A transcriptomic model to predict increase in fibrous cap thickness in response to high-dose statin treatment: Validation by serial intracoronary OCT imaging

EBioMedicine. 2019 Jun;44:41-49. doi: 10.1016/j.ebiom.2019.05.007. Epub 2019 May 22.

Abstract

Background: Fibrous cap thickness (FCT), best measured by intravascular optical coherence tomography (OCT), is the most important determinant of plaque rupture in the coronary arteries. Statin treatment increases FCT and thus reduces the likelihood of acute coronary events. However, substantial statin-related FCT increase occurs in only a subset of patients. Currently, there are no methods to predict which patients will benefit. We use transcriptomic data from a clinical trial of rosuvastatin to predict if a patient's FCT will increase in response to statin therapy.

Methods: FCT was measured using OCT in 69 patients at (1) baseline and (2) after 8-10 weeks of 40 mg rosuvastatin. Peripheral blood mononuclear cells were assayed via microarray. We constructed machine learning models with baseline gene expression data to predict change in FCT. Finally, we ascertained the biological functions of the most predictive transcriptomic markers.

Findings: Machine learning models were able to predict FCT responders using baseline gene expression with high fidelity (Classification AUC = 0.969 and 0.972). The first model (elastic net) using 73 genes had an accuracy of 92.8%, sensitivity of 94.1%, and specificity of 91.4%. The second model (KTSP) using 18 genes has an accuracy of 95.7%, sensitivity of 94.3%, and specificity of 97.1%. We found 58 enriched gene ontology terms, including many involved with immune cell function and cholesterol biometabolism.

Interpretation: In this pilot study, transcriptomic models could predict if FCT increased following 8-10 weeks of rosuvastatin. These findings may have significance for therapy selection and could supplement invasive imaging modalities.

Keywords: Optical coherence tomography; Personalized medicine; Predictive modeling; Statin.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Algorithms
  • Biomarkers
  • Computational Biology / methods
  • Female
  • Gene Expression Profiling* / methods
  • Gene Ontology
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / administration & dosage
  • Male
  • Middle Aged
  • Models, Biological*
  • Plaque, Atherosclerotic / diagnosis*
  • Plaque, Atherosclerotic / drug therapy
  • Plaque, Atherosclerotic / etiology*
  • Prognosis
  • ROC Curve
  • Tomography, Optical Coherence
  • Transcriptome*
  • Treatment Outcome

Substances

  • Biomarkers
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors