PRECOND user guide

PRECOND user guide
PRECOND user guide
PsN 4.4.8
Revised 2015-04-17
In order to increase the numerical stability of the variance covariance matrix
computation, the precond script creates and runs a linearly re-parameterised
model of the original model that is less sensitive to rounding errors. We refer
to this process as preconditioning and the created model as the preconditioned model. Through numerical experiments[1] using published nonlinear
mixed effect models, it has been found that the preconditioning can reduce
the computational environment dependency, increase the chance of successful
covariance computation, and unveil un-identifiability of the model parameters.
Preconditioning will automatically first run the model normally and if the
covariance step fails get the R-matrix from that run using that to precondition the model. Obtained R-matrix is decomposed using eigendecomposition
and used to linearly re-parameterise the model in a way that the R-matrix of
the preconditioned model is close to an identity matrix. This will reduce the
influence of the rounding error for the computation of R matrix and often
avoid the R-matrix appearing to be non-positive semi-definite. The precond
script will initiate the modelfit of the preconditioned model and then convert back the obtained estimated parameter and covariance matrix to the
parameter scale of the original model.
Preconditioning can also be used for the modelfits with successful covariance step to verify that the resulting computation is not influenced by the
computational error.
Preconditioning of the model will only help to stabilise the computation
so that if the model is fundamentally unidentifiable (or have other issues)
then the covariance step of the preconditioned model should not be successful.
precond run1.mod
Input and options
Required input
The only required argument is a model file.
Optional input
With this option, the preconditioning will be conducted regardless of if the covariance step of the original model is successful or
not. Using this option and comparing raw_results_<modelname>.csv
and base_raw_results.csv, we can observe how much the result
of the standard error calculation is influenced by the computation instability. In addition by comparing the ofv and the estimated parameters appearing in raw_results_<modelname>.csv
and base_raw_results.csv, if the model is not identifiable, one
may find two different sets of parameters with the same maximised likelihood.
-pre = precond_dir1
With this option the user can also specify a directory. If the
modelfit directory is specified then the R-matrix is automatically extracted. If precond directory is specified then we can
precondition the already preconditioned model. This will allow
us to iteratively precondition deeply ill-conditioned model. In
order for the iterative preconditioning to work properly, “precMatrix" file should be unmodified and available in the specified
precond directory.
-pre = run1.rmt
With this option the user can manually specify the R-matrix
that will be used for preconditioning. In addition, a modelfit
directory created by the execute command of PsN can be specified and R-matrix will be extracted from the directory. In
addition, any symmetric matrix can be provided as a .csv file
or NONMEM matrix file; however, the specified matrix needs
to be similar to R-matrix to improve the computational stability (i.e., using covariance matrix will reduce the computational
-update_model = filename
Copy the model with updated inital thetas to your work directory
Optional input for methodological research
Use cholesky decomposition of the preconditioning matrix instead of eigendecomposition. With this option the preconditioning matrix provided by -pre option should be similar to
variance covariance matrix or the inverse of R matrix. (i.e., R
matrix should not be used with this option)
-cov = result.cov
This option will break the normal execution flow and only perform a conversion of a covariance matrix of the preconditioned
model to the covariance matrix of the original model. If this
option is set no model will be run.
With this option, precond will not execute any NONMEM run.
It will only compute the eigenvalues of the matrix that were to
be used for the preconditioning. Use this option with -verbose
Use LU decomposition of the preconditioning matrix instead
of eigendecomposition. With this option the preconditioning
matrix provided by -pre option should be similar to variance
covariance matrix or the inverse of R matrix. (i.e., R matrix
should not be used with this option)
Turn off decomposition of preconditioning matrix.
-output_model = run1_repara.mod
This option will break the normal execution flow and have precond only create the preconditioned model without running it.
The model will be created with the specified name.
After the model is preconditioned the initial estimate is perturbed to the direction of the eigenvector that is corresponding negative eigenvalue of the R-matrix. This will increase the
chance of finding the final parameter estimate that is not at
the saddle point so that the R-matrix of the preconditioned
model will be a positive semi-definite matrix.
Print the eigenvalues of the matrix that will be used to precondition the model.
-rawres_input = filename
Create the preconditioning matrix from the supplied raw_results
-offset_rawres = N
Only relevant in combination with -rawres_input. Default 1.
The number of result lines to skip in the input raw results file
before starting to read final parameter estimates. In a regular
bootstrap raw_results file, and also in an initial_estimates.csv
file from an sse run, the first line of estimates refers to the input
model with the full dataset, so therefore the default offset is 1.
-in_filter = comma separated list of conditions
Only relevant in combination with -rawres_input. Default not
used. The parameter estimates lines in the file can be filtered
on values in the different columns. When specifying which column(s) the filtering should be based on, the exact column name
must be used, e.g. minimization_successful. Filtering can only
be based on columns with numeric values. The allowed relations are .gt. (greater than), .lt. (less than) and .eq. (equal
to). If the value in the filter column is ’NA’ then that parameter set will be skipped, regardless of the defined filter relation.
Conditions are separated with commas. If the remaining number of lines after filtering is smaller than -samples, sse will stop
with an error message. Then the user must either change the
filtering rules or change -samples. If the user has created a file
with parameter estimates outside of PsN, filtering can be done
on any numeric column in that file. Do not set column headers
containing .eq. or .lt. or .gt. in the user-generated file as this
would interfere with the in_filter option syntax.
Output of the first normal run will copied as if running a regular execute to
the model directory. The raw_results can be found in the precond directory
under the name base_raw_results.csv If the preconditioning step was run the
results from that run will not be copied to your model directory but can be
found in the precond directory:
• The covariance matrix of the preconditioned run can be found in the
<modelname>.cov file
• Rawresults of the precondition run with parameters on the original
scale are in the raw_results_<modelname>.csv
• A copy of the model with updated initial estimates can be found in
In the terminal window, the precond script printout the condition number
of the R matrix that will be used to precondition. A larger condition number
means a more computationally unstable original model. If the covariance step
of the preconditioned model fails then the precond script will display the
eigenvalues of the R matrix of the preconditioned model with the condition
number and number of negative eigenvalues.
Known issues
• The current implementation cannot handle the model file with $MIX
• Preconditioning does not honour the original parameter bounds hence
the NONMEM run can fail if there are some implicit assumption on the
range of the parameters. For the parameters that need to be positive
(or negative) we suggest the users to absolute value of the parameter,
e.g., abs(THETA(1)).
• The current implementation of precond script only precondition THETA
variables, if the user wishes to precondition also the ETA and EPS
variables, we suggest the users to code ETA and EPS variables using
THETA, e.g., THETA(11)*EPS(1), $SIGMA 1 FIX.
• Using the option $COV MATRIX=R in the model will currently not
work. The user can use PRINT=R option to obtain R matrix and then
calculate 2R−1 outside of NONMEM (e.g., using R).
Actions if covariance step fails when preconditioning
• If covariance matrix cannot be obtained, run precond script with
-pre=precond_dir1 option.
Every time the covariance matrix cannot be obtained through preconditioning, a message on the command line would suggest the next option to
try. In addition, after every preconditioning, compare the raw_results files
in the original model fit directory and the precond directory to make sure
that OFV and esimated parameters are approximately the same. If OFVs
are similar and a parameter is significantly different, then the model is most
likely to be an unidentifiable model and no further attempt to obtain the
covariance matrix should be made.
Below is a simple diagram of the internal automated precond workflow. Some
automatic minor modifications of the model will be made before precond will
do its first run to make sure that the R-matrix will be created.
add COV,
to model
run model
covariance step
get R-matrix
from run
[1] Yasunori Aoki, Rikard Nordgren and Andrew C. Hooker, Preconditioning of Nonlinear Mixed Effect models for Stabilization of the
Covariance Matrix Computation, 2015, PAGE. Abstracts of the
Annual Meeting of the Population Approach Group in Europe,
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