Add getRxNpars to api. This allows the development version of
babelmixr2 to better check what model is loaded and unload/reload
as necessary.
Add rxUdfUiControl() to rxode2 user function to get control
information from something like nlmixr2
Bug fix for api, the censoring function pointer has been updated
(#801).
Query rxode2.verbose.pipe at run time instead of requiring it to
be set before loading rxode2.
Have correct values at boundaries for logit, expit, probit,
and probitInv (instead of NA). For most cases this does not
break anything.
Add a new style of user function that modifies the ui while
parsing or just before using the function (in the presence of
data).
Used the new user function interface to allow all random functions
in rxode2 ui functions to be named. For example, you can use
rxnorm(sd=3) instead of having to use rxnorm(0, 3), although
rxnorm() still works.
The model properties was moved from $params to $props so it does
not conflict with the low level rxode2 model $params
Error when specifying wd without modName
With Linear and midpoint of a time between two points, how rxode2
handles missing values has changed. When the missing value is lower
than the requested time, it will look backward until it finds the
first non-missing value (or if all are missing start looking
forward). When the missing value is higher than the requested time,
the algorithm will look forward until it finds the first non-missing
value (or if all are missing, start looking backward).
The order of ODEs is now only determined by the order of cmt() and
d/dt(). Compartment properties, tad() and other compartment
related variables no no longer affect compartment sorting. The
option rxode2.syntax.require.ode.first no longer does anything.
The handling of zeros "safely" has changed (see #775)
when safeZero=TRUE and the denominator of a division expression
is zero, use the Machine's small number/eps (you can see this
value with .Machine$double.eps)
when saveLog=TRUE and the x in the log(x) is less than or
equal to zero, change this to log(eps)
when safePow=TRUE and the expression x^y has a zero for x
and a negative number for y replace x with eps.
Since the protection for divide by zero has changed, the results will also change. This is a more conservative protection mechanism than was applied previously.
Random numbers from rxode2 are different when using dop853,
lsoda or indLin methods. These now seed the random numbers in
the same way as liblsoda, so the random number provided will be
the same with different solving methods.
The arguments saved in the rxSolve for items like thetaMat will
be the reduced matrices used in solving, not the full matrices (this
will likely not break very many items)
iCov is no longer merged to the event dataset. This makes solving
with iCov slightly faster (#743)You can remove covariances for every omega by piping with %>% ini(diag()) you can be a bit more granular by removing all
covariances that have either eta.ka or eta.cl by: %>% ini(diag(eta.ka, eta.cl)) or anything with correlations with
eta.cl with %>% ini(diag(eta.cl))
You can also remove individual covariances by %>% ini(-cov(a, b))
or %>% ini(-cor(a,b)).
You can specify the type of interpolation applied for added dosing
records (or other added records) for columns that are kept with the
keep= option in rxSolve(). This new option is
keepInterpolation and can be locf for last observation carried
forward, nocb which is the next observation carried backward, as
well as NA which puts a NA in all imputed data rows. See #756.
Note: when interpolation is linear/midpoint for factors/characters it changes to locf with a warning (#759)
Also note, that the default keep interpolation is na
Now you can specify the interpolation method per covariate in the model:
linear(var1, var2) says both var1 and var2 would use linear
interpolation when they are a time-varying covariate. You could
also use linear(var1)
locf() declares variables using last observation carried forward
nocb() declares variables using next observation carried backward
midpoint() declares variables using midpoint interpolation
linear(), locf(), locb(), midpoint(), params(), cmt()
and dvid() declarations are now ignored when loading a rxode2
model with rxS()
Strings can be assigned to variables in rxode2.
Strings can now be enclosed with a single quote as well as a double
quote. This limitation was only in the rxode2 using string since
the R-parser changes single quotes to double quotes. (This has no
impact with rxode2({}) and ui/function form).
More robust string encoding for symengine (adapted from
utils::URLencode() and utils::URLdecode())
Empty arguments to rxRename() give a warning (#688)
Promoting from covariates to parameters with model piping (via ini()) now
allows setting bounds (#692)
Added assertCompartmentName(), assertCompartmentExists(),
assertCompartmentNew(), testCompartmentExists(),
assertVariableExists() testVariableExists(),
assertVariableNew(), assertVariableName(), and
assertParameterValue() to verify that a value is a valid nlmixr2
compartment name, nlmixr2 compartment/variable exists in the model,
variable name, or parameter value (#726; #733)
Added assertRxUnbounded(), testRxUnbounded(), warnRxBounded()
to allow nlmixr2 warn about methods that ignore boundaries #760
Added functions tad0(), tafd0(), tlast0() and tfirst0() that
will give 0 instead of NA when the dose has not been
administered yet. This is useful for use in ODEs since NAs will
break the solving (so can be used a bit more robustly with models
like Weibull absorption).
rxode2 is has no more binary link to lotri, which means that
changes in the lotri package will not require rxode2 to be
recompiled (in most cases) and will not crash the system.
rxode2 also has no more binary linkage to PreciseSums
The binary linkage for dparser is reduced to C structures only,
making changes in dparser less likely to cause segmentation faults
in rxode2 if it wasn't recompiled.
A new model property has been added to $props$cmtProp and
$statePropDf. Both are data-frames showing which compartment has
properties (currently ini, f, alag, rate and dur)
in the rxode2 ui model. This comes from the lower
level model variable $stateProp which has this information
encoded in integers for each state.
A new generic method rxUiDeparse can be used to deparse meta
information into more readable expressions; This currently by
default supports lower triangular matrices by lotri, but can be
extended to support other types of objects like 'nlmixr2's
foceiControl() for instance.
Fix ui$props$endpoint when the ui endpoint is defined in terms of
the ode instead of lhs. See #754
Fix ui$props when the ui is a linear compartment model without ka defined.
Model extraction modelExtract() will now extract model properties. Note that the model property of alag(cmt) and lag(cmt) will give the same value. See #745
When assigning reserved variables, the parser will error. See #744
Linear interpolation will now adjust the times as well as the values
when NA values are observed.
Fix when keeping data has NA values that it will not crash R; Also
fixed some incorrect NA interpolations. See #756
When using cmt() sometimes the next statement would be corrupted
in the normalized syntax (like for instance locf); This bug was
fixed (#763)
keep will now error when trying to keep items that are in the
rxode2 output data-frame and will be calculated (#764)
rxode2parse, rxode2random, and
rxode2et into this package; The changes in each of the packages are
now placed here:Make the stacking more flexible to help rxode2 have more types of plots
Add toTrialDuration by Omar Elashkar to convert event data to trial duration data
Fix Issue #23 and prefer variable values over NSE values
Fix dollar sign accessing of objects (like data frames), as pointed out by @frbrz (issue #16)
Use rxode2parse functions for internal event table creation (where
they were moved to).
Dropped C++14 and let the system decide.
Split off et(), eventTable() and related functions.
Also split off rxStack() and rxCbindStudyIndividual() in this
package.
Added a NEWS.md file to track changes to the package.
<random> to boost::random. Since this is not dependent on the
compiler, it makes the random numbers generated from Mac, Windows
and Linux the same for every distribution. Unfortunately with a new
random number transformation, the simulation results will likely be
different than they were before. The exception to this is the
uniform number, which was always the same between platforms.m1mac)Added function dfWishart which gives (by simulation) an
approximation of the degrees of freedom of a Wishart to match a
rse value.
Added function swapMatListWithCube which swaps omegaList with
omegaCube values
Ensure that the outputs are integers (instead of long integers) as requested by CRAN for some checking functions.
rxode2parse to allow etTrans to be moved thereInitial release of rxode2random, which separates the parallel
safe, random number generation from 'rxode2' into a separate package to
reduce 'rxode2' compilation time. This should make CRAN maintenance
a bit easier.
Added a NEWS.md file to track changes to the package.
SET_TYPEOF which is no
longer part of the C R API.Added a evid suffix of 60 for cases where evid=2 adds an on event (fixes tad() calculation in certain edge cases)
Initialize all variables to NA
Removed linear compartment solutions with gradients from rxode2parse (and rxode2) when compiled with intel c++ compiler (since it crashes while compiling).
Fixed m1mac string issues as requested by CRAN
Added ability to query R user functions in a rxode2 model (will force single threaded solve)
Moved core rxFunParse and rxRmFunParse here so that C and R user
function clashes can be handled
Model variables now tracks which compartments have a lag-time defined
For compartment with steady state doses (NONMEM equivalent SS=1,
SS=2), an additional tracking time-point is added at to track the
time when the lagged dose is given. As an upshot, the lagged dose
will start at the steady state concentration shifted by + ii - lag
in rxode2 (currently for ode systems only)
This release calculates non bio-availability adjusted duration for all rates instead of trying to figure the rate duration during solving.
Make double assignment an error, ie a <- b <-
NA times are ignored (with warning)
Steady state bolus doses with addl are treated as non steady state
events (like what is observed in NONMEM)
Timsort was upgraded; drop radix support in rxode2 structure
etTrans now supports keeping logical vectors (with the appropriate
version of rxode2).
Security fixes were applied as requested by CRAN
data.table explicitly in the R code (before was imported only in C/C++ code)'linCmt()' translations of 'alpha', 'beta', 'gamma', 'k21', 'k31', 'vc' now error instead of ignoring 'gamma' and 'k31' to give 2 cmt solution
transit compartment internal code now changes dose to 0.0 when no
dose has been administered to the depot compartment. This way dosing
to the central compartment (without dosing to the transit
compartment) will not give a NA for the depot compartment (and
consequently for the central compartment)
Moved rxDerived here and added tests for it here as well.
Moved etTransParse here and added tests for it here as well (makes
up most of etTrans). In addition the following changes were made
to etTransParse()/etTrans():
The internal translation (etTrans()) will not drop times when
infusions stop. Before, if the infusion stopped after the last
observation the time when the infusion stopped would be dropped.
This interferes with linCmt() models.
Breaking change/bug fix evid=2 are considered observations when
translating data to internal rxode2 event structure
Fix edge case to find infusion duration when it is the first item of the dosing record at time 0.
Fixed a bug for certain infusions where the rate, ii and/or
ss data items were dropped from the output when addDosing=TRUE
Also have internal functions to convert between classic NONMEM events and rxode2 events
Have an internal function that gives information on the linear compartmental model translation type, which could be useful for babelmixr2
'time' in model is now case insensitive
Use function declaration in rxode2parseGetTranslation() to
determine thread safety of functions available to rxode2
Add check for correct number of function arguments to parser.
Like R, known functions can be assigned as a variable and the
function can still be called (while not changing the variable
value). For example you can have a variable gamma as well as a
function gamma().
Fix garbled error messages that occur with certain messages.
Fixed errors that occurred when using capitalized AMT variables in the model.
Bug fix for strict prototypes
Removed sprintf as noted by CRAN
Made rxode2parse dll binary independent of rxode2()
Make sure that the object is a uncompressed rxode2 ui for solving with rxSolve (See #661)
Fix #670 by using the last simulated observation residual when there are trailing doses.
Create a function to see if a rxode2 solve is loaded in memory
(rxode2::rxSolveSetup())
Create a new function that fixes the rxode2 population values in the
model (and drops them in the initial estimates); rxFixPop()
Pendantic no-remap (as requested by CRAN)
gcc USBAN fix (as requested by CRAN)
rxUi compression now defaults to fast compression
Fixes String literal formatting issues as identified by CRAN (#643)
Removes linear compartment solutions with gradients for intel c++ compiler (since they crash the compiler).
Steady state with lag times are no longer shifted by the lag time
and then solved to steady state by default. In addition the steady
state at the original time of dosing is also back-calculated. If you
want the old behavior you can bring back the option with
ssAtDoseTime=FALSE.
"dop853" now uses the hmax/h0 values from the rxControl() or
rxSolve(). This may change some ODE solving using "dop853"
When not specified (and xgxr is available), the x axis is no longer assumed to be in hours
User defined functions can now be R functions. For many of these R
functions they can be converted to C with rxFun() (you can see the
C code afterwards with rxC("funName"))
Parallel solving of models that require sorting (like modeled lag times, modeled duration etc) now solve in parallel instead of downgrading to single threaded solving
Steady state infusions with a duration of infusions greater than the inter-dose interval are now supported.
Added $symengineModelNoPrune and $symengineModelPrune for
loading models into rxode2 with rxS()
When plotting and creating confidence intervals for multiple
endpoint models simulated from a rxode2 ui model, you can
plot/summarize each endpoint with sim. (ie. confint(model, "sim") or plot(model, sim)).
If you only want to summarize a subset of endpoints, you can focus
on the endpoint by pre-pending the endpoint with sim. For example
if you wanted to plot/summarize only the endpoint eff you would
use sim.eff. (ie confint(model, "sim.eff") or plot(model, sim.eff))
Added model$simulationIniModel which prepend the initial
conditions in the ini({}) block to the classic rxode2({}) model.
Now model$simulationModel and model$simulationIniModel will save
and use the initialization values from the compiled model, and will
solve as if it was the original ui model.
Allow ini(model) <- NULL to drop ini block and as.ini(NULL)
gives ini({}) (Issue #523)
Add a function modelExtract() to extract model lines to allow
modifying them and then changing the model by piping or simply
assigning the modified lines with model(ui) <- newModifiedLines
Add Algebraic mu-referencing detection (mu2) that allows you to express mu-referenced covariates as:
cl <- exp(tcl + eta.cl + wt_cl * log(WT/70.5))
Instead of the
cl <- exp(tcl + eta.cl + wt_cl * log.WT.div.70.5)
That was previously required (where log.WT.div.70.5 was calculated
in the data) for mu expressions. The ui now has more information to
allow transformation of data internally and transformation to the old
mu-referencing style to run the optimization.
Allow steady state infusions with a duration of infusion greater than the inter-dose interval to be solved.
Solves will now possibly print more information when issuing a "could not solve the system" error
The function rxSetPipingAuto() is now exported to change the way you
affect piping in your individual setup
Allow covariates to be specified in the model piping, that is mod %>% model(a=var+3, cov="var") will add "var" as a covariate.
When calculating confidence intervals for rxode2 simulated objects
you can now use by to stratify the simulation summary. For
example you can now stratify by gender and race by: confint(sim, "sim", by=c("race", "gender"))
When calculating the intervals for rxode2 simulated objects you
can now use ci=FALSE so that it only calculates the default
intervals without bands on each of the percentiles; You can also
choose not to match the secondary bands limits with levels but use
your own ci=0.99 for instance
A new function was introduced meanProbs() which calculates the
mean and expected confidence bands under either the normal or t
distribution
A related new function was introduced that calculates the mean and
confidence bands under the Bernoulli/Binomial distribution
(binomProbs())
When calculating the intervals for rxode2 simulated objects you
can also use mean=TRUE to use the mean for the first level of
confidence using meanProbs(). For this confidence interval you can
override the n used in the confidence interval by using n=#. You
can also change this to a prediction interval instead using
pred=TRUE.
Also when calculating the intervals for rxode2 simulated object
you can also use mean="binom" to use the binomial distributional
information (and ci) for the first level of confidence using
binomProbs(). For this confidence interval you can override the
n used in the confidence interval by using n=#. You can also
change this to a prediction interval instead using pred=TRUE. With
pred=TRUE you can override the number of predicted samples with
m=#
When plotting the confint derived intervals from an rxode2
simulation, you can now subset based on a simulated value like
plot(ci, Cc) which will only plot the variable Cc that you
summarized even if you also summarized eff (for instance).
When the rxode2 ui is a compressed ui object, you can modify the ini
block with $ini <- or modify the model block with $model <-.
These are equivalent to ini(model) <- and model(model) <-,
respectively. Otherwise, the object is added to the user defined
components in the function (ie $meta). When the object is
uncompressed, it simply assigns it to the environment instead (just
like before).
When printing meta information that happens to be a lotri
compatible matrix, use lotri to express it instead of the default
R expression.
Allow character vectors to be converted to expressions for piping (#552)
rxAppendModel() will now take an arbitrary number of models and
append them together; It also has better handling of models with
duplicate parameters and models without ini() blocks (#617 / #573
/ #575).
keep will now also keep attributes of the input data (with special
handling for levels); This means a broader variety of classes will
be kept carrying more information with it (for example ordered
factors, data frame columns with unit information, etc)
Piping arguments append for ini() and model() have been
aligned to perform similarly. Therefore ini(append=) now can take
expressions instead of simply strings and model(append=) can also
take strings. Also model piping now can specify the integer line
number to be modified just like the ini() could. Also
model(append=FALSE) has been changed to model(append=NULL).
While the behavior is the same when you don't specify the argument,
the behavior has changed to align with ini() when piping. Hence
model(append=TRUE) will append and model(append=FALSE) will now
pre-pend to the model. model(append=NULL) will modify lines like
the behavior of ini(append=NULL). The default of model(line)
modifying a line in-place still applies. While this is a breaking
change, most code will perform the same.
Labels can now be dropped by ini(param=label(NULL)). Also
parameters can be dropped with the idiom model(param=NULL) or
ini(param=NULL) changes the parameter to a covariate to align with
this idiom of dropping parameters
rxRename has been refactored to run faster
Add as.model() for list expressions, which implies model(ui) <- ui$lstExpr will assign model components. It will also more
robustly work with character vectors
Simulated objects from rxSolve now can access the model variables
with $rxModelVars
Simulation models from the UI now use rxerr.endpoint instead of
err.endpoint for the sigma residual error. This is to align
with the convention that internally generated variables start with
rx or nlmixr
Sorting only uses timsort now, and was upgraded to the latest version from Morwenn
Simulating/solving from functions/ui now prefers params over omega
and sigma in the model (#632)
Piping does not add constants to the initial estimates
When constants are specified in the model({}) block (like k <- 1), they will not
be to the ini block
Bug fix for geom_amt() when the aes transformation has x
Bug fix for some covariate updates that may affect multiple compartment models (like issue #581)
xgxrCRAN requested that FORTRAN kind be changed as it was not portable;
This was commented code, and simply removed the comment.
Bug-fix for geom_amt(); also now uses linewidth and at least ggplot2 3.4.0
Some documentation was cleaned up from rxode2 2.0.13
A bug was fixed so that the zeroRe() function works with correlated omega
values.
A bug was fixed so that the rename() function works with initial
conditions for compartments (cmt(0))
A new function zeroRe() allows simple setting of omega and/or sigma values
to zero for a model (#456)
Diagonal zeros in the omega and sigma matrices are treated as
zeros in the model. The corresponding omega and sigma matrices
drop columns/rows where the diagonals are zero to create a new
omega and sigma matrix for simulation. This is the same idiom
that NONMEM uses for simulation from these matrices.
Add the ability to pipe model estimates from another model by
parentModel %>% ini(modelWithNewEsts)
Add the ability to append model statements with piping using %>% model(x=3, append=d/dt(depot)), still supports appending with
append=TRUE and pre-pending with append=NA (the default is to
replace lines with append=FALSE)
rxSolve's keep argument will now maintain character and factor classes from input data with the same class (#190)
Parameter labels may now be modified via ini(param = label("text")) (#351).
Parameter order may be modified via the append argument to ini()
when piping a model. For example, ini(param = 1, append = 0) or
ini(param = label("text"), append = "param2") (#352).
If lower/upper bounds are outside the required bounds, the adjustment is displayed.
When initial values are piped that break the model's boundary condition reset the boundary to unbounded and message which boundary was reset.
Added as.rxUi() function to convert the following objects to
rxUi objects: rxode2, rxModelVars, function. Converting
nlmixr2 fits to rxUi will be placed in the s3 method in the
corresponding package.
assertRxUi(x) now uses as.rxUi() so that it can be extended
outside of rxode2/nlmixr2.
rxode2 now supports addl with ss doses
Moved rxDerived to rxode2parse (and re-exported it here).
Added test for transit compartment solving in absence of dosing to the
transit compartment (fixed in rxode2parse but solving tested
here)
Using ini() without any arguments on a rxode2 type function will
return the ini() block. Also added a method ini(mod) <- iniBlock to modify the ini block is you wish. iniBlock should
be an expression.
Using model() without any arguments on a rxode2 type function
will return the model() block. Also added a new method
model(mod) <- modelBlock
Added a new method rxode2(mod) <- modFunction which allows
replacing the function with a new function while maintaining the
meta information about the ui (like information that comes from
nonmem2rx models). The modFunction should be the body of the
new function, the new function, or a new rxode2 ui.
rxode2 ui objects now have a $sticky item inside the internal
(compressed) environment. This $sticky tells what variables to
keep if there is a "significant" change in the ui during piping or
other sort of model change. This is respected during model piping,
or modifying the model with ini(mod)<-, model(mod)<-,
rxode2(mod)<-. A significant change is a change in the model
block, a change in the number of estimates, or a change to the value
of the estimates. Estimate bounds, weather an estimate is fixed or
estimate label changes are not considered significant.
Added as.ini() method to convert various formats to an ini
expression. It is used internally with ini(mod)<-. If you want to
assign something new that you can convert to an ini expression, add
a method for as.ini().
Added as.model() method to convert various formats to a model
expression. It is used internally with model(mod)<-. If you want to
assign something new that you can convert to a model expression, add
a method for as.model().
Give a more meaningful error for 'rxode2' ui models with only error expressions
Break the ABI requirement between roxde2() and rxode2parse()
The new rxode2parse will fix the sprintf exclusion shown on CRAN.
Time invariant covariates can now contain 'NA' values.
When a column has 'NA' for the entire id, now 'rxode2' warns about both the id and column instead of just the id.
To fix some CRAN issues in 'nlmixr2est', make the version dependency explicit.
Remove log likelihoods from 'rxode2' to reduce compilation time and increase maintainability of 'rxode2'. They were transferred to 'rxode2ll' (requested by CRAN).
Remove the parsing from 'rxode2' and solved linear compartment code and move to 'rxode2parse' to reduce the compilation time (as requested by CRAN).
Remove the random number generation from 'rxode2' and move to 'rxode2random' to reduce the compilation time (as requested by CRAN).
Remove the event table translation and generation from 'rxode2' and move to 'rxode2et' to reduce the compilation time (as requested by CRAN).
Change the rxode2 ui object so it is a compressed, serialized
object by default. This could reduce the C stack size problem
that occurs with too many environments in R.
Warn when ignoring items during simulations
Export a method to change 'rxode2' solve methods into internal integers
Bug fix for time invariant covariates identified as time variant
covariate when the individual's time starts after 0.
rxgamma now only allows a rate input. This aligns with the
internal rxode2 version of rxgamma and clarifies how this will
be used. It is also aligned with the llikGamma function used for
generalized likelihood estimation.
ui cauchy simulations now follow the ui for normal and t
distributions, which means you can combine with transformations.
This is because the cauchy is a t distribution with one degree
of freedom.
ui dnorm() and norm() are no longer equivalent to add(). Now
it allows you to use the loglik llikNorm() instead of the standard
nlmixr2 style focei likelihood. This is done by adding dnorm()
at the end of the line. It also means dnorm() now doesn't take
any arguments.
Vandercorput normal removed (non-random number generator)
Allow models in the nlmixr2 form without an ini({}) block
Allow model piping of an omega matrix by f %>% ini(omegaMatrix)
Standard models created with rxode2() can no be piped into a model function
Families of log-likelihood were added to rxode2 so that mixed
likelihood nonlinear mixed effects models may be specified and run.
The memory footprint of a rxode2 solving has been reduced
Piping now allow named strings (issue #249)
rxode2's symengine would convert sqrt(2) to M_SQRT_2 when it
should be M_SQRT2. This has been fixed; it was most noticeable in
nlmixr2 log-likelihood estimation methods
rxode2 treats DV as a non-covariate with etTran (last time it
would duplicate if it is in the model). This is most noticeable in
the nlmixr2 log-likelihood estimation methods.
A new flag (rxFlag) has been created to tell you where in the
rxode2 solving process you are. This is useful for debugging. If
outputting this variable it will always be 11 or calculating the
left handed equations. If you are using in conjunction with the
printf() methods, it is a double variable and should be formatted
with "%f".
An additional option of fullPrint has been added to rxode2()
which allows rprintf() to be used in almost all of rxode2()
steps (inductive linearization and matrix exponential are the
exception here) instead of just the integration ddt step. It
defaults to FALSE.
Removed accidental ^S from news as requested by CRAN.
Bug fix for more complicated mu-referencing.
Change rxode2 md5 to only depend on the C/C++/Fortran code and
headers not the R files. That way if there is binary compatibility
between nlmixr2est and rxode2, a new version of nlmixr2est
will not need to be submitted to CRAN.
The options for rxControl and rxSolve are more strict.
camelCase is now always used. Old options like add.cov and
transit_abs are no longer supported, only addCov is supported.
A new option, sigdig has been added to rxControl(), which
controls some of the more common significant figure options like
atol, rtol, ssAtol, ssRtol, with a single option.
For simulations, $simulationSigma now assumes a diagonal matrix.
The sigma values are assumed to be standard normal, and uncorrelated
between endpoints. Simulation with uncertainty will still draw from
this identity diagonal matrix
Parallel solving now seeds each simulation per each individual based on the initial seed plus the simulation id. This makes the simulation reproducible regardless of the number of cores running the simulation.
Solved objects now access the underlying rxode model with $rxode2
instead of $rxode
Since this change names, rxode2, rxode and RxODE all perform
the same function.
Options were changed from RxODE.syntax to rxode2.syntax.
Assigning states with rxode2.syntax.assign.state (was
RxODE.syntax.assign.state) is no longer supported.
Enforcing "pure" assignment syntax with = syntax is no longer
supported so rxode2.syntax.assign is no longer supported (was
RxODE.syntax.assign).
Since R supports ** as an exponentiation operator, the pure syntax
without ** can no longer be enabled. Hence
rxode2.syntax.star.pow (was RxODE.syntax.star.pow) no longer has
any effect.
The "pure" syntax that requires a semicolon can no longer be
enabled. Therefore rxode2.syntax.require.semicolon (was
RxODE.syntax.require.semicolon) no longer has any effect.
The syntax state(0) can no longer be turned
off. rxode2.syntax.allow.ini0 (was RxODE.syntax.allow.ini0) has
been removed.
Variable with dots in variable and state names like
state.name works in R. Therefore, "pure" syntax of excluding . values
from variables cannot be enforced with rxode2.syntax.allow.dots
(was RxODE.syntax.allow.dots).
The mnemonic et(rate=model) and et(dur=model) mnemonics have
been removed. rate needs to be set to -1 and -2 manually instead.
The function rxode2Test() has been removed in favor of using testthat
directly.
Transit compartments need to use a new evid, evid=7. That being
said, the transitAbs option is no longer supported.
ID columns in input parameter data frames are not sorted or merged
with original dataset any more; The underlying assumption of ID
order should now be checked outside of rxode2(). Note that the
event data frame is still sorted.
The UI functions of nlmixr have been ported to work in rxode2
directly.
rxModelVars({}) is now supported.
You may now combine 2 models in rxode2 with rxAppendModel(). In
fact, as long as the first value is a rxode2 evaluated ui model, you can
use c/rbind to bind 2 or more models together.
You may now append model lines with piping using %>% model(lines, append=TRUE) you can also pre-pend lines by %>% model(lines, append=NA)
You may now rename model variables, states and defined parameters
with %>% rxRename(new=old) or if dplyr is loaded: %>% rename(new=old)
You can fix parameters with %>% ini(tcl=fix) or %>% ini(fix(tcl)) as well as unfix parameters with
%>% ini(tcl=unfix) or %>% ini(unfix(tcl))
Strict R headers are enforced more places
Since there are many changes that could be incompatible, this
version has been renamed to rxode2
rxode2() printout no longer uses rules and centered headings to
make it display better on a larger variety of systems.
tad() and related time features only reset at the start of an
infusion (as opposed to starting at the beginning and end of an
infusion)Fix subject initialization of focei problem (#464)
Fix LHS offset to allow internal threading and more parallel processing in the future.
Remove warnings for duration and rate
Don't export pillar methods any more (simply register at load if present)
As requested by CRAN, change fortran and C binding for BLAS an LINPACK
Fix the LTO issue that CRAN identified.
Move the omp files so they come first to support clang13, as identified by CRAN.
For now, be a little more conservative in dur() and rate()
warnings because linCmt() models in nlmixr currently produce
irrelevant warnings.
Always calculate "nolhs" for using numeric differences when the inner problem. This allows the inner problem to fallback to a finite difference approximation to the focei objective function.
Updated the parser C code grammar using latest dparser CRAN package
Added a new cbind function that is used to mix data frame input with
simulated individual parameters and residual parameters,
rxCbindStudyIndividual().
Now data frame input can be mixed with simulating from omega and sigma matrices (though not yet in nested simulations)
Race conditions when simulating random numbers is solved by chunking each simulation into groups that will always be performed per each thread. This way the simulation is now reproducible regardless of load. Because of the chunking, simulations with random numbers generated inside of it are now threaded by default (though a warning is produced about the simulation only be reproducible when run with the same number of threads)
Simulations were double checked and made sure to use the engine reserved for each core run in parallel; Some of the random generators were not taking random numbers from the correct engine, which was corrected. Therefore, simulations from this version are expected to be different (in parallel) than previous versions.
Added function rxSetSeed() to set the internal RxODE seed instead
of grabbing it from a uniform random number tied to the original R
seed. This will avoid the possibility of duplicate
seeds
and is the best practice.
Updating parameter pointers is done once per ID and locked based on ID to remove the recursion in #399, but still have the correct behavior see #430
Parsing updated to retain "param()" in normalized model, #432.
Handle edge case of interpolation at first index correctly, fixes #433
Instead of storing each dose information sequentially, store dose
information at the same index of the evid defining the dose. This
memory rewrite is to fix the issue #435.
Start using strict headers as it is required for the forthcoming
release of Rcpp. Thanks to Dirk Eddelbuettel for some of the
fixes and alerting us to this change.
Check arguments for add.dosing() more strictly. See Issue #441
Issue a warning when either dur() or rate() is in the model but
the modeled rate and duration is not included in the event table.
When the data requires a modeled rate and modeled duration but it is not in the model, warn about the mismatch in data
Added a back-door for debugging. If you specify
options(RxODE.debug=TRUE) then each solve saves the solving
information to the file "last-rxode.qs" before actually solving
the system.
Only will try to solve RxODE problems on compatible models; If the model is not supported it will throw an error instead of crashing (See #449)
Turn off parallel ODE solving whenever the system needs to sort times based on model dosing. Currently this type of solving is not thread safe.
Update timsort headers to latest version.
At the request of CRAN, stripping the debugging symbols for the CRAN release is no longer performed. This means a larger binary size for RxODE in this release.
At the request of CRAN the liblsoda code has been changed so that
the memory in C defined by _C() is now defined by _rxC(). This
will be seen in some of the error messages, which will no longer
match the error messages of unmodified liblsoda.
iCov behavior has shifted to merge on the input event dataset.
See Issue #409; This is more in line with expectations of iCov
behavior, and reduces the amount of code needed to maintain iCov.
The iCov in the pipeline is no longer supported because it simply
is a merge with the event dataset.
This can be a breaking change depending on the code you use. Note
that clinical trial simulations, resampling is likely better than
trying to fill out iCov for every individual which was the prior
use.
Bug fix for crashes with string covariates or factor covariates,
issue #410. Also factor column names are compared with case
insensitivity just like the rest of the column names for event
tables or data sets in RxODE.
Change syntax vignette to use markdown option
screenshot.force=FALSE. This should get rid of the webshot
error
Change to depend on dparser 1.3.0, which has some memory fixes
RxODE imports but does not link to checkmate any longer. This change
should make recompilation of RxODE to work with different releases
of checkmate unnecessary.
Default Solaris solver changed back to "lsoda"
Fix Bug #393, where in certain circumstances rxSolve(...,theta=)
did not solve for all subjects.
Will not ignore NEWS and README when building the package so that
they will show up on CRAN. You can also access the news by
news(package="RxODE")
Changed ODR model names from time id to _rx followed by the
md5 hash id and a per-session counter id; For packages the id is
_rxp followed by the md5 hash and a per-session counter id.
Changed qs to be more conservative in hash creation. Add a check
hash as well as NOT using altrep stringfish representation.
Maintenance release -- use std::floor and cast variables to
double for internal C functions. This should allow a successful
compile on Solaris CRAN.
Changed units from an Imports to a Suggests to allow testing on
Solaris rhub
Changed ODR model names from time id to _rx followed by the
md5 hash id; For packages the id is _rxp followed by the md5
hash.
Removed AD linear compartment solutions for Windows R 3.6, though
they still work for Windows R 4.0 (You can get them back for Windows
R 3.6 if you install BH 1.66.0-1 and then recompile from source).
nlmixr to fail with solved systems on Windows 3.6.
Currently the Stan Headers do not compile on this system so they are
disabled at this time.RxODE imports but does not link to qs any longer; This change
should make recompilation of RxODE to work with different releases
of qs unnecessary.
RxODE now checks for binary compatibility for Rcpp, dparser,
checkmate, and PreciseSums
RxODE can only use supported functions (could be breaking); You may
add your own functions with rxFun and their derivatives with rxD
RxODE now uses its own internal truncated multivariate normal
simulations based on the threefry sitmo library. Therefore random
numbers generated within RxODE like providing
rxSolve(...,omega=) will have different results with this new
random number generator. This was done to allow internal re-sampling
of sigmas/etas with thread-safe random number generators (calling R
through mvnfast or R's simulation engines are not thread safe).
RxODE now moved the precise sum/product type options for sum()
and prod() to rxSolve or rxControl
cvPost now will returned a named list of matrices if the input
matrix was named
rxSolve will now return an integer id instead of a factor id
when id is integer or integerish (as defined by checkmate).
Otherwise a factor will be returned.
When mixing ODEs and linCmt() models, the linCmt() compartments
are 1 and possibly 2 instead of right after the last internal ODE.
This is more aligned with how PK/PD models are typically defined.
EVID=3 and EVID=4 now (possibly) reset time as well. This
occurs when the input dataset is sorted before solving.
When EVID=2 is present, an evid column is output to distinguish
evid=0 and evid=2
Add the ability to order input parameters with the param()
pseudo-function
Add the ability to resample covariates with resample=TRUE or
resample=c("SEX", "CRCL"). You can resample all the covariates by
ID with resampleID=TRUE or resample the covariates without
respect to ID with resampleID=FALSE
Comparison of factors/strings is now supported in RxODE; Therefore
ID=="Study-1" is now allowed.
Completion for elements of rxSolve() objects, and et()
objects have been added (accessed through $)
Completion of rxSolve() arguments are now included since they are
part of the main method
Allow simulation with zero matrices, that provide the simulation
without variability. This affects rxSolve as well as rxMvnrnd and
cvPost (which will give a zero matrix whenever one is specified)
et() can dose with length(amt) > 1 as long as the other
arguments can create a event table.
Rstudio notebook output makes more sense
Printing upgraded to cli 2.0
Caching of internal C data setup is now supported increasing speed
of optim code when:
inits do not change (though you can specify them as cmt(0)=...
in the model and change them by parameters)Allow while(logical) statements with ability to break out if them
by break. The while has an escape valve controlled by maxwhere
which by default is 10000 iterations. It can be change with
rxSolve(..., maxwhere = NNN)
Allow accessing different time-varying components of an input dataset for each individual with:
lag(var, #)lead(var, #)first(var)last(var)diff(var)Each of these are similar to the R lag, lead, first, last and
diff. However when undefined, it returns NA
Allow sticky left-handed side of the equation; This means for an observation the left handed values are saved for the next observations and then reassigned to the last calculated value.
This allows NONMEM-style of calculating parameters like tad:
mod1 <-RxODE({
KA=2.94E-01;
CL=1.86E+01;
V2=4.02E+01;
Q=1.05E+01;
V3=2.97E+02;
Kin=1;
Kout=1;
EC50=200;
C2 = centr/V2;
C3 = peri/V3;
d/dt(depot) =-KA*depot;
d/dt(centr) = KA*depot - CL*C2 - Q*C2 + Q*C3;
d/dt(peri) = Q*C2 - Q*C3;
d/dt(eff) = Kin - Kout*(1-C2/(EC50+C2))*eff;
if (!is.na(amt)){
tdose <- time
} else {
tad <- time - tdose
}
})
It is still simpler to use:
mod1 <-RxODE({
KA=2.94E-01;
CL=1.86E+01;
V2=4.02E+01;
Q=1.05E+01;
V3=2.97E+02;
Kin=1;
Kout=1;
EC50=200;
C2 = centr/V2;
C3 = peri/V3;
d/dt(depot) =-KA*depot;
d/dt(centr) = KA*depot - CL*C2 - Q*C2 + Q*C3;
d/dt(peri) = Q*C2 - Q*C3;
d/dt(eff) = Kin - Kout*(1-C2/(EC50+C2))*eff;
tad <- time - tlast
})
If the lhs parameters haven't been defined yet, they are NA
Now the NONMEM-style newind flag can be used to initialize lhs
parameters.
Added tad(), tad(cmt) functions for time since last dose and time
since last dose for a compartment; Also added time after first dose
and time after first dose for a compartment tafd(), tafd(cmt);
time of last dose tlast(), tlast(cmt) and dose number
dosenum() (currently not for each compartment)
Changed linear solved systems to use "advan" style linCmt()
solutions, to allow correct solutions of time-varying covariates
values with solved systems; As such, the solutions may be slightly
different. Infusions to the depot compartment are now supported.
Added sensitivity auto-differentiation of linCmt() solutions.
This allows sensitivities of linCmt() solutions and enables
nlmixr focei to support solved systems.
C++14When calculating the empirical Bayesian estimates for with rxInner
(used for nlmixr's 'focei') ignore any variable beginning with rx_
and nlmixr_ to hide internal variables from table output. This
also added tad=tad() and dosenum=dosenum() to the ebe output
allowing grouping by id, dose number and use TAD for individual plot
stratification.
Added ability to prune branching with rxPrune. This converts
if/else or ifelse to single line statements without any
if/then branching within them.
Added ability to take more complex conditional expressions, including:
ifelse(expr, yes, no)x = (x==1)*1 + (!(x==1))*2if (logic){ expr} else if (logic) {expr} else {}. The preferred
syntax is still only if/else and the corresponding parsed code
reflects this preference.
ifelse is not allowed as an ODE compartment or a variable.Switched to symengine instead of using sympy
sympy, though some functions in
sympy are no longer accessible.Added new ODE solving method "indLin", or inductive linearization. When the full model is a linear ODE system this becomes simply the matrix exponential solution. Currently this requires a different setup.
Added arbitrary function definition to RxODE using rxFun
rxD. When taking deviates without a derivative function, RxODE
will use numerical differences.Will error if RxODE does not know of a function that you are trying to use; This could be a breaking change. Currently:
math.h are supportedrxFun and rxDAdded NA, NaN, Inf and +Inf handling to a RxODE model. Can
be useful to diagnose problems in models and provide alternate
solutions. In addition, added R-like functions is.nan, is.na,
is.finite and is.infinite which can be called within the RxODE
block.
Allowed the following data variables can be accessed (but not assigned or used as a state):
cmtdvidaddlssamtrateid which requires calling the id as factor ID=="1" for
instance.Kept evid and ii as restricted items since they are not part of
the covariate table and are restricted in use.
Added the following random number generators; They are thread safe
(based on threefry sitmo and c++11) and your simulations with
them will depend on the number of cores used in your simulation (Be
careful about reproducibility with large number of threads; Also
use parallel-solve type of RxODE simulations to avoid the birthday
problem).
During ODE solving, the values of these are 0, but while
calculating the final output the variable is randomized at least for
every output. These are:
rxnorm() and rxnormV() (low discrepancy normal)rxcauchy()rxchisq()rxexp()rxf()rxgamma()rxbeta()rxgeom()rxpois()rxt()rxunif()rxweibull()In addition, while initializing the system, the following values are simulated and retained for each individual:
rinorm() and rinormV() (low discrepancy normal)ricauchy()richisq()riexp()rif()rigamma()ribeta()rigeom()ripois()rit()riunif()riweibull()Added simeta() which simulates a new eta when called based
on the possibly truncated normal omega specified by the original
simulation. This simulation occurs at the same time as the ODE is
initialized or when an ODE is missing, before calculating the final
output values. The omega will reflect whatever study is being simulated.
Added simeps() which simulates a new eps from the possibly
truncated normal sigma at the same time as calculating the final
output values. Before this time, the sigma variables are zero.
All these change the solving to single thread by default to make sure the simulation is reproducible. With high loads/difficult problems the random number generator may be on a different thread and give a different number than another computer/try.
Also please note that the clang and gcc compiler use different
methods to create the more complex random numbers. Therefore
MacOS random numbers will be different than Linux/Windows at
this time (with the exception of uniform numbers).
These numbers are still non-correlated random numbers (based on the sitmo test) with the exception of the vandercorput distributions, so if you increase the number of threads (cores=...) the results should still be valid, though maybe harder to reproduce. The faster the random number generation, the more likely these results will be reproduced across platforms.
Added the ability to integrate standard deviations/errors of omega diagonals and sigma diagonals. This is done by specifying the omega diagonals in the theta matrix and having them represent the variabilities or standard deviations. Then these standard deviations are simulated along with the correlations using the IJK correlation matrix (omega dimension < 10) or a correlation matrix or Inverse Wishart-based correlation matrix (omega dimension > 10). The information about how to simulate this is in the variability simulation vignette.
Now have a method to use lotri to simulate between occasion
variability and other levels of nesting.
Added lower gamma functions See Issue #185
Upgraded comparison sort to timsort 2.0.1
Changed in-place sort to a modified radix sort from
data.table. The radix search was modified to:
RxODE internal solved structuresNA/NaN values of timeChanged method for setting/getting number of threads based on
data.table's method
Added function rxDerived which will calculate derived parameters
for 1, 2, and 3 compartment models
More descriptive errors when types of input are different than expected
Moved many C functions to C++. CRAN OpenMP support requires C++ only when C and C++ are mixed. See:
https://stackoverflow.com/questions/54056594/cran-acceptable-way-of-linking-to-openmp-some-c-code-called-from-rcpp
No longer produces C code that create the model variables. Instead,
use qs to serialize, compress and encode in base91 and then write
the string into the C file. The qs package then decodes all of
that into the model variables. This also increases the compilation
speed for models in RxODE.
Pre-compile RxODE headers once (if cache is enabled), which increases compilation speed for models in RxODE
RxODE's translation from the mini-language to C has been refactored
Occasionally RxODE misidentified dual lhs/param values. An
additional check is performed so that this does not happen.
For solved matrices with similar names (like "tadd" and "tad")
RxODE will now prefer exact matches instead of the first match
found when accessing the items with $tad.
A fix where all ID information is kept with keep=c(""..."")
Transit compartment models using the transit ODE or variable are
now allowed. Also check for more internally parsed items (see
Issue #145).
Bug fix for etSeq and etRep where greater than 2 items were
mis-calculated
ggplot2 3.3.0NAs in RxODE datasetNEWS.md file to track changes to the package