library(admiral)
library(dplyr)
library(lubridate)
library(admiraldev)
library(admiralvaccine)
library(pharmaversesdtm)
library(metatools)

# Load source datasets
data("is_vaccine")
data("suppis_vaccine")
data("admiralvaccine_adsl")

# Convert blanks into NA
is <- convert_blanks_to_na(is_vaccine)
suppis <- convert_blanks_to_na(suppis_vaccine)
adsl <- convert_blanks_to_na(admiralvaccine_adsl)

is_suppis <- combine_supp(is, suppis)

adis_avisit <- is_suppis %>%
  mutate(
    AVISITN = as.numeric(VISITNUM),
    AVISIT = case_when(
      VISITNUM == 10 ~ "Visit 1",
      VISITNUM == 20 ~ "Visit 2",
      VISITNUM == 30 ~ "Visit 3",
      VISITNUM == 40 ~ "Visit 4",
      is.na(VISITNUM) ~ NA_character_
    )
  )

adis_atpt <- adis_avisit %>%
  mutate(
    ATPTN = as.numeric(VISITNUM / 10),
    ATPT = case_when(
      VISITNUM == 10 ~ "Visit 1 (Day 1)",
      VISITNUM == 20 ~ "Visit 2 (Day 31)",
      VISITNUM == 30 ~ "Visit 3 (Day 61)",
      VISITNUM == 40 ~ "Visit 4 (Day 121)",
      is.na(VISITNUM) ~ NA_character_
    ),
    ATPTREF = case_when(
      VISITNUM %in% c(10, 20) ~ "FIRST TREATMENT",
      VISITNUM %in% c(30, 40) ~ "SECOND TREATMENT",
      is.na(VISITNUM) ~ NA_character_
    )
  )

# ADT derivation
# Add also PPROTFL from ADSL (to avoid additional merges) in order to derive
# PPSRFL at step 11.
adis_adt <- derive_vars_dt(
  dataset = adis_atpt,
  new_vars_prefix = "A",
  dtc = ISDTC,
  highest_imputation = "M",
  date_imputation = "mid",
  flag_imputation = "none"
)

# ADY derivation
# Attach RFSTDTC from ADSL in order to derive ADY
adis_ady <- adis_adt %>%
  derive_vars_merged(
    dataset_add = adsl,
    new_vars = exprs(RFSTDTC, PPROTFL),
    by_vars = exprs(STUDYID, USUBJID)
  ) %>%
  mutate(
    RFSTDT = as.Date(RFSTDTC)
  ) %>%
  derive_vars_dy(
    reference_date = RFSTDT,
    source_vars = exprs(ADT)
  ) %>%
  select(-RFSTDT)

# Create record duplication in order to plot both original and LOG10 parameter values.
# Add also records related to 4fold.
# Please, keep or modify PARAM values according to your purposes.

is_log <- adis_ady %>%
  mutate(DERIVED = "LOG10")

is_4fold <- adis_ady %>%
  mutate(DERIVED = "4FOLD")

is_log_4fold <- adis_ady %>%
  mutate(DERIVED = "LOG10 4FOLD")

adis_der <- bind_rows(adis_ady, is_log, is_4fold, is_log_4fold) %>%
  arrange(STUDYID, USUBJID, VISITNUM, ISSEQ, !is.na(DERIVED)) %>%
  mutate(DERIVED = if_else(is.na(DERIVED), "ORIG", DERIVED))


adis_paramcd <- adis_der %>%
  mutate(
    # PARAMCD: for log values, concatenation of L and ISTESTCD.
    PARAMCD = case_when(
      DERIVED == "ORIG" ~ ISTESTCD,
      DERIVED == "LOG10" ~ paste0(ISTESTCD, "L"),
      DERIVED == "4FOLD" ~ paste0(ISTESTCD, "F"),
      # As per CDISC rule, PARAMCD should be 8 charcaters long. Please, adapt if needed
      DERIVED == "LOG10 4FOLD" ~ paste0(substr(ISTESTCD, 1, 6), "LF")
    )
  )


# Update param_lookup dataset with your PARAM values.
param_lookup <- tribble(
  ~PARAMCD, ~PARAM, ~PARAMN,
  "J0033VN", "J0033VN Antibody", 1,
  "I0019NT", "I0019NT Antibody", 2,
  "M0019LN", "M0019LN Antibody", 3,
  "R0003MA", "R0003MA Antibody", 4,
  "J0033VNL", "LOG10 (J0033VN Antibody)", 11,
  "I0019NTL", "LOG10 (I0019NT Antibody)", 12,
  "M0019LNL", "LOG10 (M0019LN Antibody)", 13,
  "R0003MAL", "LOG10 (R0003MA Antibody)", 14,
  "J0033VNF", "4FOLD (J0033VN Antibody)", 21,
  "I0019NTF", "4FOLD (I0019NT Antibody)", 22,
  "M0019LNF", "4FOLD (M0019LN Antibody)", 23,
  "R0003MAF", "4FOLD (R0003MA Antibody)", 24,
  "J0033VLF", "LOG10 4FOLD (J0033VN Antibody)", 31,
  "I0019NLF", "LOG10 4FOLD (I0019NT Antibody)", 32,
  "M0019LLF", "LOG10 4FOLD (M0019LN Antibody)", 33,
  "R0003MLF", "LOG10 4FOLD (R0003MA Antibody)", 34
)

adis_param_paramn <- derive_vars_merged_lookup(
  dataset = adis_paramcd,
  dataset_add = param_lookup,
  new_vars = exprs(PARAM, PARAMN),
  by_vars = exprs(PARAMCD)
)
#> All `PARAMCD` are mapped.

adis_parcat1_cutoff <- adis_param_paramn %>%
  mutate(
    PARCAT1 = ISCAT,
    # Please, define your additional cutoff values. Delete if not needed.
    CUTOFF02 = 4,
    CUTOFF03 = 8
  )

adis_or <- adis_parcat1_cutoff %>%
  filter(DERIVED == "ORIG") %>%
  derive_var_aval_adis(
    lower_rule = ISLLOQ / 2,
    middle_rule = ISSTRESN,
    upper_rule = ISULOQ,
    round = 2
  )

adis_log_or <- adis_parcat1_cutoff %>%
  filter(DERIVED == "LOG10") %>%
  derive_var_aval_adis(
    lower_rule = log10(ISLLOQ / 2),
    middle_rule = log10(ISSTRESN),
    upper_rule = log10(ISULOQ),
    round = 2
  )

adis_4fold <- adis_parcat1_cutoff %>%
  filter(DERIVED == "4FOLD") %>%
  derive_var_aval_adis(
    lower_rule = ISLLOQ,
    middle_rule = ISSTRESN,
    upper_rule = ISULOQ,
    round = 2
  )

adis_log_4fold <- adis_parcat1_cutoff %>%
  filter(DERIVED == "LOG10 4FOLD") %>%
  derive_var_aval_adis(
    lower_rule = log10(ISLLOQ),
    middle_rule = log10(ISSTRESN),
    upper_rule = log10(ISULOQ),
    round = 2
  )

adis_aval_sercat1 <- bind_rows(adis_or, adis_log_or, adis_4fold, adis_log_4fold) %>%
  mutate( # AVALU derivation (please delete if not needed for your study)
    AVALU = ISSTRESU,

    # SERCAT1 derivation
    SERCAT1 = case_when(
      ISBLFL == "Y" & !is.na(AVAL) & !is.na(ISLLOQ) & AVAL < ISLLOQ ~ "S-",
      ISBLFL == "Y" & !is.na(AVAL) & !is.na(ISLLOQ) & AVAL >= ISLLOQ ~ "S+",
      ISBLFL == "Y" & (is.na(AVAL) | is.na(ISLLOQ)) ~ "UNKNOWN"
    )
  )


# Update param_lookup2 dataset with your SERCAT1N values.
param_lookup2 <- tribble(
  ~SERCAT1, ~SERCAT1N,
  "S-", 1,
  "S+", 2,
  "UNKNOWN", 3,
  NA_character_, NA_real_
)

adis_sercat1n <- derive_vars_merged_lookup(
  dataset = adis_aval_sercat1,
  dataset_add = param_lookup2,
  new_vars = exprs(SERCAT1N),
  by_vars = exprs(SERCAT1)
)
#> All `SERCAT1` are mapped.


# DTYPE derivation.
# Please update code when <,<=,>,>= are present in your lab results (in ISSTRESC)

if (any(names(adis_sercat1n) == "ISULOQ") == TRUE) {
  adis_dtype <- adis_sercat1n %>%
    mutate(DTYPE = case_when(
      DERIVED %in% c("ORIG", "LOG10") & !is.na(ISLLOQ) &
        ((ISSTRESN < ISLLOQ) | grepl("<", ISORRES)) ~ "HALFLLOQ",
      DERIVED %in% c("ORIG", "LOG10") & !is.na(ISULOQ) &
        ((ISSTRESN > ISULOQ) | grepl(">", ISORRES)) ~ "ULOQ",
      TRUE ~ NA_character_
    ))
}

if (any(names(adis_sercat1n) == "ISULOQ") == FALSE) {
  adis_dtype <- adis_sercat1n %>%
    mutate(DTYPE = case_when(
      DERIVED %in% c("ORIG", "LOG10") & !is.na(ISLLOQ) &
        ((ISSTRESN < ISLLOQ) | grepl("<", ISORRES)) ~ "HALFLLOQ",
      TRUE ~ NA_character_
    ))
}

# BASETYPE derivation
adis_basetype <- derive_basetype_records(
  adis_dtype,
  basetypes = exprs("VISIT 1" = AVISITN %in% c(10, 30))
)

# BASE derivation
adis_base <- derive_var_base(
  adis_basetype,
  by_vars = exprs(STUDYID, USUBJID, PARAMN),
  source_var = AVAL,
  new_var = BASE,
  filter = VISITNUM == 10
)


# ABLFL derivation
adis_ablfl <- restrict_derivation(
  adis_base,
  derivation = derive_var_extreme_flag,
  args = params(
    by_vars = exprs(STUDYID, USUBJID, PARAMN),
    order = exprs(STUDYID, USUBJID, VISITNUM, PARAMN),
    new_var = ABLFL,
    mode = "first"
  ),
  filter = VISITNUM == 10 & !is.na(BASE)
) %>%
  arrange(STUDYID, USUBJID, !is.na(DERIVED), VISITNUM, PARAMN)


# BASECAT derivation
adis_basecat <- adis_ablfl %>%
  mutate(
    BASECAT1 = case_when(
      !grepl("L", PARAMCD) & BASE < 10 ~ "Titer value < 1:10",
      !grepl("L", PARAMCD) & BASE >= 10 ~ "Titer value >= 1:10",
      grepl("L", PARAMCD) & BASE < 10 ~ "Titer value < 1:10",
      grepl("L", PARAMCD) & BASE >= 10 ~ "Titer value >= 1:10"
    )
  )

adis_chg <- restrict_derivation(
  adis_basecat,
  derivation = derive_var_chg,
  filter = AVISITN > 10
)

adis_r2b <- restrict_derivation(
  adis_chg,
  derivation = derive_var_analysis_ratio,
  args = params(
    numer_var = AVAL,
    denom_var = BASE
  ),
  filter = AVISITN > 10
) %>%
  arrange(STUDYID, USUBJID, DERIVED, ISSEQ) %>%
  select(-DERIVED)

adis_crit <- derive_vars_crit(
  dataset = adis_r2b,
  prefix = "CRIT1",
  crit_label = "Titer >= ISLLOQ",
  condition = !is.na(AVAL) & !is.na(ISLLOQ),
  criterion = AVAL >= ISLLOQ
)

period_ref <- create_period_dataset(
  dataset = adsl,
  new_vars = exprs(APERSDT = APxxSDT, APEREDT = APxxEDT, TRTA = TRTxxA, TRTP = TRTxxP)
)

adis_trt <- derive_vars_joined(
  adis_crit,
  dataset_add = period_ref,
  by_vars = exprs(STUDYID, USUBJID),
  filter_join = ADT >= APERSDT & ADT <= APEREDT,
  join_type = "all"
)

adis_ppsrfl <- adis_trt %>%
  mutate(PPSRFL = if_else(VISITNUM %in% c(10, 30) & PPROTFL == "Y", "Y", NA_character_))

# Get list of ADSL variables not to be added to ADIS
adsl_vars <- exprs(RFSTDTC, PPROTFL)

adis <- derive_vars_merged(
  dataset = adis_ppsrfl,
  dataset_add = select(admiralvaccine_adsl, !!!negate_vars(adsl_vars)),
  by_vars = exprs(STUDYID, USUBJID)
)