Package {ncar}

Noncompartmental Analysis for Pharmacokinetic Report

Description

It can report a noncompartmental analysis (NCA) with industrial strength.

Details

The main functions are

pdfNCA to produce PDF file format NCA.
rtfNCA to produce rtf file format NCA.

Author(s)

Kyun-Seop Bae <k@acr.kr>

References

1. Gabrielsson J, Weiner D. Pharmacokinetic and Pharmacodynamic Data Analysis - Concepts and Applications. 5th ed. 2016.

2. Shargel L, Yu A. Applied Biopharmaceutics and Pharmacokinetics. 7th ed. 2015.

3. Rowland M, Tozer TN. Clinical Pharmacokinetics and Pharmacodynamics - Concepts and Applications. 4th ed. 2011.

4. Gibaldi M, Perrier D. Pharmacokinetics. 2nd ed. revised and expanded. 1982.

Examples

# Theoph and Indometh data: dose in mg, conc in mg/L, time in h

# Output to PDF file
#pdfNCA(fileName="NCA-Theoph.pdf", Theoph, key="Subject", colTime="Time",
#       colConc="conc", dose=320, doseUnit="mg", timeUnit="h", concUnit="mg/L")
#pdfNCA(fileName="NCA-Theoph.pdf", Theoph, key=c("Subject", "Wt"), colTime="Time",
#       colConc="conc", dose=320, doseUnit="mg", timeUnit="h", concUnit="mg/L")
#pdfNCA(fileName="NCA-Indometh.pdf", Indometh, key="Subject", colTime="time",
#       colConc="conc", adm="Infusion", dur=0.5, dose=25, doseUnit="mg",
#       timeUnit="h", concUnit="mg/L")


# Output to RTF file
#rtfNCA(fileName="NCA-Theoph.rtf", Theoph, key="Subject", colTime="Time",
#       colConc="conc", dose=320, doseUnit="mg", timeUnit="h", concUnit="mg/L")
#rtfNCA(fileName="NCA-Theoph.rtf", Theoph, key=c("Subject", "Wt"), colTime="Time",
#       colConc="conc", dose=320, doseUnit="mg", timeUnit="h", concUnit="mg/L")
#rtfNCA(fileName="NCA-Indometh.rtf", Indometh, key="Subject", colTime="time",
#       colConc="conc", adm="Infusion", dur=0.5, dose=25, doseUnit="mg",
#       timeUnit="h", concUnit="mg/L")

Internal Functions

Description

Internal functions

Details

These are not to be called by the user.

Convert sNCA output table to text form

Description

This converts the table output of sNCA to text form output.

Usage

Res2Txt(ResNCA, x, y, dose = 0, adm = "Extravascular", dur = 0, doseUnit = "mg", 
        down = "Linear")

Arguments

Value

Text form output from the coversion of table form output

Author(s)

Kyun-Seop Bae <k@acr.kr>

See Also

txtNCA, pdfNCA, rtfNCA

Examples

x = Theoph[Theoph$Subject=="1","Time"]
y = Theoph[Theoph$Subject=="1","conc"]
z = NonCompart::sNCA(x, y, dose=320, doseUnit="mg", concUnit="mg/L", timeUnit="h")
Res2Txt(z, x, y)  

Round Half Away from Zero

Description

This is an ordinary rounding function, so called round half away from zero

Usage

Round(x, n = 0)

Arguments

Details

The function round in R base rounds to the even number, i.e. round(0.5) is 0 not 1. If you want rounding 0.5 be 1, you can use this Round function. This function is for the consistency with other software like MS-Excel, SAS.

Value

ordinarily rounded value

Author(s)

Kyun-Seop Bae <k@acr.kr>

References

See wikipedia subject "Rounding"

Examples

(x = 1:10 - 0.5)
Round(x)
round(x) # compare with the above

NCA Report Configuration Table

Description

Contains the names and order of column of return table/text in outputs

Usage

RptCfg

Format

A data frame with 48 observations on the following 10 variables.

PPTESTCD

a character vector of CDISC SDTM PPTESTCD

SYNONYM

a character vector of CDISC SDTM PPTESTCD Synonym

NCI

a character vector of NCI peferred terms

WNL

a character vector of WinNonlin(R) software variables

ExtravascularDefault

a numeric vector of ordering in report for extravascular administration, Zero means exclusion in the report.

ExtravascularWNL

a numeric vector of WinNonlin(R) style ordering in report for extravascular administration, Zero means exclusion in the report.

BolusDefault

a numeric vector of ordering in report for extravascular administration, Zero means exclusion in the report.

BolusWNL

a numeric vector of WinNonlin(R) style ordering in report for extravascular administration, Zero means exclusion in the report.

InfusionDefault

a numeric vector of ordering in report for extravascular administration, Zero means exclusion in the report.

InfusionWNL

a numeric vector of WinNonlin(R) style ordering in report for extravascular administration, Zero means exclusion in the report.

Details

This table should exist in this package.

Add Acrobat-Reader signature fields to a report PDF

Description

Insert empty digital-signature form fields (AcroForm /Sig fields) into a PDF so it can be signed in Adobe Acrobat Reader (the free reader) with one click: open the PDF, click a field, and sign with a Digital ID. The field is added with a pure base-R PDF incremental update, with no external tools or packages, so it works wherever R does. It is designed for the simple PDFs produced by pdfIQ and pdfOQ.

Acrobat Reader can also sign a PDF that has no field at all (“All tools” > “Use a certificate” > “Digitally sign”, then drag a rectangle). This function only makes the workflow click-to-sign by pre-placing labelled fields.

Usage

addSigField(pdf, out = pdf, page = 1L,
            fieldNames = c("Performed_by", "Reviewed_by"), rects = NULL)

Arguments

Details

The function appends an incremental-update section that adds an /AcroForm to the document catalog (with /SigFlags 3), one /Widget signature annotation per field, and the field references to the page's /Annots. The original content is left untouched. The resulting fields are unsigned; the actual cryptographic signature is applied by Acrobat Reader using the signer's Digital ID. Only classic cross-reference-table PDFs are supported (those written by R's pdf device); the function stops on cross-reference-stream PDFs.

Value

Invisibly, the output path. A PDF with signature fields is written as a side effect.

Author(s)

Kyun-Seop Bae <k@acr.kr>

See Also

pdfIQ, pdfOQ, signPDF

Examples

#pdfIQ("ncar-IQ-Report.pdf", performedBy = "Kyun-Seop Bae")
#addSigField("ncar-IQ-Report.pdf")          # adds Performed_by / Reviewed_by fields
## or in one step:
#pdfIQ("ncar-IQ-Report.pdf", performedBy = "Kyun-Seop Bae", sigField = TRUE)
## then open in Acrobat Reader and click each field to sign with your Digital ID.

Installation Qualification (IQ) report to a pdf file

Description

Generate a self-contained PDF report that documents whether the ncar / NonCompart packages are correctly installed, intact, loadable, and operational in the user's own R environment. It is intended as Installation Qualification (IQ) evidence, in the spirit of the WinNonlin validation suite. The report uses only base R and the package's own pdf helpers, so it requires no LaTeX, pandoc, or other external tools.

Usage

pdfIQ(fileName = "ncar-IQ-Report.pdf", pkgs = c("ncar", "NonCompart"),
      functional = TRUE, performedBy = "", paper = "auto", sigField = FALSE)

Arguments

Details

The report contains: (1) the test environment (R version, platform, OS, locale, library paths); (2) installed package versions, locations and declared-dependency version satisfaction; (3) file integrity via checkMD5sums (PASS when files match the MD5 manifest, FAIL on mismatch, WARN when no manifest is present, e.g. for a local source install rather than a CRAN install); (4) namespace load and presence of core exported functions; (5) the optional functional verification; an overall QUALIFIED / NOT QUALIFIED verdict; a signature block; and a sessionInfo appendix.

Value

Invisibly returns a list with elements fileName, qualified (logical), checks (a data frame of every check with its Section, Item, Result and Status), and the counts nPass, nFail, nWarn. A PDF file is written to fileName as a side effect.

Author(s)

Kyun-Seop Bae <k@acr.kr>

See Also

pdfNCA, txtNCA, checkMD5sums, sessionInfo

Examples

#pdfIQ()
#pdfIQ(fileName = "MyInstall-IQ.pdf", performedBy = "Jane Doe")
#res <- pdfIQ()
#res$qualified
#res$checks

NCA output to pdf file

Description

This output NCA result in a pdf file.

Usage

pdfNCA(fileName = "Temp-NCA.pdf", concData, key = "Subject", colTime = "Time", 
       colConc = "conc", dose = 0, adm = "Extravascular", dur = 0, 
       doseUnit = "mg", timeUnit = "h", concUnit = "ug/L", down="Linear", 
       R2ADJ = 0, MW = 0, SS = FALSE, iAUC = "", excludeDelta = 1, UsePoints = NULL,
       performedBy = "")

Arguments

Value

Author(s)

Kyun-Seop Bae <k@acr.kr>

See Also

help, txtNCA, rtfNCA

Examples

#pdfNCA(fileName="NCA-Theoph.pdf", Theoph, key="Subject", colTime="Time", 
#       colConc="conc", dose=320, doseUnit="mg", timeUnit="h", concUnit="mg/L")
#pdfNCA(fileName="NCA-Theoph.pdf", Theoph, key=c("Subject", "Wt"), colTime="Time",
#       colConc="conc", dose=320, doseUnit="mg", timeUnit="h", concUnit="mg/L")
#pdfNCA(fileName="NCA-Indometh.pdf", Indometh, key="Subject", colTime="time", 
#       colConc="conc", adm="Infusion", dur=0.5, dose=25, doseUnit="mg", 
#       timeUnit="h", concUnit="mg/L")

Operational Qualification (OQ) report to a pdf file

Description

Generate a self-contained PDF report that documents whether the NonCompart noncompartmental analysis engine (as used through ncar) reproduces pre-specified reference results on the user's own machine, within a pre-specified relative tolerance. It is intended as Operational Qualification (OQ) evidence, in the spirit of the WinNonlin computational-engine verification. The report uses only base R, NonCompart, and the package's own pdf helpers, so it requires no LaTeX, pandoc, or other external tools.

Usage

pdfOQ(fileName = "ncar-OQ-Report.pdf", cases = NULL, tol = 0.001,
      refDir = system.file("OQ", package = "ncar"), performedBy = "",
      paper = "auto", sigField = FALSE)

Arguments

Details

For each case the function runs tblNCA on the (frozen) input data, maps the CDISC PPTESTCD result columns to WinNonlin parameter names using the internal RptCfg table, matches comparable parameters to the reference table (robust to % vs . naming), and compares every parameter for every subject. A case passes only when all of its comparisons pass.

The bundled reference values are WinNonlin 6.4 NCA outputs. These establish concordance with the de-facto reference implementation (Tier B); they are not, by themselves, an independent verification. Independent (Tier A) anchors (hand-calculated edge cases, published textbook values) are a planned addition.

Value

Invisibly returns a list with elements fileName, qualified (logical), tol, nCases, nFailCases, and results (a per-case list with status, comparison counts, maximum relative difference, and any failed comparisons). A PDF file is written to fileName.

Author(s)

Kyun-Seop Bae <k@acr.kr>

See Also

pdfIQ, pdfNCA, tblNCA

Examples

#pdfOQ()
#res <- pdfOQ(fileName = "MyEngine-OQ.pdf", performedBy = "Jane Doe")
#res$qualified
#res$results[[1]]$maxRD

Performance Qualification (PQ) report to a pdf file

Description

Generate a self-contained PDF report documenting a Performance Qualification (PQ) of noncompartmental analysis for the user's own data and intended workflow. Whereas pdfOQ compares the engine to fixed reference values, PQ runs the analysis the user actually intends to run, on the user's (or representative) data, and checks that the result is reproducible, scientifically plausible, and (optionally) matches the user's pre-specified expected values, with a documented, signed record including a fingerprint (md5) of the input data. The report uses the package's own pdf helpers (no LaTeX) and the signature/approval page is placed first.

Usage

pdfPQ(fileName = "ncar-PQ-Report.pdf", concData, key = "Subject",
      colTime = "Time", colConc = "conc", ..., expected = NULL,
      acceptance = NULL, performedBy = "", paper = "auto", sigField = FALSE)

Arguments

Details

The report contains: the intended-use inputs and the input-data md5 fingerprint; the PQ acceptance criteria; a reproducibility check (the analysis is re-run on the same data and must reproduce identical results); per-profile performance/plausibility checks (Cmax > 0, Cmax >= Clast, Tmax within the observed time range, AUClast > 0, and for profiles with a terminal slope: AUCINF_obs >= AUClast, AUC %Extrap within limit, adjusted R-squared above limit, half-life positive and finite); an optional comparison to user-supplied expected values; an overall QUALIFIED / NOT QUALIFIED verdict; and a sessionInfo appendix.

PQ acceptance criteria and the choice of representative data are the user's responsibility; this function provides the tool and configurable defaults.

Value

Invisibly, a list with fileName, qualified, paper, results (the tblNCA table), reproducible, profiles (per-profile checks), fingerprint, nProfFail, nNonEval, and expected. A PDF is written to fileName.

Author(s)

Kyun-Seop Bae <k@acr.kr>

See Also

pdfIQ, pdfOQ, tblNCA

Examples

#Theoph2 <- as.data.frame(Theoph); Theoph2$Subject <- as.numeric(as.character(Theoph2$Subject))
#pdfPQ("MyStudy-PQ.pdf", Theoph2, "Subject", "Time", "conc", dose = 320,
#      concUnit = "mg/L", performedBy = "Kyun-Seop Bae", sigField = TRUE)

NCA output to rtf file

Description

This output NCA result in a rtf file.

Usage

rtfNCA(fileName = "Temp-NCA.rtf", concData, key = "Subject", colTime = "Time", 
       colConc = "conc", dose = 0, adm = "Extravascular", dur = 0, 
       doseUnit = "mg", timeUnit = "h", concUnit = "ug/L", down="Linear", 
       R2ADJ = 0, MW = 0, SS = FALSE, iAUC = "", excludeDelta = 1, UsePoints = NULL)

Arguments

Value

Author(s)

Kyun-Seop Bae <k@acr.kr>

See Also

help, txtNCA, pdfNCA

Examples

#rtfNCA(fileName="NCA-Theoph.rtf", Theoph, key="Subject", colTime="Time", 
#       colConc="conc", dose=320, doseUnit="mg", timeUnit="h", concUnit="mg/L")
#rtfNCA(fileName="NCA-Theoph.rtf", Theoph, key=c("Subject", "Wt"), colTime="Time",
#       colConc="conc", dose=320, doseUnit="mg", timeUnit="h", concUnit="mg/L")
#rtfNCA(fileName="NCA-Indometh.rtf", Indometh, key="Subject", colTime="time", 
#       colConc="conc", adm="Infusion", dur=0.5, dose=25, doseUnit="mg", 
#       timeUnit="h", concUnit="mg/L")

Digitally sign and verify a PDF report

Description

Apply a cryptographic digital signature to a (report) PDF, as an alternative to the print-sign-scan workflow, and verify it. signPDF signs the PDF bytes with the signer's private key (RSA or EC) using SHA-256 and writes a detached signature sidecar ‘<pdf>.sig’ (and, by default, the signer's public key ‘<pdf>.pubkey.pem’). verifyPDF confirms, with the signer's public key or certificate, that the PDF is byte-for-byte intact and was signed by that key (tamper-evidence and non-repudiation). These functions require the openssl package.

This is a detached signature (a separate ‘.sig’ file), not a PAdES signature embedded inside the PDF; embedding a visible in-viewer signature requires a dedicated PDF tool (e.g. Adobe Acrobat or ‘⁠pyhanko⁠’). The detached signature is cryptographically equivalent for integrity and non-repudiation.

Usage

signPDF(pdf, key, password = NULL, signer = "", role = "",
        sigFile = paste0(pdf, ".sig"), writePubkey = TRUE)

verifyPDF(pdf, sigFile = paste0(pdf, ".sig"), pubkey = paste0(pdf, ".pubkey.pem"))

Arguments

Value

signPDF invisibly returns a list with the sidecar path, the PDF sha256, the signer, and the public-key fingerprint; it writes the ‘.sig’ sidecar as a side effect. verifyPDF invisibly returns TRUE only if both the signature is valid and the recorded hash matches, and prints a human-readable result.

Author(s)

Kyun-Seop Bae <k@acr.kr>

See Also

pdfIQ, pdfOQ, writeMD5

Examples

#key <- openssl::rsa_keygen()
#openssl::write_pem(key, "signer_key.pem")
#pdfIQ("ncar-IQ-Report.pdf", performedBy = "Kyun-Seop Bae")
#signPDF("ncar-IQ-Report.pdf", "signer_key.pem", signer = "Kyun-Seop Bae")
#verifyPDF("ncar-IQ-Report.pdf")

Text output of NCA for one subject

Description

This is the text form output.

Usage

txtNCA(x, y, dose = 0, adm = "Extravascular", dur = 0, doseUnit = "mg", 
       timeUnit = "h", concUnit = "ug/L", iAUC = "", down="Linear", R2ADJ=0, 
       MW = 0, SS = FALSE, excludeDelta = 1, UsePoints = NULL)

Arguments

Value

Author(s)

Kyun-Seop Bae <k@acr.kr>

See Also

help, pdfNCA, rtfNCA

Examples

# For one subject
txtNCA(Theoph[Theoph$Subject=="1","Time"], Theoph[Theoph$Subject=="1","conc"], 
       dose=320, doseUnit="mg", concUnit="mg/L", timeUnit="h")

# or equivalently
x = Theoph[Theoph$Subject=="1","Time"]
y = Theoph[Theoph$Subject=="1","conc"]
txtNCA(x, y, dose=320, doseUnit="mg", concUnit="mg/L", timeUnit="h")

# For all subjects
IDs = sort(as.numeric(unique(Theoph[,"Subject"])))
nID = length(IDs)
Res = vector()
for (i in 1:nID) {
  tRes = txtNCA(Theoph[Theoph[,"Subject"]==IDs[i],"Time"], 
                Theoph[Theoph[,"Subject"]==IDs[i],"conc"], 
                dose=320, concUnit="mg/L")
  tRes = c(paste("ID =", IDs[i]), tRes, "")
  Res = c(Res, tRes)
}
Res

Write the MD5 integrity manifest for an installed package

Description

Write the standard R ‘MD5’ manifest into an installed package directory so that checkMD5sums (and pdfIQ) can verify file integrity. The manifest records the md5 checksum of every installed file. It is the same ‘MD5’ file that CRAN ships and that R's own installer writes; packages installed from CRAN already contain it, but a local source install usually does not (which is why the IQ integrity check then reports WARN). Run writeMD5() once, immediately after installing the package, to record the trusted baseline; thereafter checkMD5sums() detects any later modification of the installed files.

Usage

writeMD5(pkg = "ncar", lib.loc = NULL)

Arguments

Details

The manifest is written in the format used by checkMD5sums: one line per file, <md5sum> *<relative-path>. The ‘MD5’ file itself is excluded. The function uses only the exported md5sum. The installed package directory must be writable.

Value

Invisibly, the path to the ‘MD5’ file that was written. Called for its side effect.

Author(s)

Kyun-Seop Bae <k@acr.kr>

See Also

pdfIQ, checkMD5sums, md5sum

Examples

#writeMD5("ncar")
#writeMD5("NonCompart")
#ncar::pdfIQ()          # the file-integrity check now reports PASS