Pre-diagnostic comorbidity pathways are associated with the timing of pulmonary hypertension outcomes: a case control study
File(s)
Published version (in press)
Author(s)
Type
Journal Article
Abstract
Background
Pulmonary hypertension (PH) is a life-threatening condition often diagnosed late due to non-specific symptoms and overlapping comorbidities with other cardiovascular and respiratory diseases. Although there have been advances in treatment, diagnostic delays are common, and patients are treated late in their disease course. Investigating the temporal ordering of recorded comorbidities may provide insight into diagnostic patterns associated with delayed PH recognition and adverse outcomes.
Methods
We identified 2,727 PH patients from the UK Biobank cohort of 440,014 participants with diseases diagnoses, and sampled two demographics-matched cohorts of chronic obstructive pulmonary disease (COPD) and heart failure (HF) with the same number of patients as the PH cohort but were not diagnosed with PH. Employing process mining, a methodology originating from business process analysis to extract temporal patterns from event logs, the temporal diagnostic sequences of comorbidity combinations preceding PH diagnosis were compared to those sequences in patients who received a final diagnosis COPD or HF. We also assessed the relative risk of mortality given different combinations of comorbidities and the genetic correlation between comorbidities.
Results
Patients diagnosed with PH had prior diagnoses of hypertension (58.1%), atrial fibrillation (31.2%), and heart failure (43.2%). Process mining revealed that the temporal order of cardiometabolic comorbidities influences the timing to diagnosis of PH, COPD and HF. Patients in which type 2 diabetes was diagnosed before systemic hypertension had received PH diagnosis 2 years and 9 months faster than the reverse sequence, where hypertension preceded diabetes. For patients with a final diagnosis of PH, HF and COPD, diagnostic sequences in which hypercholesterolemia was recorded before systemic hypertension and type 2 diabetes were associated with shorter median intervals to PH diagnosis. A sequence involving diabetes, hypertension, and hypercholesterolemia was associated with a significantly higher mortality risk (HR = 1.97; P = 0.001). Additional mortality risk factors included specific orderings of metabolic conditions and comorbidity clusters.
Conclusion
Temporal diagnostic sequences of comorbidities were associated with the timing of PH diagnosis. Our findings suggest that the presentation and ordering of metabolic diseases may serve as hypothesis-generating epidemiological indicators of PH risk. Given the limited PH subtype granularity available within UK Biobank, these findings should be interpreted within a heterogeneous PH population and require further validation in clinically characterized cohorts with detailed PH subtype information.
Pulmonary hypertension (PH) is a life-threatening condition often diagnosed late due to non-specific symptoms and overlapping comorbidities with other cardiovascular and respiratory diseases. Although there have been advances in treatment, diagnostic delays are common, and patients are treated late in their disease course. Investigating the temporal ordering of recorded comorbidities may provide insight into diagnostic patterns associated with delayed PH recognition and adverse outcomes.
Methods
We identified 2,727 PH patients from the UK Biobank cohort of 440,014 participants with diseases diagnoses, and sampled two demographics-matched cohorts of chronic obstructive pulmonary disease (COPD) and heart failure (HF) with the same number of patients as the PH cohort but were not diagnosed with PH. Employing process mining, a methodology originating from business process analysis to extract temporal patterns from event logs, the temporal diagnostic sequences of comorbidity combinations preceding PH diagnosis were compared to those sequences in patients who received a final diagnosis COPD or HF. We also assessed the relative risk of mortality given different combinations of comorbidities and the genetic correlation between comorbidities.
Results
Patients diagnosed with PH had prior diagnoses of hypertension (58.1%), atrial fibrillation (31.2%), and heart failure (43.2%). Process mining revealed that the temporal order of cardiometabolic comorbidities influences the timing to diagnosis of PH, COPD and HF. Patients in which type 2 diabetes was diagnosed before systemic hypertension had received PH diagnosis 2 years and 9 months faster than the reverse sequence, where hypertension preceded diabetes. For patients with a final diagnosis of PH, HF and COPD, diagnostic sequences in which hypercholesterolemia was recorded before systemic hypertension and type 2 diabetes were associated with shorter median intervals to PH diagnosis. A sequence involving diabetes, hypertension, and hypercholesterolemia was associated with a significantly higher mortality risk (HR = 1.97; P = 0.001). Additional mortality risk factors included specific orderings of metabolic conditions and comorbidity clusters.
Conclusion
Temporal diagnostic sequences of comorbidities were associated with the timing of PH diagnosis. Our findings suggest that the presentation and ordering of metabolic diseases may serve as hypothesis-generating epidemiological indicators of PH risk. Given the limited PH subtype granularity available within UK Biobank, these findings should be interpreted within a heterogeneous PH population and require further validation in clinically characterized cohorts with detailed PH subtype information.
Date Issued
2026-09-04
Date Acceptance
2026-08-13
Citation
BMC Pulmonary Medicine, 2026
ISSN
1471-2466
Publisher
BMC
Journal / Book Title
BMC Pulmonary Medicine
Copyright Statement
© The Author(s) 2026. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
License URL
Identifier
10.1186/s12890-026-04610-7
Subjects
Pulmonary hypertension
Process mining
Comorbidity sequence
Mortality
Longitudinal analysis
Publication Status
Published online
Date Publish Online
2026-09-04