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