1
Marshfield Clinic – DILI EHR algorithm implementation (March 5, 2013)
Administration
of drug
1) Is the drug administered between
D3 and D1? (anchor is D3, date of
acute liver injury diagnosis)
D2
Administration
of drug
Laboratory
measurements
30 days
D0
2) Are laboratory values normal
between D0 and D2? (anchor is
D2, date of drug administration)
Acute Liver
Injury
Diagnosis
D3
90 days
D1
180 days
D4
Laboratory
measurements
3) Do laboratory values reach the threshold
for DILI between D2 and D4? (anchor is D2,
date of drug administration)
Baseline population
 Biobank population for eMERGE (N=4762). Age >=18 years old.
Acute liver injury diagnosis
 Structured data (ICD-9 codes)
 Date of instance of acute liver injury code, becomes D3.
Acute liver injury related diagnoses and procedures
Disorders of bilirubin excretion
Acute and subacute necrosis of the liver
Hepatic coma (hepatorenal syndrome)
Hepatorenal syndrome
Other disorders of the liver, including chemical or drug induced
Other specified disorders of biliary tract
Jaundice, unspecified, not of newborn
Hepatomegaly
Nonspecific elevation of transaminase or lactic dehydrogenase levels
Abnormal liver function test results
ICD-9 codes
277.4
570*
572.2
572.4*
573*
576.8
782.4
789.1*
790.4*
794.8*
Administration of drugs
 Structured data (MedsManager) and NLP (FreePharma Notes).
 Date of a new medication order within 90 days prior to D3, becomes D1.
 Limited to Drug Induced Iiver Injury (DILIN) study protocol medication preparations:
ciprofloxacin, clinafloxacin, levofloxacin, moxifloxacin, norfloxacin, ofloxacin,
sparfloxacin,trovafloxacin, isoniazid, phenytoin, amoxicillin, valproic acid, nitrofurantoin,
trimethoprim,minocycline.

Laboratory measurements
 Upper limit of normal (ULN) is International Serious Events (iSAEC) study protocol
specified.
o ALP (Alkaline Phosphatase) ULN: 120 U/L (international units/liter).
o ALT (Alanine Aminotransferase) ULN: 45 U/L (international units/liter).
o Bilirubin (Indirect or Unconjugated) ULN: 40 umol/L (2.34 mg/dL).
2



Threshold laboratory values for DILI
o ALP ≥ 2x ULN.
o ALT ≥ 5x ULN.
o ALT ≥ 3x ULN AND Bilirubin ≥ 2x ULN.
All laboratory values should be below thresholds for DILI (normal) between D0 and D1.
(ALP < 2x ULN, and ALT < 3x ULN, and Bilirubin < 2x ULN).
Date laboratory values reach threshold for DILI between D2 and D4, becomes D5 (not
shown).
Excluded diagnoses
 Structured data only (ICD-9 codes)
 Chronic liver disease; Sclerosing cholangitis; organ transplantation or liver operation;
alcohol abuse/liver damage/toxic effects; viral hepatitis.
Chronic liver disease diagnosis description
Alcoholic fatty liver
Chronic hepatitis
Chronic hepatitis, unspecified
Chronic persistent hepatitis
Other chronic hepatitis
Cirrhosis of liver without mention of alcohol
Biliary cirrhosis
Other chronic nonalcoholic liver disease
Autoimmune hepatitis
Unspecified Chronic Liver Disease without Mention of Alcohol
ICD-9 code
571.0
571.4
571.40
571.41
571.49
571.5
571.6
571.8
571.42
571.9
Sclerosing cholangitis description
Cholangitis
ICD-9 code
576.1
Organ transplantation and liver therapeutic operation descriptions
ICD-9 code
996.81
996.82
996.83
996.84
996.85
996.86
996.89
998.87
998.88
996.80
V42.0
V42.1
V42.2
V42.3
V42.4
V42.5
V42.6
V42.7
V42.89
V42.81
Compl kidney transplant
Compl liver transplant
Compl heart transplant
Compl lung transplant
Complications of bone marrow transplant
Compl pancreas transplnt
Complications of other transplanted organ
Complication of intestine transplantation
Complications of transplanted organ
Complications of transplanted organ
Kidney replaced by transplant
Heart replaced by transplant
Heart valve replaced by transplant
Skin replaced by transplant
Bone replaced by transplant
Cornea replaced by transplant
Lung replaced by transplant
Liver replaced by transplant
Other specified organ or tissue replaced by transplant
Bone marrow replaced by transplant
3
Peripheral stem cells replaced by transplant
Pancreas replaced by transplant
Intestines replaced by transplantation
Unspecified organ or tissue replaced by transplant
Allogeneic bone marrow transplant with purging
Allogeneic bone marrow transplant without purging
Cord blood stem cell transplant
Autologous hematopoietic stem cell transplant with purging
Allogeneic hematopoietic stem cell transplant
Autologous bone marrow transplant with purging
Autologous bone marrow transplant without purging
Autologous hematopoietic stem cell transplant without purging
Allogeneic hematopoietic stem cell transplant without purging
Bone marrow transplant
Unilat lung transplant
Bilateral lung transplantation
Lung transplantation
Reimplantation of pancreatic tissue
Homotransplant of pancreas
Heterotransplant of pancreas
Autotransplantation of cells of islets of langerhans
Allotransplantation of cells of islets of langerhans
Transplantation of cells of islets of langerhans
Operations on pancreas: pancreatic transplant
Hepatotomy
Marsupialization of lesion of liver
Partial hepatectomy
Lobectomy of liver
Total hepatectomy
Auxiliary liver transplant
Other transplant of liver
Closure of laceration of liver
Other repair of liver
Percutaneous aspiration of liver
Extracorporeal hepatic assistance
Localized perfusion of liver
Other injection of therapeutic substance into liver
Unlisted proc 50.99
Open ablation of liver lesion or tissue
Percutaneous ablation of liver lesion or tissue
Laparoscopic ablation of liver lesion or tissue
Other and unspecified ablation of liver lesion or tissue
Other destruction of lesion of liver
ICD-9 code
V42.82
V42.83
V42.84
V42.9
41.02
41.03
41.06
41.07
41.08
41.09
41.01
41.04
41.05
41.00
33.51
33.52
33.50
52.81
52.82
52.83
52.84
52.85
52.86
52.80
50.0
50.21
50.22
50.3
50.4
50.51
50.59
50.61
50.69
50.91
50.92
50.93
50.94
50.99
50.23
50.24
50.25
50.26
50.29
Alcohol Abuse, Liver Damage, and Toxic Effects Descriptions
Alcohol Abuse, Unspecified Drinking Behavior
Alcohol Abuse, Continuous Drinking Behavior
Alcohol Abuse, Episodic Drinking Behavior
Alcohol Abuse, In Remission
Alcoholic fatty liver
Acute alcoholic hepatitis
ICD-9 code
305.00
305.01
305.02
305.03
571.0
571.1
Organ transplantation and liver therapeutic operation descriptions
4
Alcohol Abuse, Liver Damage, and Toxic Effects Descriptions
Alcoholic cirrhosis of liver
Alcoholic liver damage
Toxic effect of ethyl alcohol
Toxic effect of methyl alcohol
Toxic effect of isopropyl alcohol
Toxic effect fusel oil
Toxic effect of other specified alcohols
Toxic effect of unspecified alcohol
ICD-9 code
571.2
571.3
980.0
980.1
980.2
980.3
980.8
980.9
Viral Hepatitis Descriptions
Unspecified Viral Hepatitis Without Mention Of Hepatic Coma
Unspecified Viral Hepatitis With Hepatic Coma
Other Specified Viral Hepatitis With Hepatic Coma
Other Specified Viral Hepatitis Without Mention Of Hepatic Coma
Viral Hepatitis A Without Mention Of Hepatic Coma
Viral Hepatitis A With Hepatic Coma
Viral Hepatitis B Without Mention Of Hepatic Coma, Acute Or Unspecified
Viral Hepatitis B With Hepatic Coma, Acute Or Unspecified
Viral Hepatitis B With Hepatic Coma, Acute Or Unspecified, With Hepatitis Delta
Viral Hepatitis B, Acute Or Unspecified, With Hepatitis Delta
Acute Hepatitis C With Hepatic Coma
Hepatitis Delta Without Mention Of Active Hepatitis B Disease With Hepatic Coma
Hepatitis E With Hepatic Coma
Unspecified Viral Hepatitis C Without Hepatic Coma
Hepatitis In Viral Diseases Classified Elsewhere
Carrier Or Suspected Carrier Of Viral Hepatitis
Chronic Viral Hepatitis B Without Mention Of Hepatic Coma Or Hepatitis Delta
Viral Hepatitis B With Hepatic Coma, Chronic, Without Mention Of Hepatitis Delta
Viral Hepatitis B With Hepatic Coma, Chronic, With Hepatitis Delta
Viral Hepatitis B Without Mention Of Hepatic Coma, Chronic, With Hepatitis Delta
Other Icd9 Viral Hepatitis Carrier
Unspecified Viral Hepatitis C With Hepatic Coma
ICD-9 code
070.9
070.6
070.49
070.59
070.1
070.0
070.30
070.20
070.21
070.31
070.41
070.42
070.43
070.70
573.1
V02.60
070.32
070.22
070.23
070.33
V02.69
070.71
Algorithm results
 22 DILI cases as defined by algorithm
 1657 controls (No acute liver injury diagnoses, has exposure to drug, and no exclusion
diagnoses).
Validation steps
 Manual chart review of 10 randomly selected DILI cases (10 of 22 above).
 1 clinical reviewer (senior research coordinator)
Evaluation of algorithm-selected cases
Cases
Total algorithm selected DILI cases
True positive cases (TPs)
False positive cases (FPs)
Positive predictive value: TP/(TP+FP)
Counts
10
1
9
10%