Does anyone know what NONMEM > > > does instead? I assume that the OBJ contribution for that subject > > > cannot be calculated, so, the gradient for the dimension(s) > > > requiring that OBJ cannot be calculated. Seems like an error to > > > simply ignore the OBJ contribution from that person (resulting in > > > a lower OBJ for that function evaluation, and a bad gradient and > > > Hessian). Is that function evaluation discarded, and no gradient > > > is generated for that dimension/iteration? But I don't see a 0 > > > gradient anywhere in the output (I know, in NONMEM V, it isn't as > > > simple as one function evaluation per dimension (+1)) > > > > > > Thanks > > > > > > > > > Mark Sale M.D. Global Director, Research Modeling and Simulation > > > GlaxoSmithKline 919-483-1808 Mobile 919-522-6668 > > > _______________________________________________________ > > > > > > > > > Thanks for your help in this matter. > > > > > > Benjamin Ribba > > > > > > Therapeutic Targeting in Oncology (EA3738) University Claude > > > Bernard Lyon 1 Faculty of Medicine Lyon-Sud 165, chemin du grand > > > revoyet 69921 Oullins cedex > > > > > > Tel: +33 4 26 23 59 57 / +33 6 66 06 15 21 > > > > > > > > > > > -- > > Alison Boeckmann [EMAIL PROTECTED] > -- Alison Boeckmann [EMAIL PROTECTED]
