Structure of metadata set

The metadata data set has the following structure for the required variables:

The metadata data set has the following structure for the optional variables:

Mapping ADLB VAD to the TERM variable in the {admiral} metadata data set

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

data("lb")

adsl <- admiral_adsl
lb <- convert_blanks_to_na(lb)

Each company needs to map their lab test to a term that describes the criteria being applied. The list of terms defined in the {admiral} metadata to implement NCI-CTCAEv4 is below:

Likewise, the list of terms defined in the {admiral} metadata to implement NCI-CTCAEv5 is below: (Terms identical to NCI-CTCAEv4, except Hyperglycemia, Hyperglycemia (Fasting) and Hypophosphatemia) which are not present in NCI-CTCAEv5.

Finally, the list of terms defined in the {admiral} metadata to implement DAIDS is below:

Using CDISC data these lab tests can be mapped to the correct terms, firstly create PARAMCD, PARAM, AVAL, ANRLO and ANRHI, also some lab grading criteria require BASE and PCHG, so these would also need to be created before running derive_var_atoxgr_dir() function.

# Look-up tables ----

# Assign PARAMCD, PARAM, and PARAMN
param_lookup <- tibble::tribble(
  ~LBTESTCD, ~PARAMCD,  ~PARAM,                                             ~PARAMN,
  "ALB",     "ALB",     "Albumin (g/L)",                                    1,
  "ALP",     "ALKPH",   "Alkaline Phosphatase (U/L)",                       2,
  "ALT",     "ALT",     "Alanine Aminotransferase (U/L)",                   3,
  "ANISO",   "ANISO",   "Anisocytes",                                       4,
  "AST",     "AST",     "Aspartate Aminotransferase (U/L)",                 5,
  "BASO",    "BASO",    "Basophils (10^9/L)",                               6,
  "BASOLE",  "BASOLE",  "Basophils/Leukocytes (FRACTION)",                  7,
  "BILI",    "BILI",    "Bilirubin (umol/L)",                               8,
  "BUN",     "BUN",     "Blood Urea Nitrogen (mmol/L)",                     9,
  "CA",      "CA",      "Calcium (mmol/L)",                                 10,
  "CHOL",    "CHOLES",  "Cholesterol (mmol/L)",                             11,
  "CK",      "CK",      "Creatinine Kinase (U/L)",                          12,
  "CL",      "CL",      "Chloride (mmol/L)",                                13,
  "COLOR",   "COLOR",   "Color",                                            14,
  "CREAT",   "CREAT",   "Creatinine (umol/L)",                              15,
  "EOS",     "EOS",     "Eosinophils (10^9/L)",                             16,
  "EOSLE",   "EOSLE",   "Eosinophils/Leukocytes (FRACTION)",                17,
  "GGT",     "GGT",     "Gamma Glutamyl Transferase (U/L)",                 18,
  "GLUC",    "GLUC",    "Glucose (mmol/L)",                                 19,
  "HBA1C",   "HBA1C",   "Hemoglobin A1C (1)",                               20,
  "HCT",     "HCT",     "Hematocrit (1)",                                   21,
  "HGB",     "HGB",     "Hemoglobin (mmol/L)",                              22,
  "K",       "POTAS",   "Potassium (mmol/L)",                               23,
  "KETONES", "KETON",   "Ketones",                                          24,
  "LYM",     "LYMPH",   "Lymphocytes (10^9/L)",                             25,
  "LYMLE",   "LYMPHLE", "Lymphocytes/Leukocytes (FRACTION)",                26,
  "MACROCY", "MACROC",  "Macrocytes",                                       27,
  "MCH",     "MCH",     "Ery. Mean Corpuscular Hemoglobin (fmol(Fe))",      28,
  "MCHC",    "MCHC",    "Ery. Mean Corpuscular HGB Concentration (mmol/L)", 29,
  "MCV",     "MCV",     "Ery. Mean Corpuscular Volume (f/L)",               30,
  "MICROCY", "MICROC",  "Microcytes",                                       31,
  "MONO",    "MONO",    "Monocytes (10^9/L)",                               32,
  "MONOLE",  "MONOLE",  "Monocytes/Leukocytes (FRACTION)",                  33,
  "PH",      "PH",      "pH",                                               34,
  "PHOS",    "PHOS",    "Phosphate (mmol/L)",                               35,
  "PLAT",    "PLAT",    "Platelet (10^9/L)",                                36,
  "POIKILO", "POIKIL",  "Poikilocytes",                                     37,
  "POLYCHR", "POLYCH",  "Polychromasia",                                    38,
  "PROT",    "PROT",    "Protein (g/L)",                                    39,
  "RBC",     "RBC",     "Erythrocytes (TI/L)",                              40,
  "SODIUM",  "SODIUM",  "Sodium (mmol/L)",                                  41,
  "SPGRAV",  "SPGRAV",  "Specific Gravity",                                 42,
  "TSH",     "TSH",     "Thyrotropin (mU/L)",                               43,
  "URATE",   "URATE",   "Urate (umol/L)",                                   44,
  "UROBIL",  "UROBIL",  "Urobilinogen",                                     45,
  "VITB12",  "VITB12",  "Vitamin B12 (pmol/L)",                             46,
  "WBC",     "WBC",     "Leukocytes (10^9/L)",                              47
)

adlb <- lb %>%
  ## Add PARAMCD PARAM and PARAMN - from LOOK-UP table
  derive_vars_merged_lookup(
    dataset_add = param_lookup,
    new_vars = exprs(PARAMCD, PARAM, PARAMN),
    by_vars = exprs(LBTESTCD)
  ) %>%
  ## Calculate PARCAT1 AVAL AVALC ANRLO ANRHI
  ## Dummy the values for BASE
  mutate(
    PARCAT1 = LBCAT,
    AVAL = LBSTRESN,
    AVALC = LBSTRESC,
    ANRLO = LBSTNRLO,
    ANRHI = LBSTNRHI,
    BASE = AVAL - 10
  )
#> All `LBTESTCD` are mapped.

Another look-up table is used to add on ATOXDSCL and ATOXDSCH using PARAMCD. ATOXDSCL holds the terms for grading low lab values, and ATOXDSCH holds the terms for grading high lab values. The names of these variables can be user-defined. ATOXDSCL and ATOXDSCH are the link from ADLB data to the {admiral} metadata that holds the grading criteria.

# Assign ATOXDSCL and ATOXDSCH to hold lab grading terms
# ATOXDSCL and ATOXDSCH hold terms defined by NCI-CTCAEv4.
grade_lookup <- tibble::tribble(
  ~PARAMCD, ~ATOXDSCL,                    ~ATOXDSCH,
  "ALB",    "Hypoalbuminemia",            NA_character_,
  "ALKPH",  NA_character_,                "Alkaline phosphatase increased",
  "ALT",    NA_character_,                "Alanine aminotransferase increased",
  "AST",    NA_character_,                "Aspartate aminotransferase increased",
  "BILI",   NA_character_,                "Blood bilirubin increased",
  "CA",     "Hypocalcemia",               "Hypercalcemia",
  "CHOLES", NA_character_,                "Cholesterol high",
  "CK",     NA_character_,                "CPK increased",
  "CREAT",  NA_character_,                "Creatinine increased",
  "GGT",    NA_character_,                "GGT increased",
  "GLUC",   "Hypoglycemia",               "Hyperglycemia",
  "HGB",    "Anemia",                     "Hemoglobin increased",
  "POTAS",  "Hypokalemia",                "Hyperkalemia",
  "LYMPH",  "CD4 lymphocytes decreased",  NA_character_,
  "PHOS",   "Hypophosphatemia",           NA_character_,
  "PLAT",   "Platelet count decreased",   NA_character_,
  "SODIUM", "Hyponatremia",               "Hypernatremia",
  "WBC",    "White blood cell decreased", "Leukocytosis",
)

adlb <- adlb %>%
  derive_vars_merged(
    dataset_add = grade_lookup,
    by_vars = exprs(PARAMCD),
  )

It is now straightforward to create the grade, for low lab values the grade will be held in ATOXGRL and for high lab values the grade will be held in ATOXGRH.

Note: for NCICTCAEv5 grading, you would update meta_criteria parameter to atoxgr_criteria_ctcv5 and for DAIDS grading you would update meta_criteria parameter to atoxgr_criteria_daids

adlb <- adlb %>%
  derive_var_atoxgr_dir(
    new_var = ATOXGRL,
    tox_description_var = ATOXDSCL,
    meta_criteria = atoxgr_criteria_ctcv4,
    criteria_direction = "L",
    get_unit_expr = extract_unit(PARAM)
  ) %>%
  derive_var_atoxgr_dir(
    new_var = ATOXGRH,
    tox_description_var = ATOXDSCH,
    meta_criteria = atoxgr_criteria_ctcv4,
    criteria_direction = "H",
    get_unit_expr = extract_unit(PARAM)
  )

Note: {admiral} does not grade ‘Anemia’ or ‘Hemoglobin Increased’ because the metadata is based on the SI unit of ‘g/L’, however the CDISC data has SI unit of ‘mmol/L’. Please see SI_UNIT_CHECK variable in {admiral} metadata atoxgr_criteria_ctcv4() or atoxgr_criteria_ctcv5() or atoxgr_criteria_daids(), the metadata is in the data folder of {admiral}.

{admiral} also gives the option to combine ATOXGRL and ATOXGRH into one variable, namely ATOXGR. Grades held in ATOXGRL will be given a negative value in ATOXGR to distinguish between low and high values.

adlb <- adlb %>%
  derive_var_atoxgr()

Terms graded

Grading is implemented for those lab tests where a lab value is included in the grading definition, {admiral} does NOT try to read any other data to determine the grade, and only the ADLB VAD is used. The following CTCAE v4.0 SOC values were identified for grading, these are “Investigations”, “Metabolism and nutrition disorders” and “Blood and lymphatic system disorders”.

From these SOC values the following terms criteria is implemented in {admiral}

From SOC = “Investigations” there are 21 CTCAE v4.0 Terms:

• Activated partial thromboplastin time prolonged
• Alanine aminotransferase increased
• Alkaline phosphatase increased
• Aspartate aminotransferase increased
• Blood bilirubin increased
• CD4 lymphocytes decreased
• Cholesterol high
• CPK increased
• Creatinine increased
• Fibrinogen decreased
• GGT increased
• Haptoglobin decreased
• Hemoglobin increased
• INR increased
• Lipase increased
• Lymphocyte count decreased
• Lymphocyte count increased
• Neutrophil count decreased
• Platelet count decreased
• Serum amylase increased
• White blood cell decreased

From the SOC = “Metabolism and nutrition disorders” there are 14 CTCAE v4.0 Terms:

• Hypercalcemia
• Hyperglycemia
• Hyperkalemia
• Hypermagnesemia
• Hypernatremia
• Hypertriglyceridemia
• Hyperuricemia
• Hypoalbuminemia
• Hypocalcemia
• Hypoglycemia
• Hypokalemia
• Hypomagnesemia
• Hyponatremia
• Hypophosphatemia

From the SOC = “Blood and lymphatic system disorders” there are 2 CTCAE v4.0 Terms:

• Anemia
• Leukocytosis

Updates made to TERM

For terms “Hypocalcemia” and “Hypercalcemia” the criteria is provided for Calcium and Ionized Calcium, therefore {admiral} created a row for each in the metadata, this is noted in the COMMENT variable of the metadata:

Similarly, there is criteria applicable to Fasting Glucose as well as non-Fasting Glucose for “Hyperglycemia” so again this was split into 2 rows, and noted in the COMMENT variable. Note “Hypoglycemia” does not require to be split into 2 rows:

Assumptions made when grading

For term “INR Increased” there is the following criteria:

{admiral} assumed worst case and used both parts of the criteria for grading, so comparing lab value against ULN and also BASE. The decision made was put in the COMMENT field.

For TERM “Hyperuricemia”, the criteria for Grade 1 and Grade 3 is the same with respect to the lab value, so worse case is assumed as grade 3. The decision made was put in the COMMENT field.

A similar approach was taken for TERM “Hypokalemia” where Grade 1 and Grade 2 criteria is the same with respect to the lab value, so worse case is assumed as grade 2. The decision made was put in the COMMENT field.

Terms graded

Grading is implemented for those lab tests where a lab value is included in the grading definition, {admiral} does NOT try to read any other data to determine the grade, and only the ADLB VAD is used. The following CTCAE v5.0 SOC values were identified for grading, these are “Investigations”, “Metabolism and nutrition disorders” and “Blood and lymphatic system disorders”.

From these SOC values the following terms criteria is implemented in {admiral}

From SOC = “Investigations” there are 21 CTCAE v5.0 Terms:

• Activated partial thromboplastin time prolonged
• Alanine aminotransferase increased
• Alkaline phosphatase increased
• Aspartate aminotransferase increased
• Blood bilirubin increased
• CD4 lymphocytes decreased
• Cholesterol high
• CPK increased
• Creatinine increased
• Fibrinogen decreased
• GGT increased
• Haptoglobin decreased
• Hemoglobin increased
• INR increased
• Lipase increased
• Lymphocyte count decreased
• Lymphocyte count increased
• Neutrophil count decreased
• Platelet count decreased
• Serum amylase increased
• White blood cell decreased

Note: These are the same terms identified for NCI-CTCAEv4.

From the SOC = “Metabolism and nutrition disorders” there are 12 CTCAE v4.0 Terms:

• Hypercalcemia
• Hyperkalemia
• Hypermagnesemia
• Hypernatremia
• Hypertriglyceridemia
• Hyperuricemia
• Hypoalbuminemia
• Hypocalcemia
• Hypoglycemia
• Hypokalemia
• Hypomagnesemia
• Hyponatremia

Note: These are the same terms identified for NCI-CTCAEv4, except “Hypophosphatemia” and “Hyperglycemia” which are not in NCICTCAEv5 grading criteria.

From the SOC = “Blood and lymphatic system disorders” there are 2 CTCAE v4.0 Terms:

• Anemia
• Leukocytosis

Note: These are the same terms identified for NCI-CTCAEv4.

Updates made to TERM

For terms “Hypocalcemia” and “Hypercalcemia” the criteria is provided for Calcium and Ionized Calcium, therefore {admiral} created a row for each in the metadata, this is noted in the COMMENT variable of the metadata:

Assumptions made when grading

For terms “Alanine aminotransferase increased”, “Alkaline phosphatase increased”, “Aspartate aminotransferase increased”, “Blood bilirubin increased” and “GGT increased” the criteria is dependent on the Baseline Value BASE being normal or abnormal. For BASE to be abnormal we compare it with the Upper Limit of Normal (ULN) ANRHI, i.e. BASE > ANRHI. This means if BASE is abnormal then the grade is always zero for the baseline observation.

For term “INR Increased” there is the following criteria:

{admiral} assumed worst case and used both parts of the criteria for grading, so comparing lab value against ULN and also BASE. The decision made was put in the COMMENT field.

Similarly, for terms “Lipase Increased” and “Serum amylase increased” there is the following criteria:

{admiral} assumed worst case and implemented highest grade possible. The decision made was put in the COMMENT field.

For TERM “Hyperuricemia”, the criteria for Grade 1 and Grade 3 is the same with respect to the lab value, so worse case is assumed as grade 3. The decision made was put in the COMMENT field.

A similar approach was taken for TERM “Hypokalemia” and “Hyponatremia”. For “Hypokalemia”, where Grade 1 and Grade 2 criteria is the same with respect to the lab value, then worse case is assumed as grade 2. For “Hyponatremia”, where Grade 2 and Grade 2 criteria is the same with respect to the lab value, then worse case is assumed as grade 3. The decision made was put in the COMMENT field.

Terms graded

Grading is implemented for those lab tests where a lab value is included in the grading definition, {admiral} does NOT try to read any other data to determine the grade, and only the ADLB VAD is used. The following DAIDS SOC values were identified for grading, these are “Chemistries” and “Hematology”.

From these SOC values the following terms criteria is implemented in {admiral}

From SOC = “Chemistries” there are 31 DAIDS Terms:

• Acidosis
• Albumin, Low
• Alkaline Phosphatase, High
• Alkalosis
• ALT, High
• Amylase, High
• AST, High
• Bicarbonate, Low
• Direct Bilirubin, High
• Total Bilirubin, High
• Calcium, High
• Calcium (Ionized), High
• Calcium, Low
• Calcium (Ionized), Low
• Creatine Kinase, High
• Creatinine, High
• Glucose Fasting, High
• Glucose Nonfasting, High
• Glucose, Low
• Lactate, High
• Lipase, High
• Cholesterol, Fasting, High
• LDL, Fasting, High
• Triglycerides, Fasting, High
• Magnesium, Low
• Phosphate, Low
• Potassium, High
• Potassium, Low
• Sodium, High
• Sodium, Low
• Uric Acid, High

Note: {admiral} does not grade for TERM = “Total Bilirubin, High” when AGE <= 28 days, these criteria are in Appendix of DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events Corrected Version 2.1.

From the SOC = “Hematology” there are 11 DAIDS Terms:

• Absolute CD4+ Count, Low
• Absolute Lymphocyte Count, Low
• Absolute Neutrophil Count (ANC), Low
• Fibrinogen Decreased
• Hemoglobin, Low
• INR, High
• Methemoglobin
• PTT, High
• Platelets, Decreased
• PT, High
• WBC, Decreased

Terms with age or sex dependent grading criteria

Some terms defined in DAIDS have age or sex dependent grading criteria, {admiral} handles this in variable FILTER in the metadata. We use {admiral} function compute_duration to calculate age, see TERM = “Cholesterol, Fasting, High”:

Note: All possible values must be covered for each TERM defined, for TERM = “Absolute Lymphocyte Count, Low” and “Absolute CD4+ Count, Low” there is only grading criteria defined for age > 5 years. Therefore, we add another row with age <= 5 years and set grade to missing. Similarly, for TERM = “LDL, Fasting, High” there is only grading criteria defined for age > 2 years. Therefore, we add another row with age <= 2 years and set grade to missing.

Assumptions made when grading

For terms “INR, High”, “PT, High” and “PTT, High”, the criteria is based on subjects “not on anticoagulation therapy”, this is captured in COMMENT field.

Similarly, for terms “Absolute CD4+ Count, Low” and “Absolute Lymphocyte Count, Low”, the criteria is based on subjects “not HIV infected”, this is captured in COMMENT field.

For term “Acidosis”, “Alkalosis” and “Direct Bilirubin, High (> 28 days of age)”, {admiral} grades as high as possible, so assumes worst case and subject has “life-threatening consequences”. This is captured in COMMENT field.

Similarly, for term “Lactate, High”, {admiral} only grade 1 and 2, and there is the following criteria:

{admiral} assumed worst case and assume “without acidosis”. The decision made was put in the COMMENT field.

For TERM “Direct Bilirubin, High (<= 28 days of age)” and “Uric Acid, High” the criteria is not given in SI unit. The conversion to SI unit is in the comment field.