More on Parametric and

Nonparametric Population
Modeling: a brief Summary

InTER-Individual Variability
The variability between subjects in a
population.
Usually a single number (SD, CV%)
in parametric population models
But there may be specific subpopulation
groups
eg, fast, slow metabolizers, etc.
How describe all this with one
number?
What will you DO with it?

Nonparametric Population Models (1)

Get the entire ML distribution, a DiscreteJoint
Density: one param set per subject, + its prob.
Shape of distribution not determined by some
equation, only by the data itself.
Multiple indiv models, up to one per subject.
Can discover, locate, unsuspected
subpopulations.
Get F from intermixed IV+PO dosage.

Nonparametric Population Models (2)

The multiple models permit multiple
predictions.
Can predict precision of goal
achievement by a dosage
regimen.
Behavior is consistent.
Use IIV +/or assay SD, stated ranges.

What is the IDEAL Pop Model?

The correct structural PK/PD Model.
The collection of each subjects exactly
known parameter values for that model.
Therefore, multiple individual models,
one for each subject.
Usual statistical summaries can also be
obtained, but usually will lose info.
How best approach this ideal? NP!

NPEM can find sub-populations that can be missed

by parametric techniques

True two-parameter density

Smoothed empirical density of

20 samples from true density

Conclusions
All parameter values pretty similar
Less variation seen with IT2B
But log likelihood the least
NPEM, NPAG more likely param distribs
No spuriously high param correlations
NPAG most likely param distributions
NPEM, NPAG best suited for MM dosage
NPEM, NPAG are consistent, precise.

New - Non-parametric adaptive grid algorithm (NPAG)

Initiate by solving the ML problem on a small grid

Refine the grid around the solution by adding perturbations in

each coordinate at each support point from optimal solution at
previous stage

Solve the ML problem on the refined grid (this is a small but

numerically sensitive problem)

Iterate solve-refine-solve cycle until convergence, using

decreasing perturbations

Best of both worlds - improved solution quality with far less

computational effort!

Asymptotic stochastic convergence rate of

IT2B is 1/N1/4 vs. 1/N1/2 for NPAG and P-EM
-1

Standard deviation of estimator of mean of V

10

NPAG
P-EM
IT2B

-2

10

10

10

N - number of subjects

10