+--------------------------------------------------------------------+ | | | MU_MODEL | | | +--------------------------------------------------------------------+ MEANING: CONTEXT: Abbreviated code USAGE: MU_3=LOG(THETA(3)) V=EXP(MU_3+ETA(3)) DISCUSSION: The new methods in NONMEM are most efficiently implemented if the user supplies information on how the THETA parameters are associated arith- metically with the etas and individual parameters, wherever such a relationship holds. Calling the individual parameters phi, the rela- tionship should be phi_i=mu_i(theta)+eta(i) for each parameter i that has an eta associated with it, and mu_i is a function of THETA. The association of one or more THETA's with ETA(1) must be identified by a variable called MU_1. Similarly, the associa- tion with ETA(2) is MU_2, that of ETA(5) is MU_5, etcetera. This is called "MU Referencing", or "MU Modelling". Providing this information is as straight-forward as introducing the MU_ variables into the $PRED or $PK code by expansion of the code. For a very simple example, the original code may have the lines CL=THETA(4)+ETA(2) This may be rephrased as: MU_2=THETA(4) CL=MU_2+ETA(2) Another example would be: CL=(THETA(1)*AGE**THETA(2))*EXP(ETA(5)) V=THETA(3)*EXP(ETA(3)) which would now be broken down into two additional lines, inserting the definition of a MU as follows: MU_5= LOG(THETA(1))+THETA(2)*LOG(AGE) MU_3=LOG(THETA(3)) CL=EXP(MU_5+ETA(5)) V=EXP(MU_3+ETA(3)) Note the arithmetic relationship identified by the last two lines, where MU_5+ETA(5) and MU_3+ETA(3) are expressed. This action does not change the model in any way. If the model is formulated by the traditional typical value (TV, mean), followed by individual value, then it is straight-forward to add the MU_ references as follows: TVCL= THETA(1)*AGE**THETA(2) CL=TVCL*EXP(ETA(5)) TVV=THETA(3) V=TVV*EXP(ETA(3) MU_3=LOG(TVV) MU_5=LOG(TVCL) This also will work because only the MU_x= equations are required in order to take advantage of EM efficiency. It is not required to use the MU_ variables in the expression EXP(MU_5+ETA(5)), since the fol- lowing are equivalent: CL=TVCL*EXP(ETA(5))=EXP(LOG(TVCL)+ETA(5)=EXP(MU_5+ETA(5)) but it helps as an exercise to determine that the MU_ reference was properly transformed (in this case log transformed) so that it repre- sents an arithmetic association with the eta. An incorrect usage of MU modeling would be: MU_1=LOG(THETA(1)) MU_2=LOG(THETA(2)) MU_3=LOG(THETA(3)) CL=EXP(MU_1+ETA(2)) V=EXP(MU_2+MU_3+ETA(1)) In the above example, MU_1 is used as an arithmetic mean to ETA(2), and a composite MU_2 and MU_3 are the arithmetic means to ETA(1), which would not be correct. The association of MU_x+ETA(x) must be strictly adhered to. Once one or more thetas are modeled to a MU, the theta may not show up in any subsequent lines of code. That is, the only usage of that theta may be in its connection with MU. For example, if CL=THETA(5)*EXP(ETA(2)) it can be rephrased as MU_2=LOG(THETA(5)) CL=EXP(MU_2+ETA(2)) But later, suppose THETA(5) is used without its association with ETA(2): ... CLZ=THETA(5)*2 Then THETA(5) cannot be MU modeled, because it shows up as associated with ETA(2) in one context, but as a fixed effect without association with ETA(2) elsewhere. However, if MU_2=LOG(THETA(5)) CL=EXP(MU_2+ETA(2)) CLZ=CL*2 Then this is legitimate, as the individual parameter CL retains the association of THETA(5) with ETA(2), when used to define CLZ. That is, THETA(5) and ETA(2) may not used separately in any other part of the model, except indirectly through CL, in which their association is retained. Suppose you have: CL=THETA(5)+THETA(5)*ETA(2) One should see this as: CL=THETA(5)*(1+ETA(2)) So the way to MU model this is: MU_2=1.0 CL=THETA(5)*(MU_2+ETA(2)) Which would mean that in the end, THETA(5) is not actually MU modeled, since MU_2 does not depend on THETA(5). One would be tempted to model as follows: MU_2=THETA(5) CL=MU_2+MU_2*ETA(2) But this would be incorrect, as MU_2 and ETA(2) may not show up together in the code except as MU_2+ETA(2) or its equivalent. Thus, THETA(5) cannot be MU modeled. In such cases, remodel to the follow- ing similar format: CL=THETA(5)*EXP(ETA(2)) So that THETA(5) may be MU modeled as: MU_2=LOG(THETA(5)) CL=EXP(MU_2+ETA(2)) Sometimes, a particular parameter has a fixed effect with no random effect, such as: Km=THETA(6) with the intention that Km is unknown but constant across all sub- jects. In such cases, the THETA(6) and Km cannot be Mu referenced, and the EM efficiency will not be available in moving this Theta. However, one could assign an ETA to THETA(5), and then fix its OMEGA to a small value, such as 0.0225 =0.15^2 to represent 15% CV, if OMEGA represents proportional error. This often will allow the EM algo- rithms to efficiently move this parameter, while retaining the origi- nal intent that all subjects have similar, although not identical, Km's. Very often, inter-subject variances to parameters were removed because the FOCE had difficulty estimating a large parametered prob- lem, and so it was an artificial constraint to begin with. EM methods are much more robust, and are adept at handling large, full block OMEGA's, so you may want to incorporate as many etas as possible when using the EM methods. You should Mu reference as many of the THETA's as possible, except those pertaining to residual variance (which should be modeled through SIGMA whenever possible). If you can afford to slightly change the theta/eta relationship a little to make it MU referenced without unduly influencing the model specification or the physiological mean- ing, then it should be done. When the arithmetic mean of an ETA is associated with one or more THETA's in this way, EM methods can more efficiently analyze the prob- lem, by requiring in certain calculations only the evaluation of the MU's to determine new estimates of THETAs for the next iteration, without having to re-evaluate the predicted value for each observa- tion, which can be computationally expensive, particularly when dif- ferential equations are used in the model. For those THETA's that do not have a relationship with any ETA's, and therefore cannot be MU referenced (including THETA's associated with ETAS whose OMEGA value is fixed to 0), computationally expensive gradient evaluations must be made to provide new estimates of them for the next iteration. There is additional increased efficiency in the evaluation of the problem if the MU models are linear functions with respect to THETA. Recalling one of the previous examples above, we could re-parameterize THETA such that MU_5=THETA(1)+THETA(2)*LOG(AGE) CL=EXP(MU_5+ETA(5)) MU_3=THETA(3) V=EXP(MU_3+ETA(3)) This changes the values of THETA(1) and THETA(3) such that the re- parameterized THETA(1) and THETA(3) are the logarithm of the original parameterization of THETA(1) and THETA(3). The models are identical, however, in that the same maximum likelihood value will be achieved. The only inconvenience is having to anti-log these THETA's during post-processing. The added efficiency obtained by maintaining linear relationships between the MU's and THETA's is greatest when using the SAEM method and the MCMC Bayesian method. In the Bayesian method, THETA's that are linearly modeled with the MU variables have linear relationships with respect to the inter-subject variability, and this allows the Gibbs sampling method to be used, which is much more efficient than the Metropolis-Hastings (M-H) method. By default, NONMEM tests MU- THETA linearity by determining if the second derivative of MU with respect to THETA is nearly or equal to 0. Those THETA parameters with 0 valued second derivatives are Gibbs sampled, while all other THETAS are M-H sampled. In the Gibbs sampling method, THETA values are sam- pled from a multi-variate normal conditional density given the latest PHI=MU+ETA values for each subject, and the samples are always accepted. In M-H sampling, the sampling density used is only an approximation, so the sampled THETA values must be tested by evaluat- ing the Some additional rules for MU referencing are as follows: 1) As much as possible, define the MU's in the first few lines of $PK or $PRED. Do not define MU_ values in $ERROR. Have all the MU's particularly defined before any additional verbatim code, such as write statements. NMTRAN produces a MUMODEL2 subroutine based on the PRED or PK subroutine in FSUBS.F90, and this MUMODEL2 subroutine is frequently called with the ICALL=2 set- tings, more often than PRED or PK. The fewer code lines that MUMODEL2 has to go through to evaluate all the MU_s' the more efficient. 2) Whenever possible, have the MU variables defined unconditionally, outside IF...THEN blocks. 3) Time dependent covariates cannot be part of the MU_ equation. For example MU_3=THETA(1)*TIME+THETA(2) should not be done. Or, consider MU_3=THETA(2)/WT Where WT varies with time. This would also not be suitable. However, we could phrase as MU_3=THETA(2) CL=WT*(MU_3+ETA(3)) is fine, where MU_3 represents a population mean clearance per unit weight, which is constant with time, and more universal among subjects, whereas CL is the non-wieght normalized clear- ance, than depends on a person's weight, which could vary with time as well. The MU variables may vary with inter-occasion, but not with time. 4) Starting with NONMEM 7.2, NMTRAN's CHECKMU subroutine attempts to | look for errors in MU modeling. If it appears that there may be | errors, then there are messages such as | (MU_WARNING 13) MU_001: DOES NOT HAVE ADDITIVE ASSOCIATION WITH ETA(001)| Such warnings do not affect the outputs from NMTRAN. FSUBS is | generated as usual. Sometimes the warnings may be ignored (see | "Model parameters as log t-Distributed", below.) Sometimes warn- | ings may not be generated when they should be. Thus, the user | must pay close attention to following the rules. | Option NOCHECKMU of the $ABBR record may be used to prevent NM- | TRAN from attempting to check the MU model statements. Examples show examples of MU modeling for various problem types. Study these examples carefully. When transposing your own code, begin with simple problems and work your way to more complex problems. At this point one may wonder why bother inserting MU references in your code. MU referencing only needs to be done if you are using one of the new EM or Gibbs sampling methods to improve their efficiency. The EM methods may be performed without MU references, but it will be several fold slower than the FOCE method, and the problem may not even optimize successfully. For simple two compartment models, the new EM methods are slower than FOCE even with the MU references. But, for 3 compartment models, or numerical integration problems, the improvement in speed by the EM methods, properly MU modeled, can be 5-10 fold faster than with FOCE. Example 6 described at the end of the SIGL section is one example where importance sampling solves this problem in 30 minutes, with R matrix standard error, versus FOCE which takes 2-10 hours or longer, and without even requesting the $COV step. So, for complex PK/PD problems that take a very long time in FOCE, it is well worth putting in MU references and using one of the EM methods, even if you may need to rephrase some of the fixed/random (theta/eta) effects relation- ships. In addition, FOCE is a linearized optimization method, and is less accurate than the EM and Bayesian methods when data are sparse or when the posterior density for each individual is highly non-normal. Model parameters as log t-Distributed in the Population | Sometimes one may suspect that PK/PD model parameters are actually log | t-distributed among the population, with degrees of freedom NU, | instead of the usual log normal distributed. | See INTRODUCTION TO NONMEM 7, MU Referencing | An example of simulation and analysis of such data is given as | ..\examples\tdist6_sim.ctl | ..\examples\tdist6.ctl: | ..\examples\tdist7.ctl | Note that constructions such as | CL=EXP(MU_1+ETA(1)*SQRT((EXP(CLR)-1.0)/CLR)) | violate the strict MU_x+ETA(x) rule recommended for EM analysis, | because the term SQRT((EXP(CLR)-1.0)/CLR) is multiplied by ETA(1). | NM-TRAN will generate a number of MU_WARNING messages. Nonetheless | for this example, the importance sampling works quite well, and the | MU_WARNING messages may be ignored. REFERENCES: Guide Introduction_7Go to main index.Created by nmhelp2html v. 1.0 written by Niclas Jonsson (Modified by AJB 5/2006,11/2007,10/2012)