The course of pulmonary hypertension (PH) makes physicians underestimate its real prevalence resulting in inadequate disease management, poor control and inferior outcomes [link]. Disease-specific data collections, such as PH registries, may inform and improve the caregivers' adjustments, decrease time to diagnosis, and support treatment decisions in real world clinical practice.

The most common and explicit terminology which is used by clinicians in guidance and management of patients with PH is the World Symposium on Pulmonary Hypertension Clinical Classification (WSCC) [link]. There are 5 specific groups in which PH patients can be classified according to pathogenesis and practical relevance (Table 1).

Table 1 - Clinical classification of pulmonary hypertension (6th World Symposium on Pulmonary Hypertension, February 2018)

1 PAH

1.1 Idiopathic PAH

1.2 Heritable PAH

1.3 Drug- and toxin-induced PAH

1.4 PAH associated with:

1.4.1 Connective tissue disease

1.4.2 HIV infection

1.4.3 Portal hypertension

1.4.4 Congenital heart disease

1.4.5 Schistosomiasis

1.5 PAH long-term responders to calcium channel blockers

1.6 PAH with overt features of venous/capillaries (PVOD/PCH) involvement

1.7 Persistent PH of the newborn syndrome

2 PH due to left heart disease

2.1 PH due to heart failure with preserved LVEF

2.2 PH due to heart failure with reduced LVEF

2.3 Valvular heart disease

2.4 Congenital/acquired cardiovascular conditions leading to post-capillary PH

3 PH due to lung disease and/or hypoxia

3.1 Obstructive lung disease

3.2 Restrictive lung disease

3.3 Other lung disease with mixed restrictive/obstructive pattern

3.4 Hypoxia without lung disease

3.5 Developmental lung disorders

4 PH due to pulmonary artery obstructions

4.1 Chronic thromboembolic PH

4.2 Other pulmonary artery obstructions

5 PH with unclear and/or multifactorial mechanisms

5.1 Hematologic disorders

5.2 Systemic and metabolic disorders

5.3 Others

5.4 Complex congenital heart disease

Another clinically relevant classification of PH into 5 groups is the World Health Organization Classification (WHO) which essentially overlaps with WSCC but is less detailed::

Group 1 - Pulmonary arterial hypertension (PAH)

Group 2 - Pulmonary hypertension due to left-sided heart disease

Group 3 - Pulmonary hypertension due to lung diseases and/or hypoxia

Group 4 - Chronic thromboembolic pulmonary hypertension (CTEPH)

Group 5 - Pulmonary hypertension with unclear or multifactorial etiologies, including hematologic disorders (eg, myeloproliferative disorders), systemic disorders (eg, sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, vasculitis), metabolic disorders (eg, glycogen storage disease, Gaucher disease, thyroid disorders), and miscellaneous conditions (eg, tumor obstruction, mediastinal fibrosis, chronic renal failure on dialysis).

WSCC terms can not be fully mapped to the SNOMED terminology in 1-to-1 fashion due to differences in diagnosis representation (Appendix 1). However, this does not create any real limitations in studies and may be solved by using the post-coordinated expressions in phenotyping or creation of new pre-coordinated Condition concepts.

The recording and differentiation of a diagnosis of PH can be complex in a variety of data sources. Clinicians usually record the diagnosis in fashion that is not appropriate for subsequent analysis (e.g. free text or unstructured data), thus mapping and harmonization steps are crucial.

The real world data (RWD) assets may have several ways to define PH diagnosis:

• Development of custom, registry-defined dictionaries.
• Utilization of existing terminologies according to registry protocols.

Due to database design principles the source concept definition may not be trivial. Sometimes source_code and source_code_descrition may be only defined as a concatenation of different dependent variables or fields (Table 2).

Table 2 - PH source terms representation examples

field1	field2	field3	field4
PULMONARY ARTERIAL HYPERTENSION	PAH ASSOCIATED WITH...	CONNECTIVE TISSUE DISEASE	SYSTEMIC SCLEROSIS/SCLERODERMA
PULMONARY ARTERIAL HYPERTENSION	HERITABLE PAH	BMPR2
PH	UNCLEAR MULTIFACTORIAL MECHANISMS	HEMATOLOGIC DISORDERS
PULMONARY HYPERTENSION DUE TO LUNG DISEASES AND/OR HYPOXIA	INTERSTITIAL LUNG DISEASE
PULMONARY HYPERTENSION DUE TO LEFT HEART DISEASE	LEFT VENTRICULAR SYSTOLIC DYSFUNCTION
PULMONARY ARTERIAL HYPERTENSION	PAH ASSOCIATED WITH..	PORTAL HYPERTENSION
CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION
PULMONARY ARTERIAL HYPERTENSION	PULMONARY VENO-OCCLUSIVE DISEASE AND/OR PULMONARY CAPILLARY HEMANGIOMATOSIS

The Medical Dictionary for Regulatory Activities (MedDRA), hierarchically structured and licensed vocabulary, is also used in many sources. The structure of the vocabulary predisposes to only a limited number of codes to be exactly used in real-world databases (RWD), like registries.

We analyzed the MedDRA terminology, its utilization and cross vocabulary relationships based on SNOMED-MedDRA initiative mappings and mappings built during the current project. The mappings and MedDRA PH terms usage in the RWD are shown in the Appendix 2.

Based on our experience, not the entire collection of the MedDRA terms is used in the RWD (we found that it is only about ~28% (15/54) of codes). Outstanding codes are mapped to the SNOMED terms, mostly to the Pulmonary Hypertension axis. However, 15% (8/54) of MedDRA terms are not related to that. Only 11 codes of SNOMED were used to cover 31 MedDRA terms.

Such peculiarities are important to be mentioned as they reflect internal discrepancies between classification systems. Such differences determine the need to build the concept sets based on specific terms rather than to rely on conflicting hierarchies of different classification systems.

The EHR is an alternative data source used in observational research. It mostly uses the International Classification of Disease (ICD) and its versions.

Currently a variety of ICD versions, both chronological and regional, are ingested into OMOP CDM. The most common coding systems for EHR are ICD10 (ex-U.S. data) and ICD10CM (U.S data). The examples of codes, their descriptions and diagnostic entities reliable for the code with appropriate SNOMED targets are shown in Appendixes 3 and 4.

The ICD terminology is less detailed than SNOMED or WSCC, but still a widely used option in the PH-related data sources.

The Systematized Nomenclature of Medicine clinical terms (SNOMED CT) is an OMOP CDM standard to track the condition dynamics. SNOMED terminology has a very explicit set of pre-coordinated concepts covering PH condition and its subtypes.

At glance, SNOMED and other PH terminologies, like ICD, have almost an identical set of concepts and attributes to address the diagnosis subtypes; however, in fact the classification principles and, therefore, the hierarchical relationships between concepts make full matching impossible. Distinct SNOMED codes may be the ancestors for codes coming from distinct ancestry groups in other terminologies. Such discrepancies do not make any of the terminology improper, but reflect the differences in their origination and, therefore, require special methods of its utilization and analysis.

The example of “Pulmonary hypertension due to interstitial lung disease” ancestry is shown on Figure 1.

Figure 1 - “Pulmonary hypertension due to interstitial lung disease” concept and its hierarchical representation in SNOMED

We’ve figured out that in some cases, PH registries provide detailed information on PH diagnosis that is not captured in the Standard vocabulary. The SNOMED terminology, being the OMOP Standard, is still an acceptable option to represent the semantics of these source codes. Even if pre-coordinated terms are missing, the information still can be preserved in the post-coordinated way as 1-to-many mapping (table 3, row 1).

Only a little number of source codes requires new concept creation to reflect their full granularity. They have some overlapping features such as “and/or” discriminator in their names, a well known data standards naming issue. The codes we recommend to be created as the OMOP Extension terms:

• Drugs and toxins induced pulmonary arterial hypertension;
• Pulmonary hypertension with unclear and/or multifactorial mechanisms;
• Heritable PAH: ALK-1/ENG/SMAD9/CAV1/KCNK3.

The SNOMED is the constantly evolving terminology with active collaborators ready to create new concepts based on the users’ demand. Thus, we expect that new revisions of WSCC will be covered by the SNOMED soon.

Table 3 - Source PH terms to SNOMED mapping

Source code description		SNOMED code	SNOMED description
PULMONARY ARTERIAL HYPERTENSION|PAH ASSOCIATED WITH...||CONNECTIVE TISSUE DISEASE|SYSTEMIC SCLEROSIS/SCLERODERMA		697903007	Pulmonary arterial hypertension associated with connective tissue disease
		89155008	Systemic sclerosis
PULMONARY ARTERIAL HYPERTENSION|HERITABLE PAH|BMPR2		697899000	Heritable pulmonary arterial hypertension due to BMPR2 mutation
Group I: Pulmonary Arterial Hypertension|Idiopathic PAH (IPAH)		697898008	Idiopathic pulmonary arterial hypertension
PH|UNCLEAR MULTIFACTORIAL MECHANISMS|HEMATOLOGIC DISORDERS		697917003	Pulmonary hypertension due to hematological disorder
Group IV: Chronic Thromboembolic Pulmonary Hypertension (CTEPH)		233947005	Chronic thromboembolic pulmonary hypertension
PULMONARY HYPERTENSION DUE TO LUNG DISEASES AND/OR HYPOXIA|INTERSTITIAL LUNG DISEASE		697912009	Pulmonary hypertension due to interstitial lung disease
PULMONARY HYPERTENSION DUE TO LEFT HEART DISEASE|LEFT VENTRICULAR SYSTOLIC DYSFUNCTION		697925001	Pulmonary hypertension due to systolic systemic ventricular dysfunction
PULMONARY ARTERIAL HYPERTENSION|PAH ASSOCIATED WITH...||PORTAL HYPERTENSION		445237003	Pulmonary arterial hypertension associated with portal hypertension

The coverage of the PH terms, used in the variety of the sources, by the OMOP Standard vocabulary is around 80% (1-to-1 match). The remaining terms can be mapped in 1-to-many fashion that doesn’t substantially affect cohort building in OMOP CDM. The coverage may be further improved by creating new concepts and/or using mapping strategies as:

• Post-coordination of several standard terms to be picked using the “at the same day” criterion in cohorts.
• Introduction of relationships between database entities (fact_relationship or modifier of event such as meas_event_field_concept_id and obs_event_field_concept_id fields).

In order to store the grouping variable originating from the source (e.g. WHO Classification) we may recommend to map the source terms to the measurement_concept_id and specific value_as_concept_id in the LOINC vocabulary (Table 4). The approach still has some limitations as LOINC terms are identical to WHO Classification only and don’t support any other classifications, but it’s still a powerful method to ease the querying of patients.

Table 4 - LOINC terms to be used for mapping of PH grouping variables

LOINC event description	LOINC event code	LOINC value description	LOINC value code
Pulmonary hypertension [Class]	95932-0	Group 1: Pulmonary arterial hypertension (PAH)	LA31114-4
		Group 2: Pulmonary Hypertension due to left heart disease	LA31115-1
		Group 3: Pulmonary Hypertension due to chronic lung disease and hypoxemia	LA31116-9
		Group 4: Chronic Thromboembolic Pulmonary Hypertension (CTEPH)	LA31117-7
		Group 5: Pulmonary hypertension due to unclear multifactorial mechanisms	LA31118-5

Source code description	SNOMED code	SNOMED description	Comment
1 PAH
1.1 Idiopathic PAH	697898008	Idiopathic pulmonary arterial hypertension
1.2 Heritable PAH	697897003	Heritable pulmonary arterial hypertension
1.3 Drug- and toxin-induced PAH	233945002	Pulmonary arterial hypertension induced by drug	The exact causation may be specified as Condition/Drug exposure linked with fact_relationship OR new concept : Drug or toxin induced pulmonary arterial hypertension OMOP5160885 OMOP Extension
	OR
	697901009	Pulmonary arterial hypertension induced by toxin	The exact causation may be specified as Condition/Drug exposure linked with fact_relationship OR new concept: Drug or toxin induced pulmonary arterial hypertension OMOP5160885 OMOP Extension
1.4 PAH associated with:
1.4.1 Connective tissue disease	697903007	Pulmonary arterial hypertension associated with connective tissue disease	The exact causation may be specified as Condition/Observation linked with fact_relationship
1.4.2 HIV infection	697904001	Pulmonary arterial hypertension associated with HIV infection
1.4.3 Portal hypertension	445237003	Pulmonary arterial hypertension associated with portal hypertension
1.4.4 Congenital heart disease	697905000	Pulmonary arterial hypertension associated with congenital heart disease	The exact causation may be specified as Condition/Observation linked with fact_relationship OR new concept to be added on demand
1.4.5 Schistosomiasis	697907008	Pulmonary arterial hypertension associated with schistosomiasis
1.5 PAH long-term responders to calcium channel blockers	Not covered by SNOMED		May be stored in OMOP as hierarchical parent + separate record in Condition/Observation
1.6 PAH with overt features of venous/capillaries (PVOD/PCH) involvement	Not covered by SNOMED		May be stored in OMOP as hierarchical parent + separate record in Condition/Observation
1.7 Persistent PH of the newborn syndrome	233815004	Persistent pulmonary hypertension of the newborn
2 PH due to left heart disease	472790001	Pulmonary hypertension due to left heart disease
2.1 PH due to heart failure with preserved LVEF	697926000	Pulmonary hypertension due to diastolic systemic ventricular dysfunction
2.2 PH due to heart failure with reduced LVEF	697925001	Pulmonary hypertension due to systolic systemic ventricular dysfunction
2.3 Valvular heart disease	697927009	Pulmonary hypertension due to left-sided valvular heart disease
2.4 Congenital/acquired cardiovascular conditions leading to post-capillary PH	Not covered by SNOMED		May be stored in OMOP as hierarchical parent + separate record in Condition/Observation
3 PH due to lung disease and/or hypoxia	697910001	Pulmonary hypertension due to lung disease and/or hypoxia
3.1 Obstructive lung disease	OMOP5160883	Pulmonary hypertension due to lung disease	May be stored in OMOP as hierarchical parent + separate record in Condition/Observation
3.2 Restrictive lung disease	OMOP5160883	Pulmonary hypertension due to lung disease	May be stored in OMOP as hierarchical parent + separate record in Condition/Observation
3.3 Other lung disease with mixed restrictive/obstructive pattern	697913004	Pulmonary hypertension due to pulmonary disease with mixed restrictive and obstructive pattern
3.4 Hypoxia without lung disease	OMOP5160884	Pulmonary hypertension due to hypoxia	To be stored as hierarchical parent
3.5 Developmental lung disorders	697916007	Pulmonary hypertension due to developmental abnormality of the lung
4 PH due to pulmonary artery obstructions	Not covered by SNOMED
4.1 Chronic thromboembolic PH	233947005	Chronic thromboembolic pulmonary hypertension
4.2 Other pulmonary artery obstructions	233946001	Large vessel pulmonary hypertension
5 PH with unclear and/or multifactorial mechanisms	Not covered by SNOMED
5.1 Hematologic disorders	697917003	Pulmonary hypertension due to hematological disorder
5.2 Systemic and metabolic disorders	Not covered by SNOMED		May be stored in OMOP as hierarchical parent (generic) + separate record in Condition/Observation
5.3 Others	Stored in OMOP as hierarchical parent
5.4 Complex congenital heart disease	Not covered by SNOMED		May be stored in OMOP as hierarchical parent (generic) + separate record in Condition/Observation

* - MedDRA codes and concept classes are not shown here due to the license restrictions (link).

MedDRA description	Concept code	Concept name	PH branch in SNOMED	Found in the RWD
Pulmonary hypertension aggravated	10964002	Progressive pulmonary hypertension	+	+
Hypertension pulmonary aggravated	10964002	Progressive pulmonary hypertension	+	+
Pulmonary arterial hypertension	11399002	Pulmonary arterial hypertension	+	+
Pulmonary arterial hypertension WHO functional class III	11399002	Pulmonary arterial hypertension	+	+
Pulmonary arterial hypertension WHO functional class IV	11399002	Pulmonary arterial hypertension	+	+
Pulmonary arterial hypertension WHO functional class I	11399002	Pulmonary arterial hypertension	+	+
Pulmonary arterial hypertension WHO functional class II	11399002	Pulmonary arterial hypertension	+	+
Pulmonary hypertension WHO functional class IV	70995007	Pulmonary hypertension	+	+
Pulmonary hypertension WHO functional class III	70995007	Pulmonary hypertension	+	+
Pulmonary hypertension WHO functional class II	70995007	Pulmonary hypertension	+	+
Pulmonary hypertension WHO functional class I	70995007	Pulmonary hypertension	+	+
Hypertension pulmonary	70995007	Pulmonary hypertension	+	+
Pulmonary hypertension	70995007	Pulmonary hypertension	+	+
Pulmonary hypertension NOS	70995007	Pulmonary hypertension	+	+
Pulmonary hypertension NOS aggravated	70995007	Pulmonary hypertension	+	+
Pulmonary hypertension secondary	88223008	Secondary pulmonary hypertension	+	+
Secondary pulmonary arterial hypertension	88223008	Secondary pulmonary hypertension	+	+
Newborn persistent pulmonary hypertension	233815004	Persistent pulmonary hypertension of the newborn	+	+
Persistent pulmonary hypertension of the newborn	233815004	Persistent pulmonary hypertension of the newborn	+	+
Chronic thromboembolic pulmonary hypertension	233947005	Chronic thromboembolic pulmonary hypertension	+	+
CTEPH	233947005	Chronic thromboembolic pulmonary hypertension	+	+
Portopulmonary hypertension	445237003	Pulmonary arterial hypertension associated with portal hypertension	+	+
Eisenmenger's syndrome	445928005	Eisenmenger's syndrome	+	+
Familial (FPAH)	697897003	Heritable pulmonary arterial hypertension	+	+
Familial pulmonary arterial hypertension	697897003	Heritable pulmonary arterial hypertension	+	+
Primary pulmonary hypertension	697898008	Idiopathic pulmonary arterial hypertension	+	+
Pulmonary hypertension primary	697898008	Idiopathic pulmonary arterial hypertension	+	+
Idiopathic (IPAH)	697898008	Idiopathic pulmonary arterial hypertension	+	+
Idiopathic pulmonary arterial hypertension	697898008	Idiopathic pulmonary arterial hypertension	+	+
Associated with (APAH)	697902002	Associated pulmonary arterial hypertension	+	+
Associated with pulmonary arterial hypertension	697902002	Associated pulmonary arterial hypertension	+	+
Pulmonary arterial hypertension WHO functional class I	OMOP5160879	Pulmonary hypertension WHO (World Health Organization) functional class: I		+
Pulmonary arterial hypertension WHO functional class II	OMOP5160880	Pulmonary hypertension WHO (World Health Organization) functional class: II		+
Pulmonary arterial hypertension WHO functional class III	OMOP5160881	Pulmonary hypertension WHO (World Health Organization) functional class: III		+
Pulmonary arterial hypertension WHO functional class IV	OMOP5160882	Pulmonary hypertension WHO (World Health Organization) functional class: IV		+
Pulmonary hypertension WHO functional class I	OMOP5160879	Pulmonary hypertension WHO (World Health Organization) functional class: I		+
Pulmonary hypertension WHO functional class II	OMOP5160880	Pulmonary hypertension WHO (World Health Organization) functional class: II		+
Pulmonary hypertension WHO functional class III	OMOP5160881	Pulmonary hypertension WHO (World Health Organization) functional class: III		+
Pulmonary hypertension WHO functional class IV	OMOP5160882	Pulmonary hypertension WHO (World Health Organization) functional class: IV		+
Acute cor pulmonale	49584005	Acute cor pulmonale		+
Cor pulmonale acute	49584005	Acute cor pulmonale		+
Chronic cor pulmonale	79955004	Chronic cor pulmonale		+
Cor pulmonale chronic	79955004	Chronic cor pulmonale		+
Cor pulmonale	83291003	Cor pulmonale		+
Chronic pulmonary heart disease	87837008	Chronic pulmonary heart disease		+
Chronic pulmonary heart disease unspecified	87837008	Chronic pulmonary heart disease		+
Right-to-left cardiac shunt	441826000	Right to left cardiac shunt		+
Acute pulmonary heart disease	67189007	Acute pulmonary heart disease
Chronic pulmonary heart disease, unspecified	87837008	Chronic pulmonary heart disease
Cor pulmonale NOS	83291003	Cor pulmonale
Disease heart pulmonary	274096000	Pulmonary heart disease
Heart disease pulmonary	274096000	Pulmonary heart disease
Pulmonary hypertensions	70995007	Pulmonary hypertension	+
Congenital pulmonary hypertension	697897003	Heritable pulmonary arterial hypertension	+
Pulmonary artery wall hypertrophy	251039005	Pulmonary artery finding
Pulmonary hypertensive crisis	11399002	Pulmonary arterial hypertension	+
Right ventricular hypertension	461321006	Right ventricular hypertension
Right-to-left atrial shunt	441826000	Right to left cardiac shunt
Right-to-left ventricular shunt	441826000	Right to left cardiac shunt
Alveolar capillary dysplasia	708028001	Congenital pulmonary alveolar capillary dysplasia
Coronary sinus dilatation	253323000	Coronary sinus abnormality
Alveolar capillary dysplasia with misalignment of pulmonary veins	447275002	Alveolar capillary dysplasia with pulmonary venous misalignment

ICD10 code	ICD10 description	SNOMED code	SNOMED description
I27.0	Primary pulmonary hypertension	11399002	Pulmonary arterial hypertension
I27.2	Other secondary pulmonary hypertension	88223008	Secondary pulmonary hypertension
P29.3	Persistent fetal circulation	233815004	Persistent pulmonary hypertension of the newborn

ICD10CM code	ICD10CM description	Diagnostic category related to the ICD10CM code	SNOMED code	SNOMED description
I27.0	Primary pulmonary hypertension	Primary pulmonary hypertension	11399002	Pulmonary arterial hypertension
I27.2	Other secondary pulmonary hypertension	Other secondary pulmonary hypertension	88223008	Secondary pulmonary hypertension
I27.20	Pulmonary hypertension, unspecified	Pulmonary hypertension, unspecified Pulmonary hypertension NOS	70995007	PHT - Pulmonary hypertension
I27.21	Secondary pulmonary arterial hypertension	Secondary pulmonary arterial hypertension (Associated) (drug-induced) (toxin-induced) pulmonary arterial hypertension NOS (Associated) drug-induced) (toxin-induced) (secondary) group 1 pulmonary hypertension	88223008	Secondary pulmonary hypertension
I27.22	Pulmonary hypertension due to left heart disease	Pulmonary hypertension due to left heart disease Group 2 pulmonary hypertension	472790001	Pulmonary hypertension due to left heart disease
I27.23	Pulmonary hypertension due to lung diseases and hypoxia	Pulmonary hypertension due to lung diseases and hypoxia Group 3 pulmonary hypertension	697910001	Pulmonary hypertension due to lung disease and/or hypoxia
I27.24	Chronic thromboembolic pulmonary hypertension	Chronic thromboembolic pulmonary hypertension Group 4 pulmonary hypertension	233947005	Chronic thromboembolic pulmonary hypertension
I27.29	Other secondary pulmonary hypertension	Other secondary pulmonary hypertension Group 5 pulmonary hypertension	88223008	Secondary pulmonary hypertension
I27.83	Eisenmenger's syndrome	Eisenmenger's syndrome	445928005	Eisenmenger's syndrome
P29.3	Persistent fetal circulation	Persistent fetal circulation	233815004	Persistent pulmonary hypertension of the newborn
P29.30	Pulmonary hypertension of newborn	Pulmonary hypertension of newborn	233815004	Persistent pulmonary hypertension of the newborn
P29.38	Other persistent fetal circulation	Other persistent fetal circulation	233815004	Persistent pulmonary hypertension of the newborn