Identification and Validation of Hemophilia-Related Outcomes on Japanese Electronic Medical Record Database (Hemophilia-REAL V Study)

Figures & data

Figure 1 Flow diagram of patients’ selection and validation.

Note: *We used Japanese written language (Kanji) when searching of “hemophilia A” in electronic medical record (EMR).

Table 1 Characteristics of Patients with Congenital Hemophilia A of Kurashiki Central Hospital

Variable		Congenital Hemophilia A (n = 31)
Mean age, standard deviation (range)		37.6 ± 21.1	(1–90)
Male, n, (%)		31	(100.0%)
Severity, n, (%)	Severe	13	(41.9%)
	Moderate	10	(32.3%)
	Mild	8	(25.8%)
History of prophylactic factor replacement therapy, n, (%)		16	(51.6%)
History of factor VIII inhibitor, n, (%)		3	(9.7%)
History of immune tolerance induction, n, (%)		2	(6.5%)

Table 2 Diagnostic Value of Algorithm of Outcome Conditions: Disease (Hemophilia A)

Outcome Definition	Algorithm	True Positive (n)	False Positive (n)	False Negative (n)	True Negative (n)	Sensitivity (%, 95% CI)	Specificity (%, 95% CI)	PPV (%, 95% CI)	NPV (%, 95% CI)
Hemophilia A	ICD-10 diagnosis or Suspected code D66 (EMR)	31	96	0	1033718	100.0 (88.8–100.0)	100.0 (100.0–100.0)	24.4 (17.2–32.8)	100.0 (100.0–100.0)
	ICD-10 diagnosis code D66 (EMR)	29	18	2	1033796	93.5 (78.6–99.2)	100.0 (100.0–100.0)	61.7 (46.4–75.5)	100.0 (100.0–100.0)
	ICD-10 diagnosis code D66 (Claim data)	22	8	9	1033806	71.0 (52.0–85.8)	100.0 (100.0–100.0)	73.3 (54.1–87.7)	100.0 (100.0–100.0)
	ICD-10 code D66 in DPC data (diagnosis that triggered hospitalization or diagnosis with highest medical cost)	10	1	21	1033813	32.3 (16.7–51.4)	100.0 (100.0–100.0)	90.9 (58.7–99.8)	100.0 (100.0–100.0)
	Administration of factor VIII products	20	1	11	1033813	64.5 (45.4–80.8)	100.0 (100.0–100.0)	95.2 (76.2–99.9)	100.0 (100.0–100.0)
	ICD-10 diagnosis code D66 in EMR and administration of factor VIII products without administration of factor lX products (See Appendix 6)	20	1	11	1033813	64.5 (45.4–80.8)	100.0 (100.0–100.0)	95.2 (76.2–99.9)	100.0 (100.0–100.0)
	Administration of factor VIII products excepting those with universal insurance coverage for vWD	20	1	11	1033813	64.5 (45.4–80.8)	100.0 (100.0–100.0)	95.2 (76.2–99.9)	100.0 (100.0–100.0)
	ICD-10 diagnosis code D66 in EMR and administration of factor VIII products excepting those with universal insurance coverage for vWD	20	1	11	1033813	64.5 (45.4–80.8)	100 (100–100)	95.2 (76.2–99.9)	100 (100–100)
	ICD-10 diagnosis code D66 in EMR without acquired hemophilia disease name in EMR	29	18	2	1033796	93.5 (78.6–99.2)	100 (100–100)	61.7 (46.4–75.5)	100 (100–100)
	ICD-10 diagnosis code D66 in EMR without Acquired hemophilia disease name in EMR (male patients)	29	12	2	1033800	93.5 (78.6–99.2)	100 (100–100)	73.3 (54.1–87.7)	100 (100–100)

Abbreviations: DPC, diagnosis procedure combination; EMR, electronic medical record; PPV, positive predictive value; NPV, negative predictive value; vWD, von Willebrand Disease.

Table 3 Diagnostic Value of Algorithm of Outcome Conditions: Disease Characteristics and Treatment

Outcome Definition	Algorithm	True Positive (n)	False Positive (n)	False Negative (n)	True Negative (n)	Sensitivity (%, 95% CI)	Specificity (%, 95% CI)	PPV (%, 95% CI)	NPV (%, 95% CI)
Disease severity (Severe hemophilia A)	Initial test results of factor VIII activity < 1%	8	3	5	31	61.5 (31.6–86.1)	91.2 (76.3–98.1)	72.7 (39.0–94.0)	86.1 (70.5–95.3)
	Minimum test results of factor VIII activity < 1%	9	8 *	4	26	69.2 (38.6–90.9)	76.5 (58.8–89.3)	52.9 (27.8–77.0)	86.7 (69.3–96.2)
History of factor VIII inhibitor	Laboratory test results of ≥ 0.6 BU/mL factor VIII inhibitor	2	7 *	1	37	66.7 (9.4–99.2)	84.1 (69.9–93.4)	22.2 (2.8–60.0)	97.4 (86.2–99.9)
	Administration of bypassing products **	2	0	1	44	66.7 (9.4–99.2)	100.0 (92.0–100.0)	100.0 (15.8–100.0)	97.8 (88.2–99.9)
History of prophylactic factor replacement therapy	Medical claim with a Japanese procedural code of C101 or C153 ***)	12	3	4	28	75.0 (47.6–92.7)	90.3 (74.2–98.0)	80.0 (51.9–95.7)	87.5 (71.0–96.5)
	Administration of factor VIII (≥ 10 bottles per month)	12	3	4	28	75.0 (47.6–92.7)	90.3 (74.2–98.0)	80.0 (51.9–95.7)	87.5 (71.0–96.5)
	For 3 months	8	0	8	31	50 (24.7–75.3)	100 (88.8–100)	100 (63.1–100)	79.5 (63.5–90.7)
	Administration of ≥ 10,000 units/month of factor VIII products	13	3	3	28	81.3 (54.4–96.0)	90.3 (74.2–98.0)	81.3 (54.4–96.0)	90.3 (74.2–98.0)
	For 3 months	8	1	8	30	50.0 (24.7–75.3)	96.8 (83.3–99.9)	88.9 (51.8–99.7)	78.9 (62.7–90.4)

Notes: Diagnostic values were calculated based on patients receiving a diagnosis or suspected code D66. *The Minimum test results of factor VIII activity < 1% and Laboratory test results ≥ 0.6 BU/mL factor VIII inhibitor algorithms yielded false positives in some patients because patients receiving a diagnosis or suspected code D66 (ICD-10) included severe acquired hemophilia with factor VIII inhibitor. We defined these patients as false positives. **See Appendix 7. ***Medical claim of C101 is the management fee for home drug injection, and that of C153 is the fee for needle prescription.

Abbreviations: DPC, diagnosis procedure combination; PPV, positive predictive value; NPV, negative predictive value.

Table 4 Diagnostic Value of Algorithms of Outcome Conditions: Hemophilia A-Related Events

Outcome Definition	Algorithm	Total Event (n)	True Positive (n)	False Positive (n)	Sensitivity (%, 95% CI)	PPV (%, 95% CI)
Intracranial bleeding	ICD-10 diagnosis code of related disease * (EMR)	4	3	6	75.0 (19.4–99.4)	33.3 (7.5–70.1)
	With hospitalization on the same day	4	2	0	50.0 (6.8–93.2)	100.0 (15.8–100)
	With factor Vlll ^# or bypassing products	4	1	4	25.0 (0.6–80.6)	20.0 (0.5–71.6)
Gastrointestinal bleeding	ICD-10 diagnosis code of related disease ** (EMR)	9	1	3	11.1 (0.3–48.2)	25.0 (0.6–80.6)
	ICD-10 diagnosis code of related disease ** (EMR) and administration of factor VIII products/bypass products	9	1	2	11.1 (0.3–48.2)	33.3 (0.8–90.6)
Major joint bleeding	ICD-10 diagnosis code of related disease *** (EMR)	302	5	13	1.7 (0.5–3.8)	27.8 (9.7–53.5)
	With administration of factor VIII products/bypass products	302	3	4	1.0 (0.2–2.9)	42.9 (9.9–81.6)

Notes: *Head trauma or intracranial bleeding-related ICD-10 = I600/I601/I602/I603/I604/I605/I606/I607/I608/I609/I610/I611/I612/I613/I614/I615/I616/I618/I619/I620/I621/I629/P520/P521/P522/P523/P524/P525/P526/P528/P529; **Gastrointestinal bleeding-related ICD-10 = K228/K250/K260/K270/K272/K274/K276/K280/K282/K284/K286/K573/K625/K661/K768/K838/K922/S361/S368/S369; ***Major joint bleeding-related ICD-10 = M2506/M2509/S500/S800/T140. ^# See Appendix 5.

Abbreviations: EMR, electronic medical record; PPV, positive predictive value.

Table 5 Characteristics of Patients with a Diagnosis of ICD-10 D66

	Kurashiki Central Hospital Data from the RWD Database		RWD Database
Patients’ baseline characteristics
Patient number	47		646
Sex (male n, %)	41	(87.2%)	550	(85.1%)
Age at data extraction (mean ± standard deviation)	43.9 ± 23.3		40.2 ± 24.1
Hemophilia-related characteristics
Age when the patients received ICD-10 diagnosis code D66 (mean ± standard deviation)	31.7 ± 25.2		28.1 ± 25.1
Factor VIII activity level *
< 1%	17	(36.2%)	195	(30.2%)
≥ 1%, < 5%	7	(14.9%)	50	(7.7%)
≥ 5%, < 40%	7	(14.9%)	104	(16.1%)
History of factor VIII inhibitor (≥ 0.6 BU/mL) **	9	(19.1%)	39	(6.0%)
Administration of factor VIII	21	(44.7%)	199	(30.8%)
Co-morbid disease ***
Hypertension	9	(19.1%)	101	(15.6%)
Diabetes mellitus	17	(36.2%)	110	(17.0%)
Hyperlipidemia	8	(17.0%)	61	(9.4%)
Arteriosclerosis	2	(4.3%)	21	(3.3%)
Cardiovascular disease	24	(51.1%)	143	(22.1%)
Ischemic heart disease	14	(29.8%)	72	(11.1%)
Arrhythmia	11	(23.4%)	65	(10.0%)
Cerebrovascular disease	13	(27.7%)	59	(9.1%)

Notes: *Factor VIII activity level was estimated using the lowest laboratory test results of factor VIII activity in each patient. **History of factor VIII inhibitor was defined as laboratory test results of factor VIII inhibitor level ≥ 0.6 BU/mL even once. ***See Appendix 2.