Early diagnosis of persons with von Willebrand disease using a machine learning algorithm and real-world data

Figures & data

Figure 1. Key project phases of the machine learning approach to identify potentially undiagnosed symptomatic patients with VWD. HCP, healthcare professional; VWD, von Willebrand disease.

Table 1. Main predictors used to develop the prediction model.

Group	Variable	Details/examples
Demographics	Sex	Male/female
	Age group	Groups 2–11, 12–17, 18–30, 31–40, 41–50, 51–65, >65 years
Bleeding	Frequency of all bleeding and bleeding by area	HMB, eye bleeding, oral bleeding, digestive bleeding, respiratory bleeding, epistaxis bleeding, etc
	Specialty	PCP, hematologist, OB/GYN, gastroenterologist, etc, seen for specific bleeding type
	Number of unique specialties seen for bleeding-related procedures	Nasal cauterization, general cauterization, uterine ablation, IUD, etc
	Number of unique specialties seen for bleeds	PCP, OB/GYN, pediatrician, emergency, gastroenterologist, hematologist, surgeon, NP/PA, urologist, ENT, dentist
	Bleeding product use	Number of treatment types, use of DDAVP, aminocaproic acid or tranexamic acid, oral contraceptives, Mirena®, LILETTA®, Skyla®, Kyleena®, Paragard®
	Frequency of all procedures used to stop bleeding	Nasal cauterization, general cauterization, uterine ablation, IUD, etc
	Frequency of suture claims	All, simple, intermediate, complex suture procedure
Place of service	POS events	Hospitalization, ER, outpatient visit frequency
Diagnostic tests	Diagnostic test/blood count	Partial thromboplastin time, platelet aggregation, fibrinolysis coagulopathy, blood chemistry panel, GP1bM, fibrinogen activity test
Anemia	Anemia	All anemia, iron deficiency, unspecified anemia, acute posthemorrhagic
Blood transfusions	Frequency of blood transfusions	Any blood transfusion, common blood transfusion, young blood transfusion
Comorbidity	Comorbidities	Hypertension, hyperlipidemia, abdominal pain, headache, back pain radiculopathy, anxiety, etc

DDAVP, 1-deamino-8-D-arginine vasopressin; ENT, ear, nose, and throat; ER, emergency room; GP1bM, glycoprotein-IbM; GYN, gynecologist; HMB, heavy menstrual bleeding; IUD, intrauterine device; NP, nurse practitioner; OB, obstetrician; PA, physician assistant; PCP, primary care provider; POS, place of service.

Table 2. Selection criteria.

	Symptomatic diagnosed	Symptomatic undiagnosed (suspected to have VWD)
Inclusion criteria	Must have a history of 2+ VWD diagnosis claims OR 1+ VWD diagnosis claims and 1+ history of prescription of VWF concentrate At least 60 days from the first VWD diagnosis/prescription of VWF concentrate to the last VWD diagnosis/prescription of concentrate AND Index date of first VWD diagnosis claim comes prior to first VWF concentrate prescription claim Prediagnosis symptomatic: 1+ bleeding code in 2 years before the index date	No history of VWD diagnosis or VWF concentrate prescription claim AND history and/or treatment claims for bleeding including 2+ bleeding diagnoses OR 1+ bleeding diagnosis and 1+ diagnosis of a general bleeding disorder OR 2+ procedures to stop bleeding^a OR 1+ procedures to stop bleeding^a and 1+ bleeding diagnosis OR 1+ bleeding diagnosis and 1+ prescription with drugs to treat bleeding
Time frame	At least 24 months of continuous enrollment prior to initial diagnosis	At least 24 months of continuous enrollment within the most recent 2 years of data
Exclusion criteria	Prediagnosis symptomatic: 1+ bleeding claim in 2 years prior to index date for hemophilia A/acquired hemophilia A, aortic stenosis, extracorporeal membrane oxygenation, or ventricular assist devices	1+ hemophilia A or acquired hemophilia diagnosis claim 1+ coagulation disorders claims or other conditions 2+ diagnosis claims of less relevant general bleeding disorder (menstrual, genitourinary, or digestive bleeds; anemia, unspecified)
N	5981	4,869,518

Prescription in selection criteria refers to prescription medication or procedure to stop bleeding.

^aProcedures to stop bleeding include cauterization and uterine ablation.

VWD, von Willebrand disease; VWF, von Willebrand factor.

Table 3. Models and cutoff probability applied in male and female patients of undiagnosed cohort.

Sex	Selected model	Accuracy (%)	PPV (%)	Sensitivity (%)	Cutoff probability (%)	Persons with suspected, undiagnosed VWD (N = 48,902)
Female	Random forest	84	93	73	80	28,463
Male	Gradient boosting machine	85	92	77	80	20,439

PPV, positive predictive value; VWD, von Willebrand disease.

Figure 2. Age distribution.

Figure 3. Key characteristics of symptomatic patients suspected to have undiagnosed VWD. ^aRespiratory bleeding includes: epistaxis, hemorrhage from throat, hemorrhage from respiratory passages, unspecified, hemorrhage from other sites in respiratory passages, hemoptysis. ^bBlood chemistry panel tests include: collection of venous blood by venipuncture, blood count, comprehensive metabolic panel, lipid panel, basic metabolic panel, ferritin, hemoglobin glycosylated (A1c), iron, iron binding capacity; hemoglobin. ^cThe products used to treat bleeding are not mutually exclusive; patients may have received combinations of treatments. DDAVP, 1-deamino-8-D-arginine vasopressin; ER, emergency room; FVIII:C, factor VIII coagulant activity; IUD, intrauterine device; PTT, partial thromboplastin time; VWD, von Willebrand disease; VWF, von Willebrand factor; VWF:Ag, von Willebrand factor antigen; VWF:RCo, VWF ristocetin cofactor.