From fd12c154e9625e7563c6f0551a1a6defd0c0a507 Mon Sep 17 00:00:00 2001 From: Bill Denney Date: Tue, 2 Jan 2018 09:26:00 -0500 Subject: [PATCH] Update "Methods Used for Dose-Aware Concentration Interpolation/Extrapolation" vignette --- DESCRIPTION | 4 +- ...-Aware-Interpolation-and-Extrapolation.Rmd | 60 +- ...Aware-Interpolation-and-Extrapolation.html | 5343 +++++------------ 3 files changed, 1408 insertions(+), 3999 deletions(-) diff --git a/DESCRIPTION b/DESCRIPTION index a9fc27dd..d6da7ab3 100644 --- a/DESCRIPTION +++ b/DESCRIPTION @@ -1,8 +1,8 @@ Package: PKNCA Type: Package Title: Perform Pharmacokinetic Non-Compartmental Analysis -Version: 0.8.3.9002 -Date: 2018-01-01 +Version: 0.8.3.9003 +Date: 2018-01-02 Authors@R: c( person("Bill", "Denney", email="wdenney@humanpredictions.com", role=c("aut", "cre")), person("Clare", "Buckeridge", email="clare.buckeridge@pfizer.com", role="aut"), diff --git a/vignettes/Methods-for-Dose-Aware-Interpolation-and-Extrapolation.Rmd b/vignettes/Methods-for-Dose-Aware-Interpolation-and-Extrapolation.Rmd index 7ba2f0bd..69c7560c 100644 --- a/vignettes/Methods-for-Dose-Aware-Interpolation-and-Extrapolation.Rmd +++ b/vignettes/Methods-for-Dose-Aware-Interpolation-and-Extrapolation.Rmd @@ -19,37 +19,23 @@ library(dplyr) Interpolation and extrapolation with awareness of doses occurring before, at the same time of, or after the requested interpolation time point must account for many interactions. To ensure clarity in the interpolation/extrapolation methods and the decisions made by the algorithm, each potential choice is listed below with its accompanying calculation method. The code used to generate the table is the same as the code within the function. ```{r generatecombs, echo=FALSE} -event.before <- - data.frame(event.before=c(NA, "conc", "dose", "dose", "both", "both"), - iv.bolus.before=c(NA, NA, FALSE, TRUE, FALSE, TRUE)) -event.at <- - data.frame(event.at=c(NA, "conc", "dose", "dose", "both", "both"), - iv.bolus.at=c(NA, NA, FALSE, TRUE, FALSE, TRUE)) -event.after <- - data.frame(event.after=c(NA, "conc", "dose", "both")) -time.request <- - data.frame(after=c(FALSE, TRUE)) - method.choices <- names(PKNCA:::interp.extrap.conc.dose.select) method.choices <- factor(method.choices, levels=method.choices, ordered=TRUE) all.combs <- - merge( - merge( - merge(event.before, event.at), - event.after), - time.request) -all.combs$Method <- "" + expand.grid(event_before=setdiff(unlist(PKNCA:::event_choices_interp.extrap.conc.dose), "output_only"), + event=setdiff(unlist(PKNCA:::event_choices_interp.extrap.conc.dose), "none"), + event_after=setdiff(unlist(PKNCA:::event_choices_interp.extrap.conc.dose), "output_only"), + Method="", + stringsAsFactors=FALSE) for (n in method.choices) { mask <- - PKNCA:::interp.extrap.conc.dose.select[[n]]$select(all.combs) - mask.overlap <- mask & - !(all.combs$Method %in% "") - all.combs$Method[mask & ! mask.overlap] <- n - #all.combs$Method[mask.overlap] <- paste(all.combs$Method[mask.overlap], n, sep="; ") - #cat(n, sum(mask), "\n") + do.call(PKNCA:::interp.extrap.conc.dose.select[[n]]$select, + list(x=all.combs), + envir=environment(pk.nca)) + all.combs$Method[mask] <- n } all.combs <- @@ -63,21 +49,9 @@ The method list below is described and sorted in order of how many scenarios the For each of the summary tables below, the column headers are as follows: -* **Event Before**: The type of event immediately before the time of the requested output may be one of the following: - * *NA*: No event - * *dose*: A dosing event without a simultaneous concentration measure - * *conc*: A concentration measurement without a simultaneous dose - * *both*: A dosing event at the same time as a concentration measurement -* **IV Bolus Before**: If the "Event Before" the requested output time was a "dose" or "both", was the dose an IV bolus? - * *TRUE*: Yes, it was an IV bolus. - * *FALSE*: No, it was not an IV bolus. - * *NA*: It was not a dose. +* **Event Before**: The type of event before the time of the requested output may be one of the following * **Event At**: The equivalent to "Event Before" but for the event occurring at the requested output time. -* **IV Bolus At**: The equivalent to "IV Bolus Before" but for the event occurring at the requested output time. * **Event After**: The equivalent to "Event Before" but for the next event occurring after the requested output time. -* **Instant After**: Should the time of the output be considered instantaneously after the requested output time? "After" only has an effect relative to an IV bolus. - * *TRUE*: Yes, the output is immediately after. - * *FALSE*: No, the output is immediately before. ```{r methodsummary, results="asis", echo=FALSE} methodorder <- names(sort(summary(factor(all.combs$Method)), decreasing=TRUE)) @@ -87,11 +61,9 @@ for (n in methodorder) { cat(PKNCA:::interp.extrap.conc.dose.select[[n]]$description, "\n\n", sep="") print(knitr::kable( all.combs[all.combs$Method %in% n, - c("event.before", "iv.bolus.before", - "event.at", "iv.bolus.at", "event.after", - "after")], + c("event_before","event", "event_after")], row.names=FALSE, - col.names=c("Event Before", "IV Bolus Before", "Event At", "IV Bolus At", "Event After", "Instant After"))) + col.names=c("Event Before", "Event At", "Event After"))) cat("\n") } ``` @@ -100,11 +72,7 @@ for (n in methodorder) { ```{r methodlisting, echo=FALSE} knitr::kable( - all.combs[,c("event.before", "iv.bolus.before", - "event.at", "iv.bolus.at", "event.after", - "after", "Method")], + all.combs[,c("event_before", "event", "event_after", "Method")], row.names=FALSE, - col.names=c("Event Before", "IV Bolus Before", - "Event At", "IV Bolus At", "Event After", - "Instant After", "Method Used")) + col.names=c("Event Before", "Event At", "Event After", "Method Used")) ``` diff --git a/vignettes/Methods-for-Dose-Aware-Interpolation-and-Extrapolation.html b/vignettes/Methods-for-Dose-Aware-Interpolation-and-Extrapolation.html index e6b37c1b..d8c9b065 100644 --- a/vignettes/Methods-for-Dose-Aware-Interpolation-and-Extrapolation.html +++ b/vignettes/Methods-for-Dose-Aware-Interpolation-and-Extrapolation.html @@ -4,7 +4,7 @@ - + @@ -43,1002 +43,736 @@

Methods

The method list below is described and sorted in order of how many scenarios the method is applied to in the list.

For each of the summary tables below, the column headers are as follows:

-
-

Copy

+
+

Observed concentration

Copy the input concentration at the given time to the output.

- - - - - - - - - + + + - - - - - - + + + - - - - - - + + + - - - - - - + + + - - - - - + + - - - - - + + - - - - - - + + + - - - - - - + + + - - - - - - + + + - - - - - - + + + - - - - - + + - - - - - - + + + - - - - - + + - - - - - + + - - - - - + + - - - - - + + - - + - - - - - - + - + - - + - - - + - - + - - - - - - - - - - - - - - - - - - - - - - - - + + + - - - - - - + + + - - - - + + - - - - - - - + + + - - - - - - + + + - - - - + + - - - - - - - + + + - - - - - - + + + - - - - + + - - - - - + + + + + + + - + + + + + - - + + - - - - - + - - - + - - + - - - + - - + - - - + - - - - + - + - - + - - - + - - + + - - - - - - - - - + + + - - - - - - + + + - - - - - - + + + - - - - - - + + + - - - - - - + + + - - - - + + - - - - - + - + - - - - - + + - - - - - + + - - - - - - + + + - - - - - - + + + - - - - + + - - - - - - + + - - - - - - + + + - - - - - - + + + - - - - - - + + + - - + + + + + + + - - - + + + + + + + + + + + + + + + - - + - - - - - - + - + - - + - - - + - - + - - + - - - - - + + - - - - - + + + - - - - - - - - - - - + + + + + + + + + + + + + + + + + + + + + + + + - - - - + - - - - - + + - - - - - + + - - - - + - - - - - + + - - - - - + + + - - - - - - - - - + + + + + + + + + + + + - - - - - - - + + + - - - - - - + + + + + - - - - - - - - - - - + + + + + + + + + + + + + +
Event BeforeIV Bolus Before Event AtIV Bolus At Event AfterInstant After
NANAbothFALSENAFALSEconcconcconc
NANAbothFALSENATRUEconcconcconc_dose
NANAbothFALSEbothFALSEconcconcconc_dose_iv_bolus_after
NANAbothFALSEbothTRUEconcconcdose
NANAbothFALSE concFALSEconcdose_iv_bolus_after
NANAbothFALSE concTRUEconcnone
NANAbothFALSEdoseFALSEconcconc_doseconc
NANAbothFALSEdoseTRUEconcconc_doseconc_dose
NANAbothTRUENAFALSEconcconc_doseconc_dose_iv_bolus_after
NANAbothTRUEbothFALSEconcconc_dosedose
NANAbothTRUE concFALSEconc_dosedose_iv_bolus_after
NANAbothTRUEdoseFALSEconcconc_dosenone
NANA concNANAFALSEconc_dose_iv_bolus_afterconc
NANA concNANATRUEconc_dose_iv_bolus_afterconc_dose
NANA concNAbothFALSEconc_dose_iv_bolus_afterdose
NANA concNAbothTRUEconc_dose_iv_bolus_afternone
NANAconc_dose concNA concFALSE
NANAconcNAconc_dose concTRUEconc_dose
NANAconc_dose concNAdoseFALSEconc_dose_iv_bolus_after
NANAconc_dose concNA doseTRUE
bothFALSEbothFALSENAFALSE
bothFALSEbothFALSENATRUE
bothFALSEbothFALSEbothFALSEconc_doseconcdose_iv_bolus_after
bothFALSEbothFALSEbothTRUEconc_doseconcnone
bothFALSEbothFALSEconc_doseconc_dose concFALSE
bothFALSEbothFALSEconcTRUEconc_doseconc_doseconc_dose
bothFALSEbothFALSEdoseFALSEconc_doseconc_doseconc_dose_iv_bolus_after
bothFALSEbothFALSEconc_doseconc_dose doseTRUE
bothFALSEbothTRUENAFALSEconc_doseconc_dosedose_iv_bolus_after
bothFALSEbothTRUEbothFALSEconc_doseconc_dosenone
bothFALSEbothTRUEconc_doseconc_dose_iv_bolus_after concFALSE
bothFALSEbothTRUEconc_doseconc_dose_iv_bolus_afterconc_dose
conc_doseconc_dose_iv_bolus_after doseFALSE
conc_doseconc_dose_iv_bolus_afternone
bothFALSEconc_dose_iv_bolus_afterconc concNANAFALSE
bothFALSEconc_dose_iv_bolus_after concNANATRUEconc_dose
bothFALSEconc_dose_iv_bolus_after concNAbothFALSEconc_dose_iv_bolus_after
bothFALSEconc_dose_iv_bolus_after concNAbothTRUEdose
bothFALSEconcNAconc_dose_iv_bolus_after concFALSEdose_iv_bolus_after
bothFALSEconc_dose_iv_bolus_after concNAconcTRUEnone
bothFALSEconc_dose_iv_bolus_afterconc_dose concNAdoseFALSE
bothFALSEconcNAdoseTRUEconc_dose_iv_bolus_afterconc_doseconc_dose
bothTRUEbothFALSENAFALSEconc_dose_iv_bolus_afterconc_doseconc_dose_iv_bolus_after
bothTRUEbothFALSENATRUEconc_dose_iv_bolus_afterconc_dosedose
bothTRUEbothFALSEbothFALSEconc_dose_iv_bolus_afterconc_dosedose_iv_bolus_after
bothTRUEbothFALSEbothTRUEconc_dose_iv_bolus_afterconc_dosenone
bothTRUEbothFALSEdoseconc concFALSE
bothTRUEbothFALSEdose concTRUEconc_dose
bothTRUEbothFALSE doseFALSEconcconc_dose_iv_bolus_after
bothTRUEbothFALSE doseTRUEconcdose
bothTRUEbothTRUENAFALSEdoseconcdose_iv_bolus_after
bothTRUEbothTRUEbothFALSEdoseconcnone
bothTRUEbothTRUEdoseconc_dose concFALSE
bothTRUEbothTRUE doseFALSEconc_doseconc_dose
bothTRUEconcNANAFALSEdoseconc_doseconc_dose_iv_bolus_after
bothTRUEconcNANATRUEdoseconc_dosedose
bothTRUEconcNAbothFALSEdoseconc_dosedose_iv_bolus_after
bothTRUEdoseconc_dosenone
doseconc_dose_iv_bolus_after concNAbothTRUE
doseconc_dose_iv_bolus_afterconc_dose
doseconc_dose_iv_bolus_afterdose
doseconc_dose_iv_bolus_afternone
bothTRUEdose_iv_bolus_after concNA concFALSE
bothTRUEconcNAdose_iv_bolus_after concTRUEconc_dose
bothTRUEdose_iv_bolus_after concNAdoseFALSEconc_dose_iv_bolus_after
bothTRUEdose_iv_bolus_after concNA doseTRUE
dose_iv_bolus_after concNAbothFALSENAFALSEdose_iv_bolus_after
dose_iv_bolus_after concNAbothFALSENATRUEnone
dose_iv_bolus_afterconc_dose concNAbothFALSEbothFALSE
concNAbothFALSEbothTRUEdose_iv_bolus_afterconc_doseconc_dose
dose_iv_bolus_afterconc_doseconc_dose_iv_bolus_after
dose_iv_bolus_afterconc_dosedose
dose_iv_bolus_afterconc_dosedose_iv_bolus_after
dose_iv_bolus_afterconc_dosenone
none concNAbothFALSE concFALSE
none concNAbothFALSEconcTRUEconc_dose
none concNAbothFALSEdoseFALSEconc_dose_iv_bolus_after
none concNAbothFALSE doseTRUE
none concNAbothTRUENAFALSEdose_iv_bolus_after
none concNAbothTRUEbothFALSEnone
noneconc_dose concNAbothTRUEconcFALSE
concNAbothTRUEnoneconc_doseconc_dose
noneconc_doseconc_dose_iv_bolus_after
noneconc_dose doseFALSE
concNAconcNANAFALSEnoneconc_dosedose_iv_bolus_after
concNAconcNANATRUEnoneconc_dosenone
noneconc_dose_iv_bolus_after concNAconcNAbothFALSE
concNAconcNAbothTRUEnoneconc_dose_iv_bolus_afterconc_dose
noneconc_dose_iv_bolus_afterdose
noneconc_dose_iv_bolus_afternone
+
+
+

Impossible combinations

+

The event combination cannot exist.

+ + + + + + + + + + - - - - - + + - + + + + - + + + + - + + - - - - - + + - - - - - + + - - - - - - + + + - - - - - - + + + - - - - - - + + + - - - - - - + + + - - - - - - + + + - - - - + + + + + + + - + + + + + - - - - - - + + + + + - - - - - - - - - - - + + + - - - - - - + + + - - - - + + - - - - - - - + + + - - - - - - + + + + + - - - - - - - - - - - + + + - - - - - - + + + - - - - - - + + + - - - - - - + + + - - - - - + + - - - - - + + - - - - - + + - - - - - + + - - - - - + + - - - - - + + - - - - + + - - - - - - - + + + - - - - - - + + + + + - - - - - - - - - - - + + + - - - - - - + + + - - - - + + - - - - - - - + + + - - - - - - + + + + + - - - - - - - - - - - + + + - - - - - - + + + - - - - - - + + + - - - - - - + + + - - - - - - + + + - - - - - - + + + + + + + + + + + + + + + + + + + + + + +
Event BeforeEvent AtEvent After
concNAconcNAconcFALSEconc_dose_iv_bolus_afterconc_dose_iv_bolus_after
concNAconc_dose_iv_bolus_afterdose_iv_bolus_after
concNAdose_iv_bolus_afterconc_dose_iv_bolus_after
concTRUEdose_iv_bolus_afterdose_iv_bolus_after
concNAconcNAdoseFALSEoutput_onlyconc_dose_iv_bolus_after
concNAconcNAdoseTRUEoutput_onlydose_iv_bolus_after
doseFALSEbothFALSENAFALSEconc_doseconc_dose_iv_bolus_afterconc_dose_iv_bolus_after
doseFALSEbothFALSENATRUEconc_doseconc_dose_iv_bolus_afterdose_iv_bolus_after
doseFALSEbothFALSEbothFALSEconc_dosedose_iv_bolus_afterconc_dose_iv_bolus_after
doseFALSEbothFALSEbothTRUEconc_dosedose_iv_bolus_afterdose_iv_bolus_after
doseFALSEbothFALSEconcFALSEconc_doseoutput_onlyconc_dose_iv_bolus_after
doseFALSEbothFALSEconc_doseoutput_onlydose_iv_bolus_after
conc_dose_iv_bolus_afterconc_dose_iv_bolus_after concTRUE
conc_dose_iv_bolus_afterconc_dose_iv_bolus_afterconc_dose
doseFALSEbothFALSEdoseFALSEconc_dose_iv_bolus_afterconc_dose_iv_bolus_afterconc_dose_iv_bolus_after
conc_dose_iv_bolus_afterconc_dose_iv_bolus_after doseFALSEbothFALSEdoseTRUE
doseFALSEbothTRUENAFALSEconc_dose_iv_bolus_afterconc_dose_iv_bolus_afterdose_iv_bolus_after
doseFALSEbothTRUEbothFALSEconc_dose_iv_bolus_afterconc_dose_iv_bolus_afternone
doseFALSEbothTRUEconc_dose_iv_bolus_afterdose_iv_bolus_after concFALSE
doseFALSEbothTRUEdoseFALSEconc_dose_iv_bolus_afterdose_iv_bolus_afterconc_dose
doseFALSEconcNANAFALSEconc_dose_iv_bolus_afterdose_iv_bolus_afterconc_dose_iv_bolus_after
conc_dose_iv_bolus_afterdose_iv_bolus_after doseFALSEconcNANATRUE
doseFALSEconcNAbothFALSEconc_dose_iv_bolus_afterdose_iv_bolus_afterdose_iv_bolus_after
doseFALSEconcNAbothTRUEconc_dose_iv_bolus_afterdose_iv_bolus_afternone
doseFALSEconcNAconcFALSEconc_dose_iv_bolus_afteroutput_onlyconc_dose_iv_bolus_after
doseFALSEconcNAconcTRUEconc_dose_iv_bolus_afteroutput_onlydose_iv_bolus_after
doseFALSEconcNAdoseFALSEconc_dose_iv_bolus_afterconc_dose_iv_bolus_after
doseFALSEconcNAdoseTRUEconc_dose_iv_bolus_afterdose_iv_bolus_after
doseTRUEbothFALSENAFALSEdose_iv_bolus_afterconc_dose_iv_bolus_after
doseTRUEbothFALSENATRUEdose_iv_bolus_afterdose_iv_bolus_after
doseTRUEbothFALSEbothFALSEoutput_onlyconc_dose_iv_bolus_after
doseTRUEbothFALSEbothTRUEoutput_onlydose_iv_bolus_after
doseTRUEbothFALSEdose_iv_bolus_afterconc_dose_iv_bolus_after concFALSE
doseTRUEbothFALSEconcTRUEdose_iv_bolus_afterconc_dose_iv_bolus_afterconc_dose
doseTRUEbothFALSEdoseFALSEdose_iv_bolus_afterconc_dose_iv_bolus_afterconc_dose_iv_bolus_after
dose_iv_bolus_afterconc_dose_iv_bolus_after doseTRUEbothFALSEdoseTRUE
doseTRUEbothTRUENAFALSEdose_iv_bolus_afterconc_dose_iv_bolus_afterdose_iv_bolus_after
doseTRUEbothTRUEbothFALSEdose_iv_bolus_afterconc_dose_iv_bolus_afternone
doseTRUEbothTRUEdose_iv_bolus_afterdose_iv_bolus_after concFALSE
doseTRUEbothTRUEdoseFALSEdose_iv_bolus_afterdose_iv_bolus_afterconc_dose
doseTRUEconcNANAFALSEdose_iv_bolus_afterdose_iv_bolus_afterconc_dose_iv_bolus_after
dose_iv_bolus_afterdose_iv_bolus_after doseTRUEconcNANATRUE
doseTRUEconcNAbothFALSEdose_iv_bolus_afterdose_iv_bolus_afterdose_iv_bolus_after
doseTRUEconcNAbothTRUEdose_iv_bolus_afterdose_iv_bolus_afternone
doseTRUEconcNAconcFALSEdose_iv_bolus_afteroutput_onlyconc_dose_iv_bolus_after
doseTRUEconcNAconcTRUEdose_iv_bolus_afteroutput_onlydose_iv_bolus_after
doseTRUEconcNAdoseFALSEnoneconc_dose_iv_bolus_afterconc_dose_iv_bolus_after
doseTRUEconcNAdoseTRUEnoneconc_dose_iv_bolus_afterdose_iv_bolus_after
nonedose_iv_bolus_afterconc_dose_iv_bolus_after
nonedose_iv_bolus_afterdose_iv_bolus_after
noneoutput_onlyconc_dose_iv_bolus_after
noneoutput_onlydose_iv_bolus_after
@@ -1050,977 +784,455 @@

Doses with no concentrations between

Event Before -IV Bolus Before Event At -IV Bolus At Event After -Instant After -both -FALSE -NA -NA -NA -FALSE - - -both -FALSE -NA -NA -NA -TRUE - - -both -FALSE -NA -NA +conc_dose dose -FALSE +conc -both -FALSE -NA -NA +conc_dose dose -TRUE +conc_dose -both -FALSE +conc_dose dose -FALSE -NA -FALSE +conc_dose_iv_bolus_after -both -FALSE +conc_dose +dose dose -FALSE -NA -TRUE -both -FALSE +conc_dose dose -FALSE -both -FALSE +dose_iv_bolus_after -both -FALSE +conc_dose dose -FALSE -both -TRUE +none -both -FALSE -dose -FALSE -conc -FALSE +conc_dose +output_only +conc_dose -both -FALSE +conc_dose +output_only dose -FALSE -conc -TRUE -both -FALSE dose -FALSE dose -FALSE +conc -both -FALSE dose -FALSE dose -TRUE +conc_dose -both -FALSE dose -TRUE -NA -FALSE +dose +conc_dose_iv_bolus_after -both -FALSE dose -TRUE -both -FALSE +dose +dose -both -FALSE dose -TRUE -conc -FALSE +dose +dose_iv_bolus_after -both -FALSE dose -TRUE dose -FALSE +none -both -TRUE dose -FALSE -NA -FALSE +output_only +conc_dose -both -TRUE dose -FALSE -NA -TRUE - - -both -TRUE +output_only dose -FALSE -both -FALSE - -both -TRUE -dose -FALSE -both -TRUE + + +
+
+

Extrapolation

+

Extrapolate from a concentration to a dose

+ + + + + + + + - - + - - - - - - - + + - - - - + - + - - + - - - - + - - - + - - + - - - + - - - - - + + - - - - - - + + + + - - - - - + + - - - - - + + - - - - - + + + - - - - - + - - - - - + + - - - - - + + + - - - - - - - - - - - - - - - - - - - + + + - - - - - - - + +
Event BeforeEvent AtEvent After
bothTRUEconc doseFALSE concFALSE
bothTRUEdoseFALSE concTRUEdoseconc_dose
bothTRUEdoseFALSEconc doseFALSEconc_dose_iv_bolus_after
bothTRUEconc doseFALSE doseTRUE
bothTRUEconc doseTRUENAFALSEdose_iv_bolus_after
bothTRUEconc doseTRUEbothFALSEnone
bothTRUEdoseTRUE concFALSEoutput_onlydose
bothTRUEdoseTRUEdoseFALSEconcoutput_onlynone
conc_dose_iv_bolus_after doseFALSENANANAFALSEconc
conc_dose_iv_bolus_after doseFALSENANANATRUEconc_dose
conc_dose_iv_bolus_after doseFALSENANAbothFALSEconc_dose_iv_bolus_after
conc_dose_iv_bolus_afterdose doseFALSENANAbothTRUE
conc_dose_iv_bolus_after doseFALSENANAdoseFALSEdose_iv_bolus_after
conc_dose_iv_bolus_after doseFALSENANAdoseTRUEnone
conc_dose_iv_bolus_afteroutput_only doseFALSEdoseFALSENAFALSE
doseFALSEdoseFALSENATRUE
doseFALSEdoseFALSEbothFALSEconc_dose_iv_bolus_afteroutput_onlynone
doseFALSEdoseFALSEbothTRUE
+
+
+

Immediately after an IV bolus without a concentration next

+

Cannot calculate C0 without a concentration after an IV bolus; return NA.

+ + + + + + + + - - - - - - - - - - - - - - - - - - - - - - - - - - - + - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - + + + + - - - - - - - - - - - + + + - + - - - - - - - - + + + - - - - + - - - - - + + - - - - - + + - - - - + - - - - - + + - - - - - + + + - - - - - - - - - - - + + +
Event BeforeEvent AtEvent After
doseFALSEdoseFALSEconcFALSE
doseFALSEdoseFALSE concTRUE
doseFALSEdoseFALSEdoseFALSE
doseFALSEdoseFALSEdose_iv_bolus_after doseTRUE
doseFALSEdoseTRUENAFALSE
doseFALSEdoseTRUEbothFALSE
doseFALSEdoseTRUE concFALSE
doseFALSEdoseTRUEdoseFALSEdose_iv_bolus_afternone
conc_dosedose_iv_bolus_after doseTRUEdoseFALSENAFALSE
doseTRUEdoseFALSENATRUEconc_dosedose_iv_bolus_afternone
doseTRUEdose_iv_bolus_after doseFALSEbothFALSE
doseTRUEdoseFALSEbothTRUEdose_iv_bolus_afternone
dose_iv_bolus_after doseTRUEdoseFALSE concFALSE
dose_iv_bolus_after doseTRUEdoseFALSEconcTRUEconc_dose
dose_iv_bolus_after doseTRUEdoseFALSEdoseFALSEconc_dose_iv_bolus_after
dose_iv_bolus_after doseTRUE doseFALSEdoseTRUE
dose_iv_bolus_after doseTRUEdoseTRUENAFALSEdose_iv_bolus_after
dose_iv_bolus_after doseTRUEdoseTRUEbothFALSEnone
nonedose_iv_bolus_after doseTRUEdoseTRUEconcFALSE
doseTRUEdoseTRUEdoseFALSEnonedose_iv_bolus_afternone
-
-

Immediately after an IV bolus without a concentration next

-

Cannot calculate C0 without a concentration after an IV bolus; return NA.

+
+

Before all events

+

Interpolation before any events is NA or zero (0) depending on the value of conc.origin. conc.origin defaults to zero which is the implicit assumption that a complete washout occurred and there is no endogenous source of the analyte.

- - - - - - - - - - - - - - - - - - - - - - - + - + - - + - - - + - - - - - - - - - - + - - - - - - - - - - - + - - - - - - - - - - - - + - - - - - - - - - - + - - - + - - - - + - + + + - - - - - - - - - - - + + + - - - - + + - - - - - - - + + + + + +
Event BeforeIV Bolus Before Event AtIV Bolus At Event AfterInstant After
bothFALSEbothTRUENATRUE
bothFALSEbothTRUEbothTRUE
bothFALSEbothTRUEnone doseTRUEconc
bothFALSEnone doseTRUENATRUEconc_dose
bothFALSEdoseTRUEbothTRUE
bothFALSEnone doseTRUEdoseTRUE
bothTRUEbothTRUENATRUEconc_dose_iv_bolus_after
bothTRUEbothTRUEbothTRUE
bothTRUEbothTRUEnone doseTRUE
bothTRUE doseTRUENATRUE
bothTRUEnone doseTRUEbothTRUEdose_iv_bolus_after
bothTRUEdoseTRUEnone doseTRUEnone
noneoutput_only concNAbothTRUENATRUE
concNAbothTRUEbothTRUEnoneoutput_onlyconc_dose
concNAbothTRUEnoneoutput_only doseTRUE
concNAdoseTRUENATRUEnoneoutput_onlynone
+
+
+

Immediately after an IV bolus with a concentration next

+

Calculate C0 for the time immediately after an IV bolus. First, attempt using log slope back-extrapolation. If that fails, use the first concentration after the dose as C0.

+ + + + + + + + - - - - - - - + - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - + + + - - - - - - + + + - - - - - - + + + - - - - - + + - - - - - + + - - - - - - + + + - - - - - - + + +
Event BeforeEvent AtEvent After
concNAdoseTRUEbothTRUE
dose_iv_bolus_after concNAdoseTRUEdoseTRUE
doseFALSEbothTRUENATRUE
doseFALSEbothTRUEbothTRUE
doseFALSEbothTRUEdoseTRUE
doseFALSEdoseTRUENATRUE
doseFALSEdoseTRUEbothTRUE
doseFALSEdoseTRUEdoseTRUEconcdose_iv_bolus_afterconc_dose
doseTRUEbothTRUENATRUEconc_dosedose_iv_bolus_afterconc
doseTRUEbothTRUEbothTRUEconc_dosedose_iv_bolus_afterconc_dose
doseTRUEbothTRUEdoseTRUEdose_iv_bolus_afterconc
doseTRUEdoseTRUENATRUEdose_iv_bolus_afterconc_dose
doseTRUEdoseTRUEbothTRUEnonedose_iv_bolus_afterconc
doseTRUEdoseTRUEdoseTRUEnonedose_iv_bolus_afterconc_dose
-
-

Before all events

-

Interpolation before any events is NA or zero (0) depending on the value of conc.origin. conc.origin defaults to zero which is the implicit assumption that a complete washout occurred and there is no endogenous source of the analyte.

+
+

Interpolation

+

With concentrations before and after and not an IV bolus before, interpolate between observed concentrations.

- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - + - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - + + - - - - + + - - - - - + + - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - + + + - - - - - - - + +
Event BeforeIV Bolus Before Event AtIV Bolus At Event AfterInstant After
NANANANANAFALSE
NANANANANATRUE
NANANANAbothFALSE
NANANANAbothTRUE
NANANANA concFALSE
NANANANAoutput_only concTRUE
NANANANAdoseFALSE
NANANANAdoseTRUE
NANAbothTRUENATRUE
NANAbothTRUEbothTRUE
NANAbothTRUE concTRUE
NANAbothTRUEdoseTRUE
NANAdoseFALSENAFALSE
NANAdoseFALSENATRUE
NANAdoseFALSEbothFALSE
NANAdoseFALSEbothTRUEoutput_onlyconc_dose
NANAdoseFALSEconc_doseoutput_only concFALSE
NANAdoseFALSEconc_dose_iv_bolus_afteroutput_only concTRUE
NANAdoseFALSEdoseFALSE
NANAdoseFALSEdoseTRUE
NANAdoseTRUENAFALSE
NANAdoseTRUENATRUE
NANAdoseTRUEbothFALSEconc_dose_iv_bolus_afteroutput_onlyconc_dose
NANAdoseTRUEbothTRUE
+
+
+

After an IV bolus with a concentration next

+

First, calculate C0 using log slope back-extrapolation (falling back to the first post-dose concentration if that fails). Then, interpolate between C0 and the first post-dose concentration.

+ + + + + + + + - - - - - - - - - - - - + + - - - - - - - - - - - - - - - + + +
Event BeforeEvent AtEvent After
NANAdoseTRUEconcFALSE
NANAdoseTRUEdose_iv_bolus_afteroutput_only concTRUE
NANAdoseTRUEdoseFALSE
NANAdoseTRUEdoseTRUEdose_iv_bolus_afteroutput_onlyconc_dose
@@ -2032,537 +1244,65 @@

After an IV bolus without a concentration next

Event Before -IV Bolus Before Event At -IV Bolus At Event After -Instant After -both -TRUE -NA -NA -NA -FALSE +dose_iv_bolus_after +output_only +dose -both -TRUE -NA -NA -NA -TRUE - - -both -TRUE -NA -NA -both -FALSE +dose_iv_bolus_after +output_only +none - -both -TRUE -NA -NA -both -TRUE + + +
+
+

Dose as the last event in the timeline and requesting a concentration after

+

Cannot estimate the concentration after a dose without concentrations after the dose, return NA.

+ + + + + + + + - - - - - - + + + - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
Event BeforeEvent AtEvent After
bothTRUENANAdoseFALSEconc_doseoutput_onlynone
bothTRUENANAdoseTRUE
doseTRUENANANAFALSE
doseTRUENANANATRUE
doseTRUENANAbothFALSE
doseTRUENANAbothTRUE
doseTRUENANAdoseFALSE
doseTRUENANAdoseTRUE
-
-
-

Concentration, nothing or dose but not(dose, IV bolus, After), nothing or dose

-

Extrapolate when the previous measurement is a concentration, and the current event is a dose or nothing. If the previous concentration measurement is below the limit of quantification (zero), then return zero.

- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
Event BeforeIV Bolus BeforeEvent AtIV Bolus AtEvent AfterInstant After
concNANANAdoseFALSE
concNANANAdoseTRUE
concNAdoseFALSEbothFALSE
concNAdoseFALSEbothTRUE
concNAdoseFALSEconcFALSE
concNAdoseFALSEconcTRUE
concNAdoseFALSEdoseFALSE
concNAdoseFALSEdoseTRUE
concNAdoseTRUEbothFALSE
concNAdoseTRUEconcFALSE
concNAdoseTRUEdoseFALSE
-
-
-

Immediately after an IV bolus with a concentration next

-

Calculate C0 for the time immediately after an IV bolus. First, attempt using log slope back-extrapolation. If that fails, use the first concentration after the dose as C0.

- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - + +
Event BeforeIV Bolus BeforeEvent AtIV Bolus AtEvent AfterInstant After
bothFALSEbothTRUEconcTRUE
bothFALSEdoseTRUEconcTRUE
bothTRUEbothTRUEconcTRUE
bothTRUEdoseTRUEconcTRUE
concNAbothTRUEconcTRUE
concNAdoseTRUEconcTRUE
doseFALSEbothTRUEconcTRUE
doseFALSEdoseTRUEconcTRUE
doseTRUEbothTRUEconcTRUE
doseTRUEdoseTRUEconcTRUEoutput_onlynone
-
-

Interpolation

-

With concentrations before and after and not an IV bolus before, interpolate between observed concentrations.

+
+

Dose before, concentration after without a dose

+

If the concentration at the dose is estimable, interpolate. Otherwise, NA.

- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
Event BeforeIV Bolus Before Event AtIV Bolus At Event AfterInstant After
bothFALSENANAbothFALSE
bothFALSENANAbothTRUE
bothFALSENANAconcFALSE
bothFALSENANAconcTRUE
concNANANAbothFALSE
concNANANAbothTRUE
concNANANAconcFALSE
concNANANAconcTRUE
-
-
-

After all events, concentration before

-

Extrapolate from the concentration data after the last dose.

- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
Event BeforeIV Bolus BeforeEvent AtIV Bolus AtEvent AfterInstant After
concNANANANAFALSE
concNANANANATRUE
concNA doseFALSENAFALSE
concNAdoseFALSENATRUE
concNAdoseTRUENAFALSE
-
-
-

After an IV bolus with a concentration next

-

First, calculate C0 using log slope back-extrapolation (falling back to the first post-dose concentration if that fails). Then, interpolate between C0 and the first post-dose concentration.

- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
Event BeforeIV Bolus BeforeEvent AtIV Bolus AtEvent AfterInstant After
bothTRUENANAconcFALSE
bothTRUENANAconcTRUE
doseTRUENANAconcFALSE
doseTRUENANAconcTRUE
-
-
-

After a dose with no event and a concentration after

-

If there is a non-IV bolus dose before, nothing at the current time, and a concentration after, extrapolate from prior data to the concentration at the time of dosing then interpolate between the dosing time and the requested output time.

- - - - - - - - - - - - - - - - - + - - - - - - - - -
Event BeforeIV Bolus BeforeEvent AtIV Bolus AtEvent AfterInstant After
doseFALSENANAoutput_only concFALSE
doseFALSENANAconcTRUE
@@ -2574,2606 +1314,1307 @@

Appendix: Complete Methods Table

Event Before -IV Bolus Before Event At -IV Bolus At Event After -Instant After -Method Used - - - - -NA -NA -NA -NA -NA -FALSE -Before all events - - -NA -NA -NA -NA -NA -TRUE -Before all events - - -NA -NA -NA -NA -both -FALSE -Before all events - - -NA -NA -NA -NA -both -TRUE -Before all events - - -NA -NA -NA -NA -conc -FALSE -Before all events - - -NA -NA -NA -NA -conc -TRUE -Before all events - - -NA -NA -NA -NA -dose -FALSE -Before all events - - -NA -NA -NA -NA -dose -TRUE -Before all events - - -NA -NA -both -FALSE -NA -FALSE -Copy - - -NA -NA -both -FALSE -NA -TRUE -Copy - - -NA -NA -both -FALSE -both -FALSE -Copy - - -NA -NA -both -FALSE -both -TRUE -Copy - - -NA -NA -both -FALSE -conc -FALSE -Copy - - -NA -NA -both -FALSE -conc -TRUE -Copy - - -NA -NA -both -FALSE -dose -FALSE -Copy - - -NA -NA -both -FALSE -dose -TRUE -Copy - - -NA -NA -both -TRUE -NA -FALSE -Copy - - -NA -NA -both -TRUE -NA -TRUE -Before all events - - -NA -NA -both -TRUE -both -FALSE -Copy - - -NA -NA -both -TRUE -both -TRUE -Before all events - - -NA -NA -both -TRUE -conc -FALSE -Copy - - -NA -NA -both -TRUE -conc -TRUE -Before all events - - -NA -NA -both -TRUE -dose -FALSE -Copy - - -NA -NA -both -TRUE -dose -TRUE -Before all events - - -NA -NA -conc -NA -NA -FALSE -Copy - - -NA -NA -conc -NA -NA -TRUE -Copy - - -NA -NA -conc -NA -both -FALSE -Copy - - -NA -NA -conc -NA -both -TRUE -Copy - - -NA -NA -conc -NA -conc -FALSE -Copy - - -NA -NA -conc -NA -conc -TRUE -Copy - - -NA -NA -conc -NA -dose -FALSE -Copy - - -NA -NA -conc -NA -dose -TRUE -Copy - - -NA -NA -dose -FALSE -NA -FALSE -Before all events - - -NA -NA -dose -FALSE -NA -TRUE -Before all events - - -NA -NA -dose -FALSE -both -FALSE -Before all events - - -NA -NA -dose -FALSE -both -TRUE -Before all events - - -NA -NA -dose -FALSE -conc -FALSE -Before all events - - -NA -NA -dose -FALSE -conc -TRUE -Before all events - - -NA -NA -dose -FALSE -dose -FALSE -Before all events - - -NA -NA -dose -FALSE -dose -TRUE -Before all events - - -NA -NA -dose -TRUE -NA -FALSE -Before all events - - -NA -NA -dose -TRUE -NA -TRUE -Before all events - - -NA -NA -dose -TRUE -both -FALSE -Before all events - - -NA -NA -dose -TRUE -both -TRUE -Before all events - - -NA -NA -dose -TRUE -conc -FALSE -Before all events - - -NA -NA -dose -TRUE -conc -TRUE -Before all events - - -NA -NA -dose -TRUE -dose -FALSE -Before all events - - -NA -NA -dose -TRUE -dose -TRUE -Before all events - - -both -FALSE -NA -NA -NA -FALSE -Doses with no concentrations between - - -both -FALSE -NA -NA -NA -TRUE -Doses with no concentrations between - - -both -FALSE -NA -NA -both -FALSE -Interpolation - - -both -FALSE -NA -NA -both -TRUE -Interpolation - - -both -FALSE -NA -NA -conc -FALSE -Interpolation - - -both -FALSE -NA -NA -conc -TRUE -Interpolation - - -both -FALSE -NA -NA -dose -FALSE -Doses with no concentrations between - - -both -FALSE -NA -NA -dose -TRUE -Doses with no concentrations between - - -both -FALSE -both -FALSE -NA -FALSE -Copy - - -both -FALSE -both -FALSE -NA -TRUE -Copy - - -both -FALSE -both -FALSE -both -FALSE -Copy - - -both -FALSE -both -FALSE -both -TRUE -Copy - - -both -FALSE -both -FALSE -conc -FALSE -Copy - - -both -FALSE -both -FALSE -conc -TRUE -Copy - - -both -FALSE -both -FALSE -dose -FALSE -Copy - - -both -FALSE -both -FALSE -dose -TRUE -Copy - - -both -FALSE -both -TRUE -NA -FALSE -Copy - - -both -FALSE -both -TRUE -NA -TRUE -Immediately after an IV bolus without a concentration next - - -both -FALSE -both -TRUE -both -FALSE -Copy - - -both -FALSE -both -TRUE -both -TRUE -Immediately after an IV bolus without a concentration next - - -both -FALSE -both -TRUE -conc -FALSE -Copy - - -both -FALSE -both -TRUE -conc -TRUE -Immediately after an IV bolus with a concentration next - - -both -FALSE -both -TRUE -dose -FALSE -Copy - - -both -FALSE -both -TRUE -dose -TRUE -Immediately after an IV bolus without a concentration next +Method Used + + -both -FALSE conc -NA -NA -FALSE -Copy - - -both -FALSE conc -NA -NA -TRUE -Copy - - -both -FALSE conc -NA -both -FALSE -Copy +Observed concentration -both -FALSE conc -NA -both -TRUE -Copy +conc +conc_dose +Observed concentration -both -FALSE conc -NA conc -FALSE -Copy +conc_dose_iv_bolus_after +Observed concentration -both -FALSE conc -NA conc -TRUE -Copy +dose +Observed concentration -both -FALSE conc -NA -dose -FALSE -Copy +conc +dose_iv_bolus_after +Observed concentration -both -FALSE conc -NA -dose -TRUE -Copy +conc +none +Observed concentration -both -FALSE -dose -FALSE -NA -FALSE -Doses with no concentrations between +conc +conc_dose +conc +Observed concentration -both -FALSE -dose -FALSE -NA -TRUE -Doses with no concentrations between +conc +conc_dose +conc_dose +Observed concentration -both -FALSE -dose -FALSE -both -FALSE -Doses with no concentrations between +conc +conc_dose +conc_dose_iv_bolus_after +Observed concentration -both -FALSE +conc +conc_dose dose -FALSE -both -TRUE -Doses with no concentrations between +Observed concentration -both -FALSE -dose -FALSE conc -FALSE -Doses with no concentrations between +conc_dose +dose_iv_bolus_after +Observed concentration -both -FALSE -dose -FALSE conc -TRUE -Doses with no concentrations between +conc_dose +none +Observed concentration -both -FALSE -dose -FALSE -dose -FALSE -Doses with no concentrations between +conc +conc_dose_iv_bolus_after +conc +Observed concentration -both -FALSE -dose -FALSE -dose -TRUE -Doses with no concentrations between +conc +conc_dose_iv_bolus_after +conc_dose +Observed concentration -both -FALSE -dose -TRUE -NA -FALSE -Doses with no concentrations between +conc +conc_dose_iv_bolus_after +conc_dose_iv_bolus_after +Impossible combinations -both -FALSE +conc +conc_dose_iv_bolus_after dose -TRUE -NA -TRUE -Immediately after an IV bolus without a concentration next +Observed concentration -both -FALSE -dose -TRUE -both -FALSE -Doses with no concentrations between +conc +conc_dose_iv_bolus_after +dose_iv_bolus_after +Impossible combinations -both -FALSE -dose -TRUE -both -TRUE -Immediately after an IV bolus without a concentration next +conc +conc_dose_iv_bolus_after +none +Observed concentration -both -FALSE +conc dose -TRUE conc -FALSE -Doses with no concentrations between +Extrapolation -both -FALSE -dose -TRUE conc -TRUE -Immediately after an IV bolus with a concentration next +dose +conc_dose +Extrapolation -both -FALSE -dose -TRUE +conc dose -FALSE -Doses with no concentrations between +conc_dose_iv_bolus_after +Extrapolation -both -FALSE +conc dose -TRUE dose -TRUE -Immediately after an IV bolus without a concentration next - - -both -TRUE -NA -NA -NA -FALSE -After an IV bolus without a concentration next - - -both -TRUE -NA -NA -NA -TRUE -After an IV bolus without a concentration next - - -both -TRUE -NA -NA -both -FALSE -After an IV bolus without a concentration next - - -both -TRUE -NA -NA -both -TRUE -After an IV bolus without a concentration next +Extrapolation -both -TRUE -NA -NA -conc -FALSE -After an IV bolus with a concentration next - - -both -TRUE -NA -NA conc -TRUE -After an IV bolus with a concentration next - - -both -TRUE -NA -NA dose -FALSE -After an IV bolus without a concentration next +dose_iv_bolus_after +Extrapolation -both -TRUE -NA -NA +conc dose -TRUE -After an IV bolus without a concentration next - - -both -TRUE -both -FALSE -NA -FALSE -Copy - - -both -TRUE -both -FALSE -NA -TRUE -Copy - - -both -TRUE -both -FALSE -both -FALSE -Copy - - -both -TRUE -both -FALSE -both -TRUE -Copy +none +Extrapolation -both -TRUE -both -FALSE conc -FALSE -Copy +dose_iv_bolus_after +conc +Immediately after an IV bolus with a concentration next -both -TRUE -both -FALSE conc -TRUE -Copy +dose_iv_bolus_after +conc_dose +Immediately after an IV bolus with a concentration next -both -TRUE -both -FALSE -dose -FALSE -Copy +conc +dose_iv_bolus_after +conc_dose_iv_bolus_after +Impossible combinations -both -TRUE -both -FALSE +conc +dose_iv_bolus_after dose -TRUE -Copy - - -both -TRUE -both -TRUE -NA -FALSE -Copy - - -both -TRUE -both -TRUE -NA -TRUE Immediately after an IV bolus without a concentration next -both -TRUE -both -TRUE -both -FALSE -Copy +conc +dose_iv_bolus_after +dose_iv_bolus_after +Impossible combinations -both -TRUE -both -TRUE -both -TRUE +conc +dose_iv_bolus_after +none Immediately after an IV bolus without a concentration next -both -TRUE -both -TRUE conc -FALSE -Copy +output_only +conc +Interpolation -both -TRUE -both -TRUE conc -TRUE -Immediately after an IV bolus with a concentration next +output_only +conc_dose +Interpolation -both -TRUE -both -TRUE -dose -FALSE -Copy +conc +output_only +conc_dose_iv_bolus_after +Impossible combinations -both -TRUE -both -TRUE +conc +output_only dose -TRUE -Immediately after an IV bolus without a concentration next +Extrapolation -both -TRUE conc -NA -NA -FALSE -Copy +output_only +dose_iv_bolus_after +Impossible combinations -both -TRUE conc -NA -NA -TRUE -Copy +output_only +none +Extrapolation -both -TRUE +conc_dose +conc conc -NA -both -FALSE -Copy +Observed concentration -both -TRUE +conc_dose conc -NA -both -TRUE -Copy +conc_dose +Observed concentration -both -TRUE +conc_dose conc -NA -conc -FALSE -Copy +conc_dose_iv_bolus_after +Observed concentration -both -TRUE -conc -NA +conc_dose conc -TRUE -Copy +dose +Observed concentration -both -TRUE +conc_dose conc -NA -dose -FALSE -Copy +dose_iv_bolus_after +Observed concentration -both -TRUE +conc_dose conc -NA -dose -TRUE -Copy +none +Observed concentration -both -TRUE -dose -FALSE -NA -FALSE -Doses with no concentrations between +conc_dose +conc_dose +conc +Observed concentration -both -TRUE -dose -FALSE -NA -TRUE -Doses with no concentrations between +conc_dose +conc_dose +conc_dose +Observed concentration -both -TRUE -dose -FALSE -both -FALSE -Doses with no concentrations between +conc_dose +conc_dose +conc_dose_iv_bolus_after +Observed concentration -both -TRUE +conc_dose +conc_dose dose -FALSE -both -TRUE -Doses with no concentrations between +Observed concentration -both -TRUE -dose -FALSE -conc -FALSE -Doses with no concentrations between +conc_dose +conc_dose +dose_iv_bolus_after +Observed concentration -both -TRUE -dose -FALSE -conc -TRUE -Doses with no concentrations between +conc_dose +conc_dose +none +Observed concentration -both -TRUE -dose -FALSE -dose -FALSE -Doses with no concentrations between +conc_dose +conc_dose_iv_bolus_after +conc +Observed concentration -both -TRUE -dose -FALSE -dose -TRUE -Doses with no concentrations between +conc_dose +conc_dose_iv_bolus_after +conc_dose +Observed concentration -both -TRUE -dose -TRUE -NA -FALSE -Doses with no concentrations between +conc_dose +conc_dose_iv_bolus_after +conc_dose_iv_bolus_after +Impossible combinations -both -TRUE +conc_dose +conc_dose_iv_bolus_after dose -TRUE -NA -TRUE -Immediately after an IV bolus without a concentration next +Observed concentration -both -TRUE -dose -TRUE -both -FALSE -Doses with no concentrations between +conc_dose +conc_dose_iv_bolus_after +dose_iv_bolus_after +Impossible combinations -both -TRUE -dose -TRUE -both -TRUE -Immediately after an IV bolus without a concentration next +conc_dose +conc_dose_iv_bolus_after +none +Observed concentration -both -TRUE +conc_dose dose -TRUE conc -FALSE Doses with no concentrations between -both -TRUE +conc_dose dose -TRUE -conc -TRUE -Immediately after an IV bolus with a concentration next +conc_dose +Doses with no concentrations between -both -TRUE +conc_dose dose -TRUE -dose -FALSE +conc_dose_iv_bolus_after Doses with no concentrations between -both -TRUE +conc_dose dose -TRUE dose -TRUE -Immediately after an IV bolus without a concentration next - - -conc -NA -NA -NA -NA -FALSE -After all events, concentration before - - -conc -NA -NA -NA -NA -TRUE -After all events, concentration before - - -conc -NA -NA -NA -both -FALSE -Interpolation - - -conc -NA -NA -NA -both -TRUE -Interpolation - - -conc -NA -NA -NA -conc -FALSE -Interpolation - - -conc -NA -NA -NA -conc -TRUE -Interpolation +Doses with no concentrations between -conc -NA -NA -NA +conc_dose dose -FALSE -Concentration, nothing or dose but not(dose, IV bolus, After), nothing or dose +dose_iv_bolus_after +Doses with no concentrations between -conc -NA -NA -NA +conc_dose dose -TRUE -Concentration, nothing or dose but not(dose, IV bolus, After), nothing or dose - - -conc -NA -both -FALSE -NA -FALSE -Copy - - -conc -NA -both -FALSE -NA -TRUE -Copy - - -conc -NA -both -FALSE -both -FALSE -Copy - - -conc -NA -both -FALSE -both -TRUE -Copy +none +Doses with no concentrations between +conc_dose +dose_iv_bolus_after conc -NA -both -FALSE -conc -FALSE -Copy +Immediately after an IV bolus with a concentration next -conc -NA -both -FALSE -conc -TRUE -Copy +conc_dose +dose_iv_bolus_after +conc_dose +Immediately after an IV bolus with a concentration next -conc -NA -both -FALSE -dose -FALSE -Copy +conc_dose +dose_iv_bolus_after +conc_dose_iv_bolus_after +Impossible combinations -conc -NA -both -FALSE +conc_dose +dose_iv_bolus_after dose -TRUE -Copy - - -conc -NA -both -TRUE -NA -FALSE -Copy - - -conc -NA -both -TRUE -NA -TRUE Immediately after an IV bolus without a concentration next -conc -NA -both -TRUE -both -FALSE -Copy +conc_dose +dose_iv_bolus_after +dose_iv_bolus_after +Impossible combinations -conc -NA -both -TRUE -both -TRUE +conc_dose +dose_iv_bolus_after +none Immediately after an IV bolus without a concentration next +conc_dose +output_only conc -NA -both -TRUE -conc -FALSE -Copy +Interpolation -conc -NA -both -TRUE -conc -TRUE -Immediately after an IV bolus with a concentration next +conc_dose +output_only +conc_dose +Doses with no concentrations between -conc -NA -both -TRUE -dose -FALSE -Copy +conc_dose +output_only +conc_dose_iv_bolus_after +Impossible combinations -conc -NA -both -TRUE +conc_dose +output_only dose -TRUE -Immediately after an IV bolus without a concentration next +Doses with no concentrations between -conc -NA -conc -NA -NA -FALSE -Copy +conc_dose +output_only +dose_iv_bolus_after +Impossible combinations -conc -NA -conc -NA -NA -TRUE -Copy +conc_dose +output_only +none +Dose as the last event in the timeline and requesting a concentration after +conc_dose_iv_bolus_after conc -NA conc -NA -both -FALSE -Copy +Observed concentration +conc_dose_iv_bolus_after conc -NA -conc -NA -both -TRUE -Copy +conc_dose +Observed concentration +conc_dose_iv_bolus_after conc -NA -conc -NA -conc -FALSE -Copy +conc_dose_iv_bolus_after +Observed concentration +conc_dose_iv_bolus_after conc -NA -conc -NA -conc -TRUE -Copy +dose +Observed concentration +conc_dose_iv_bolus_after conc -NA -conc -NA -dose -FALSE -Copy +dose_iv_bolus_after +Observed concentration +conc_dose_iv_bolus_after conc -NA -conc -NA -dose -TRUE -Copy +none +Observed concentration +conc_dose_iv_bolus_after +conc_dose conc -NA -dose -FALSE -NA -FALSE -After all events, concentration before +Observed concentration -conc -NA -dose -FALSE -NA -TRUE -After all events, concentration before +conc_dose_iv_bolus_after +conc_dose +conc_dose +Observed concentration -conc -NA -dose -FALSE -both -FALSE -Concentration, nothing or dose but not(dose, IV bolus, After), nothing or dose +conc_dose_iv_bolus_after +conc_dose +conc_dose_iv_bolus_after +Observed concentration -conc -NA +conc_dose_iv_bolus_after +conc_dose dose -FALSE -both -TRUE -Concentration, nothing or dose but not(dose, IV bolus, After), nothing or dose +Observed concentration -conc -NA -dose -FALSE -conc -FALSE -Concentration, nothing or dose but not(dose, IV bolus, After), nothing or dose +conc_dose_iv_bolus_after +conc_dose +dose_iv_bolus_after +Observed concentration -conc -NA -dose -FALSE -conc -TRUE -Concentration, nothing or dose but not(dose, IV bolus, After), nothing or dose +conc_dose_iv_bolus_after +conc_dose +none +Observed concentration +conc_dose_iv_bolus_after +conc_dose_iv_bolus_after conc -NA -dose -FALSE -dose -FALSE -Concentration, nothing or dose but not(dose, IV bolus, After), nothing or dose +Impossible combinations -conc -NA -dose -FALSE -dose -TRUE -Concentration, nothing or dose but not(dose, IV bolus, After), nothing or dose +conc_dose_iv_bolus_after +conc_dose_iv_bolus_after +conc_dose +Impossible combinations -conc -NA -dose -TRUE -NA -FALSE -After all events, concentration before +conc_dose_iv_bolus_after +conc_dose_iv_bolus_after +conc_dose_iv_bolus_after +Impossible combinations -conc -NA +conc_dose_iv_bolus_after +conc_dose_iv_bolus_after dose -TRUE -NA -TRUE -Immediately after an IV bolus without a concentration next +Impossible combinations -conc -NA -dose -TRUE -both -FALSE -Concentration, nothing or dose but not(dose, IV bolus, After), nothing or dose +conc_dose_iv_bolus_after +conc_dose_iv_bolus_after +dose_iv_bolus_after +Impossible combinations -conc -NA -dose -TRUE -both -TRUE -Immediately after an IV bolus without a concentration next +conc_dose_iv_bolus_after +conc_dose_iv_bolus_after +none +Impossible combinations -conc -NA +conc_dose_iv_bolus_after dose -TRUE conc -FALSE -Concentration, nothing or dose but not(dose, IV bolus, After), nothing or dose +Extrapolation -conc -NA +conc_dose_iv_bolus_after dose -TRUE -conc -TRUE -Immediately after an IV bolus with a concentration next +conc_dose +Extrapolation -conc -NA -dose -TRUE +conc_dose_iv_bolus_after dose -FALSE -Concentration, nothing or dose but not(dose, IV bolus, After), nothing or dose +conc_dose_iv_bolus_after +Extrapolation -conc -NA +conc_dose_iv_bolus_after dose -TRUE dose -TRUE -Immediately after an IV bolus without a concentration next +Extrapolation +conc_dose_iv_bolus_after dose -FALSE -NA -NA -NA -FALSE -Doses with no concentrations between +dose_iv_bolus_after +Extrapolation +conc_dose_iv_bolus_after dose -FALSE -NA -NA -NA -TRUE -Doses with no concentrations between +none +Extrapolation -dose -FALSE -NA -NA -both -FALSE -Doses with no concentrations between +conc_dose_iv_bolus_after +dose_iv_bolus_after +conc +Impossible combinations -dose -FALSE -NA -NA -both -TRUE -Doses with no concentrations between +conc_dose_iv_bolus_after +dose_iv_bolus_after +conc_dose +Impossible combinations -dose -FALSE -NA -NA -conc -FALSE -After a dose with no event and a concentration after +conc_dose_iv_bolus_after +dose_iv_bolus_after +conc_dose_iv_bolus_after +Impossible combinations +conc_dose_iv_bolus_after +dose_iv_bolus_after dose -FALSE -NA -NA -conc -TRUE -After a dose with no event and a concentration after +Impossible combinations -dose -FALSE -NA -NA -dose -FALSE -Doses with no concentrations between +conc_dose_iv_bolus_after +dose_iv_bolus_after +dose_iv_bolus_after +Impossible combinations -dose -FALSE -NA -NA -dose -TRUE -Doses with no concentrations between +conc_dose_iv_bolus_after +dose_iv_bolus_after +none +Impossible combinations -dose -FALSE -both -FALSE -NA -FALSE -Copy +conc_dose_iv_bolus_after +output_only +conc +Interpolation -dose -FALSE -both -FALSE -NA -TRUE -Copy +conc_dose_iv_bolus_after +output_only +conc_dose +Interpolation -dose -FALSE -both -FALSE -both -FALSE -Copy +conc_dose_iv_bolus_after +output_only +conc_dose_iv_bolus_after +Impossible combinations +conc_dose_iv_bolus_after +output_only dose -FALSE -both -FALSE -both -TRUE -Copy +Extrapolation -dose -FALSE -both -FALSE -conc -FALSE -Copy +conc_dose_iv_bolus_after +output_only +dose_iv_bolus_after +Impossible combinations -dose -FALSE -both -FALSE -conc -TRUE -Copy +conc_dose_iv_bolus_after +output_only +none +Extrapolation dose -FALSE -both -FALSE -dose -FALSE -Copy +conc +conc +Observed concentration dose -FALSE -both -FALSE -dose -TRUE -Copy +conc +conc_dose +Observed concentration dose -FALSE -both -TRUE -NA -FALSE -Copy +conc +conc_dose_iv_bolus_after +Observed concentration dose -FALSE -both -TRUE -NA -TRUE -Immediately after an IV bolus without a concentration next +conc +dose +Observed concentration dose -FALSE -both -TRUE -both -FALSE -Copy +conc +dose_iv_bolus_after +Observed concentration dose -FALSE -both -TRUE -both -TRUE -Immediately after an IV bolus without a concentration next +conc +none +Observed concentration dose -FALSE -both -TRUE +conc_dose conc -FALSE -Copy +Observed concentration dose -FALSE -both -TRUE -conc -TRUE -Immediately after an IV bolus with a concentration next +conc_dose +conc_dose +Observed concentration dose -FALSE -both -TRUE -dose -FALSE -Copy +conc_dose +conc_dose_iv_bolus_after +Observed concentration dose -FALSE -both -TRUE +conc_dose dose -TRUE -Immediately after an IV bolus without a concentration next +Observed concentration dose -FALSE -conc -NA -NA -FALSE -Copy +conc_dose +dose_iv_bolus_after +Observed concentration dose -FALSE -conc -NA -NA -TRUE -Copy +conc_dose +none +Observed concentration dose -FALSE +conc_dose_iv_bolus_after conc -NA -both -FALSE -Copy +Observed concentration dose -FALSE -conc -NA -both -TRUE -Copy +conc_dose_iv_bolus_after +conc_dose +Observed concentration dose -FALSE -conc -NA -conc -FALSE -Copy +conc_dose_iv_bolus_after +conc_dose_iv_bolus_after +Impossible combinations dose -FALSE -conc -NA -conc -TRUE -Copy +conc_dose_iv_bolus_after +dose +Observed concentration dose -FALSE -conc -NA -dose -FALSE -Copy +conc_dose_iv_bolus_after +dose_iv_bolus_after +Impossible combinations dose -FALSE -conc -NA -dose -TRUE -Copy +conc_dose_iv_bolus_after +none +Observed concentration dose -FALSE dose -FALSE -NA -FALSE +conc Doses with no concentrations between dose -FALSE dose -FALSE -NA -TRUE +conc_dose Doses with no concentrations between dose -FALSE dose -FALSE -both -FALSE +conc_dose_iv_bolus_after Doses with no concentrations between dose -FALSE dose -FALSE -both -TRUE +dose Doses with no concentrations between dose -FALSE dose -FALSE -conc -FALSE +dose_iv_bolus_after Doses with no concentrations between dose -FALSE dose -FALSE -conc -TRUE +none Doses with no concentrations between dose -FALSE -dose -FALSE -dose -FALSE -Doses with no concentrations between +dose_iv_bolus_after +conc +Immediately after an IV bolus with a concentration next dose -FALSE -dose -FALSE -dose -TRUE -Doses with no concentrations between +dose_iv_bolus_after +conc_dose +Immediately after an IV bolus with a concentration next dose -FALSE -dose -TRUE -NA -FALSE -Doses with no concentrations between +dose_iv_bolus_after +conc_dose_iv_bolus_after +Impossible combinations dose -FALSE +dose_iv_bolus_after dose -TRUE -NA -TRUE Immediately after an IV bolus without a concentration next dose -FALSE -dose -TRUE -both -FALSE -Doses with no concentrations between +dose_iv_bolus_after +dose_iv_bolus_after +Impossible combinations dose -FALSE -dose -TRUE -both -TRUE +dose_iv_bolus_after +none Immediately after an IV bolus without a concentration next dose -FALSE -dose -TRUE +output_only conc -FALSE -Doses with no concentrations between +Dose before, concentration after without a dose dose -FALSE -dose -TRUE -conc -TRUE -Immediately after an IV bolus with a concentration next +output_only +conc_dose +Doses with no concentrations between dose -FALSE -dose -TRUE -dose -FALSE -Doses with no concentrations between +output_only +conc_dose_iv_bolus_after +Impossible combinations dose -FALSE -dose -TRUE +output_only dose -TRUE -Immediately after an IV bolus without a concentration next +Doses with no concentrations between dose -TRUE -NA -NA -NA -FALSE -After an IV bolus without a concentration next +output_only +dose_iv_bolus_after +Impossible combinations dose -TRUE -NA -NA -NA -TRUE -After an IV bolus without a concentration next +output_only +none +Dose as the last event in the timeline and requesting a concentration after -dose -TRUE -NA -NA -both -FALSE -After an IV bolus without a concentration next +dose_iv_bolus_after +conc +conc +Observed concentration -dose -TRUE -NA -NA -both -TRUE -After an IV bolus without a concentration next +dose_iv_bolus_after +conc +conc_dose +Observed concentration -dose -TRUE -NA -NA +dose_iv_bolus_after conc -FALSE -After an IV bolus with a concentration next +conc_dose_iv_bolus_after +Observed concentration +dose_iv_bolus_after +conc dose -TRUE -NA -NA +Observed concentration + + +dose_iv_bolus_after conc -TRUE -After an IV bolus with a concentration next +dose_iv_bolus_after +Observed concentration + + +dose_iv_bolus_after +conc +none +Observed concentration -dose -TRUE -NA -NA -dose -FALSE -After an IV bolus without a concentration next +dose_iv_bolus_after +conc_dose +conc +Observed concentration -dose -TRUE -NA -NA -dose -TRUE -After an IV bolus without a concentration next +dose_iv_bolus_after +conc_dose +conc_dose +Observed concentration -dose -TRUE -both -FALSE -NA -FALSE -Copy +dose_iv_bolus_after +conc_dose +conc_dose_iv_bolus_after +Observed concentration +dose_iv_bolus_after +conc_dose dose -TRUE -both -FALSE -NA -TRUE -Copy +Observed concentration -dose -TRUE -both -FALSE -both -FALSE -Copy +dose_iv_bolus_after +conc_dose +dose_iv_bolus_after +Observed concentration -dose -TRUE -both -FALSE -both -TRUE -Copy +dose_iv_bolus_after +conc_dose +none +Observed concentration -dose -TRUE -both -FALSE +dose_iv_bolus_after +conc_dose_iv_bolus_after conc -FALSE -Copy +Impossible combinations -dose -TRUE -both -FALSE -conc -TRUE -Copy +dose_iv_bolus_after +conc_dose_iv_bolus_after +conc_dose +Impossible combinations -dose -TRUE -both -FALSE -dose -FALSE -Copy +dose_iv_bolus_after +conc_dose_iv_bolus_after +conc_dose_iv_bolus_after +Impossible combinations +dose_iv_bolus_after +conc_dose_iv_bolus_after dose -TRUE -both -FALSE -dose -TRUE -Copy +Impossible combinations -dose -TRUE -both -TRUE -NA -FALSE -Copy +dose_iv_bolus_after +conc_dose_iv_bolus_after +dose_iv_bolus_after +Impossible combinations -dose -TRUE -both -TRUE -NA -TRUE -Immediately after an IV bolus without a concentration next +dose_iv_bolus_after +conc_dose_iv_bolus_after +none +Impossible combinations +dose_iv_bolus_after dose -TRUE -both -TRUE -both -FALSE -Copy +conc +Immediately after an IV bolus without a concentration next +dose_iv_bolus_after dose -TRUE -both -TRUE -both -TRUE +conc_dose Immediately after an IV bolus without a concentration next +dose_iv_bolus_after dose -TRUE -both -TRUE -conc -FALSE -Copy +conc_dose_iv_bolus_after +Immediately after an IV bolus without a concentration next +dose_iv_bolus_after dose -TRUE -both -TRUE -conc -TRUE -Immediately after an IV bolus with a concentration next +dose +Immediately after an IV bolus without a concentration next +dose_iv_bolus_after dose -TRUE -both -TRUE -dose -FALSE -Copy +dose_iv_bolus_after +Immediately after an IV bolus without a concentration next +dose_iv_bolus_after dose -TRUE -both -TRUE -dose -TRUE +none Immediately after an IV bolus without a concentration next -dose -TRUE +dose_iv_bolus_after +dose_iv_bolus_after conc -NA -NA -FALSE -Copy +Impossible combinations + + +dose_iv_bolus_after +dose_iv_bolus_after +conc_dose +Impossible combinations + + +dose_iv_bolus_after +dose_iv_bolus_after +conc_dose_iv_bolus_after +Impossible combinations +dose_iv_bolus_after +dose_iv_bolus_after dose -TRUE +Impossible combinations + + +dose_iv_bolus_after +dose_iv_bolus_after +dose_iv_bolus_after +Impossible combinations + + +dose_iv_bolus_after +dose_iv_bolus_after +none +Impossible combinations + + +dose_iv_bolus_after +output_only conc -NA -NA -TRUE -Copy +After an IV bolus with a concentration next + + +dose_iv_bolus_after +output_only +conc_dose +After an IV bolus with a concentration next +dose_iv_bolus_after +output_only +conc_dose_iv_bolus_after +Impossible combinations + + +dose_iv_bolus_after +output_only dose -TRUE +After an IV bolus without a concentration next + + +dose_iv_bolus_after +output_only +dose_iv_bolus_after +Impossible combinations + + +dose_iv_bolus_after +output_only +none +After an IV bolus without a concentration next + + +none +conc conc -NA -both -FALSE -Copy +Observed concentration -dose -TRUE +none conc -NA -both -TRUE -Copy +conc_dose +Observed concentration -dose -TRUE +none conc -NA -conc -FALSE -Copy +conc_dose_iv_bolus_after +Observed concentration +none +conc dose -TRUE +Observed concentration + + +none conc -NA +dose_iv_bolus_after +Observed concentration + + +none conc -TRUE -Copy +none +Observed concentration -dose -TRUE +none +conc_dose conc -NA -dose -FALSE -Copy +Observed concentration +none +conc_dose +conc_dose +Observed concentration + + +none +conc_dose +conc_dose_iv_bolus_after +Observed concentration + + +none +conc_dose dose -TRUE +Observed concentration + + +none +conc_dose +dose_iv_bolus_after +Observed concentration + + +none +conc_dose +none +Observed concentration + + +none +conc_dose_iv_bolus_after conc -NA -dose -TRUE -Copy +Observed concentration + + +none +conc_dose_iv_bolus_after +conc_dose +Observed concentration -dose -TRUE -dose -FALSE -NA -FALSE -Doses with no concentrations between +none +conc_dose_iv_bolus_after +conc_dose_iv_bolus_after +Impossible combinations +none +conc_dose_iv_bolus_after dose -TRUE -dose -FALSE -NA -TRUE -Doses with no concentrations between +Observed concentration -dose -TRUE -dose -FALSE -both -FALSE -Doses with no concentrations between +none +conc_dose_iv_bolus_after +dose_iv_bolus_after +Impossible combinations -dose -TRUE -dose -FALSE -both -TRUE -Doses with no concentrations between +none +conc_dose_iv_bolus_after +none +Observed concentration +none dose -TRUE -dose -FALSE conc -FALSE -Doses with no concentrations between +Before all events +none dose -TRUE -dose -FALSE -conc -TRUE -Doses with no concentrations between +conc_dose +Before all events +none dose -TRUE -dose -FALSE -dose -FALSE -Doses with no concentrations between +conc_dose_iv_bolus_after +Before all events +none dose -TRUE -dose -FALSE dose -TRUE -Doses with no concentrations between +Before all events +none dose -TRUE -dose -TRUE -NA -FALSE -Doses with no concentrations between +dose_iv_bolus_after +Before all events +none dose -TRUE +none +Before all events + + +none +dose_iv_bolus_after +conc +Immediately after an IV bolus with a concentration next + + +none +dose_iv_bolus_after +conc_dose +Immediately after an IV bolus with a concentration next + + +none +dose_iv_bolus_after +conc_dose_iv_bolus_after +Impossible combinations + + +none +dose_iv_bolus_after dose -TRUE -NA -TRUE Immediately after an IV bolus without a concentration next -dose -TRUE -dose -TRUE -both -FALSE -Doses with no concentrations between +none +dose_iv_bolus_after +dose_iv_bolus_after +Impossible combinations -dose -TRUE -dose -TRUE -both -TRUE +none +dose_iv_bolus_after +none Immediately after an IV bolus without a concentration next -dose -TRUE -dose -TRUE +none +output_only conc -FALSE -Doses with no concentrations between +Before all events -dose -TRUE -dose -TRUE -conc -TRUE -Immediately after an IV bolus with a concentration next +none +output_only +conc_dose +Before all events -dose -TRUE -dose -TRUE -dose -FALSE -Doses with no concentrations between +none +output_only +conc_dose_iv_bolus_after +Impossible combinations +none +output_only dose -TRUE -dose -TRUE -dose -TRUE -Immediately after an IV bolus without a concentration next +Before all events + + +none +output_only +dose_iv_bolus_after +Impossible combinations + + +none +output_only +none +Before all events @@ -5186,7 +2627,7 @@

Appendix: Complete Methods Table

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