News for R package httk
Changes in version 2.0.1 (February 28, 2020)
New function set_httk_precision is now used throughout code to enforce a standard set of significant figures (4) and precision (nothing less than 1e-9).
Added calc_hepatic_clearance wrapper function for calc_hep_clearance to allow backwards compatibility
Fixed output of calc_mc_oral_equivalent (was sometimes returning all samples unasked, thank you Dan Dawson)
Revised get_chemid to not crash in certain cases (thank you, Shannon Bell)
Revised Linakis et al. (submitted) vignette
Changes in version 2.0.0 (February 10, 2020)
New generic inhalation PBPK model included, consistent with Linakis et al. (submitted) "Development and Evaluation of a High Throughput Inhalation Model for Organic Chemicals"
New chemical specific parameters for volatile chemicals have been added:
43 in human
41 in rat
Rewrote underlying code to allow more easy integration of new models. (goodbye, spaghetti code!)
Rewritten funtions include:
calc_analytic_css
calc_mc_css
convert_httkpop (renamed from convert_httk)
solve_* model functions
get_cheminfo
Renamed a few httk-pop functions for clarity:
httkpop_biotophys_default replaces httkpop_bio
convert_httkpop replaces convert_httk
New functions introduced:
solve_model (mostly used by solve_* model functions)
calc_mc_tk (performs Monte Carlo simulation using a solve_* function)
Models must be much more thoroughly described now, with all relevant information placed in modelinfo_* files in the /R directory.
New model-specific functions introduced:
analytic_css_*: Model-specific analytic steady-state solution
convert_httkpop_*: Model-specific functions for converting HTTK-pop
biometrics to model parameters
EPA's DSSTox Chmeical Structure ID's (DTXSIDs, see http://comptox.epa.gov/dashboard/) now work as chemical identifiers in addition to name and CAS.
Results now truncated to appropriate significant figures (4) and precision (1e-12).
Beta testing and bug reports provided by Xiaoqing Chang.
New physiological parameters have been added for monkeys
To decrease package size the load image option of load_sipes2017 was eliminated
Added vignette for Figure 6 from Frank, Christopher L., et al. "Defining toxicological tipping points in neuronal network development." Toxicology and Applied Pharmacology 354 (2018): 81-93.
Changes in version 1.10.1 (Septmeber 9, 2019)
Bug fixes (thank you David Trudel).
Changed all file name starting letters to lowercase.
Changes in version 1.10.0 (July 9, 2019)
This version is consistent with the submitted manuscript Wambaugh et al.
"Assessing Toxicokinetic Uncertainty and Variability in Risk Prioritization"
New human experimental measurements of fup and Clint are reported for 418 and 467 chemicals, respectively.
Data on both fup and Clint are jointly available for 389 of those chemicals.
Clint and fup values can now be either numeric values (as before) or distributions characterized by as "MEDIAN,LOWER95TH,UPPER95TH,PVALUE" for Clint and "MEDIAN,LOWER95TH,UPPER95TH" for fup. The code has been substantially revised to accomodate this.
Added a minimum.Funbound.plasma since some of the Bayesian estimates are very low and at some point the values seem implausible. A value of 0.0001 was selected since it half the lowest reported measured value. Setting minimum.Funbound.plasma=0 removes this restriction.
Monte Carlo coefficient of variation for Clint and fup has been divided into separate values for uncertainty (from measurement) and variability (population/genetic). Default values for coefficients of variation are fup.meas.cv=0.4,
clint.meas.cv=0.3, fup.pop.cv=0.3, clint.pop.cv=0.3, (from Wambaugh et al, submitted). Note that most of the new fup mesurements have a lower CV than 0.3.
All documentation converted to roxygen2 format.
Vignette names have been updated to make the related publication clear.
All references to "fub" have been converted to "fup" where appropriate.
Rewrote calc_analytic_css to handle all models in the same manner.
Corrected error where non-human species were using the incorrect p-value for Clint when default.to.human=TRUE (human p-value is now used). (thank you Jason Phillips and Shyam Patel for bug report).
Changed arguments "mg" and "mol" for output.units in calc_mc_oral_equivalent to "mgpkgpday" and "umolpkgpday". (idea from Katie Paul-Friedman)
Shyam Patel (Sciome) identified an error in how flow means were scaled by age in httk-pop Monte Carlo sampler.
Changed httk-pop argument "fup.censor" to "fup.censored.dist".
Armitage et al. (2014) model functions now work with input of vectors (to work well with data.table) or input of data.table
Added the physchem parameters needed to run Armitage model
Updated honda.ivive, reduced to 4 options as in Honda et al. (2019) Figure 8 panels a-d, changed "plasma.binding" to "bioactive.free.invivo", and exported function to allow user to call help file
Added concentration as an option set by honda.ivive
Added concentration = "tissue" as an option to calc_css functions
Added bioactive.free.invivo as an option to calc_analytic_css functions, and calc_mc functions
Function get_physchem_param: exported and now works with vectors of CAS and/or parameters
Fixed calc_mc_css warnings
Changes in version 1.9.2 (April 22, 2019)
Updated tests to reflect correct model predictions.
Fixed errors that was causing the 3compartmentss and 1compartment models to not work with Monte Carlo. (thank you Johanna Nyffeler for bug report).
Changes in version 1.9.1 (April 15, 2019)
Fixed signficant errors in calc_analytic_css that was causing Css to be over-estimated roughly 10x, therefore reducing the oral equivalent dose 10x (thank you Nisha Sipes for bug report).
Changes in version 1.9 (February 4, 2019)
This version is consistent with the submitted version of Honda et al. "Using the Concordance of In Vitro and In Vivo Data to Evaluate Extrapolation Assumptions"
New rat-specific in vitro TK data provided for 65 chemicals.
New functions for calculating in vitro disposition armitage_eval, armitage_estimate_sarea (thank you James Armitage)
Added arguments to IVIVE functions (e.g., calc_mc_css) to use sets of assumptions identified by Honda et al. (e.g., IVIVE="Honda1")(thank you Katie Paul-Friedman)
Changed all model parameter sets to include physico-chemical properties to better facilitate Monte Carlo analysis
Updated load_sipes2017 to be much faster by loading an image by default
Updated help files for Sipes2017 and load_sipes2017.
get_wetmore functions changed to get_lit
httkpop_bio exported to user functions (fx name since changed to 'httkpop_biotophys_default')
Corrected mistake in get_cheminfo help file: exlude.fub.zero defaults to FALSE for 3compartmentss and TRUE for others
Corrected (thank you Jason Phillips), updated, and added pKa values from Strope et al., 2018
For time point after first dose: bug now corrected when not starting at time 0(thank you Xiaoqing Chang)
Corrected calc_mc_css bug: species passed to monte_carlo function
Added figures to help files of solve functions
Added hematocrit argument to calc_rblood2plasma
Made amounts in 1comp model not scaled by body weight, adding BW to parameters for that model thank you Tom Moxon)
Converted all phys-chem properties except pKa to values predicted by OPERA (Mansouri et al., 2018)
Added missing logP and MW for some chemicals from OPERA
Renamed and added vignettes
Moved code base to Bitbucket internally (thank you Sean Watford and Jeremy Dunne)
Changes in version 1.8 (January 23, 2018)
This version is consistent with the published version of Pearce et al. "Evaluation and calibration of high-throughput predictions of chemical distribution to tissues". This version containins calibrations for tisse:plasma partition coefficient calibration predictions.
Added arguments for whether or not to use new calibration regressions (regression) and adjusted Funbound.plasma (adjusted.Funbound.plasma).
Data from ADMET used in Sipes et al. (2017) is now included as Sipes2017 and can be added with the new function: load_sipes2017().
New data has been added from an IVIVE evaluation of toxicokinetics (Wambaugh et al. 2018).
Funbound.plasma values from Wetmore 2012 and 2013 that were previously rounded to 2 decimal places are now rounded to 3, resulting in additional compounds with measurable Funbound.plasma that were otherwise assumed to be below the
limit of detection.
pKa data is now readable when values are separated by a semicolon rather than a comma. These values were previously misread as neutral.
Partition coefficients can now be predicted without calculating all of them, using the tissues argument.
Calc_mc_css runs faster when not using httkpop and calculating Rblood2plasma, now only calculated once.
New data are added to chem.invivo.PK.data and chem.invivo.PK.summary.data.
chem.lists is updated, and is.pharma has been added as a function.
A new table is included: chem.invivo.PK.aggregate data
Corrected calc_mc_css bug: daily.dose now working as an argument (previously
only running as 1).
calc_analytic_css does not recalculate all partition coefficients when specifying a tissue.
logP values from EPISuite or valued NA have been replaced with predictions from OPERA where available.
hepatic.bioavailability is added as a parameter to the models 1compartment (parameterize_1comp) and 3compartmentss (parameterize_steadystate) and now used with these models (multiplied by the dose and Fgutabs).
kinhabs and kdermabs, both of which were unused in the models, are removed.
modelPBTK.c, the source file for the pbtk model, now has updated variable names, and corresponding changes are made in solve_pbtk.
The time step immediately after addition of dose is added to better capture peak concentration for iv dosing.
kgutabs default changed to 2.18.
Changes in version 1.7 (July 15, 2017)
This version is consistent with the JSS publication of Pearce et al. "httk: R Package for High-Throughput Toxicokinetics".
Corrected minor bugs including: corrected intrinsic clearances for (about 10) compounds from Brown 2007, corrected output message from calc_mc_css
Corrected Funbound.plasma used for predicting partitioning into interstitial protein (negligible difference in predictions)
Corrected bug in calculating Rblood2plasma in calc_mc_css, and added faster method for calculating Rblood2plasma for 3compartmentss.
changes in version 1.6 (June 8, 2017)
This version includes data and modifications as reported in the recently submitted Pearce et al. paper "Evaluation and Calibration of High-Throughput Predictions of Chemical Distribution to Tissues".
The Schmitt (2008) method for partition coefficients has been modified and calibrated using experimental data.
The new method is now default, although the previous approach is available (set regression=FALSE and Funbound.plasma.pc.correction=FALSE for other models).
The membrane affinity regression is new and always used in place of the old.
Added function available_rblood2plasma
In vivo Rblood2plasma used when available
well-stirred blood correction and restrictive.clearance options added
New in vitro data from Uchimura 2010, brown 2007 and Pirovano 2016, Gulden 2002
Tonnelier Funbound.plasma values of 0.005 changed to 0 in
chem.physical_and_invitro.data
New tissue.data table with Ruark 2014 that contains different formatting with human and rat specific data
parameterize_schmitt: added force.human.fub argument
added plasma protein and neutral lipid volume fractions to physiology.data for use in package
calc_mc_css: defaults to direct resampling. no longer coerces species to human when httkpop=T. When another species is entered, a warning is thrown and the function behaves as if httkpop=F.
updated help file references and examples
corrected parameterize_3comp default.to.human bug: always set to false
removed temperature from schmitt parameters
overwrite 0 values for Fubound.plasma when overwrite=F in add_chemtable
added vignette for generating partition coefficient plots
added dsstox info: new columns: "DSSTox_Substance_Id","Structure_Formula", or "Substance_Type". overwrote: MW and SMILES
added pc.data and obach2008 tables
httkpop option in calc_mc_css: well-stirred correction and new Funbound.plasma used by default. New partition coefficients used with other models by default.
Changes in version 1.5 (March 3, 2017)
This version is consistent with Ring et al. "Identifying populations sensitive to environmental chemicals by simulating toxicokinetic variability", which is accepted for publication at Environment International. Revisions include models, data, and vignettes for "httk-pop" functionality. "httk-pop" allows
Monte Carlo simulation of physiological variability using data from the National Health and Nutrition Examination Survey. This new human variability functionality is the new default, although the previous approach is available (set httkpop=FALSE).
default.to.human argument added to calc_hepatic_clearance and calc_stats.
calc_hepatic_clearance and calc_total_clearance do not necessarily require all parameters.
Argument "tissue" added to calc_analytic_css, calc_mc_css, and
calc_mc_oral_equiv, enabling tissue specific calculations in addition to plasma.
Corrected minor bug for get_cheminfo.
calc_dow: fraction neutral argument changed to fraction charged, thus treating zwitterions as neutrals
Corrected bug in monte_carlo: Upper bound placed at limit of detection for censored params truncated normal distribution. However, this has no impact on the default case where the limit of detection is .01 the mean .005 because of the small standard deviation size (.0015). Only large coefficients of variation or Funbound.plasma values close to the limit of detection would be
affected.
Multiple iv doses enabled in solve functions.
get_rblood2plasma function added to retrieve in vivo Rblood2plasma from chem.physical_and_invitro.data.
Changes in version: 1.4 (February 3, 2016)
This revision incorporates changes suggested by the reviewers of Pearce et al. "httk: R Package for High-Throughput Toxicokinetics", which was accepted, pending minor revision, in the Journal of Statistical Software (now included in vignettes).
Table name "PK.physiology.data" changed to "physiology.data".
Changes in version 1.3 (October 14, 2015)
This revision adds ~200 more chemicals (from two recent publications including Wetmore et al. 2015) and make several small changes to improve usability and stability.
Changes in version 1.2 (May 11, 2015)
This version is consistent with a newly submitted article Pearce et al. "httk: R Package for High-Throughput Toxicokinetics" to the Journal of Statistical SoftwareJ describing use of this package.
This revision changes some model parameter names to follow a more systematic naming convention.
Minor bugs have been corrected.
Version 1.1
Initial public (CRAN) release (March 6, 2015).