billdenney · Oct 26, 2026 · Oct 10, 2026 · Oct 10, 2026 · Oct 10, 2026 · Oct 10, 2026
diff --git a/.github/workflows/book.yml b/.github/workflows/book.yml
@@ -41,6 +41,11 @@ jobs:
             any::conflicted
             any::visNetwork
             any::tidyr
+            any::units
+            any::lme4
+            any::lmerTest
+            any::emmeans
+            any::cdiscdata
             github::humanpred/pknca
 
       # Fails the job (non-zero exit) if any documented example check fails

diff --git a/CLAUDE.md b/CLAUDE.md
@@ -4,7 +4,7 @@ This file provides guidance to Claude Code when working in this repository.
 
 ## What This Is
 
-A Quarto book documenting the [PKNCA](https://github.com/humanpred/pknca) R package (≥ 0.12.2).
+A Quarto book documenting the [PKNCA](https://github.com/humanpred/pknca) R package (≥ 0.13.0).
 Every parameter, option, and user-facing function is covered with runnable examples verified against live PKNCA output; the `pk.calc.*` calculation functions are indexed in the Developer Reference.
 
 **Book repo:** https://github.com/humanpred/pknca-book  
@@ -20,16 +20,16 @@ quarto preview       # live preview with auto-reload
 
 ```r
 # Install dependencies (once)
-remotes::install_github("humanpred/pknca")  # >= 0.12.2 required
-install.packages(c("knitr", "rmarkdown", "dplyr", "ggplot2", "conflicted", "testthat", "visNetwork"))
+remotes::install_github("humanpred/pknca")  # >= 0.13.0 required
+install.packages(c("knitr", "rmarkdown", "dplyr", "ggplot2", "conflicted", "testthat", "visNetwork", "tidyr", "units", "lme4", "lmerTest", "emmeans"))
 ```
 
 ## Project Structure
 
 ```
 _quarto.yml              # book config: title, author, chapters, site-url, navbar
 index.qmd                # introduction + What's new per version
-user/                    # 19 User Guide chapters
+user/                    # 25 User Guide chapters
 dev/                     # 2 Developer Reference chapters
 validate.R               # numeric self-check of key documented examples (Rscript validate.R; exits 1 on failure)
 .github/workflows/book.yml  # CI: runs validate.R, renders, deploys to GitHub Pages on push to main
@@ -39,7 +39,7 @@ _book/                   # rendered output (gitignored)
 ## Conventions
 
 - **Datasets:** `datasets::Theoph` (extravascular) and `datasets::Indometh` (intravascular)
-- **PKNCA version:** ≥ 0.12.2
+- **PKNCA version:** ≥ 0.13.0
 - **Code chunks:** `eval: true` — every chunk must run without error
 - **No `suppressWarnings()`** hiding real issues — fix root causes
 - **Each page is self-contained:** load packages at the top of every `.qmd`

diff --git a/CONTRIBUTING.md b/CONTRIBUTING.md
@@ -55,7 +55,7 @@ For each item, classify it:
 |---|---|
 | New NCA parameter | new `add.interval.col()` entry |
 | New option | new key in `PKNCA.options()` |
-| New function | e.g. `normalize()` in 0.12.2 |
+| New function | e.g. `be_assess()` in 0.13.0 |
 | Changed behavior | existing function works differently |
 | Bug fix | may invalidate an existing example |
 
@@ -102,9 +102,10 @@ as.data.frame(o_nca) |>
 
 **Known gotchas:**
 
-- **Tobit half-life** — set `lloq` on `PKNCAconc()`; in PKNCA ≥ 0.12.2 it is passed through to `pk.calc.half.life()` automatically, so the full `pk.nca()` pipeline works with `options = list(hl_method = "tobit")`. (Older versions required calling `pk.calc.half.life()` directly.)
-- **Sparse AUMC** — only set `sparse_aumclast = TRUE`. Explicitly requesting `sparse_auc_se = TRUE` alongside it triggers an internal type error.
-- **`normalize()`** — replaces the original parameters (does not append). To keep both, `bind_rows()` before and after.
+- **Tobit half-life** — set `lloq` on `PKNCAconc()`; in PKNCA ≥ 0.13.0 it is passed through to `pk.calc.half.life()` automatically, so the full `pk.nca()` pipeline works with `options = list(hl_method = "tobit")`. (Older versions required calling `pk.calc.half.life()` directly.)
+- **Sparse parameters** — use the standard names (`auclast`, `aucinf.obs`, …); with `PKNCAconc(sparse = TRUE)` their `_se` and `_df` companions are calculated with them. The `sparse_*` names are deprecated.
+- **Tobit with imputation** — until the LLOQ is carried onto imputed rows (pknca PR 678), combining `hl_method = "tobit"` with `impute = "start_conc0"` errors; examples show Tobit without imputation.
+- **`normalize()`** — on a data frame it replaces the original parameters (does not append); on a `PKNCAresults` object it appends the normalized rows.
 - **New option defaults** — always verify with `PKNCA.options("option_name")` before documenting the default.
 
 ---
@@ -131,7 +132,7 @@ as.data.frame(o_nca) |>
 - Add new sections or update existing ones in the relevant `.qmd` files.
 - Tag new features with `(≥ X.Y.Z)` so readers know when they were introduced.
 - Keep the shared dataset pattern consistent across pages.
-- If the new version introduces new functions, add them to the `:::callout-note` pkgdown reference footer at the bottom of the relevant chapter(s). The link pattern is `[function()]( https://humanpred.github.io/pknca/reference/function.html)`.
+- If the new version introduces new functions, add them to the `:::callout-note` pkgdown reference footer at the bottom of the relevant chapter(s). The link pattern is `[function()](https://humanpred.github.io/pknca/reference/function.html)`.
 
 ---
 
@@ -141,7 +142,7 @@ as.data.frame(o_nca) |>
 quarto render
 ```
 
-- Watch for **red error output** in the console — chunks that error are flagged even though `execute: error: false` suppresses them in the HTML output.
+- Watch for **red error output** in the console — with `execute: error: false`, a chunk that errors stops the render.
 - Fix the code, not the error suppression.
 
 Before pushing, run the numeric self-check, which verifies that key documented examples still produce correct values:
@@ -219,26 +220,32 @@ Template:
 ```
 _quarto.yml          # book config (title, author, chapters)
 index.qmd            # introduction + What's new
-user/                # 19 User Guide chapters
-  workflow.qmd       # PKNCAconc → PKNCAdose → PKNCAdata → pk.nca; all options
-  intervals.qmd      # interval data frame; full parameter catalog
-  auc-methods.qmd    # AUC types; integration methods; AUMC; aucabove; time_above
-  halflife.qmd       # λz regression; Tobit; quality filters; lambda.z.corrxy
-  extravascular.qmd  # oral/SC; BLQ; tmin; lag time
-  intravascular.qmd  # IV bolus; C0; IV infusion; ceoi; MRT
-  multiple-dose.qmd  # steady-state parameters; tau detection
-  superposition.qmd  # predicting multiple-dose from single-dose
-  tss.qmd            # time to steady state
-  urine-excretion.qmd# ae; fe; clr; volpk; ermax; ertmax; ertlst; clr.*.dn
-  sparse.qmd         # sparse_auclast; sparse AUMC; derived sparse params
-  postprocessing.qmd # exclude(); normalize(); .dn parameters; PKNCA.set.summary
-  units.qmd          # pknca_units_table(); preferred units; conversions
-  imputation.qmd     # built-in imputation methods; custom methods
-  dose-aware-interpolation.qmd  # interp.extrap.conc.dose; .dose AUCint variants
-  custom-parameters.qmd         # add.interval.col(); registering new parameters
-  utilities.qmd      # geomean; geocv; clean.conc.*; assert_conc_time
-  regulatory.qmd     # PP domain; PPEXCLFL; summary() for CSR tables
-  validation.qmd     # testthat suite; version pinning; spot-checks
+user/                # 25 User Guide chapters (order in _quarto.yml)
+  workflow.qmd                  # PKNCAconc → PKNCAdose → PKNCAdata → pk.nca
+  intervals.qmd                 # Interval data frame
+  auto-intervals.qmd            # Interval builder vs legacy
+  auc-methods.qmd               # auclast/aucall/aucinf
+  halflife.qmd                  # Point selection controls
+  extravascular.qmd             # BLQ handling
+  intravascular.qmd             # IV bolus
+  multiple-dose.qmd             # deg.fluc
+  superposition.qmd             # Predicting multiple-dose profiles from single-dose data
+  tss.qmd                       # pk.tss.monoexponential
+  urine-excretion.qmd           # ae
+  secondary-parameters.qmd      # interval_id/_ref
+  sparse.qmd                    # Serial/batch designs
+  sparse-uncertainty.qmd        # Yuan vs delta method (sparse_lambda_z_se)
+  bioequivalence.qmd            # be_assess()
+  data-quality.qmd              # pknca_missing_samples()
+  postprocessing.qmd            # exclude()
+  units.qmd                     # pknca_units_table()
+  datetime.qmd                  # POSIXct/Date times
+  imputation.qmd                # start_conc0
+  dose-aware-interpolation.qmd  # interp.extrap.conc.dose
+  custom-parameters.qmd         # add.interval.col()
+  utilities.qmd                 # clean.conc.*
+  regulatory.qmd                # CDISC output
+  validation.qmd                # testthat suite
 dev/                 # Developer Reference
   architecture.qmd   # class hierarchy; interval column system; formalsmap
   function-deps.qmd  # parameter dependency graph

diff --git a/README.md b/README.md
@@ -2,14 +2,14 @@
 
 [![Render and deploy book](https://github.com/humanpred/pknca-book/actions/workflows/book.yml/badge.svg)](https://github.com/humanpred/pknca-book/actions/workflows/book.yml)
 
-A comprehensive **Quarto book** documenting the [PKNCA](https://github.com/humanpred/pknca) R package (≥ 0.12.2) with runnable examples throughout. Every parameter, option, and user-facing function is covered and verified against live PKNCA output; the underlying `pk.calc.*` calculation functions are indexed in the Developer Reference.
+A comprehensive **Quarto book** documenting the [PKNCA](https://github.com/humanpred/pknca) R package (≥ 0.13.0) with runnable examples throughout. Every parameter, option, and user-facing function is covered and verified against live PKNCA output; the underlying `pk.calc.*` calculation functions are indexed in the Developer Reference.
 
 **Live book:** https://humanpred.github.io/pknca-book/
 
 ## Build locally
 
 ```r
-# Install PKNCA 0.12.2
+# Install PKNCA 0.13.0 or later
 remotes::install_github("humanpred/pknca")
 ```
 
@@ -22,29 +22,35 @@ open _book/index.html
 
 ## Contents
 
-### User Guide (19 chapters)
+### User Guide (25 chapters)
 
 | Chapter | Topics |
 |---|---|
-| [Workflow](user/workflow.qmd) | PKNCAconc → PKNCAdose → PKNCAdata → pk.nca; all 21 options with defaults |
-| [Interval selection & parameter catalog](user/intervals.qmd) | Interval data frame structure; group matching; the full parameter catalog, rendered live from the registry |
-| [AUC types & integration methods](user/auc-methods.qmd) | auclast/aucall/aucinf; partial AUC; lin up/log down vs linear vs lin-log; aucabove; time_above; AUMC; cav.int |
-| [Half-life & terminal phase](user/halflife.qmd) | Curve stripping; adj.r.squared.factor; quality filters; Tobit regression; lambda.z.corrxy |
-| [Extravascular (oral/SC)](user/extravascular.qmd) | BLQ handling; imputation strategies; tmin; lag time; multiple peaks |
-| [Intravascular (IV)](user/intravascular.qmd) | IV bolus NCA; C0 back-extrapolation; IV infusion with ceoi; MRT correction |
-| [Multiple-dose / steady-state](user/multiple-dose.qmd) | deg.fluc; swing; PTR; Cav; tau detection |
+| [Workflow](user/workflow.qmd) | PKNCAconc → PKNCAdose → PKNCAdata → pk.nca; default intervals; all options with defaults; update() |
+| [Interval selection & parameter catalog](user/intervals.qmd) | Interval data frame; pknca_interval_table(); presets; interval_add_*(); impute columns; validation; the parameter catalog, rendered live |
+| [Automatic intervals & dosing regimens](user/auto-intervals.qmd) | Interval builder vs legacy; find.dose.regimen(); find.tau(); nominal times; regimen changes; classed warnings |
+| [AUC types & integration methods](user/auc-methods.qmd) | auclast/aucall/aucinf; dose-aware partial AUCs; lin up/log down vs linear vs lin-log; AUMC; aumcint; aumciv |
+| [Half-life & terminal phase](user/halflife.qmd) | Point selection controls; Tobit regression; exclusion rules; get_halflife_fit()/get_halflife_curve(); lambda.z.corrxy |
+| [Extravascular (oral/SC)](user/extravascular.qmd) | BLQ handling; imputation; tmin; lag time; f.obs pointer; cl/vz/vss/mrt families |
+| [Intravascular (IV)](user/intravascular.qmd) | IV bolus; C0 back-extrapolation; auciv*; IV infusion; cl.iv/vz.iv; MRT correction |
+| [Multiple-dose / steady-state](user/multiple-dose.qmd) | deg.fluc; swing; PTR; Cav; tau detection; mrt.md/vss.md; accumulation |
 | [Superposition](user/superposition.qmd) | Predicting multiple-dose profiles from single-dose data |
 | [Time to steady state](user/tss.qmd) | pk.tss.monoexponential; pk.tss.stepwise.linear; pk.tss |
-| [Urine excretion](user/urine-excretion.qmd) | ae; fe; clr.*; volpk; ermax/ertmax/ertlst; clr.*.dn |
-| [Sparse PK sampling](user/sparse.qmd) | sparse_auclast + SE + df; sparse AUMC; mrt/cl/kel.sparse.last |
-| [Post-processing](user/postprocessing.qmd) | exclude(); normalize(); 17 .dn parameters; PKNCA.set.summary; get_halflife_points |
-| [Units](user/units.qmd) | pknca_units_table() S3 generic; PKNCAdata method; preferred units; conversions |
-| [Imputation](user/imputation.qmd) | start_conc0; start_predose; start_cmin; custom imputation methods |
-| [Dose-aware interpolation](user/dose-aware-interpolation.qmd) | interp.extrap.conc.dose; .dose AUCint variants |
-| [Custom parameters](user/custom-parameters.qmd) | add.interval.col; registering new NCA parameters |
-| [Utility functions](user/utilities.qmd) | geomean; geocv; clean.conc.*; assert_conc_time |
-| [Regulatory & CDISC](user/regulatory.qmd) | PP domain column mapping; CDISC output format; exclusion tracking; summary() for CSR tables |
-| [Validation & testing](user/validation.qmd) | testthat suite; version pinning; manual AUClast spot-check |
+| [Urine excretion](user/urine-excretion.qmd) | ae; fe; renal clearance in one run; volpk; ermax/ertmax/ertlst; erint/erlst |
+| [Secondary parameters](user/secondary-parameters.qmd) | interval_id/_ref; interval_add_secondary(); bioavailability (f.*); ratio.*; renal clearance; composed units |
+| [Sparse PK sampling](user/sparse.qmd) | Serial/batch designs; auclast etc. with _se/_df; start_conc0; BLQ rule; summary with SE; sparse_bootstrap() |
+| [Sparse AUC to infinity & its uncertainty](user/sparse-uncertainty.qmd) | Yuan vs delta method (sparse_lambda_z_se); IV bolus C0; recommendations; prior work |
+| [Bioequivalence](user/bioequivalence.qmd) | be_assess(); ABE/ABEL/RSABE/NTID/HVNTID/descriptive; crossover, replicate, parallel; sparse bootstrap route |
+| [Data quality checks](user/data-quality.qmd) | pknca_missing_samples(); exclude_nca_tmax_coverage(); LLOQ and input validation |
+| [Post-processing](user/postprocessing.qmd) | exclude(); exclusion rules; normalize(); .dn parameters; summary() options; PKNCA.set.summary |
+| [Units](user/units.qmd) | pknca_units_table(); automatic units; preferred units; timeu and tau; conversions |
+| [Date-time data & time references](user/datetime.qmd) | POSIXct/Date times; time references; date-time intervals; PPSTINT/PPENINT/PPTPTREF/PPRFTDTC |
+| [Imputation](user/imputation.qmd) | start_conc0; start_predose; start_predose_conc0; start_cmin; end_conc_drop; chaining order; custom methods |
+| [Dose-aware interpolation](user/dose-aware-interpolation.qmd) | interp.extrap.conc.dose; dose-aware aucint rules |
+| [Custom parameters](user/custom-parameters.qmd) | add.interval.col(); FUN_sparse; pknca_ref(); registering new NCA parameters |
+| [Utility functions](user/utilities.qmd) | clean.conc.*; interp.extrap.conc(); check.interval.specification(); get.parameter.deps(); route helpers; assert_* |
+| [Regulatory & CDISC](user/regulatory.qmd) | CDISC output; pknca_cdisc_codes(); PPANMETH; PPGRPID; exclusion tracking; summary() for CSR tables |
+| [Validation & testing](user/validation.qmd) | testthat suite; version pinning; manual AUClast spot-check; PPANMETH |
 
 ### Developer Reference (2 chapters)
 
@@ -53,16 +59,9 @@ open _book/index.html
 | [Architecture](dev/architecture.qmd) | Internal structure of PKNCA |
 | [Function dependencies](dev/function-deps.qmd) | Parameter dependency graph |
 
-## What's new in PKNCA 0.12.2
+## What's new in PKNCA 0.13.0
 
-- **Tobit regression** for half-life — handles BLQ terminal-phase observations via censored likelihood
-- **`normalize()` / `normalize_by_col()`** — normalize results by any column (body weight, BSA, etc.)
-- **`tmin`** — time of minimum concentration; **`first.tmin`** option
-- **Sparse AUMC** (`sparse_aumclast`, SE, df) and derived parameters (`mrt.sparse.last`, `cl.sparse.last`, `kel.sparse.last`)
-- **New urine parameters**: `volpk`, `ermax`, `ertmax`, `ertlst`, `clr.last.dn`, `clr.obs.dn`, `clr.pred.dn`
-- **`lambda.z.corrxy`** — correlation between time and log-concentration for the λz regression window
-- **`pknca_units_table()`** now an S3 generic with a `PKNCAdata` method
-- **`allow_partial_missing_units`** option
+See the book's [introduction](index.qmd) for the full list.  Highlights: automatic intervals rebuilt from the dosing regimen (breaking); secondary parameters (bioavailability `f.obs` etc., ratios, renal clearance) in one run; bioequivalence (`be_assess()`); sparse NCA with standard parameter names, the delta-method AUC to infinity, and `sparse_bootstrap()`; dose-aware partial AUCs; data quality checks; date-time data and CDISC time references.
 
 ## Related
 

diff --git a/_quarto.yml b/_quarto.yml
@@ -9,7 +9,7 @@ book:
   title: "PKNCA: Noncompartmental Analysis in R"
   author: "Teun M. Post"
   date: today
-  description: "A comprehensive guide to the PKNCA R package (≥ 0.12.2) — covering every function, parameter, and workflow with runnable examples."
+  description: "A comprehensive guide to the PKNCA R package (≥ 0.13.0) — covering every function, parameter, and workflow with runnable examples."
   repo-url: https://github.com/humanpred/pknca-book
   repo-actions: [issue, edit]
   favicon: ""
@@ -27,6 +27,7 @@ book:
       chapters:
         - user/workflow.qmd
         - user/intervals.qmd
+        - user/auto-intervals.qmd
         - user/auc-methods.qmd
         - user/halflife.qmd
         - user/extravascular.qmd
@@ -35,9 +36,14 @@ book:
         - user/superposition.qmd
         - user/tss.qmd
         - user/urine-excretion.qmd
+        - user/secondary-parameters.qmd
         - user/sparse.qmd
+        - user/sparse-uncertainty.qmd
+        - user/bioequivalence.qmd
+        - user/data-quality.qmd
         - user/postprocessing.qmd
         - user/units.qmd
+        - user/datetime.qmd
         - user/imputation.qmd
         - user/dose-aware-interpolation.qmd
         - user/custom-parameters.qmd