In pmxcode: Create Pharmacometric Models

Instructions

This pmxcode module supports the creation of univariate models for execution of stepwise covariate analysis in NONMEM. This is implemented sequentially for each step of forward covariate selection and backward elimination. For each step, 3 actions are required and are performed in one of the tab panels:

The selection of a reference model (in REFERENCE MODEL)
The definition of parameter/covariate relationships (in COVARIATE EFFECTS)
The creation of the univariate models (in UNIVARIATE MODELS)

Reference model

In this panel, you must upload a reference model for the intended step of each step of forward covariate selection and backward elimination. This is done using the SELECT REFERENCE MODEL button. Once uploaded, the model code is shown in a text editing field that allows you to make any modification you see fit.

Note that that this pmxcode module relies on the NONMEM coding and commenting conventions implemented in its model library module. In particular, it requires that the typical value of any parameter X is defined by the TVX variable. Additionally, because the module assumes independence between additive and multiplicative covariate effects, the module requires that the intercept part of the typical value of any parameter X is defined by the TVXI variable.

To facilitate the implementation of these requirements, at step 1 of forward covariate selection, you can use the CONVERT button to automatically modify the code of the uploaded reference model. This modified version will be used as reference for creation of univariate models instead of the uploaded code.

Definition of parameter/covariate relationships

Parameter/covariate relationships are defined for each step of the forward selection or backward elimination stages using the table provided in the interface. Since NONMEM execution can take time, the covariate effect definitions can be saved (using the button) in a .csv file and later uploaded (using the ) for further modifications.

The interface table includes multiple columns:

Parameter and covariate must be entered as single variables in the eponymous columns (using alphanumeric characters only);
The Type column defines whether the covariate is discrete or continuous variables;
The Functional form column defines the mathematical form of the relationship: "Linear", "Power", or "Exponential" for continuous variables and "Additive", "Proportional", or "Direct proportional" for discrete variables;
Any centering value of the covariate effect must be entered in the Center value for continuous covariate;
The initial estimate of the covariate effect must be entered in the eponymous column;
For discrete covariates with > 2 categories, non-reference categories are each associated with a specific dichotomous flag and initial estimate. The flags must be entered in the Dichotomous flags for discrete covariate column separated by colons without spaces and estimates must be entered in a similar fashion (and corresponding order) in the Initial estimate column. For instance, to define the effects of renal function categories, one can enter "RFMILD:RFMOD:RFSEV" in the flag column and "0.1:0.2:0.3" in the estimate column.
The Action column defines what action will be taken based upon the information entered in the row: "Create" to create a control stream, "Do not create" to perform no action, "Select" to indicate that the covariate effect was selected at a particular forward selection step, and "Remove" to indicate that the covariate effect to be removed at a particular backward elimination step.

Use the and buttons to add and delete rows in the interface table. Table content can also be copied () and pasted (). You can also click on to create a new step by duplicating the content of the current step (selected covariate effect will be filtered out based upon the Action column selection). For step 1 of backward elimination, you can also click on to extract the list of parameter/covariate relationships that were previously included in the reference model.

Note that :

The variables (parameters, covariates, and flags) must be defined in the NONMEM control stream in the \$INPUT, \$PRED, or \$PK block.
If covariates and flags need to be defined in the control stream, this must be done prior to ;-- COVARIATE EFFECT START.
The downloaded .csv files will contain the following data column: Stage, Step, Parameter, Covariate, Type, Function, Center, Flags, Initial, and Action.

Creation of univariate models

Univariate models are automatically created by click on the CREATE button after selecting the stage of analysis ("Forward selection" or "Backward elimination") and the step of analysis (1, 2, 3, etc.). Optionally, you can define the folder in which the univariate model files will be saved using the SELECT MODEL DIRECTORY. You will have to download and save the files at this location using the EXTRACT ALL button. This button only shows up after creation of the univariate runs.

Nota that, if the uploaded reference model uses PsN convention, the univariate model files will be named runX.mod, with X being a 3 or 4-digit number starting at the value set in the field entitled "Run nº start at". If the uploaded reference model uses standard NONMEM convention and a user-defined named, the univariate model files will use a different naming convention: \<prefix>-\<parameter>-\<covariate>-\<function>-\<number>.ctl

where \<prefix> is the value set in the FIlename prefix field, \<parameter> and \<covariate> are the variables involved in the relationship, \<function> is either "lin", "pow", "exp", "add", "prop" or "dirprop" based upon the selected functional form, and \<number> is a 2-digit number.

After creation of the univariate model code, you can see the content of each file in LIST OF UNIVARIATE MODELS tab and look at checks performs across all univariate models in the CHECKS tab.