Positive predictive value of diagnosis coding for hemolytic anemias in the Danish National Patient Register

Figures & data

Table 1 Diagnosis overview

ICD-10	Extracted diagnoses (%)	Herlev database	Primary review	Secondary review	Total verified
D550 – (G6PD) deficiency	–	0	2	0	2
D552 – (PK) deficiency	–	0	1	0	1
D56 – Thalassemia	130 (31.55)	8	20	8	36
D560 – Alpha-thalassemia	–	19	4	0	23
D561 – Beta-thalassemia	–	41	1	1	43
D563 – Thalassemia trait	–	0	5	0	5
D57 – Sickle cell anemia	25 (6.07)	0	3	1	4
D572 – Double heterozygous sickling disorders	–	2	0	0	2
D572a – Hb-SC disease	–	4	1	0	5
D572d – Sickle cell thalassemia	–	5	1	0	6
D573 – Heterozygous hemoglobin S	–	6	0	0	6
D580 – Hereditary spherocytosis (HS)	72 (17.48)	–	–	–	–
D580 – HS, cat 0	–	0	36	8	44
D580 – HS, cat 1a	–	0	0	3	3
D580 – HS, cat 1b	–	0	0	2	2
D580 – HS, cat 1c	–	0	0	9	9
D580 – HS, cat 2	–	0	0	7	7
D581 – Hereditary elliptocytosis	1 (0.24)	0	1	0	1
D582 – Other hemoglobinopathies	2 (0.49)	0	2	1	3
D582e – Hb-E disease	–	3	0	1	4
D589 – Hereditary hemolytic anemia, unspecified	19 (4.61)	0	0	1	1
D590 – Drug-induced AIHA	5 (1.21)	0	1	1	2
D591 – AIHA, endogenous	129 (31.31)	0	80	15	95
D591a – Cold agglutinin	5 (1.21)	0	16	3	19
D592 – Drug-induced non-AIHA	4 (0.97)	0	1	1	2
D594 – Other non-AIHA	14 (3.40)	0	7	1	8
D594c – Toxic hemolytic anemia	1 (0.24)	0	0	0	0
D595 – Paroxysmal nocturnal hemoglobinuria	5 (1.21)	0	4	0	4
D599 – Acquired hemolytic anemia, unspecified	–	0	9	9	18
Uncertain diagnosis	–	0	0	20	20
No hemolytic disorder	–	0	35	2	37
Total	412	88	230	94	412

Note: The lowercase suffix on D572, D582, D591, and D594 is a specific part of the Danish implementation of ICD-10.

Abbreviations: ICD-10, International Classification of Diseases Tenth Revision; G6PD, glucose-6-phosphate dehydrogenase; PK, pyruvate kinase; cat, category; AIHA, autoimmune hemolytic anemia; Hb-SC, sickle cell–haemoglobin C; Hb-E, hemoglobin E.

Figure 1 Numbers of patients with extracted and verified diagnosis of hemolytic anemia.

Notes: The hexagons represent reviews. The patients from the cohort with a prior hemoglobinopathy diagnosis were first reviewed in the database for former positive tests for hemoglobinoathy at Herlev Hospital. Unresolved cases proceeded along with the nonhemoglobinopathy patients to the primary and if necessary secondary review.

Table 2 Definition of congenital hemolytic diseases

Disease	ICD-10	Core criteria
Congenital
Thalassemia	D56	Positive hemoglobin electrophoresis/HPLC and/or gene test
Sickle cell anemia	D57	Positive hemoglobin electrophoresis/HPLC and confirmatory gene test
Hereditary spherocytosis	D588	Hemolysis + reticulocytosis + family history of hemolysis + negative antiglobulin test + increased osmotic fragility or positive EMA test.
Hereditary elliptocytosis	D581	Increased osmotic fragility, elliptocytes, and family history
Other hemoglobinopathies	D582	Positive hemoglobin electrophoresis/HPLC or gene test
Hereditary hemolytic anemia, unspecified	D589	Hemolysis + anemia + family history or congenital lifelong hemolysis and no better explanation available

Abbreviations: ICD-10, International Classification of Diseases Tenth Revision; HPLC, high-pressure liquid chromatography; EMA, eosin-5′-maleimide.

Table 3 Definition of acquired hemolytic diseases

Disease	ICD-10	Core criteria	Supplementary criteria
Acquired
Drug-induced autoimmune and nonautoimmune hemolytic anemia	D590 + D592	Onset correlated with new medicine, and vanished after discontinuation and no prior history of hemolysis; preferably provocation test	If D590, preferably presence of antibodies
Autoimmune hemolytic anemia	D591	Presence of erythrocyte antigen-specific autoantibodies	Concomitant sensitization with C3d
Chronic cold hemagglutinin disease	D591a	Presence of cold-type autoantibodies	Sensitization only with C3d
Other nonautoimmune hemolytic anemias	D594	Presence of schistocytes and relevant cause (eg, sarcoma) and symptoms abate after removal of potential cause
Toxic hemolytic anemia	D594a	Presence of potential hemolytic toxin and symptoms abate after removal of potential cause
Paroxysmal nocturnal hemoglobinuria	D595	Presence of CD59- and CD55-deficient erythrocytes and granulocytes/monocytes by flow cytometry of peripheral blood
Acquired hemolytic anemia, unspecified	D599	Hemolysis + anemia + known onset and no better explanation available	No family history

Note: The lowercase suffix on D591 and D594 is a specific part of the Danish implementation of ICD-10.

Abbreviation: ICD-10, International Classification of Diseases Tenth Revision.

Table 4 Categories of hereditary spherocytosis

Category	Probability of hereditary spherocytosis	Criteria
0	Definite	Hemolysis, reticulocytosis, family history of hemolysis (preferably exact diagnosis in first-degree relative), negative antiglobulin test, and increased osmotic fragility or positive EMA test
1	Probable	A. Hemolysis, reticulocytosis, negative antiglobulin test, spherocytes, Scandinavian ethnicity and no better explanation, or B. Highly increased osmotic fragility, reticulocytosis, negative antiglobulin test, Scandinavian ethnicity and no better explanation, or C. Hemolysis splenomegaly and splenectomy, negative antiglobulin test, spherocytosis, Scandinavian ethnicity and no better explanation
2	Likely	Cases fitting category 0, or 1A–C but missing data on one of the following: antiglobulin test, family history, osmotic fragility test, or peripheral smear
Exclusion	Unlikely	Other well-defined hemolytic anemia or negative EMA test (when performed)

Abbreviation: EMA, eosin-5′-maleimide.

Table 5 Table of results – PPV of specific diagnoses

ICD diagnosis	Extraction	Review	Agreement	Disagreement	PPV
Congenital hemolysis
Congenital hemolysis	249	200	197	52	79.1 (73.5–84.0)
Congenital hemolysis, nonsurgical	235	200	197	38	83.8 (78.5–88.3)
D55x Enzyme deficiencies
D56x Thalassemia
D57x Sickle cell anemia
D582x Other hemoglobinopathies
D580 Hereditary spherocytosis (0–1)
D581a Hereditary elliptocytosis
D582x Other hemoglobinopathies
D588 Other hereditary hemolytic anemia
D589 Hereditary hemolytic anemia
Hemoglobinopathies	157	137	132	25	84.1 (77.4–89.4)
Hemoglobinopathies, nonsurgical	144	137	132	12	91.7 (85.9–95.6)
D56x Thalassemia
D57x Sickle cell anemia
D582x Other hemoglobinopathies
D56 Thalassemia	130	113	107	23	82.3 (74.7–88.4)
D56 Thalassemia, nonsurgical	122	113	107	15	87.7 (80.5–93.0)
D56 Thalassemia		36
D560 Alpha-thalassemia		23
D561 Beta-thalassemia		43
D563 Thalassemia minor		5
D572d Sickle cell thalassemia		6
D57 Sickle cell anemia	25	23	18	7
D57 Sickle cell anemia		4
D572 Double heterozygous sickling disorders		2
D572a Hb-SC disease		5
D572d Sickle cell thalassemia		6
D573 Heterozygous hemoglobin S		6
D580 Hereditary spherocytosis (0–1)	72	58	51	21	70.8 (58.9–81.0)
D580 Hereditary spherocytosis (0–2)	72	65	58	14	80.6 (69.5–88.9)
D581a Hereditary elliptocytosis	1	1	1	0
D582 Other hemoglobinopathies	2	7	1	1
D582 Other hemoglobinopathies		3
D582e Hb-E disease		4
D588 Other hereditary hemolytic anemia	2	0	0	2
D589 Hereditary hemolytic anemia, unspecified	17	1	0	17
Acquired
Acquired hemolysis	163	148	136	27	83.4 (76.8–88.8)
D590 AIHA, drug-induced		2
D591x Other AIHA, non-drug-induced		13
D592 Hemolytic nonautoimmune anemia		2
D594x Other hemolytic nonautoimmune		7
D595 Paroxysmal nocturnal hemoglobinuria		4
D598 Other acquired hemolytic anemia		5
D599 Acquired hemolytic anemia, unspecified		3
D590 AIHA, drug-induced	5	2	0	5
D591 AIHA, not drug-induced	134	114	105	29	78.4 (70.4–85.0)
D591a Cold-agglutinin disease		19
D592 Hemolytic nonautoimmune anemia	4	2	2	2
D594 Other hemolytic nonautoimmune	14	8	5	9
D594c Toxic hemolytic anemia	1	0	0	1
D595 Paroxysmal nocturnal hemoglobinuria	5	4	4	1

Notes: The lowercase suffix on D572, D582, D591, and D594 refers to the specific Danish implementation of ICD-10 using lowercase letters to denote subtypes. Bold figures refer to classification lines (congital versus acquired) and major subgroups (congenital all forms, all forms of hemoglobinopathies thalassemia, sickle cell anaemia, and spherocytosis, all forms of acquired hemolysis and AIHA [not drug-induced]).

Abbreviations: ICD-10, International Classification of Diseases Tenth Revision; AIHA, autoimmune hemolytic anemia; PPV, positive predictive value; Hb-SC, sickle cell–hemoglobin C; Hb-E, hemoglobin E.

Table 6 Table of results – overall hemolysis

ICD diagnosis	Extraction	Review	Agreement	Disagreement	PPV
1994–2011
Overall hemolysis	412	359	359	53	87.1 (83.5–90.2)
Male (all ages)	178	158	158	20	88.8 (83.2–93.0)
Female (all ages)	234	201	201	33	85.9 (80.8–90.1)
Male, female 0–18 (Y)	141	138	138	3	97.9 (93.9–99.6)
Male, female 18+ (Y)	271	221	221	50	81.6 (76.4–86.0)
Overall hemolysis, nonsurgical	396	359	359	37	90.7 (87.4–93.3)
Male, nonsurgical (all ages)	169	158	158	11	93.5 (88.7–96.7)
Female, nonsurgical (all ages)	227	201	201	26	88.6(83.7–92.4)
Male, female 0–18 (Y), nonsurgical	141	138	138	3	97.9 (93.9–99.6)
Male, female 18+ (Y), nonsurgical	255	221	221	34	86.7 (81.9–90.6)
1994–2002
Overall hemolysis	145	124	124	21	85.5 (78.7–90.8)
Male (all ages)	69	63	63	6	91.3 (82.0–96.7)
Female (all ages)	76	61	61	12	80.3 (69.5–88.5)
Male, female 0–18 (Y)	59	56	56	3	94.9 (85.9–98.9)
Male, female 18+ (Y)	86	68	68	18	79.1 (69.0–87.1)
Overall hemolysis nonsurgical	139	124	124	15	89.2 (82.8–93.8)
Male, nonsurgical (all ages)	66	63	63	3	95.4 (87.3–99.1)
Female, nonsurgical (all ages)	73	61	61	12	83.6 (73.1–91.2)
Male, female 0–18 (Y), nonsurgical	59	56	56	3	94.9 (85.9–98.9)
Male, female 18+ (Y), nonsurgical	80	68	68	12	85.0 (75.3–92.0)
2003–2011
Overall hemolysis	267	235	235	32	88.0 (83.5–91.7)
Male (all ages)	109	95	95	14	87.2 (79.4–92.8)
Female (all ages)	158	140	140	18	88.6 (82.6–93.1)
Male, female 0–18 (Y)	82	82	82	0	100 (95.6–100)
Male, female 18+ (Y)	185	153	153	32	82.7 (76.5–87.9)
Overall hemolysis nonsurgical	257	235	235	22	91.4 (87.3–94.6)
Male, nonsurgical (all ages)	103	95	95	8	92.2 (85.3–96.6)
Female, nonsurgical (all ages)	154	140	140	14	90.9 (85.2–94.9)
Male, female 0–18 (Y), nonsurgical	82	82	82	0	100 (95.6–100)
Male, female 18+ (Y), nonsurgical	175	153	153	22	87.4 (81.6–92.0)

Notes: Values in parenthesis denote 95% CI. Bold figures refer to subgroups according to time period and diagnosis made in non-surgical departments.

Abbreviations: ICD-10, International Classification of Diseases Tenth Revision; PPV, positive predictive value; CI, confidence interval; Y, year.

Table S1 Included diagnoses

Included diagnoses	ICD-10 code
Hereditary hemolysis
Enzyme deficiencies	D55
(G6PD) deficiency, (PK) deficiency and others
Hemoglobinopathies
Thalassemia	D56
Alpha-/Beta-thalassemia, thalassemia trait
Sickle cell anemia	D57, M140c, N082c, H368c, M904
Other hemoglobinopathies	D582
Erythrocyte membrane defects
Hereditary spherocytosis	D580
Hereditary elliptocytosis	D581
Hereditary stomatocytosis	D588a
Other hereditary hemolytic anemia	D588, D589
Acquired hemolysis
Autoimmune hemolytic anemia	D591
Drug-induced immune and nonimmune hemolysis	D590, D592
Cold-agglutinin disease	D591a
Cold hemoglobinuria	D596a
Other nonimmune hemolysis	D594, D594c
Paroxysmal nocturnal hemoglobinuria	D595

Note: The lowercase suffix is a specific Danish implementation of ICD-10 using lowercase letters to denote subtypes.

Abbreviations: G6PD, glucose-6-phosphate dehydrogenase; PK, Pyruvate kinase; ICD-10, International Classification of Diseases Tenth Revision.

Table S2 Excluded diagnoses

Excluded diagnoses	ICD-8/ICD-10 code
ICD-8 diagnosis code of hemolysis	28209, 28219, 28229, 28230, 28239, 28249, 28250, 28258, 28259, 28299, 28390, 28391, 28392, 28393, 28395, 28399, 28649, 28659, 28690, 28699, 44649, 99751, 390448
Vitamin-B12 deficiency	D51
Folic acid deficiency	D52
Cardiovascular disease including heart valve disease before and up to 1 year after index disease diagnosis date
Condition with artificial heart valve	Z952, Z953, Z954
Mechanical hemolysis	D594a

Note: The lowercase suffix is a specific Danish implementation of ICD-10 using lowercase letters to denote subtypes.

Abbreviation: ICD, International Classification of Diseases.