Hello Everyone, I am using PsN enabled SCM option in Pirana to analyze selection of covariates in the PK 2- Comp model. As long as I am using just linear and exponential covariate model, everything runs fine. However, as soon as I add power-model in the mix, "some" power models involving continuous covariates on parameters fail to run and it gives me the following error: "HESSIAN OF POSTERIOR DENSITY IS NON-POSITIVE-DEFINITE DURING SEARCH" I understand that individual PK parameter search might be moving into 0 or negative territory. I am trying to fix it but didn't have much success. I have set lower bounds, removed lower bounds, changed order of model in valid states option in scm configuration file, dataset doesn't contain any 0 or negative value, but nothing is working. FYI: I don't need to test hockey-stick relation as literature and data doesn't support it, power model can only be used on continuous covariates and I have turned on parallel states option. This is how part of my scm results, followed by scm configuration file, followed by base model for PK 2-Comp looks like:
MODEL TEST BASE OFV NEW OFV TEST OFV (DROP) GOAL dDF SIGNIFICANT PVAL CLAGE-2 PVAL 2618.02603 2616.67228 1.35375 > 3.84150 1 0.244620 CLAGE-5 PVAL 2618.02603 2616.36273 1.66330 > 3.84150 1 0.197160 CLAGE-4 PVAL 2618.02603 2616.65232 1.37371 > 3.84150 1 0.241180 CLBMI-2 PVAL 2618.02603 2612.96657 5.05946 > 3.84150 1 YES! 0.024492 CLBMI-5 PVAL 2618.02603 FAILED FAILED > 3.84150 1 999 SCM FILE: " search_direction=both p_forward=0.05 p_backward=0.01 continuous_covariates=BMI,AGE categorical_covariates=USER,SEX parallel_states=1 retries=2 threads=6 tweak_inits=1 ;;1-NotIncluded, 2-LINEAR, 3-Hockey Stick Relation, 4-Exponential, 5-Power [test_relations] CL=AGE,SEX,BMI,USER V1=AGE,SEX,BMI,USER V2=AGE,SEX,BMI,USER Q=AGE,SEX,BMI,USER [valid_states] continuous = 1,2,5,4 categorical = 1,2 " NONMEM Control Stream: $SUBROUTINE ADVAN3 TRANS4 $PK TVV1 = THETA(1) ;Central Volume of distribution in L V1 = TVV1*EXP(ETA(1)) TVCL = THETA(2) CL = TVCL*EXP(ETA(2)) ; Clearance L/h TVQ = THETA(3) Q = TVQ*EXP(ETA(3)) ;Intercompartment Clearance TVV2 = THETA(4) V2 = TVV2*EXP(ETA(4)) ;Peripheral volume in L S1=V1 $ERROR IPRED=F Y= F + F*ERR(1); Proportional Error $THETA (0, 16); [V1] based on PK 2 Comp (0, 255); [CL] based on PK 2 Comp (0, 33.5); [Q] based on PK 2 Comp (0, 29.7); [V2] based on PK 2 Comp $OMEGA (0, 0.08); [P] omega(1,1) (0, 0.159); [P] omega(2,2) (0, 0.140); [P] omega(3,3) (0, 0.19); [P] omega(4,4) $SIGMA (0, 0.06) ;sigma1 $EST METHOD=1 PRINT=5 MAXEVAL=9999 SIG=3 NOABORT Regards, Sumeet K. Singla Ph.D. Candidate Division of Pharmaceutics and Translational Therapeutics College of Pharmacy | University of Iowa Iowa City, Iowa sumeet-sin...@uiowa.edu<mailto:sumeet-sin...@uiowa.edu> 518.577.5881
