Lab Grading

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, currently {admiral} has implemented NCI-CTCAEv4, NCI-CTCAEv5 and DAIDS grading criteria. In future releases {admiral} may look to implement further grading criteria.

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

The NCI-CTCAEv5 criteria can be found under the heading Common Terminology Criteria for Adverse Events (CTCAE)v5.0

The DAIDS grading criteria can be found here: https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-event-grading-tables .

The DAIDS criteria can be found under the heading DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events Corrected Version 2.1

Grading metadata

{admiral} will store a metadata data set for each set of grading criteria in the data folder of {admiral}. Currently, we have atoxgr_criteria_ctcv4() for NCI-CTCAEv4, atoxgr_criteria_ctcv5() for NCI-CTCAEv5 and atoxgr_criteria_daids() for DAIDS. Each metadata data set has 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”
FILTER Only required for DAIDS grading. Variable to hold code that filters the lab data based on contents of column SUBGROUP. Character R code that is valid within a filter function call.
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”
SUBGROUP Only required for DAIDS grading. Description of subgroup of lab data. Character “> 15 years of age”.
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”.

Handling floating points when comparing numeric values

When comparing numeric values, for example AVAL > 1.1*ANRHI, unexpected results can occur due to floating point issues. To solve this issue {admiral} used the signif() function on both side of the equation, the number of significant digits used to compare is passed into the function derive_var_atoxgr_dir() via the argument signif_dig. Please see documentation of the function for more details and the blog post How admiral handles floating points for more context.

Creating the lab grade

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:

TERM
Anemia
Leukocytosis
Activated partial thromboplastin time prolonged
Alanine aminotransferase increased
Alkaline phosphatase increased
Aspartate aminotransferase increased
Blood bilirubin increased
CD4 lymphocytes decreased
Cholesterol high
CPK increased



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.

TERM
Anemia
Leukocytosis
Activated partial thromboplastin time prolonged
Alanine aminotransferase increased
Alkaline phosphatase increased
Aspartate aminotransferase increased
Blood bilirubin increased
CD4 lymphocytes decreased
Cholesterol high
CPK increased



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

TERM
Acidosis
Albumin, Low
Alkaline Phosphatase, High
Alkalosis
ALT, High
Amylase, High
AST, High
Bicarbonate, Low
Direct Bilirubin, High
Total Bilirubin, High


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 = ifelse(
      is.na(LBSTRESN) | as.character(LBSTRESN) != LBSTRESC,
      LBSTRESC,
      NA
    ),
    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}.

TERM SI_UNIT_CHECK
Anemia g/L
Leukocytosis 10^9/L
CD4 lymphocytes decreased 10^9/L
Cholesterol high mmol/L
Fibrinogen decreased g/L
Hemoglobin increased g/L
Lymphocyte count decreased 10^9/L
Lymphocyte count increased 10^9/L
Neutrophil count decreased 10^9/L
Platelet count decreased 10^9/L


{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()


ATOXDSCL ATOXDSCH ATOXGRL ATOXGRH ATOXGR
CD4 lymphocytes decreased NA 1 NA -1
Hypoalbuminemia NA 1 NA -1
Hypoalbuminemia NA 1 NA -1
Hypoalbuminemia NA 1 NA -1
Hypoalbuminemia NA 1 NA -1
Hypoalbuminemia NA 1 NA -1
Hypoalbuminemia NA 1 NA -1
Hypoalbuminemia NA 1 NA -1
Hypoalbuminemia NA 1 NA -1
Hypoalbuminemia NA 1 NA -1

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:

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

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

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:

TERM COMMENT
Hypercalcemia Split Corrected Calcium and Ionized Calcium into 2 separate terms.
Hypercalcemia (Ionized) Split Corrected Calcium and Ionized Calcium into 2 separate terms.
Hypocalcemia Split Corrected Calcium and Ionized Calcium into 2 separate terms.
Hypocalcemia (Ionized) Split Corrected Calcium and Ionized Calcium into 2 separate terms.


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:


TERM COMMENT
Hyperglycemia (Fasting) Split Fasting Glucose and Glucose into 2 separate terms.
Hyperglycemia Split Fasting Glucose and Glucose into 2 separate terms.
Hypoglycemia NA


Assumptions made when grading

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


TERM Grade_1
INR increased >1 - 1.5 x ULN; >1 - 1.5 times above baseline if on anticoagulation


{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.


TERM COMMENT
INR increased Take worst case and assume “on anticoagulation”


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.


TERM Grade_1 Grade_3 COMMENT
Hyperuricemia >ULN - 10 mg/dL (0.59 mmol/L) without physiologic consequences >ULN - 10 mg/dL (0.59 mmol/L) with physiologic consequences Take worst case and assume “with physiologic consequences”


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.


TERM Grade_1 Grade_2 COMMENT
Hypokalemia <LLN - 3.0 mmol/L <LLN - 3.0 mmol/L; symptomatic; intervention indicated Take worst case and assume “symptomatic OR intervention indicated”


NCI-CTCAEV5 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 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:

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

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

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:

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:

TERM COMMENT
Hypercalcemia Split Corrected Calcium and Ionized Calcium into 2 separate terms.
Hypercalcemia (Ionized) Split Corrected Calcium and Ionized Calcium into 2 separate terms.
Hypocalcemia Split Corrected Calcium and Ionized Calcium into 2 separate terms.
Hypocalcemia (Ionized) Split Corrected Calcium and Ionized Calcium into 2 separate terms.


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:


TERM Grade_1
INR increased >1.2 - 1.5 x ULN; >1 - 1.5 x baseline if on anticoagulation; monitoring only indicated


{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.


TERM COMMENT
INR increased Take worst case and assume “on anticoagulation”


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


TERM Grade_2 Grade_3 Grade_4
Lipase increased >1.5 - 2.0 x ULN; >2.0 - 5.0 x ULN and asymptomatic >2.0 - 5.0 x ULN with signs or symptoms; >5.0 x ULN and asymptomatic >5.0 x ULN and with signs or symptoms
Serum amylase increased >1.5 - 2.0 x ULN; >2.0 - 5.0 x ULN and asymptomatic >2.0 - 5.0 x ULN with signs or symptoms; >5.0 x ULN and asymptomatic >5.0 x ULN and with signs or symptoms


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


TERM COMMENT
INR increased Take worst case and assume “on anticoagulation”
Serum amylase increased Take worst case and assume “signs and symptoms”


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.


TERM Grade_1 Grade_3 COMMENT
Hyperuricemia >ULN without physiologic consequences >ULN with physiologic consequences Take worst case and assume “with physiologic consequences”


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.


TERM Grade_1 Grade_2 Grade_3 COMMENT
Hypokalemia <LLN - 3.0 mmol/L Symptomatic with <LLN - 3.0 mmol/L; intervention indicated <3.0 - 2.5 mmol/L; hospitalization indicated Take worst case and assume “symptomatic”
Hyponatremia <LLN - 130 mmol/L 125-129 mmol/L and asymptomatic 125-129 mmol/L symptomatic; 120-124 mmol/L regardless of symptoms Take worst case and assume “symptomatic”


DAIDS 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 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:

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:

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”:

TERM FILTER
Cholesterol, Fasting, High compute_duration(start_date = BRTHDT, end_date = LBDT, trunc_out = TRUE, out_unit = “years”, add_one = FALSE, type = “interval”) >= 18 | is.na(BRTHDT) | is.na(LBDT)
Cholesterol, Fasting, High compute_duration(start_date = BRTHDT, end_date = LBDT, trunc_out = TRUE, out_unit = “years”, add_one = FALSE, type = “interval”) < 18 | is.na(BRTHDT) | is.na(LBDT)


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.

TERM FILTER GRADE_CRITERIA_CODE
LDL, Fasting, High compute_duration(start_date = BRTHDT, end_date = LBDT, trunc_out = TRUE, out_unit = “years”, add_one = FALSE, type = “interval”) <= 2 | is.na(BRTHDT) | is.na(LBDT) NA_character_
Absolute CD4+ Count, Low compute_duration(start_date = BRTHDT, end_date = LBDT, trunc_out = TRUE, out_unit = “years”, add_one = FALSE, type = “interval”) <= 5 | is.na(BRTHDT) | is.na(LBDT) NA_character_
Absolute Lymphocyte Count, Low compute_duration(start_date = BRTHDT, end_date = LBDT, trunc_out = TRUE, out_unit = “years”, add_one = FALSE, type = “interval”) <= 5 | is.na(BRTHDT) | is.na(LBDT) NA_character_

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.


TERM COMMENT
INR, High Assume “not on anticoagulation”
PTT, High Assume “not on anticoagulation”
PT, High Assume “not on anticoagulation”


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.


TERM COMMENT
Absolute CD4+ Count, Low Assume “not HIV infected”
Absolute Lymphocyte Count, Low Assume “not HIV infected”


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.


TERM COMMENT
Acidosis Assume “with lifethreatening consequences”
Alkalosis Assume “with lifethreatening consequences”
Direct Bilirubin, High Assume worst case of “lifethreatening consequences (e.g., signs and symptoms of liver failure)”


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


TERM Grade_1
Lactate, High ULN to < 2.0 x ULN without acidosis


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


TERM COMMENT
Lactate, High Assume “without acidosis” (only grade 1 and 2)


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.


TERM FILTER COMMENT
Direct Bilirubin, High compute_duration(start_date = BRTHDT, end_date = LBDT, trunc_out = TRUE, out_unit = “days”, add_one = FALSE) <= 28 | is.na(BRTHDT) | is.na(LBDT) 17.1 used as conversion from “mg/dL” to “umol/L”
Uric Acid, High NA To convert “mmol/L” to “umol/L” multiply by 1000


Conclusion

With NCI-CTCAEv4, NCI-CTCAEv5 and DAIDS grading now implemented, {admiral} may look to implement other industry standard grading criteria. 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.