RESUMEN
BACKGROUND: Coronary heart disease (CHD) is the leading cause of death in the world. Unfortunately, many of the key diagnostic tools for CHD are insensitive, invasive, and costly; require significant specialized infrastructure investments; and do not provide information to guide postdiagnosis therapy. In prior work using data from the Framingham Heart Study, we provided in silico evidence that integrated genetic-epigenetic tools may provide a new avenue for assessing CHD. METHODS AND RESULTS: In this communication, we use an improved machine learning approach and data from 2 additional cohorts, totaling 449 cases and 2067 controls, to develop a better model for ascertaining symptomatic CHD. Using the DNA from the 2 new cohorts, we translate and validate the in silico findings into an artificial intelligence-guided, clinically implementable method that uses input from 6 methylation-sensitive digital polymerase chain reaction and 10 genotyping assays. Using this method, the overall average area under the curve, sensitivity, and specificity in the 3 test cohorts is 82%, 79%, and 76%, respectively. Analysis of targeted cytosine-phospho-guanine loci shows that they map to key risk pathways involved in atherosclerosis that suggest specific therapeutic approaches. CONCLUSIONS: We conclude that this scalable integrated genetic-epigenetic approach is useful for the diagnosis of symptomatic CHD, performs favorably as compared with many existing methods, and may provide personalized insight to CHD therapy. Furthermore, given the dynamic nature of DNA methylation and the ease of methylation-sensitive digital polymerase chain reaction methodologies, these findings may pave a pathway for precision epigenetic approaches for monitoring CHD treatment response.
RESUMEN
Aim: The Framingham Risk Score (FRS) and atherosclerotic cardiovascular disease (ASCVD) Pooled Cohort Equation (PCE) for predicting risk for incident coronary heart disease (CHD) work poorly. To improve risk stratification for CHD, we developed a novel integrated genetic-epigenetic tool. Materials & methods: Using machine learning techniques and datasets from the Framingham Heart Study (FHS) and Intermountain Healthcare (IM), we developed and validated an integrated genetic-epigenetic model for predicting 3-year incident CHD. Results: Our approach was more sensitive than FRS and PCE and had high generalizability across cohorts. It performed with sensitivity/specificity of 79/75% in the FHS test set and 75/72% in the IM set. The sensitivity/specificity was 15/93% in FHS and 31/89% in IM for FRS, and sensitivity/specificity was 41/74% in FHS and 69/55% in IM for PCE. Conclusion: The use of our tool in a clinical setting could better identify patients at high risk for a heart attack.
Lay abstract Current lipid-based methods for assessing risk for coronary heart disease (CHD) have limitations. Conceivably, incorporating epigenetic information into risk prediction algorithms may be beneficial, but underlying genetic variation obscures its effects on risk. In order to develop a better CHD risk assessment method, we used artificial intelligence to identify genome-wide genetic and epigenetic biomarkers from two independent datasets of subjects characterized for incident CHD. The resulting algorithm significantly outperformed the current assessment methods in independent test sets. We conclude that artificial intelligence-moderated genetic-epigenetic algorithms have considerable potential as clinical tools for assessing risk for CHD.