Introduction

This vignette explains some of the more advanced options of {admiral} related to higher order functions. A higher order function is a function that takes another function as input. By introducing these higher order functions, we intend to give the user greater power over our derivation functions, whilst trying to negate the need for adding additional {admiral} functions or arguments, or the user needing many separate steps.

The functions covered here are:

• call_derivation(): Call a single derivation multiple times with some arguments being fixed across iterations and others varying
• restrict_derivation(): Execute a single derivation on a subset of the input dataset
• slice_derivation(): The input dataset is split into slices (subsets) and for each slice a single derivation is called separately. Some or all arguments of the derivation may vary depending on the slice.

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

data("admiral_adsl")
data("ae")
data("vs")
adsl <- admiral_adsl
ae <- convert_blanks_to_na(ae)
vs <- convert_blanks_to_na(vs)

adae <- ae %>%
  left_join(adsl, by = c("STUDYID", "USUBJID")) %>%
  derive_vars_dt(
    new_vars_prefix = "AST",
    dtc = AESTDTC,
    highest_imputation = "M"
  ) %>%
  mutate(TRTEMFL = if_else(ASTDT >= TRTSDT, "Y", NA_character_))

Call Derivation

This function exists purely for convenience to save the user repeating numerous similar derivation function calls. It is best used when multiple derived variables have very similar specifications with only slight variations.

As an example, imagine the case where all the parameters in a BDS ADaM required both a highest value flag and a lowest value flag.

Here is an example of how to achieve this without using call_derivation():

vs_without <- vs %>%
  derive_var_extreme_flag(
    by_vars = exprs(USUBJID, VSTESTCD),
    order = exprs(VSORRES, VSSEQ),
    new_var = AHIFL,
    mode = "last"
  ) %>%
  derive_var_extreme_flag(
    by_vars = exprs(USUBJID, VSTESTCD),
    order = exprs(VSORRES, VSSEQ),
    new_var = ALOFL,
    mode = "first"
  )

Here is an example of how to achieve the same with using call_derivation(), where any different arguments are passed using params():

vs_with <- vs %>%
  call_derivation(
    derivation = derive_var_extreme_flag,
    variable_params = list(
      params(new_var = AHIFL, mode = "last"),
      params(new_var = ALOFL, mode = "first")
    ),
    by_vars = exprs(USUBJID, VSTESTCD),
    order = exprs(VSORRES, VSSEQ)
  )

In the example, you can see how in these higher order functions, derivation is where the user supplies the name of the derivation function to apply, with no trailing parentheses required. Then variable_params is used to pass a list of the different arguments needed for each derived variable.

The advantage of this higher order function would be further highlighted with examples where more than two variable derivations had similar needs, such as the below case where multiple time to AE parameters are derived in one call. Note that this example relies on pre-defined tte_source objects, as explained at Creating a BDS Time-to-Event ADaM.

adaette <- call_derivation(
  derivation = derive_param_tte,
  variable_params = list(
    params(
      event_conditions = list(ae_event),
      set_values_to = exprs(PARAMCD = "TTAE")
    ),
    params(
      event_conditions = list(ae_ser_event),
      set_values_to = exprs(PARAMCD = "TTSERAE")
    ),
    params(
      event_conditions = list(ae_sev_event),
      set_values_to = exprs(PARAMCD = "TTSEVAE")
    ),
    params(
      event_conditions = list(ae_wd_event),
      set_values_to = exprs(PARAMCD = "TTWDAE")
    )
  ),
  dataset_adsl = adsl,
  source_datasets = list(adsl = adsl, adae = adae),
  censor_conditions = list(lastalive_censor)
)

Developing your ADaM scripts this way using call_derivation() could give the following benefits:

• code becomes more efficient and readable
• maintenance would be eased in case of specification changes
• downstream quality checking would require less effort

Restrict Derivation

The idea behind this function is that sometimes you want to apply a derivation only for certain records from the input dataset. Introducing restrict_derivation() therefore gives the users the ability to achieve this across any function, without each function needing to have such an argument to allow for this.

An example would be if you wanted to flag the first occurring AE with the highest severity for each patient, but you only wanted to do this for records occurring on or after study day 1.

Here is how you could achieve this using restrict_derivation(), where the function arguments are passed using params() and the restriction criteria is given using filter:

ae <- ae %>%
  mutate(TEMP_AESEVN = as.integer(factor(AESEV, levels = c("SEVERE", "MODERATE", "MILD")))) %>%
  restrict_derivation(
    derivation = derive_var_extreme_flag,
    args = params(
      new_var = AHSEVFL,
      by_vars = exprs(USUBJID),
      order = exprs(TEMP_AESEVN, AESTDY, AESEQ),
      mode = "first"
    ),
    filter = AESTDY >= 1
  )

Slice Derivation

This function in a way combines the features of the above two. It allows a single derivation to be applied with different arguments for different slices (subsets) of records from the input dataset. You could do this with separate restrict_derivation() calls for each different set of records, but slice_derivation() allows to achieve this in one call.

An example would be if you wanted to achieve the same derivation as above for records occurring on or after study day 1, but for pre-treatment AEs you wanted to flag only the last occurring AE.

Here is how you could achieve this using slice_derivation(), where the function arguments are passed using params() and via the different slices controlled by filter:

ae <- ae %>%
  slice_derivation(
    derivation = derive_var_extreme_flag,
    args = params(
      new_var = AHSEV2FL,
      by_vars = exprs(USUBJID)
    ),
    derivation_slice(
      filter = AESTDY >= 1,
      args = params(order = exprs(TEMP_AESEVN, AESTDY, AESEQ), mode = "first")
    ),
    derivation_slice(
      filter = TRUE,
      args = params(order = exprs(AESTDY, AESEQ), mode = "last")
    )
  )

As you can see in the example, the derivation_slice ordering is important. Here we addressed all the AEs on or after study day 1 first, and then we used filter = TRUE option to catch all remaining records (in this case pre-treatment AEs).

The ordering is perhaps shown even more when we look at the below example where three slices are taken. Remember that observations that match with more than one slice are only considered for the first matching slice. So in this case we’re creating a flag for each patient for the record with the first severe AE, and then the first moderate AE, and finally flagging the last occurring AE where not severe or moderate.

ae <- ae %>%
  slice_derivation(
    derivation = derive_var_extreme_flag,
    args = params(
      new_var = AHSEV3FL,
      by_vars = exprs(USUBJID)
    ),
    derivation_slice(
      filter = AESEV == "SEVERE",
      args = params(order = exprs(AESTDY, AESEQ), mode = "first")
    ),
    derivation_slice(
      filter = AESEV == "MODERATE",
      args = params(order = exprs(AESTDY, AESEQ), mode = "first")
    ),
    derivation_slice(
      filter = TRUE,
      args = params(order = exprs(AESTDY, AESEQ), mode = "last")
    )
  )

The order is only important when the slices are not mutually exclusive, so in the above case the moderate AE slice could have been above the severe AE slice, for example, and there would have been no difference to the result. However the third slice had to come last to check all remaining (i.e. not severe or moderate) records only.