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:
Work directly with RxODE internal solved
structures
Assume no infinite values or NA/NaN
values of time
Always sort time in ascending order
Changed sorting to run in a single thread instead of taking over all the threads like data.table
Changed 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