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Disentangling the phenotypic patterns of hypertension and chronic hypotension
William W Stead1, Adam Lewis2, Nunzia B Giuse3
1Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
Insights
New blood pressure categories (hypertension, hypotension, and normal) reveal distinct patterns across the phenome. This approach aids in understanding complex blood pressure mechanisms and identifying potential research hypotheses.
Area of Science:
- Cardiovascular Medicine
- Genomics
- Biostatistics
Background:
- Current blood pressure (BP) categories primarily focus on cardiac risk.
- Understanding the interplay of mechanisms that increase or decrease BP is crucial for new insights.
- A novel classifier categorizes individuals into upper (hypertension), lower (hypotension), and middle (normal) BP zones.
Purpose of the Study:
- To develop and apply a classifier for mutually exclusive BP categories (hypertension, hypotension, normal).
- To examine the epidemiologic and phenotypic patterns associated with these BP categories across the medical phenome.
- To identify potential new research hypotheses by analyzing the balance of BP-regulating mechanisms.
Main Methods:
- Classified 832,560 electronic health records into BP categories (hypertension, hypotension, normal).
- Compared BP category frequencies by sex and age, and visualized pressure distributions.
- Conducted Phenome-wide Association Studies (PheWAS) for hypertension and hypotension, comparing results with knowledgebases.
Main Results:
- BP categories demonstrated distinct distributions of systolic, diastolic, and mean arterial pressures.
- 85% of identified associations aligned with existing knowledgebase data.
- Phenotypic patterns for hypertension and hypotension overlapped for some conditions and were distinct for others, suggesting complex interactions.
Conclusions:
- Paired PheWAS methods offer a phenome-wide approach to differentiate hypertension and hypotension.
- The developed classifier serves as a foundation for BP categorization and further research.
- Further validation and clinical significance studies are needed for the classifier and identified hypotheses, particularly regarding low diastolic pressure.
Objective:
2017 blood pressure (BP) categories focus on cardiac risk. We hypothesize that studying the balance between mechanisms that increase or decrease BP across the medical phenome will lead to new insights. We devised a classifier that uses BP measures to assign individuals to mutually exclusive categories centered in the upper (Htn), lower (Hotn) and middle (Naf) zones of the BP spectrum; and examined the epidemiologic and phenotypic patterns of these BP-categories.
Methods:
We classified a cohort of 832,560 deidentified electronic health records by BP-category; compared the frequency of BP-categories and four subtypes of Htn and Hotn by sex and age-decade; visualized the distributions of systolic, diastolic, mean arterial and pulse pressures stratified by BP-category; and ran Phenome-wide Association Studies (PheWAS) for Htn and Hotn. We paired knowledgebases for hypertension and hypotension and computed aggregate knowledgebase status (KB-status) indicating known associations. We assessed alignment of PheWAS results with KB-status for phecodes in the knowledgebase, and paired PheWAS correlations with KB-status to surface phenotypic patterns.
Results:
BP-categories represent distinct distributions within the multimodal distributions of systolic and diastolic pressure. They are centered in the upper, lower, and middle zones of mean arterial pressure and provide a different signal than pulse pressure. For phecodes in the knowledgebase, 85% of positive correlations align with KB-status. Phenotypic patterns for Htn and Hotn overlap for several phecodes and are separate for others. Our analysis suggests five candidates for hypothesis testing research, two where the prevalence of the association with Htn or Hotn may be under appreciated, three where mechanisms that increase and decrease blood pressure may be affecting one another's expression.
Conclusion:
PairedPheWAS methods may open a phenome-wide path to disentangling hypertension and chronic hypotension. Our classifier provides a starting point for assigning individuals to BP-categories representing the upper, lower, and middle zones of the BP spectrum. 4.7 % of individuals matching 2017 BP categories for normal, elevated BP or isolated hypertension, have diastolic pressure < 60. Research is needed to fine-tune the classifier, provide external validation, evaluate the clinical significance of diastolic pressure < 60, and test the candidate hypotheses.
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