Re: Time to Event Model

On 15/08/2011 8:55 p.m., Friederike Kanefendt wrote: > Dear NMusers, > > I try to model the influence of an intervention on Time-To-Event (disease progression) data with NM7 based on the presentation of Nick Holford (PAGE 2011). > > One problem might be that I have only data from 21 patients with 11 event data (DV=1) and 10 right censored data (DV=0)... > > The treatment influences the hazard rate. > > (h(t)=h_0 (t)*exp(BETA*X). > > For X I tested disease progression (DPRG) -affected by ON or OFF treatment-, free drug concentration (C), or the AUC at steady state (AUC_SS). > > Unfortunately, the estimation aborted with different ERROR messages: > > 1) for Concentration > > NUMERICAL DIFFICULTIES WITH INTEGRATION ROUTINE. > > NO. OF REQUIRED SIGNIFICANT DIGITS IN SOLUTION VECTOR > > TO DIFFERENTIAL EQUATIONS, 4, MAY BE TOO LARGE. > > 0PROGRAM TERMINATED BY OBJ --> setting TOL to lower values has no influence > > 2) for AUC_SS and DPRG > > CONDITIONAL LIKELIHOOD SET TO NEGATIVE VALUE > > WITH INDIVIDUAL 1 (IN INDIVIDUAL RECORD ORDERING), DATA RECORD 1 > > Does someone have experience with that kind of error or have any idea what could be the problem? > > Attached you find my control file and a part of the structure of the data set > > Thanks in advance. > > Best regards, > > Friederike > > I have a data set with dosing events and dummy observations for the PK model as well as one row with event/exclusion > > ID TIME AMT DV MDV CLx Vx ... > > 1, 0, 50, 0, 1, 30, 2000 > > 1, 23.83, 0, 0, 1, 30, 2000 > > 1, 24, 50, 0, 1, 30, 2000 > > 1, 47.83, 0, 0, 1, 30, 2000 > > 1, 48, 50, 0, 1, 30, 2000 > > ... > > 1, 8280, 0, 1, 0, 30, 2000 ; progression (event) > > 2, 0, 50, 0, 1, 35, 1800 > > 2, 23.83, 0, 0, 1, 35, 1800 > > 2, 24, 50, 0, 1, 35, 1800 > > 2, 47.83, 0, 0, 1, 35, 1800 > > 2, 48, 50, 0, 1, 35, 1800 > > ... > > 2, 4236, 0, 0, 0, 35, 1800 ; censored > > ... > > $INPUT ID TIME AMT DV MDV CLx Vx ... > > $DATA data.csv > > $SUBROUTINE ADVAN6 TOL=4 > > $MODEL > > NCOMP=5 > > COMP=(DEPOT) > > COMP=(CENTRAL) > > COMP=(PERI) > > COMP=(MET) > > COMP=(HAZ) > > $THETA (0,0.5) ; 1 TH_BLHAZ - Baseline Hazard > > $THETA (0.01) ; 2 TH_BETA - Factor > > $THETA (5) ; 3 TH_EFFECT > > $THETA (0,5) ; 4 TH_INTRI > > $THETA (0,0.5) ; 5 TH_SLOPE > > $OMEGA 0 FIX ; 1 ETA_HAZ > > $OMEGA 0.1 ; 2 ETA_BETA > > $OMEGA 0.1 ; 3 ETA_EFFECT > > $OMEGA 0.1 ; 4 ETA_INTRI > > $OMEGA 0.1 ; 5 ETA_SLOPE > > $PK > > ;HAZARD > > TVBLHAZ = THETA(1) > > BLHAZ = TVBLHAZ*EXP(ETA(1)) > > TVBETA = THETA(2) > > BETA = TVBETA*EXP(ETA(2)) > > ;SYMPTOMATIC TREATMENT EFFECT > > EFFECT = THETA(3)*EXP(ETA(3)) ; TREATMENT EFFECT FACTOR > > ;DISEASE PROGRESS > > INTRI = THETA(4)*EXP(ETA(4)) ; INTERCEPT OF DISEASE PROGRESSION > > SLOPE = THETA(5)*EXP(ETA(5)) ; SLOPE OF DISEASE PROGRESSION > > ;PHARMACOKINETIC > > ... > > ;EXPOSURE OF TOTAL DRUG AT STEADY-STATE > > AUC_SS = DOSE/CLx+DOSE/CLM > > A_0(5)=BLHAZ > > $DES > > ... > > C=A(2)/V1+A(4)/VM > > IF(C.GE.50) THEN ; EFFECTIVE CONCENTRATION > > TREA = 1 > > ELSE > > TREA = 0 > > ENDIF > > INTRC = INTRI-EFFECT*TREA > > DPRG = INTRC+SLOPE*T > > DADT(5)=BETA*DPRG ; HAZARD RATE > > ;DADT(5)=BETA*C > > ;DADT(5)=BETA*AUC_SS > > $ERROR > > CUB = A(2)/V1+A(4)/VM > > CUMHAZ = A(5) ; CUMULATIVE HAZARD > > ;EFFECTIVE CONCENTRATION > > IF(CUB.GE.50) THEN ; CONC EFFECTIVE > > TREAT = 1 > > ELSE > > TREAT = 0 > > ENDIF > > INTR = INTRI-EFFECT*TREAT ; INTERCEPT OF DISEASE PROGRESSION > > DISPRG = INTR+SLOPE*TIME > > SURV = EXP(-CUMHAZ) ; SURVIVAL FUNCTION - probability not to have an event > > IF(DV.EQ.1) THEN ; EVENT > > HAZNOW = BLHAZ*EXP(BETA*DISPRG) ; HAZARD RATE AT THAT TIME > > Y = HAZNOW*SURV ; PDF - PROBABILITY DENSITY FUNCTION > > ELSE ; CENSORED > > Y = SURV > > ENDIF > > $ESTIMATION SIG=3 SIGL=9 MAXEVAL=9990 METHOD=COND LAPLACE LIKE PRINT=1 > > $COVARIANCE PRINT=E > > $TABLE ID TIME BLHAZ SURV HAZNOW CUMHAZ NOPRINT ONEHEADER NOAPPEND FILE=PATAB > > Friederike Kanefendt > > - PhD-Student - > > University of Bonn, Germany > > -Clinical Pharmacy- > > Phone: +49 (0)228 73-5781 > > Fax: +49(0) 228 73-9757 > > [email protected] -- Nick Holford, Professor Clinical Pharmacology Dept Pharmacology& Clinical Pharmacology University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand tel:+64(9)923-6730 fax:+64(9)373-7090 mobile:+64(21)46 23 53 email: [email protected] http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford