Dear R-users My problem is the following: 1) Suppose we have the data test.txt: Data has form: Subject age test (=binary variable) 1 0.6 0 2 2 1 3 0.9 1 ... 2) I would like solving the following differential equations: dA/dt = u*A + v*B dB/dt = -v*B -u*A in addition, the parameter u=k*t where k is a constant and t is the time. How could I implement that into nlmeODE? I tried the following procedure: a) Apply the nlmeODE function dataModel=groupedData(formula=test~age|Subject, data=read.table("E:/test.txt",header=T), labels=list(x="Age",y="testpositiv"), units=list(x="(year)",y="(+/-)")) modelform <- list(DiffEq=list( dSdt = ~ u*I-b*S, dIdt = ~ -u*I+b*S, dbdt = ~ -k ), ObsEq=list( c1 = ~ S, c2 = ~ 0, c3 = ~ 0), States=c("S","I","b"), Parms=c("u","k","start"), Init=list("start",0,0.3)) Modeleasy <- nlmeODE(modelform,dataModel) b) as far as good, now the problem if I run an estimation Modeleasy.nlme <- nlme(test ~ Modeleasy(u,k,start,age,Subject), data = dataModel, fixed=u+k+start~1, random = pdDiag(start+u~1), start=c(u=5.7,k=-2,start=-5.9), control=list(msVerbose=TRUE,tolerance=1e-1,pnlsTol=1e-1,msTol=1e-1), verbose=TRUE) plot(augPred(Modeleasy.nlme,level=0:1)) => I get always an error message "leading Minor of degree 2 is not positiv definit" Hope anybody can help me or propose an alternative method to solve that problem. Thanks a lot. Best regs... -- Dominik Heinzmann Master of Science in Mathematics, EPFL Ph.D. student in Biostatistics Institute of Mathematics University of Zurich