# Creating an OCCDS ADaM

# Introduction

This article describes creating an OCCDS ADaM. Examples are currently presented and tested in the context of `ADAE`. However, the examples could be applied to other OCCDS ADaMs such as `ADCM`, `ADMH`, `ADDV`, etc.

Note: All examples assume CDISC SDTM and/or ADaM format as input unless otherwise specified.

# Programming Workflow

- Read in Data
- Derive/Impute End and Start Analysis Date/time and Relative Day
- Derive Durations
- Derive ATC variables
- Derive Planned and Actual Treatment
- Derive Date/Date-time of Last Dose
- Derive Treatment Dose and Unit
- Derive Severity, Causality, and Toxicity Grade
- Derive Treatment Emergent Flag
- Derive Occurrence Flags
- Derive Query Variables
- Add ADSL variables
- Derive Analysis Sequence Number
- Add Labels and Attributes

## Read in Data

To start, all data frames needed for the creation of `ADAE` should be read into the environment. This will be a company specific process. Some of the data frames needed may be `AE` and `ADSL`

For example purpose, the CDISC Pilot SDTM and ADaM datasets —which are included in `{pharmaversesdtm}`— are used.

    library(admiral)
    library(dplyr, warn.conflicts = FALSE)
    library(pharmaversesdtm)
    library(lubridate)

    ae <- pharmaversesdtm::ae
    adsl <- admiral::admiral_adsl
    ex_single <- admiral::ex_single

    ae <- convert_blanks_to_na(ae)

At this step, it may be useful to join `ADSL` to your `AE` domain as well. Only the `ADSL` variables used for derivations are selected at this step. The rest of the relevant `ADSL` variables would be added later.

    adsl_vars <- exprs(TRTSDT, TRTEDT, TRT01A, TRT01P, DTHDT, EOSDT)

    adae <- derive_vars_merged(
      ae,
      dataset_add = adsl,
      new_vars = adsl_vars,
      by = exprs(STUDYID, USUBJID)
    )

USUBJID | AESEQ | AETERM | AESTDTC | TRTSDT | TRTEDT | TRT01A | TRT01P | DTHDT | EOSDT
--- | --- | --- | --- | --- | --- | --- | --- | --- | ---
01-701-1015 | 1 | APPLICATION SITE ERYTHEMA | 2014-01-03 | 2014-01-02 | 2014-07-02 | Placebo | Placebo | NA | 2014-07-02
01-701-1015 | 2 | APPLICATION SITE PRURITUS | 2014-01-03 | 2014-01-02 | 2014-07-02 | Placebo | Placebo | NA | 2014-07-02
01-701-1015 | 3 | DIARRHOEA | 2014-01-09 | 2014-01-02 | 2014-07-02 | Placebo | Placebo | NA | 2014-07-02
01-701-1023 | 3 | ATRIOVENTRICULAR BLOCK SECOND DEGREE | 2012-08-26 | 2012-08-05 | 2012-09-01 | Placebo | Placebo | NA | 2012-09-02
01-701-1023 | 1 | ERYTHEMA | 2012-08-07 | 2012-08-05 | 2012-09-01 | Placebo | Placebo | NA | 2012-09-02
01-701-1023 | 2 | ERYTHEMA | 2012-08-07 | 2012-08-05 | 2012-09-01 | Placebo | Placebo | NA | 2012-09-02
01-701-1023 | 4 | ERYTHEMA | 2012-08-07 | 2012-08-05 | 2012-09-01 | Placebo | Placebo | NA | 2012-09-02
01-703-1086 | 1 | APPLICATION SITE IRRITATION | 2012-09-13 | 2012-09-02 | 2012-12-04 | Xanomeline Low Dose | Xanomeline Low Dose | NA | 2012-12-24
01-703-1086 | 2 | APPLICATION SITE IRRITATION | 2012-09-13 | 2012-09-02 | 2012-12-04 | Xanomeline Low Dose | Xanomeline Low Dose | NA | 2012-12-24
01-703-1086 | 3 | APPLICATION SITE IRRITATION | 2012-09-13 | 2012-09-02 | 2012-12-04 | Xanomeline Low Dose | Xanomeline Low Dose | NA | 2012-12-24

## Derive/Impute End and Start Analysis Date/time and Relative Day

This part derives `ASTDTM`, `ASTDT`, `ASTDY`, `AENDTM`, `AENDT`, and `AENDY`. The function `derive_vars_dtm()` can be used to derive `ASTDTM` and `AENDTM` where `ASTDTM` could be company-specific. `ASTDT` and `AENDT` can be derived from `ASTDTM` and `AENDTM`, respectively, using function `derive_vars_dtm_to_dt()`. `derive_vars_dy()` can be used to create `ASTDY` and `AENDY`.

    adae <- adae %>%
      derive_vars_dtm(
        dtc = AESTDTC,
        new_vars_prefix = "AST",
        highest_imputation = "M",
        min_dates = exprs(TRTSDT)
      ) %>%
      derive_vars_dtm(
        dtc = AEENDTC,
        new_vars_prefix = "AEN",
        highest_imputation = "M",
        date_imputation = "last",
        time_imputation = "last",
        max_dates = exprs(DTHDT, EOSDT)
      ) %>%
      derive_vars_dtm_to_dt(exprs(ASTDTM, AENDTM)) %>%
      derive_vars_dy(
        reference_date = TRTSDT,
        source_vars = exprs(ASTDT, AENDT)
      )

USUBJID | AESTDTC | AEENDTC | ASTDTM | ASTDT | ASTDY | AENDTM | AENDT | AENDY
--- | --- | --- | --- | --- | --- | --- | --- | ---
01-701-1015 | 2014-01-03 | NA | 2014-01-03 | 2014-01-03 | 2 | NA | NA | NA
01-701-1015 | 2014-01-03 | NA | 2014-01-03 | 2014-01-03 | 2 | NA | NA | NA
01-701-1015 | 2014-01-09 | 2014-01-11 | 2014-01-09 | 2014-01-09 | 8 | 2014-01-11 23:59:59 | 2014-01-11 | 10
01-701-1023 | 2012-08-26 | NA | 2012-08-26 | 2012-08-26 | 22 | NA | NA | NA
01-701-1023 | 2012-08-07 | 2012-08-30 | 2012-08-07 | 2012-08-07 | 3 | 2012-08-30 23:59:59 | 2012-08-30 | 26
01-701-1023 | 2012-08-07 | NA | 2012-08-07 | 2012-08-07 | 3 | NA | NA | NA
01-701-1023 | 2012-08-07 | 2012-08-30 | 2012-08-07 | 2012-08-07 | 3 | 2012-08-30 23:59:59 | 2012-08-30 | 26
01-703-1086 | 2012-09-13 | 2013-01-02 | 2012-09-13 | 2012-09-13 | 12 | 2013-01-02 23:59:59 | 2013-01-02 | 123
01-703-1086 | 2012-09-13 | 2013-01-02 | 2012-09-13 | 2012-09-13 | 12 | 2013-01-02 23:59:59 | 2013-01-02 | 123
01-703-1086 | 2012-09-13 | 2013-01-02 | 2012-09-13 | 2012-09-13 | 12 | 2013-01-02 23:59:59 | 2013-01-02 | 123

See also Date and Time Imputation.

## Derive Durations

The function `derive_vars_duration()` can be used to create the variables `ADURN` and `ADURU`.

    adae <- adae %>%
      derive_vars_duration(
        new_var = ADURN,
        new_var_unit = ADURU,
        start_date = ASTDT,
        end_date = AENDT
      )

USUBJID | AESTDTC | AEENDTC | ASTDT | AENDT | ADURN | ADURU
--- | --- | --- | --- | --- | --- | ---
01-701-1015 | 2014-01-03 | NA | 2014-01-03 | NA | NA | NA
01-701-1015 | 2014-01-03 | NA | 2014-01-03 | NA | NA | NA
01-701-1015 | 2014-01-09 | 2014-01-11 | 2014-01-09 | 2014-01-11 | 3 | DAYS
01-701-1023 | 2012-08-26 | NA | 2012-08-26 | NA | NA | NA
01-701-1023 | 2012-08-07 | 2012-08-30 | 2012-08-07 | 2012-08-30 | 24 | DAYS
01-701-1023 | 2012-08-07 | NA | 2012-08-07 | NA | NA | NA
01-701-1023 | 2012-08-07 | 2012-08-30 | 2012-08-07 | 2012-08-30 | 24 | DAYS
01-703-1086 | 2012-09-13 | 2013-01-02 | 2012-09-13 | 2013-01-02 | 112 | DAYS
01-703-1086 | 2012-09-13 | 2013-01-02 | 2012-09-13 | 2013-01-02 | 112 | DAYS
01-703-1086 | 2012-09-13 | 2013-01-02 | 2012-09-13 | 2013-01-02 | 112 | DAYS

## Derive ATC variables

The function `derive_vars_atc()` can be used to derive ATC Class Variables.

It helps to add Anatomical Therapeutic Chemical class variables from `FACM` to `ADCM`.

The expected result is the input dataset with ATC variables added.

    cm <- tibble::tribble(
      ~STUDYID,  ~USUBJID,       ~CMGRPID, ~CMREFID,  ~CMDECOD,
      "STUDY01", "BP40257-1001", "14",     "1192056", "PARACETAMOL",
      "STUDY01", "BP40257-1001", "18",     "2007001", "SOLUMEDROL",
      "STUDY01", "BP40257-1002", "19",     "2791596", "SPIRONOLACTONE"
    )
    facm <- tibble::tribble(
      ~STUDYID,  ~USUBJID,       ~FAGRPID, ~FAREFID,  ~FATESTCD,  ~FASTRESC,
      "STUDY01", "BP40257-1001", "1",      "1192056", "CMATC1CD", "N",
      "STUDY01", "BP40257-1001", "1",      "1192056", "CMATC2CD", "N02",
      "STUDY01", "BP40257-1001", "1",      "1192056", "CMATC3CD", "N02B",
      "STUDY01", "BP40257-1001", "1",      "1192056", "CMATC4CD", "N02BE",
      "STUDY01", "BP40257-1001", "1",      "2007001", "CMATC1CD", "D",
      "STUDY01", "BP40257-1001", "1",      "2007001", "CMATC2CD", "D10",
      "STUDY01", "BP40257-1001", "1",      "2007001", "CMATC3CD", "D10A",
      "STUDY01", "BP40257-1001", "1",      "2007001", "CMATC4CD", "D10AA",
      "STUDY01", "BP40257-1001", "2",      "2007001", "CMATC1CD", "D",
      "STUDY01", "BP40257-1001", "2",      "2007001", "CMATC2CD", "D07",
      "STUDY01", "BP40257-1001", "2",      "2007001", "CMATC3CD", "D07A",
      "STUDY01", "BP40257-1001", "2",      "2007001", "CMATC4CD", "D07AA",
      "STUDY01", "BP40257-1001", "3",      "2007001", "CMATC1CD", "H",
      "STUDY01", "BP40257-1001", "3",      "2007001", "CMATC2CD", "H02",
      "STUDY01", "BP40257-1001", "3",      "2007001", "CMATC3CD", "H02A",
      "STUDY01", "BP40257-1001", "3",      "2007001", "CMATC4CD", "H02AB",
      "STUDY01", "BP40257-1002", "1",      "2791596", "CMATC1CD", "C",
      "STUDY01", "BP40257-1002", "1",      "2791596", "CMATC2CD", "C03",
      "STUDY01", "BP40257-1002", "1",      "2791596", "CMATC3CD", "C03D",
      "STUDY01", "BP40257-1002", "1",      "2791596", "CMATC4CD", "C03DA"
    )

    derive_vars_atc(cm, dataset_facm = facm, id_vars = exprs(FAGRPID))
    #> # A tibble: 5 × 9
    #>   STUDYID USUBJID      CMGRPID CMREFID CMDECOD       ATC1CD ATC2CD ATC3CD ATC4CD
    #>   <chr>   <chr>        <chr>   <chr>   <chr>         <chr>  <chr>  <chr>  <chr>
    #> 1 STUDY01 BP40257-1001 14      1192056 PARACETAMOL   N      N02    N02B   N02BE
    #> 2 STUDY01 BP40257-1001 18      2007001 SOLUMEDROL    D      D10    D10A   D10AA
    #> 3 STUDY01 BP40257-1001 18      2007001 SOLUMEDROL    D      D07    D07A   D07AA
    #> 4 STUDY01 BP40257-1001 18      2007001 SOLUMEDROL    H      H02    H02A   H02AB
    #> 5 STUDY01 BP40257-1002 19      2791596 SPIRONOLACTO… C      C03    C03D   C03DA

## Derive Planned and Actual Treatment

`TRTA` and `TRTP` must match at least one value of the character treatment variables in ADSL (e.g., `TRTxxA`/`TRTxxP`, `TRTSEQA`/`TRTSEQP`, `TRxxAGy`/`TRxxPGy`).

An example of a simple implementation for a study without periods could be:

    adae <- mutate(adae, TRTP = TRT01P, TRTA = TRT01A)

    count(adae, TRTP, TRTA, TRT01P, TRT01A)
    #> # A tibble: 2 × 5
    #>   TRTP                TRTA                TRT01P              TRT01A           n
    #>   <chr>               <chr>               <chr>               <chr>        <int>
    #> 1 Placebo             Placebo             Placebo             Placebo         10
    #> 2 Xanomeline Low Dose Xanomeline Low Dose Xanomeline Low Dose Xanomeline …     6

For studies with periods see the “Visit and Period Variables” vignette.

## Derive Date/Date-time of Last Dose

The function `derive_vars_joined()` can be used to derive the last dose date before the start of the event.

    ex_single <- derive_vars_dtm(
      ex_single,
      dtc = EXSTDTC,
      new_vars_prefix = "EXST",
      flag_imputation = "none"
    )

    adae <- derive_vars_joined(
      adae,
      ex_single,
      by_vars = exprs(STUDYID, USUBJID),
      new_vars = exprs(LDOSEDTM = EXSTDTM),
      join_vars = exprs(EXSTDTM),
      join_type = "all",
      order = exprs(EXSTDTM),
      filter_add = (EXDOSE > 0 | (EXDOSE == 0 & grepl("PLACEBO", EXTRT))) & !is.na(EXSTDTM),
      filter_join = EXSTDTM <= ASTDTM,
      mode = "last"
    )

USUBJID | AEDECOD | AESEQ | AESTDTC | AEENDTC | ASTDT | AENDT | LDOSEDTM
--- | --- | --- | --- | --- | --- | --- | ---
01-701-1015 | APPLICATION SITE ERYTHEMA | 1 | 2014-01-03 | NA | 2014-01-03 | NA | 2014-01-03
01-701-1015 | APPLICATION SITE PRURITUS | 2 | 2014-01-03 | NA | 2014-01-03 | NA | 2014-01-03
01-701-1015 | DIARRHOEA | 3 | 2014-01-09 | 2014-01-11 | 2014-01-09 | 2014-01-11 | 2014-01-09
01-701-1023 | ATRIOVENTRICULAR BLOCK SECOND DEGREE | 3 | 2012-08-26 | NA | 2012-08-26 | NA | 2012-08-26
01-701-1023 | ERYTHEMA | 1 | 2012-08-07 | 2012-08-30 | 2012-08-07 | 2012-08-30 | 2012-08-07
01-701-1023 | ERYTHEMA | 2 | 2012-08-07 | NA | 2012-08-07 | NA | 2012-08-07
01-701-1023 | ERYTHEMA | 4 | 2012-08-07 | 2012-08-30 | 2012-08-07 | 2012-08-30 | 2012-08-07
01-703-1086 | APPLICATION SITE IRRITATION | 1 | 2012-09-13 | 2013-01-02 | 2012-09-13 | 2013-01-02 | 2012-09-13
01-703-1086 | APPLICATION SITE IRRITATION | 2 | 2012-09-13 | 2013-01-02 | 2012-09-13 | 2013-01-02 | 2012-09-13
01-703-1086 | APPLICATION SITE IRRITATION | 3 | 2012-09-13 | 2013-01-02 | 2012-09-13 | 2013-01-02 | 2012-09-13

## Derive Treatment Dose and Unit

In a similar manner, you could derive the treatment dose and unit at the time of the event. Please note that it is assumed that the dosing intervals do not overlap. If this case occurs, the `derive_vars_joined()` call below will throw an error as handling this case is study-specific.

    ex_single <- derive_vars_dtm(
      ex_single,
      dtc = EXENDTC,
      new_vars_prefix = "EXEN",
      time_imputation = "last",
      flag_imputation = "none"
    )

    adae <- derive_vars_joined(
      adae,
      ex_single,
      by_vars = exprs(STUDYID, USUBJID),
      new_vars = exprs(DOSEON = EXDOSE, DOSEU = EXDOSU),
      join_vars = exprs(EXSTDTM, EXENDTM),
      join_type = "all",
      filter_add = (EXDOSE > 0 | (EXDOSE == 0 & grepl("PLACEBO", EXTRT))) & !is.na(EXSTDTM),
      filter_join = EXSTDTM <= ASTDTM & (ASTDTM <= EXENDTM | is.na(EXENDTM))
    )

USUBJID | AEDECOD | AESEQ | AESTDTC | AEENDTC | ASTDT | AENDT | DOSEON | DOSEU
--- | --- | --- | --- | --- | --- | --- | --- | ---
01-701-1015 | APPLICATION SITE ERYTHEMA | 1 | 2014-01-03 | NA | 2014-01-03 | NA | 0 | mg
01-701-1015 | APPLICATION SITE PRURITUS | 2 | 2014-01-03 | NA | 2014-01-03 | NA | 0 | mg
01-701-1015 | DIARRHOEA | 3 | 2014-01-09 | 2014-01-11 | 2014-01-09 | 2014-01-11 | 0 | mg
01-701-1023 | ATRIOVENTRICULAR BLOCK SECOND DEGREE | 3 | 2012-08-26 | NA | 2012-08-26 | NA | 0 | mg
01-701-1023 | ERYTHEMA | 1 | 2012-08-07 | 2012-08-30 | 2012-08-07 | 2012-08-30 | 0 | mg
01-701-1023 | ERYTHEMA | 2 | 2012-08-07 | NA | 2012-08-07 | NA | 0 | mg
01-701-1023 | ERYTHEMA | 4 | 2012-08-07 | 2012-08-30 | 2012-08-07 | 2012-08-30 | 0 | mg
01-703-1086 | APPLICATION SITE IRRITATION | 1 | 2012-09-13 | 2013-01-02 | 2012-09-13 | 2013-01-02 | 54 | mg
01-703-1086 | APPLICATION SITE IRRITATION | 2 | 2012-09-13 | 2013-01-02 | 2012-09-13 | 2013-01-02 | 54 | mg
01-703-1086 | APPLICATION SITE IRRITATION | 3 | 2012-09-13 | 2013-01-02 | 2012-09-13 | 2013-01-02 | 54 | mg

## Derive Severity, Causality, and Toxicity Grade

The variables `ASEV`, `AREL`, and `ATOXGR` can be added using simple `dplyr::mutate()` assignments, if no imputation is required.

    adae <- adae %>%
      mutate(
        ASEV = AESEV,
        AREL = AEREL
      )

## Derive Treatment Emergent Flag

To derive the treatment emergent flag `TRTEMFL`, one can call `derive_var_trtemfl()`. In the example below, we use 30 days in the flag derivation.

    adae <- adae %>%
      derive_var_trtemfl(
        trt_start_date = TRTSDT,
        trt_end_date = TRTEDT,
        end_window = 30
      )

USUBJID | TRTSDT | TRTEDT | AESTDTC | ASTDT | TRTEMFL
--- | --- | --- | --- | --- | ---
01-701-1015 | 2014-01-02 | 2014-07-02 | 2014-01-03 | 2014-01-03 | Y
01-701-1015 | 2014-01-02 | 2014-07-02 | 2014-01-03 | 2014-01-03 | Y
01-701-1015 | 2014-01-02 | 2014-07-02 | 2014-01-09 | 2014-01-09 | Y
01-701-1023 | 2012-08-05 | 2012-09-01 | 2012-08-26 | 2012-08-26 | Y
01-701-1023 | 2012-08-05 | 2012-09-01 | 2012-08-07 | 2012-08-07 | Y
01-701-1023 | 2012-08-05 | 2012-09-01 | 2012-08-07 | 2012-08-07 | Y
01-701-1023 | 2012-08-05 | 2012-09-01 | 2012-08-07 | 2012-08-07 | Y
01-703-1086 | 2012-09-02 | 2012-12-04 | 2012-09-13 | 2012-09-13 | Y
01-703-1086 | 2012-09-02 | 2012-12-04 | 2012-09-13 | 2012-09-13 | Y
01-703-1086 | 2012-09-02 | 2012-12-04 | 2012-09-13 | 2012-09-13 | Y

To derive on-treatment flag (`ONTRTFL`) in an ADaM dataset with a single occurrence date, we use `derive_var_ontrtfl()`.

The expected result is the input dataset with an additional column named `ONTRTFL` with a value of `"Y"` or `NA`.

If you want to also check an end date, you could add the `end_date` argument. Note that in this scenario you could set `span_period = TRUE` if you want occurrences that started prior to drug intake, and was ongoing or ended after this time to be considered as on-treatment.

    bds1 <- tibble::tribble(
      ~USUBJID, ~ADT,              ~TRTSDT,           ~TRTEDT,
      "P01",    ymd("2020-02-24"), ymd("2020-01-01"), ymd("2020-03-01"),
      "P02",    ymd("2020-01-01"), ymd("2020-01-01"), ymd("2020-03-01"),
      "P03",    ymd("2019-12-31"), ymd("2020-01-01"), ymd("2020-03-01")
    )
    derive_var_ontrtfl(
      bds1,
      start_date = ADT,
      ref_start_date = TRTSDT,
      ref_end_date = TRTEDT
    )
    #> # A tibble: 3 × 5
    #>   USUBJID ADT        TRTSDT     TRTEDT     ONTRTFL
    #>   <chr>   <date>     <date>     <date>     <chr>
    #> 1 P01     2020-02-24 2020-01-01 2020-03-01 Y
    #> 2 P02     2020-01-01 2020-01-01 2020-03-01 Y
    #> 3 P03     2019-12-31 2020-01-01 2020-03-01 <NA>

    bds2 <- tibble::tribble(
      ~USUBJID, ~ADT,              ~TRTSDT,           ~TRTEDT,
      "P01",    ymd("2020-07-01"), ymd("2020-01-01"), ymd("2020-03-01"),
      "P02",    ymd("2020-04-30"), ymd("2020-01-01"), ymd("2020-03-01"),
      "P03",    ymd("2020-03-15"), ymd("2020-01-01"), ymd("2020-03-01")
    )
    derive_var_ontrtfl(
      bds2,
      start_date = ADT,
      ref_start_date = TRTSDT,
      ref_end_date = TRTEDT,
      ref_end_window = 60
    )
    #> # A tibble: 3 × 5
    #>   USUBJID ADT        TRTSDT     TRTEDT     ONTRTFL
    #>   <chr>   <date>     <date>     <date>     <chr>
    #> 1 P01     2020-07-01 2020-01-01 2020-03-01 <NA>
    #> 2 P02     2020-04-30 2020-01-01 2020-03-01 Y
    #> 3 P03     2020-03-15 2020-01-01 2020-03-01 Y

    bds3 <- tibble::tribble(
      ~ADTM,              ~TRTSDTM,           ~TRTEDTM,           ~TPT,
      "2020-01-02T12:00", "2020-01-01T12:00", "2020-03-01T12:00", NA,
      "2020-01-01T12:00", "2020-01-01T12:00", "2020-03-01T12:00", "PRE",
      "2019-12-31T12:00", "2020-01-01T12:00", "2020-03-01T12:00", NA
    ) %>%
      mutate(
        ADTM = ymd_hm(ADTM),
        TRTSDTM = ymd_hm(TRTSDTM),
        TRTEDTM = ymd_hm(TRTEDTM)
      )
    derive_var_ontrtfl(
      bds3,
      start_date = ADTM,
      ref_start_date = TRTSDTM,
      ref_end_date = TRTEDTM,
      filter_pre_timepoint = TPT == "PRE"
    )
    #> # A tibble: 3 × 5
    #>   ADTM                TRTSDTM             TRTEDTM             TPT   ONTRTFL
    #>   <dttm>              <dttm>              <dttm>              <chr> <chr>
    #> 1 2020-01-02 12:00:00 2020-01-01 12:00:00 2020-03-01 12:00:00 <NA>  Y
    #> 2 2020-01-01 12:00:00 2020-01-01 12:00:00 2020-03-01 12:00:00 PRE   <NA>
    #> 3 2019-12-31 12:00:00 2020-01-01 12:00:00 2020-03-01 12:00:00 <NA>  <NA>

## Derive Occurrence Flags

The function `derive_var_extreme_flag()` can help derive variables such as `AOCCIFL`, `AOCCPIFL`, `AOCCSIFL`, and `AOCCzzFL`.

If grades were collected, the following can be used to flag first occurrence of maximum toxicity grade.

    adae <- adae %>%
      restrict_derivation(
        derivation = derive_var_extreme_flag,
        args = params(
          by_vars = exprs(USUBJID),
          order = exprs(desc(ATOXGR), ASTDTM, AESEQ),
          new_var = AOCCIFL,
          mode = "first"
        ),
        filter = TRTEMFL == "Y"
      )

Similarly, `ASEV` can also be used to derive the occurrence flags, if severity is collected. In this case, the variable will need to be recoded to a numeric variable. Flag first occurrence of most severe adverse event:

    adae <- adae %>%
      restrict_derivation(
        derivation = derive_var_extreme_flag,
        args = params(
          by_vars = exprs(USUBJID),
          order = exprs(
            as.integer(factor(
              ASEV,
              levels = c("DEATH THREATENING", "SEVERE", "MODERATE", "MILD")
            )),
            ASTDTM, AESEQ
          ),
          new_var = AOCCIFL,
          mode = "first"
        ),
        filter = TRTEMFL == "Y"
      )

USUBJID | ASTDTM | ASEV | AESEQ | TRTEMFL | AOCCIFL
--- | --- | --- | --- | --- | ---
01-701-1015 | 2014-01-03 | MILD | 1 | Y | Y
01-701-1015 | 2014-01-03 | MILD | 2 | Y | NA
01-701-1015 | 2014-01-09 | MILD | 3 | Y | NA
01-701-1023 | 2012-08-07 | MODERATE | 2 | Y | Y
01-701-1023 | 2012-08-07 | MILD | 1 | Y | NA
01-701-1023 | 2012-08-07 | MILD | 4 | Y | NA
01-701-1023 | 2012-08-26 | MILD | 3 | Y | NA
01-703-1086 | 2012-09-13 | SEVERE | 3 | Y | Y
01-703-1086 | 2012-09-13 | MODERATE | 2 | Y | NA
01-703-1086 | 2012-09-13 | MILD | 1 | Y | NA

## Derive Query Variables

For deriving query variables `SMQzzNAM`, `SMQzzCD`, `SMQzzSC`, `SMQzzSCN`, or `CQzzNAM` the `derive_vars_query()` function can be used. As input it expects a queries dataset, which provides the definition of the queries. See Queries dataset documentation for a detailed description of the queries dataset. The `create_query_data()` function can be used to create queries datasets.

The following example shows how to derive query variables for Standardized MedDRA Queries (SMQs) in ADAE.

    queries <- admiral::queries

PREFIX | GRPNAME | GRPID | SCOPE | SCOPEN | SRCVAR | TERMCHAR | TERMNUM
--- | --- | --- | --- | --- | --- | --- | ---
CQ01 | Dermatologic events | NA | NA | NA | AELLT | APPLICATION SITE ERYTHEMA | NA
CQ01 | Dermatologic events | NA | NA | NA | AELLT | APPLICATION SITE PRURITUS | NA
CQ01 | Dermatologic events | NA | NA | NA | AELLT | ERYTHEMA | NA
CQ01 | Dermatologic events | NA | NA | NA | AELLT | LOCALIZED ERYTHEMA | NA
CQ01 | Dermatologic events | NA | NA | NA | AELLT | GENERALIZED PRURITUS | NA
SMQ02 | Immune-Mediated Hypothyroidism | 20000160 | BROAD | 1 | AEDECOD | BIOPSY THYROID GLAND ABNORMAL | NA
SMQ02 | Immune-Mediated Hypothyroidism | 20000160 | BROAD | 1 | AEDECOD | BLOOD THYROID STIMULATING HORMONE ABNORMAL | NA
SMQ02 | Immune-Mediated Hypothyroidism | 20000160 | NARROW | 2 | AEDECOD | BIOPSY THYROID GLAND INCREASED | NA
SMQ03 | Immune-Mediated Guillain-Barre Syndrome | 20000131 | NARROW | 2 | AEDECOD | GUILLAIN-BARRE SYNDROME | NA
SMQ03 | Immune-Mediated Guillain-Barre Syndrome | 20000131 | NARROW | 2 | AEDECOD | MILLER FISHER SYNDROME | NA

    adae1 <- tibble::tribble(
      ~USUBJID, ~ASTDTM, ~AETERM, ~AESEQ, ~AEDECOD, ~AELLT, ~AELLTCD,
      "01", "2020-06-02 23:59:59", "ALANINE AMINOTRANSFERASE ABNORMAL",
      3, "Alanine aminotransferase abnormal", NA_character_, NA_integer_,
      "02", "2020-06-05 23:59:59", "BASEDOW'S DISEASE",
      5, "Basedow's disease", NA_character_, 1L,
      "03", "2020-06-07 23:59:59", "SOME TERM",
      2, "Some query", "Some term", NA_integer_,
      "05", "2020-06-09 23:59:59", "ALVEOLAR PROTEINOSIS",
      7, "Alveolar proteinosis", NA_character_, NA_integer_
    )

    adae_query <- derive_vars_query(dataset = adae1, dataset_queries = queries)

USUBJID | ASTDTM | AETERM | AESEQ | AEDECOD | AELLT | AELLTCD | SMQ02NAM | SMQ02CD | SMQ02SC | SMQ02SCN | SMQ03NAM | SMQ03CD | SMQ03SC | SMQ03SCN | SMQ05NAM | SMQ05CD | SMQ05SC | SMQ05SCN | CQ01NAM | CQ04NAM | CQ04CD | CQ06NAM | CQ06CD
--- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | ---
01 | 2020-06-02 23:59:59 | ALANINE AMINOTRANSFERASE ABNORMAL | 3 | Alanine aminotransferase abnormal | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA
02 | 2020-06-05 23:59:59 | BASEDOW’S DISEASE | 5 | Basedow’s disease | NA | 1 | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | Immune-Mediated Colitis | 10009888
03 | 2020-06-07 23:59:59 | SOME TERM | 2 | Some query | Some term | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA
05 | 2020-06-09 23:59:59 | ALVEOLAR PROTEINOSIS | 7 | Alveolar proteinosis | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | Immune-Mediated Pneumonitis | 20000042 | NARROW | 2 | NA | NA | NA | NA | NA

Similarly to SMQ, the `derive_vars_query()` function can be used to derive Standardized Drug Groupings (SDG).

    sdg <- tibble::tribble(
      ~PREFIX, ~GRPNAME,          ~GRPID, ~SCOPE,  ~SCOPEN, ~SRCVAR,   ~TERMCHAR,          ~TERMNUM,
      "SDG01", "Diuretics",           11, "BROAD", 1,       "CMDECOD", "Diuretic 1",       NA,
      "SDG01", "Diuretics",           11, "BROAD", 1,       "CMDECOD", "Diuretic 2",       NA,
      "SDG02", "Costicosteroids",     12, "BROAD", 1,       "CMDECOD", "Costicosteroid 1", NA,
      "SDG02", "Costicosteroids",     12, "BROAD", 1,       "CMDECOD", "Costicosteroid 2", NA,
      "SDG02", "Costicosteroids",     12, "BROAD", 1,       "CMDECOD", "Costicosteroid 3", NA,
    )
    adcm <- tibble::tribble(
      ~USUBJID, ~ASTDTM,               ~CMDECOD,
      "01",     "2020-06-02 23:59:59", "Diuretic 1",
      "02",     "2020-06-05 23:59:59", "Diuretic 1",
      "03",     "2020-06-07 23:59:59", "Costicosteroid 2",
      "05",     "2020-06-09 23:59:59", "Diuretic 2"
    )
    adcm_query <- derive_vars_query(adcm, sdg)

USUBJID | ASTDTM | CMDECOD | SDG01NAM | SDG01CD | SDG01SC | SDG01SCN | SDG02NAM | SDG02CD | SDG02SC | SDG02SCN
--- | --- | --- | --- | --- | --- | --- | --- | --- | --- | ---
01 | 2020-06-02 23:59:59 | Diuretic 1 | Diuretics | 11 | BROAD | 1 | NA | NA | NA | NA
02 | 2020-06-05 23:59:59 | Diuretic 1 | Diuretics | 11 | BROAD | 1 | NA | NA | NA | NA
03 | 2020-06-07 23:59:59 | Costicosteroid 2 | NA | NA | NA | NA | Costicosteroids | 12 | BROAD | 1
05 | 2020-06-09 23:59:59 | Diuretic 2 | Diuretics | 11 | BROAD | 1 | NA | NA | NA | NA

## Add the `ADSL` variables

If needed, the other `ADSL` variables can now be added:

    adae <- adae %>%
      derive_vars_merged(
        dataset_add = select(adsl, !!!negate_vars(adsl_vars)),
        by_vars = exprs(STUDYID, USUBJID)
      )

USUBJID | AEDECOD | ASTDTM | DTHDT | RFSTDTC | RFENDTC | AGE | AGEU | SEX
--- | --- | --- | --- | --- | --- | --- | --- | ---
01-701-1015 | APPLICATION SITE ERYTHEMA | 2014-01-03 | NA | 2014-01-02 | 2014-07-02 | 63 | YEARS | F
01-701-1015 | APPLICATION SITE PRURITUS | 2014-01-03 | NA | 2014-01-02 | 2014-07-02 | 63 | YEARS | F
01-701-1015 | DIARRHOEA | 2014-01-09 | NA | 2014-01-02 | 2014-07-02 | 63 | YEARS | F
01-701-1023 | ERYTHEMA | 2012-08-07 | NA | 2012-08-05 | 2012-09-02 | 64 | YEARS | M
01-701-1023 | ERYTHEMA | 2012-08-07 | NA | 2012-08-05 | 2012-09-02 | 64 | YEARS | M
01-701-1023 | ERYTHEMA | 2012-08-07 | NA | 2012-08-05 | 2012-09-02 | 64 | YEARS | M
01-701-1023 | ATRIOVENTRICULAR BLOCK SECOND DEGREE | 2012-08-26 | NA | 2012-08-05 | 2012-09-02 | 64 | YEARS | M
01-703-1086 | APPLICATION SITE IRRITATION | 2012-09-13 | NA | 2012-09-02 | 2012-12-24 | 71 | YEARS | M
01-703-1086 | APPLICATION SITE IRRITATION | 2012-09-13 | NA | 2012-09-02 | 2012-12-24 | 71 | YEARS | M
01-703-1086 | APPLICATION SITE IRRITATION | 2012-09-13 | NA | 2012-09-02 | 2012-12-24 | 71 | YEARS | M

## Derive Analysis Sequence Number

The function `derive_var_obs_number()` can be used for deriving `ASEQ` variable to ensure the uniqueness of subject records within the dataset.

For example, there can be multiple records present in `ADCM` for a single subject with the same `ASTDTM` and `CMSEQ` variables. But these records still differ at ATC level:

    adcm <- tibble::tribble(
      ~USUBJID,       ~ASTDTM,          ~CMSEQ, ~CMDECOD,         ~ATC1CD, ~ATC2CD, ~ATC3CD, ~ATC4CD,
      "BP40257-1001", "2013-07-05 UTC", "14",   "PARACETAMOL",    "N",     "N02",   "N02B",  "N02BE",
      "BP40257-1001", "2013-08-15 UTC", "18",   "SOLUMEDROL",     "D",     "D10",   "D10A",  "D10AA",
      "BP40257-1001", "2013-08-15 UTC", "18",   "SOLUMEDROL",     "D",     "D07",   "D07A",  "D07AA",
      "BP40257-1001", "2013-08-15 UTC", "18",   "SOLUMEDROL",     "H",     "H02",   "H02A",  "H02AB",
      "BP40257-1002", "2012-12-15 UTC", "19",   "SPIRONOLACTONE", "C",     "C03",   "C03D",  "C03DA"
    )

    adcm_aseq <- adcm %>%
      derive_var_obs_number(
        by_vars    = exprs(USUBJID),
        order      = exprs(ASTDTM, CMSEQ, ATC1CD, ATC2CD, ATC3CD, ATC4CD),
        new_var    = ASEQ,
        check_type = "error"
      )

USUBJID | ASTDTM | CMSEQ | CMDECOD | ATC1CD | ATC2CD | ATC3CD | ATC4CD | ASEQ
--- | --- | --- | --- | --- | --- | --- | --- | ---
BP40257-1001 | 2013-07-05 UTC | 14 | PARACETAMOL | N | N02 | N02B | N02BE | 1
BP40257-1001 | 2013-08-15 UTC | 18 | SOLUMEDROL | D | D07 | D07A | D07AA | 2
BP40257-1001 | 2013-08-15 UTC | 18 | SOLUMEDROL | D | D10 | D10A | D10AA | 3
BP40257-1001 | 2013-08-15 UTC | 18 | SOLUMEDROL | H | H02 | H02A | H02AB | 4
BP40257-1002 | 2012-12-15 UTC | 19 | SPIRONOLACTONE | C | C03 | C03D | C03DA | 1

## Add Labels and Attributes

Adding labels and attributes for SAS transport files is supported by the following packages:

- metacore: establish a common foundation for the use of metadata within an R session.

- metatools: enable the use of metacore objects. Metatools can be used to build datasets or enhance columns in existing datasets as well as checking datasets against the metadata.

- xportr: functionality to associate all metadata information to a local R data frame, perform data set level validation checks and convert into a transport v5 file(xpt).

NOTE: All these packages are in the experimental phase, but the vision is to have them associated with an End to End pipeline under the umbrella of the pharmaverse. An example of applying metadata and perform associated checks can be found at the pharmaverse E2E example.

# Example Scripts

ADaM | Sourcing Command
--- | ---
ADAE | `use_ad_template("ADAE")`
ADCM | `use_ad_template("ADCM")`