I select a column (WT) in my dataset as a covariate.
When I set up the covariate in the nlme fitting page (interactively, not programming*) I scale by the mean WT (I would prefer to scale by a user-set model parameter such as WT_baseline, but the program doesn't allow this) and use the checkbox to do a log transform.
This gives me tWT = log(WT/mean(WT)) which should be the same as tWT = log(WT) - log(mean(WT))
I specify clearance, CL, as [ ln(Phi_CL) ] = exp(theta1 + theta5 * tWT + eta1), using the drop down menu to specify the form.
I also specify other parameters such as intercompartmental clearance, Q, and two volumes in the same way. For example, [ ln(Phi_Q) ] = exp(theta2 + theta6 * tWT + eta2)
This yields a value for the estimate of CL, Phi_CL = exp(theta1) * exp(eta1) * exp(ln(WT/WT_baseline))^theta5, or more clearly
[ Phi_CL ] = exp(theta1) * exp(eta1) * (WT/WT_baseline)^theta5
Also [ Phi_Q ] = exp(theta2) * exp(eta2) * (WT/WT_baseline)^theta6
Similar equations for V2 and V3 follow (with theta3 and theta7, and theta3 and theta8). These equations are identical to ones that have been used successfully in a NONMEM model.
If I run the nlme fit, I get Message:
'CL = exp(theta1 + theta5 * log((WT/mean(WT))) + eta1)' is not a valid parameter covariate relationship. Type 'help CovariateModel' for more information.
Additional Messages For This Source: Message:
FixedEffectValues should be a structure with exactly one field for each fixed effect.
So the drop-down menu let me astray I guess. But the weird thing is, if I untick the "log" tick box for the covariate, the model at least runs. So, three questions.
1) What am I doing wrong in setting up the problem?
2) I guess I could create a derived value column that is ln(WT/75), and used this column, untransformed, as my covariate. In fact, I just tried this and it works fine. Is this how others are doing this?
3) I'd like to fit a smaller set of estimated values. To do so, it is common to assume that a common "flux exponent" will work to scale the clearances, and a "volume exponent" will suffice for the volumes (see “Mechanism-Based Concepts of Size and Maturity in Pharmacokinetics”, Anderson and Holford, Annu. Rev. Pharmacol. Toxicol. 2008). But
Phi_CL = exp(theta1 + eta1 + theta5 * tWt)
Phi_Q = exp(theta2 + eta2 + theta5 * tWt) % note that CL and Q both have theta5 as the flux exponent
Phi_V2 = exp(theta3 + eta3 + theta6 * tWt)
Phi_V3 = exp(theta4 + eta4 + theta6 * tWt) % note that V2 and V3 both have theta6 as the flux exponent
which eliminates theta 7 and 8, throws an error even in setup, before I can kick off a fit. Is this doable?