Hi Tim,
Are you getting a zero gradient for TH2 on the 0-th iteration? If so, this may be indicative of a coding error. You might check to make sure that THETA(2) is not being assigned to another parameter (say a fixed effect parameter) in addition to the standard deviation for the additive residual error. Note that it is the variances of the proportional and additive residual errors that can be summed for two independent random effects and not the standard deviations. So, adding the proportional and additive standard deviations in the specification of W: W = THETA(1) * IPRED + THETA(2) is not correct. If the gradient for TH2 is not zero on the 0-th iteration and you don’t find any coding errors involving say multiple assignments for TH2, but the gradient goes to zero after several iterations, this might mean you don’t have rich enough information to estimate the additive error component. If so, try fixing TH2 to 0 and just estimate the proportional error component. Make sure that you are not including any DVs (e.g., the predose sample at TIME=0) where IPRED=0 in the estimation since the proportional error is 0 and hence IWRES is undefined. Regards, Ken Kenneth G. Kowalski President Kowalski PMetrics Consulting, LLC Email: [email protected] <mailto:[email protected]> Cell: 248-207-5082 From: [email protected] <[email protected]> On Behalf Of T. Preijers Sent: Tuesday, March 5, 2024 8:09 AM To: [email protected] Subject: [NMusers] Warning obtained while running SAEM Dear NMusers, While running a simple 1-comp model in NONMEM using SAEM, we discovered a warning resulting from $ERROR. Using a SQRT( **2) describing a mixed error model resulted in zero gradients for the additive error (see Example error model 1 below). Example error model 1 $ERROR IPRED = F IRES = DV-IPRED W = SQRT(THETA(1)**2 * IPRED**2 + THETA(2)**2) IF (W.EQ.0) W = 1 IWRES = IRES/W Y = IPRED+W*ERR(1) However, when simplifying the $ERROR code omitting the use of SQRT() and THETA(x)**2 (see Example error model 2 below), a successful SAEM run was obtained. Example error model 2 $ERROR IPRED = F IRES = DV-IPRED W = THETA(1) * IPRED + THETA(2) IF (W.EQ.0) W = 1 IWRES = IRES/W Y = IPRED + W*ERR(1) Initial values for both THETAs were positive (TH1: 0.417, TH2: 0.545) and constrained with a lower boundary of 0. Moreover, the expected values for IPRED were ranged from 1-700 mg/L. Our interest lies in what has driven this error. Perhaps someone else has encountered this before? Looking forward to receiving any answers/comments! Kind regards, Dr. T. Preijers, PharmD, PhD Hospital Pharmacist and Clinical Pharmacologist Hospital Pharmacy Erasmus MC Rotterdam The Netherlands Rotterdam Clinical Pharmacometrics Group
