This technology includes a combination of 6 protein biomarkers and clinical risk factors to be used as an In Vitro Diagnostic Multivariate Index Assay (IVDMIA) that can improve the identification of individuals at high risk for atherosclerotic cardiovascular disease (ASCVD). Incorporation of novel protein biomarkers of ASCVD risk into risk assessment algorithms may improve their ability to identify individuals at high risk for ASCVD. We conducted an immunoassay profiling of 47 circulating plasma proteins in over 5,000 participants from the Framingham Heart Study (FHS) free of overt cardiovascular disease who were 40 years of age or older, and identified a panel of 6 immunoassay derived protein biomarkers that independently predicted the occurrence of new onset ASCVD above and beyond established risk factors. The IVDMIA invention described combines the values of multiple variables using an interpretation function to yield a single, patient-specific result, that is intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment or prevention of disease.