Phenomapping of patients with heart failure with preserved ejection fraction using machine learning-based unsupervised cluster analysis

Matthew W. Segar, Kershaw V. Patel, Colby Ayers, Mujeeb Basit, W. H.Wilson Tang, Duwayne Willett, Jarett Berry, Justin L. Grodin, Ambarish Pandey

Research output: Contribution to journalArticlepeer-review

172 Scopus citations


Aim: To identify distinct phenotypic subgroups in a highly-dimensional, mixed-data cohort of individuals with heart failure (HF) with preserved ejection fraction (HFpEF) using unsupervised clustering analysis. Methods and results: The study included all Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) participants from the Americas (n = 1767). In the subset of participants with available echocardiographic data (derivation cohort, n = 654), we characterized three mutually exclusive phenogroups of HFpEF participants using penalized finite mixture model-based clustering analysis on 61 mixed-data phenotypic variables. Phenogroup 1 had higher burden of co-morbidities, natriuretic peptides, and abnormalities in left ventricular structure and function; phenogroup 2 had lower prevalence of cardiovascular and non-cardiac co-morbidities but higher burden of diastolic dysfunction; and phenogroup 3 had lower natriuretic peptide levels, intermediate co-morbidity burden, and the most favourable diastolic function profile. In adjusted Cox models, participants in phenogroup 1 (vs. phenogroup 3) had significantly higher risk for all adverse clinical events including the primary composite endpoint, all-cause mortality, and HF hospitalization. Phenogroup 2 (vs. phenogroup 3) was significantly associated with higher risk of HF hospitalization but a lower risk of atherosclerotic event (myocardial infarction, stroke, or cardiovascular death), and comparable risk of mortality. Similar patterns of association were also observed in the non-echocardiographic TOPCAT cohort (internal validation cohort, n = 1113) and an external cohort of patients with HFpEF [Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction (RELAX) trial cohort, n = 198], with the highest risk of adverse outcome noted in phenogroup 1 participants. Conclusions: Machine learning-based cluster analysis can identify phenogroups of patients with HFpEF with distinct clinical characteristics and long-term outcomes.

Original languageEnglish (US)
Pages (from-to)148-158
Number of pages11
JournalEuropean Journal of Heart Failure
Issue number1
StatePublished - Jan 1 2020


  • Heart failure with preserved ejection fraction
  • Machine learning
  • Outcomes
  • Phenomapping

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


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