v2.9.0 (for R v4.0.5,***personal release***) up to 2021/04/20 - added 'project save' function; - some minor fixed and changes of GUI layouts; v2.8.9 (for R v4.0.2,***personal release***) up to 2020/09/21 - rolled back to previous version with minor ticks for normal & semi-log plots in NCAplot(); - fixed "error in xj[i] : invalid subscript type 'list'" in NCAselect() for R4.0.x; and many other I didn't remember, including NCAreglplot() & all algorithms for lambda_z calculations. v2.8.8 (for R v4.0.1,***personal release***) up to 2020/06/10 - fixed NCA plots overwritten by ODA plots in pdf output file; also fixed ODAplot() for multiple-panel plots; - disabled 'Hotellings T2' in ODA temporarily in this version since ICSNP may not be able to run normally (BANOVA()); - fixed ggplot2 errors in NCAplot(); - added minor ticks for normal & semi-log plots in NCAplot(); - updated sample size estimation using Helmut's codes; depredicated logdata() and using calc.N.power() since this release; - built for R v4.0.x; v2.8.7 (for R v3.6.1,***personal release***) up to 2019/11/23 - fixed ss_rl_GUI() the page.no detection; - fixed touch-and-show (mouse-motion) for once only; - added 'manual' for 'previously data point selections'; - set identify(..., n=24) for allowing more data points selection; it was 6 in previous version; v2.8.6 (for R v3.6.1,***personal release***) up to 2019/08/29 - fixed previous ssGUI() and logdata(); - combined ssGUI() and rl.gui() together in one GUI (ss_rl_GUI()) since release; - added more study designs to randomlist; blocksize is set to 'missing' i.e., to use defaults (blocksize = 2x # of sequence); v2.8.5 (for R v3.6.1,***personal release***) up to 2019/08/12 - fixed and adjusted GUI layouts; - used 48x48 icons to replace gbuttons; - removed the support of RData for dataset files; - added 'demo run' as a button; - added two additional widgets for xxdf & psdp; - cancelled the support of smaller GUI since this version. v2.8.4 (for R v3.5.3,***personal release***) up to 2019/04/18 - fixed the first logo(print.logo()); - used setGD() to avoid errors when running with RStudio; this also enabled 'manual selection' for lambda_z to run with RStudio; - fixed about.bear(); deleted the last empty line; - loaded GUI packages quietly; - modified zzz.R with less words; - created load.csv.data() to replace fread() to correctly identify different separators for columns and decimals; - fixed the error of 'MRT0inf_Ref' in NCAoutput() (three places) when generating *_misc_pk.csv output (thanks to roman_max through bebac Forum); - fixed version # of ssGUI() (GUI for sample size estimation); - modified csv file reading priorities; - fixed tmax_stat() to add "P value..." explanation to output text; - modified layouts of GUIs. v2.8.3-3 (for R 3.5.2,***personal release***) up to 2019/02/20 - fixed Tmax and lambda_z lists in nc_pk.txt and misc_pk.csv with NCAoutput(); it was reported by Astea in Bebac Forum; - fixed error for random# generation for output files (linux); - added one more output file for replicated crossover BE; - fixed some output files with FormatC(...) to shorten digit numbers; - fixed misc_pk.csv and pivotal.csv for parallel study. v2.8.3-2 (for R 3.5.1,***personal release***) up to 2018/08/22 - fixed fread() one more error again; - made the GUI scrollable. v2.8.3-1 (for R 3.5.1,***personal release***) up to 2018/07/19 - fixed the error of 'MRT0inf_Ref' in NCAoutput() (three places) when generating *_misc_pk.csv output (thanks to roman_max through bebac Forum); - fixed version # of ssGUI() (GUI for sample size estimation); - fixed tmax_stat() to add "P value..." explanation to output text; - fixed fread() error. v2.8.3 (for R v3.4.0,***personal release***) up to 2017/05/24 - fixed GUI properties; - fixed warning messages for IDP output; some modules may omit this message; - used gfile() to replace rchoose.files() from package rChoicedialogs; no need to used package rChoicedialogs any more, as well as Java VM; it can cause 'segmentation fault (core dump)' in x32-bit Ubunut/ Linux; unfortunately this can cause two error messages in iMac OS X; and the function of 'while{}' won't work properly under Ubuntu/Linux and iMac OS X; should be able to solved in the future; this won't affect the normal running of bear so far; - added bear ascii logo when running as 'verbose mode = TRUE'; - fixed bGUI() with no looping until selecting a data file; - fixed screen output of 'load previously selected data point'; also no more edit() and print() if verbose.mode is OFF; - fixed rl.gui() with gedit() to replace gslider() for total subject#. - fixed rl.gui() with auto setting blocksize; errors can occur in Ubuntu/Linux. v2.8.2 (for R v3.4.0,***personal release***) up to 2017/05/09 - fixed some GUI properties (again). v2.8.1 (for R v3.4.0,***personal release***) up to 2017/05/06 - fixed bGUI() again for some package limitations; - added a 'verbose mode?' button; - added a 'show text output on screen?' button; its setting will be saved in 'bearGUI.setup.rds'; hiding screen text output can speed up processing; - removed some ambiguous text outputs on screen; its setting will not be saved in 'bearGUI.setup.rds'; - did a spelling check with bGUI() and found some mis-spelling words. v2.8.0 (for R v3.4.0,***personal release***) up to 2017/05/05 - fixed bGUI() and used 'droplevels()' to remove unused factor levels for 'bearGUI.setup.rds' and this also can reduce the file size of 'bearGUI.setup.rds'; - fixed ssGUI(); when selecting demo mode, disable all selections; - fixed rl.gui for better output; - turned all "Press Enter to continue..." off, instead using Sys.sleep(2) for two-second time pause period (too short?); - fixed 'demo' mode with 'statistical analysis only' by adding 'svalue(Tmax.stat)<- FALSE' before 'enabled(Tmax.stat)<- FALSE' command in bGUI();otherwise, this may cause an error because there is no such dataset for this demo mode; - added one more button - 'Reset settings to default' at group; v2.7.9 (for R v3.4.0,***personal release***) up to 2017/05/04 - fixed check.data.err() to remove "data_err_logs.txt" when there is no error found; - fixed levels[bear.set] problem to save bear.set correctly. v2.7.8 (for R v3.3.3,***personal release***) up to 2017/04/13 - fixed some *description() file to fit RStudio spaces; - used fread() from package 'data.table' to read in all csv data files now; such as NCAcsv() & NCA.BANOVAcsv(); - automatically saved manual selection of data points; no more ask users to save or not to save (kind of silly question); such as NCAselectsave(); - fixed some cat(...) contents with less than 70 or less in length; - fixed the errors of NCAplot(); thanks to Dr. Mahmoud Hassan Teaima (2016-07-28) for all linear plot with mislabeled a 'log scale' on y axis; - added data check after reading in from a csv file for NCA; two functions added: check.data.err() and which.subj.has.err(); this feature can detect non-value or non-NA data appearing in *.csv dataset; - displayed plots on screen (device) again for Rgui/X11 or running with RStudio; on RStudio, all plots will be saved finally; - removed the functions that only be called once; - created GUI for setup and data input; also fixed many related codes; - added nonparametric statistics for Tmax for 2x2x2 crossover. v2.7.7 (for R v3.3.0,***personal release***) up to 2016/05/04 - added new logo for 2016; - fixed imported package; switched from 'gWidgets2' to 'gWidgets' since the package 'gWidgets2RGtk2' has been archived; - also fixed 'preinst.r' (v1.4); v2.7.6 (for R v3.2.3,***personal release***) up to 2016/02/11 - kept all data points with conc.= 0 when doing AUC & AUMC calculations; modified ARS(), aic(), NCA(), TTT(), TTTAIC(), and TTTARS() for trapezoidal calculation; all-linear is fine; if linear-up/log-down; it will switch back to linear when (1) C[i-1]=0 or C[i]=0; (2) C[i]>C[i-1]; and (3) C[i]=C[i-1]; - kept NCAplot() unchanged; no way to plot log(0) if there is any; it will be excluded; - fixed check.nca.data() without assigning conc. = 0 as 'NA'; instead to see if enough data points are available for £fz estimation; also fixed NCAanalyze(), NCA.BANOVAanalyze(), RepNCAanalyze(), and demomenu() & demomenu1(); - fixed title of input GUI for D. Labes' randomizeBE; - fixed go2menu() with the list of the Top menu; - fixed check.nca.data(); to add more explanations for the list of subject data; - fixed Singlego() to delete the file of 'bear.current.setting' from the second- level menu; v2.7.5 (for R v3.2.3,***personal release***) up to 2015/12/31 - added GUI for D. Labes' randomizeBE; v2.7.4 (for R v3.2.3,***personal release***) up to 2015/12/24 - fixed 'lambda_z estimate' display with the menu of '*edit set-up file'; this '£fz estimate' only works on Win7; not working on/Win10/linux-pc/Mac OSX; however the display of '£fz estimate' on R console in OK for all platforms; v2.7.3 (for R v3.2.3,***personal release***) up to 2015/12/23 - switched all packages in the package list of 'Imports' in DESCRIPTION to 'importFrom()' in NAMESPACE to fix the warning messages as v2.7.2; - update 'Multipledata.rda' (subj#15) in directory of 'inst/extdata' to be able to analyze with ARS/AIC; also fixed demomenu1() & demo_datasets_gen() with readRDS() due to "Error: bad restore file magic number..." - fixed check.nca.data() to skip manual selection of data points ('5') or loading dataset from previous manual selection ('6', *.RData). v2.7.2 (for R v3.2.3, ***personal release***) up to 2015/12/22 - fixed description_version() with adding win.version() for Win OS detection; this function starts from R v3.2.3; - fixed NCAanalyze() & NCA.BANOVAanalyze() with adding 'lambda_z_calc' to check.nca.data(); - fixed the warning message when loading bear (...) after upgrading ggplot2 to v2.0.0 as follows: --- Warning messages: 1: replacing previous import by ¡¥grid::arrow¡¦ when loading ¡¥bear¡¦ 2: replacing previous import by ¡¥grid::unit¡¦ when loading ¡¥bear¡¦ --- by removing 'grid' from "Imports" in DESCRIPTION (package 'grid' has been included in R base) and instead using 'grid::grid.raster' in the codes; v2.7.1 (for R v3.2.3, ***personal release***) - fixed "Error in lm.fit(x, y, offset = offset, singular.ok = singular.ok, ...): NA/NaN/Inf in 'y'" when calculating λz if there is any zero conc. included; replaced '0' with 'NA' now; codes included NCAanalyze(), NCA.BANOVAanalyze(), RepNCAanalyze(), demomenu() and demomenu1(); - fixed demomenu() & demomenu1() again; last time did not complete add check.nca.data(); - fixed BANOVAdata(); to delete 'bear.Current.setting.rds' if end run; - fixed NCAplot() to remove 'NA' of conc. originally coming from zero conc.; - added 'news(Version=="2.7.1",package="bear")' to browse update logs (about.bear()); not working yet in compiled mode (portable package), but in R console; - tested on new released R v3.2.3; seemed ok... - fixed NCAoutput(); first time to use '\u03BBz'(λz) to replace 'lambda_z' in NCA output file; - fixed NCA(), NCAselect(), ARS(), aic(), TTT(), TTTAIC() & TTTARS(). v2.7.0 (for R v3.2.2; ***personal release***) - added check.nca.data() for checking if the data points are proper enough to calculate the terminal elimination rate constant (lambda_z); - fixed ARS(), aic(), TTT(), TTTAIC() & TTTARS() accordingly; - modified NCAanalyze(), RepNCAanalyze() & NCA.BANOVAanalyze(); - fixed the top menu again; removed linux warning message; - fixed check.nca.data(); made it to check the dataset based on the selected lambda_z calculation methods; - fixed demomenu() & demomenu1() also; v2.6.9 (for R v3.2.2; ***personal release***) - fixed readline(...) to show only red color; - move package gdata and nlme from 'Depends' to 'Imports' to suppress noised message when doing library(bear); and it still runs fine; - fixed NCAoutput() for stat output on screen simultaneously; v2.6.8 (for R v3.2.2; ***personal release***) - fixed sizemenu() and logdata(); it used to be that sizemenu() would stop run if replicate; and logdata() kept looping; - fixed some rd files; v2.6.7 (for R v3.2.2; personal release) - switched 'show()' into 'print(*, row.names=FALSE)'; forced not to print the row numbering; - changed 'Current Setting' to display only related info; hiding all 'no' settings; - fixed NCAoutput() for sink(., split=TRUE) (i.e., to display output contents on the screen simultaneously); also simplified the code; added text for reminding user if it is a metabolite (the analyte); - fixed aic(), ARS(), TTT(), TTTAIC(), TTTARS(), NCA(); not to display from these but only to generate 'TotalData'; - fixed NCAselect() and NCA(); not to stop after manual selection of data points; - changed 'NaN' to "NA" when assigning Cl/F and Vd/F if it is a metabolite; - improve the display of "Current Setting" again; remove all "no" settings from list; - still working.... (Sept. 01, 2015) v2.6.6 (for R v3.2.2; personal release) - simplified setting schemes; no more separated plot setting since this ver.; - forced 'dose' to be input as 'mg' now; will be converted based on the unit of measured drug plasma/serum conc. (mcg/mL, ng/mL or pg/mL); - added "is metabolite?" setting; when it is a metabolite, some of PK parameters will not be able to calculate, such as Cl/F and Vd/F; the volume term is always fixed as the unit of 'mL' now; - label for y axis does not need to put conc. unit there; it will be added automatically; - changed logo of bear for 2015. v2.6.5 (for R v3.2.1; personal release) - fixed helper.func() with suggested package (plyr) using requireNamespace(); - fixed BANOVAcsv() & NCA.BANOVAdata() to keep 'NA' after loading data; - fixed RepMIXanalyze(), RepMIXoutput(), RepMIX(), MultipleParaMIX(), MultipleParaMIXoutput(), MultipleParaMIXanalyze(), ParaMIX() and ParaMIXoutput() for parameter transfer between functions; place all partial AUC parameters to the last; BANOVA() and its related functions should be fine. - tested bear with R v3.2.0 (Full of ingredient); all seem fine; - fixed the dataset of 'SingleRep_stat_demo.csv' in both demoBANOVA() and demo_datasets_gen(); - add option of 'na.action=na.exclude' to every lme() and lm(); - remove (remark)'TotalData<-na.omit(TotalData)' to keep all NAs; these NA will be ignored when doing lm() or lme(); and - fixed lm.mod() for Type III SS. v2.6.4 (for R v3.1.2) - modified lme() in RepMIX(), NCAoutput() & lme_lm.mod() with lmeControl(opt='optim', msMaxIter=1000); - added R version into description_version() (as part of outputs); - modified DESCRIPTION - Title; - added warning for the writing permission of working path at the beginning; - added citation into output files; - added the message of showing the folder name for all output files at the beginning; and - added warning for invalid selection of 'conc' for lambda_z estimation using ARS(), aic(), TTT(), TTTAIC(), and TTTARS(); not necessary for NCAselect(). v2.6.3 (for R v3.1.0) - added the tests for carryover effects and the direct formulation effects with lm.mod() for 2x2x2 crossover study based on the textbook of Clinical Trial Data Analysis Using R, Chen, D-G (Din); Peace KE. CRC Press, Taylor & Fracis Group, 2010; ISBN-10: 1439840202; Ch. 10 - "Analysis of Bioequivalence Clincial Trials"; pp.269-274. Amazon - took care of switching pAUC to be FALSE when running 'statistical analysis only'; since the demo dataset for 'statistical analysis only' does not include any pAUC parameter (demoBANOVA()); - fixed BANOVA() again to simplify the codes; - started working with new release of R v3.0.3; - fixed BANOVAcsv() for dataset input if doing pAUC; - demo dataset do not have any pAUC example for statistical-only runs; - BANOVA() for pAUC stats. and 2x2x2 crossover with multiple-dose stats.; - fixed default values for 'pAUC_start' and 'pAUC_end' with '121' & '128' (for multiple-dose), instead of '1' & '8' (for single-dose) respectively; since the 'pAUC_start' & 'pAUC_end' counts from time zero, not from one dosing interval, especially for multiple-dose; otherwise, it will cause error, such as 'Na/NaN/Inf -> y...' - fixed NCAplot() hopefully to speed-up plotting and enhance efficiency; - changed parallel study in NCAoutput() as lme(); in RepMix() the parallel uses lm(); but the results are the same. v2.6.2 (for R 3.0.2) - added lme_lm.mod() to simplify original RepMix(); - added lm.mod() to simplify original BANOVA(); also fixed an error in original BANOVA(); btw, fixed the output format of BANOVA(); - fixed BANOVAanalyze() to run BANOVAoutput() once and RepMixanalyze() to run RepMIXOutput() once; no more run 'BANOVA() -> BANOVAoutput()' since BANOVAoutput() will call BANOVA(); and also no more 'RepMix() -> RepMixOutput()' since RepMIXoutput() will call RepMIX(); more efficient now; otherwise; BANOVA() & RepMix() will run/be called twice. - fixed some typo in the display of setting guide; - re-coded with NCAcsv(), BANOVAcsv() & NCA.BANOVAcsv(); more efficient hopefully; - excluded the parallel study from icd_check(); how can I forget this? and kept the replicated crossover study; - added 'input data' to description_version(); it only works for Windows OS; - added 'input dataset' and the name of OS platform to NCAoutput(); - fixed icd_check() and abandoned using 'stop()' from it; icd.check() can be detected icd earlier than previous version since it will get work done once the dataset is loaded; only for nca data; not for anova dataset. - added 'run.demo','study.type' and 'dose.type' into setting items to reduce menu levels; - fixed 'dosing interval' in bear setting; forgot to change in the last release (v2.6.1); so this can cause error for multiple-dose; - disable dataset output for demo runs; all can be done from the top menu; - fixed CV_inter of BANOVA() when occurring negative variance components; - corrected typo in RepMix() to show CV(intra); - also fix NCAoutput() as adding ODA setting function; - integrate ODA into setting file; modify the top menu; - changed bear setup cheatsheet mode as a graphic display; - fixed setting display screen; - fixed output format for RepMIX(); - re-assigned column names for 'statistical analysis' (BANOVA()) if the imported .csv was not originally generated by bear; - change RepMIX()'s lme() with lmeControl(opt='optim') since the default 'nlminb' fails to converge frequently; - fixed the inconsistency of 90% CI for replicate crossover in 'stat_sum_output' and 'lme_output' with NCAoutput() and RepMIX(); v2.6.1 (for R 3.0.2) - added function to avoid the errors due to dummy input; - re-organize the information about how to setup bear using file.show(); testing on Windows, linux and iMac OS X platforms; iMac will work with R.app or RStudio,but not TK GUI; - added license (GPL-2|GPL-3) announcement for bear on all output or display pages; - added the output function of individual data points (IDP output) with mean & sd for each time point; - removed formfeed with NCAoutput(); it does not print correctly with a pdf printer; don't know why. - fixed on-screen display content when it is pAUC; - fixed some typo; v2.6.0 (for R 3.0.2) - decided not to implement data point interpolation for missing data value (C*) when doing partial AUC or truncated AUC analysis in bear; users may consider to use an estimate/interpolation/extrapolation for missing data when necessary beforehand; further ref. included: (1) http://forum.bebac.at/mix_entry.php?id=4655#p4681 (2) http://forum.bebac.at/mix_entry.php?id=1933&page=0&category=0&order =last_answer&descasc=DESC#p2323 - added analysis for pAUC or truncated AUC; - fixed AUMC to comply with linear-up/log-down trapezoidal rule as AUC. - added "study tracer" (footprint) to the selected menu; - create the export module for demo dataset; - enable demo dataset export through NCA and ANOVA for later testing purposes; - add 'plot.setup.rds'; plus original 'bear.setup.rds' of setup file for bear; - fixed export/import .csv and .Rdata file for 'statistical analysis' in NCAoutput(); - added bear.setup() for setup files generation; new features. - moved AUC calc. method to NCA.BANONAanalyze(); this has been changed later; - corrected some typos again; - fixed BANOVA() with no "abs()" for CV_intra values; - fixed descriptionTOST() using paste() for better display; v2.5.8 (for R v3.0.2) - fixed BE criteria with percentage (/100); sorry about this error; - disable warning message with options(warn=-1) from very beginning; - add the function of NCA saved pivotal parameters back again with automatically saving as .RData (NCAoutput()); it was disabled before, though it has been saved as .csv format; - added more output info of study design for NCAoutput(); not just multiple- dose or single-dose; now also include if it is parallel or if it is replicated; - added LL/UL as data.frame() input for replicated study as the non-replciated; - fixed AIC crashed when running multiple-dose study; and - fixed plots of regression lines (ARS, AIC, etc.) for hiding the first empty (null) plot window. v2.5.7 (for R v3.0.1) - added LL/UL as data.frame() input; not just LL. - fixed abnormal on-screen text display with Mac OS X using data.frame() input. - fixed BANOVAdata() & BANOVAcsv() with graphic menu; and also spelling check. - removed abs() from CV_intra calculation. v2.5.6 (for R v3.0.1) - added csv outputs for data point selections of linear regression to calculate lambda_z with ARS, AIC, TTT, TTTAIC & TTTARS now; it used to be only available for manual selection of data points; It's most easy function to implement so far which I cannot figure out how to do this long time ago. - fixed R^2 display on linear regression plots for terminal elim. constant (lambda_z) estimation; just a mathematical annotation (squared 2), it took me two whole nights to complete; Wow, it's not easy for this little thing... - fixed NCAselect() & NCAregplot() with plot(...,lab=c(15,15,40),...) for better looking. - fixed selection of all linear or lin-up/log-down calc. for AUC with manual selection of data points; others (AIC, ARS, TTT & etc. have been fixed last time); previously the selection does not work effectively, even the 'all linear' is selected. - corrected some typos; Is it cont. or cont'd? Answer: In formal writing use cont'd. ref. link: http://wiki.answers.com/Q/Is_it_cont_or_cont%27d (used in NCA Output). fine. - fixed 'description_pointselect()' to give more details about Windows, Linux/unix or ubuntu, and Mac OS X. - added lin-up/log-down trapezoidal AUC calc; the in-up/log-down trapezoidal method is default method now; - fix graphics in linux/unix (ubuntu), Mac OS X; use 'dev.new()' instead of 'windows(record=TRUE)'; original codes won't work any more for R v3.0 or above; - set options(digits=5) as default; v2.5.5 (for R v3.0.0) - NCA plots are switched from plot() to ggplot() now; better graphics looking; - use some helper functions from "Cookbook for R" authored by Winston Chang to use ggplot() (website); - remove console plotting now; all plots will be logged into .pdf of NCA plots; this will remove 5 R scripts from previous version; - add test/demo functions; separate from original /R directory; - add 'page break' '\f' for xxx_nca_outputs.txt; - fix bugs for the section containing the means (SD) for each formulation (by time point) in NCA output file. (thanks to Elba Romero). This is only for the situations of running NCA demo or NCA; - improve data point selection methods with correct subject labeling; - add bear cover page for nca plot and ODA plot pdf files (using library(png)); - fixed the part of data point manual selection logged as .pdf. With R3.0.0, it is still a problem; however, it is OK with R2.15.3 (miss it so much). Porbably in R3.0.0 the graphic windows have been changed as stated in its update doc. Now it should be fine. Quite different from ARS, AIC, TTT, etc.. my mistake; - remove the function to save 'TotalData' again after NCA as a .RData. It does not make any sense to do this; - remove DOA on-screen plots since all plots have been logged into a .pdf file. It's a redundancy procedure, just like on-screen NCA plots; - improve pivotal_output.csv; now it is much better than previously; - now manual data selection from previously saved .RData can also be plotted into pdf now, as well as plots of on-screen data point selection; - fix 'Tmax_ss' for multiple dose BE; the original one should be subtracted with TlastD (the time of the final dose be given); - fix NCAselect again; try to improve graphic looking for multiple dose BE dataset, especially the setting of ylim(); done. - fixed the section containing the means (SD) for each formulation (by time point) in NCA output file; it was the same for the ref. & test products in the previous version. Sorry about this; - hide on-screen linear regression plots, but still save all plots as one .pdf file; - set 'ylim=c(1e-3, 1e+5)' in all linear regression plots for lambda_z estimations; it looks much better in this case; and - all selection menu -> 'graphics=TRUE' now. v2.5.4 - please note that the previous saved .RData (before v2.5.4) will not be able to be supported in this release; users need to import the raw data from .cvs files or re-selected data points for linear regression to estimate lambda_z; sorry about that. - mostly based on BE/BA forums (with the topic of bear feature request). - grouping each run with random batch# and system date marked; more outputs from this version. and no more overwrite previous outputs now. - outlier detection analysis (ODA) is taken away from routine run; and also ODA outputs is separated; - max. data point selections for lambda_z estimation was increased to 6 (range: 2-6); - single plot for point selection now (used to be 2x2 plots), old-man version? - fix inconsistent outputs for unbalanced dataset; - incomplete dataset will be blocked before being analyzed (hopefully); - use "file.choose()" for data file loading; - total lambda_z selections outputs as .csv format (as requested by sarawuto); - pivotal and misc pk parameters output as .csv format (as requested by sarawuto); - change data() for demo functions; to adapt future R (with R v3.0); - add "extdata" directory to store demo data files as .rda format; - add linear regression line plots for lambda_z estimation for manual data points selections. - change save() and load() to saveRDS() and readRDS() for convenient scripting. - add mean (sd) plots on semilog scale (Helmut). - add alarm() and readline("...") for methods of estimation lambda_z to alert user what they should know before next step.(as requested by d_labes) - add a section containing the means (SD) for each formulation (by time point) in NCA output file (as requested by Helmut). - modify some output files. - add plots of linear regression lines for lambda_z estimation for ARS, AIC, TTT,TTT-AIC & TTT-ARS. v2.5.3 - generalized SAS-like outputs (such as ANOVA and Type III SS) with 2x2x2 crossover; - added variance model into lme() and fixed random effect in lme() for replicate study as suggested by D. Labes posted at bebac forum (browse this thread at bebac forum); - the maximum data points that can be chosen to estimation of λz is set to 4, at least 2 data points are required. The "Select the exact 3 data points" has been changed to "Select 2-4 data point"; and - other minor changes. v2.5.2 - changed anova model back to lm(log(PK)~ seq + subj:seq + prd + drug , data) as with v2.4.0; if not, this will result in error in calculation of 90% CI, as well as point estimates (thanks to Jiří Hofmann, Czech Republic). v2.5.1 - re-compiled again to change the requirement with R v2.10.0 to enable installation in MacOSX; however, bear was still compiled with R v2.11.0. v2.5.0 - added Welch t tests (also 90% CI) for a parallel BE study (thanks to Helmut Schütz); - added CVintra (intra-subject CV) calculation for a replicate BE study (lme_stat.txt) right after classical 90% CI; - hide ln(PK) list in the report of ANOVA_stat.txt/lm_stat.txt/lme_stat.txt; - completed the function of a parallel BE study with multiple-dosed (used to be single-dosed only); and - some other bugs fixed v2.4.4 - fixed the output file, Statistical_summaries.txt; i.e., Table 2: remove n1, n2 list from non-replicate or replicate crossover BE study; They only appear in Parallel BE study. v2.4.3 - changed the statistical model from linear mixed model(lme()) to linear model (lm())(similar to SAS GLM) for a parallel BE study; basically, the results obtained from lme() or lm() are the same. However, to meet the regulatory requirements (both FDA and EU), lm() has been adopted since this version. Later, the Welch t-test will be added for a parallel BE study for unequal variances in the next release. See more discussion: Post#01 and Post#02. - recompiled bear under R v.2.11.0. v2.4.2 - fixed NCA outputs for the unbalanced parallel BE study - fixed TOST descriptions - recompiled with R v2.10.1 v2.4.1 - add time/date stamp on the header or title page of text or pdf (plots) outputs (11.10(e) of 21 CRF Part 11); more to be made for Part 11... - set .pdf output format as A4 paper size. - modify all .Rd files to fit R v2.9.2 requirements - change of the name "seq:subj" to "subj(seq)" in anova with the mode of "Y ~ seq + subj:seq + per + trt" in order to be conveniently cross validated with SAS (thanks to Elmaestro) - mostly minor changes with this release v2.4.0 - add data analysis of multiple-dose (MD) ABE data - add Cook's distance for outlier detection with various criteria - fixed y-axis scaling problem v2.3.1 - fixed NCA plots of Time scale (with auto-scale) - used the difference of lsmeans between the Ref. and the Test to calculate 90% CIs for Cmax and AUCs v2.3.0 - add sample size estimation and lme analysis for the parallel BE study - add References into bear's output (such as ANOVA) - label outliers' subjects number for boxplot only if there is any (see crossover demo) - add input data summary of BA measurement (class level information, means, etc.) - add interpretations for some statistical tests (such as Hotelling T2 test) - add add Two One-Sided Tests (TOST) and Anderson-Hauck's tests (just for educational purposes ONLY) - allow users to change BE acceptance range now (not fixed on 80%-125% any more!); different countries have different regulatory basis... - show MSResidual and MSSubject(seq) values when calculating inter- and intra-subject CV - change Hotelling T2 test layout v 2.2.0 - add point estimate along with 90% CI in output file called 'Statistical_summaries.txt (suggested by D. Labes). - add sample size estimation for replicate BE study, and output re-arrangement. - add Hotelling T2 function and boxplot for outlier detection - add Quantiles for intrasubject and intersubject (with boxplot) - add replicated study for 2*2*3, 2*2*4, 2*2*5, and 2*2*6 (using lme to analyze replicated BE study) - add sample size estimation for replicated study (using 2*2*2 sample size estimation extended to 2*2*n sample size of replicate crossover design) v.2.1.0 - we add 'analysis of outliers detection' since this release. These include some normality tests, and some diagnostic plots for this functions, such as QQ plots and intra- and inter-subject residual plots. - fix intra-subject CV calculation based on ref. #6. (thanks to Helmut Schütz). v1.5.0~2.0.3 - now λz can be estimated from three methods: manual selections of the 3 exact data points, computer selection based on adjusted R sq. (ARS), and the Two-Times-Tmax (TTT) Method. - re-structure all codes of bear since v2.0.0. - add R sq. in NCA output; the original one is adjusted R sq. & changed T1/2 to T1/2(z) in NCA output file - corrected some typo errors appearing in the output files or console display - rearrange the output files with better styles: such as 3-decimal digits for 'power', etc. - built-in the data file (.RData) required for demo purposes; user doesn't need to enter/import /load it again - manual selection of the 3 exact data points can be saved now. user does not have to redo it next time. - displayed the method used to estimate λz in NCA output - changed '0.693' to ln(2) when estimating T1/2(z) (= ln(2)/λz) in NCA algorithm - changed LSM-ref and LSM-test to LSMEAN-ref and LSMEAN-test, respectively, in the output file of 'Statistical_Summaries.txt' - and many more that I just cannot remember right now... v1.1.5 - fixed the anova (lm) calculation due to the import of a .csv file. (thanks to Jiří Hofmann, Czech Republic) - added Type III SS (suggested by EIMaestro) - changed upper bound of sample size estimation from 105% to 95% (more conservative; suggested by Helmut Schütz) v1.1.4 - fixed the compatibility for iMac and Linux (thanks to Koji Shimamoto, Tokyo, Japan; also for his testing bear on iMac) v1.1.3-1.1.0 - removed the function of "Sample size estimation (raw data)"; also improve the function of "Sample size estimation (Log Transform)." - fixed the rounding error in the display of "Sample size estimation (Log transform)" (thanks to Helmut Schütz) - fixed some the format (comma, semicolon, etc.) of import data file (thanks to Helmut Schütz); users now can choose their favorite formats. - display the PATH where bear will import from and will output the all results to. - display only one graphic devices (using PageDown & PageUp to change plots) (thanks to Helmut Schütz) - display semilog (not linear) plots when choosing data points to do linear regression for λz in NCA (thanks to Helmut Schütz) - calculate CV_intra & CV_inter now (thanks to Helmut Schütz) - output both the .csv and the .RData file formats obtained from NCA; users can choose either one for anova. - use "Tests of SUBJECT(SEQUENCE) as an error term" in ANOVA output (thanks to Helmut Schütz) - changed ANOVA(GLM) to ANOVA (lm) in the menu title (thanks to ElMaestro) ----- References ----- 1. Hauschke D, Steinijans VW, Diletti E and Burke M. Sample size determination for bioequivalence assessment using a multiplicative model. J. Pharmacokin. Biopharm. 20:557-561, 1992. 2. U.S. Dept of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research. Guidance for industry. Statistical approaches to establishing bioequivalence, 2001. 3. Liu JP and Chow SC. Sample size determination for the twp one-sided tests procedure in bioequivalence. J. Pharmacokin. Biopharm. 20:101-104, 1992. 4. Schuirmann DJ. A comparison of the two one-sided tests procedure and the power approach for assessing the equivalence of average bioavailability. J. Pharmacokin. Biopharm. 15:657-680, 1987. 5. Chow SC, Liu JP. Design and Analysis of Bioavailability and Bioequivalence Studies. 2009; 3rd. ed., CRC Press, Chapman & Hall/CRC. 6. Hauschke D, Steinijans V, Pigeot I. Bioequivalence Studies in Drug Development: Mehtods and Applications, 2007; John Wiley & Sons Ltd.