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Introduction

Within the ADLB ADaM data set there is a concept of lab grading, where there is a set of criteria for particular lab tests that grade the severity or abnormality of a lab value. The grades are from 0 to 4, where grade 0 can be viewed generally as a “NORMAL” value. The higher the grade the more severe or more abnormal the lab value is. There are several sets of lab grading criteria, for the initial implementation of lab grading we will look at NCI-CTCAEv4. (In future releases admiral look to implement further grading criteria, for example NCI-CTCAEv5)

The NCI-CTCAE version 4 and 5 grading criteria can be found here: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm .

The NCI-CTCAEv4 criteria can be found under the heading Common Terminology Criteria for Adverse Events (CTCAE)v4.0

Grading metadata

admiral will store a metadata data set with required variables and optional variables, the optional variables are purely for transparency, and will contain detailed information about the grading criteria. The required variables are those used by admiral to create the grade.

Structure of metadata set

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

Variable Scope Type Example Value
TERM Term describing the criteria applied to a particular lab test. Character “Anemia”
DIRECTION The direction of the abnormality of a particular lab test value Character “L” or “H”.
SI_UNIT_CHECK Unit of lab test, to check against input data if criteria is based on absolute values. Character “mmol/L”
VAR_CHECK Comma separated list of variables used in criteria, to check input data that variables exist. Character “AVAL, ANRLO”
GRADE_CRITERIA_CODE Variable to hold code that creates grade based on defined criteria. Character R code that is a valid case statement within a mutate function call

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

Variable Scope Type Example Value
SOC System Organ Class the lab test belongs to. Character “Investigations”
GRADE_1 Grade 1 criteria for lab test, normally straight from source document. Character “>ULN - 3.0 x ULN”.
GRADE_2 Grade 2 criteria for lab test, normally straight from source document. Character “>3.0 - 5.0 x ULN”.
GRADE_3 Grade 3 criteria for lab test, normally straight from source document. Character “>5.0 - 20.0 x ULN”.
GRADE_4 Grade 4 criteria for lab test, normally straight from source document. Character “>20.0 x ULN”.
DEFINITION Definition of abnormality, normally from source document. Character “A finding based on laboratory test results that indicate an increase in the level of alanine aminotransferase (ALT or SGPT) in the blood specimen.”.
COMMENT Description of any decisions made by admiral to implement grading criteria, where grading criteria alone was ambiguous. Character “Take worst case and assume on anticoagulation”.

Creating the lab grade

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

library(admiral)
library(admiral.test)
library(dplyr)
library(stringr)
library(tibble)

data("admiral_lb")

adsl <- admiral_adsl
lb <- admiral_lb

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:


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 = vars(PARAMCD, PARAM, PARAMN),
    by_vars = vars(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 = vars(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

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


NCI-CTCAEV4 implementation

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.



Conclusion

In future releases admiral will implement further grading criteria, with NCI-CTCAE v5 being the priority. Providing tools for users to easily interact with the metadata to update criteria, based on their companies needs will also be looked at. Ideally, users should be able to create their own metadata for company specific grading schemes.