PT - JOURNAL ARTICLE AU - Luanluan Sun AU - Lisa Pennells AU - Stephen Kaptoge AU - Christopher P Nelson AU - Gad Abraham AU - Matthew Arnold AU - Steven Bell AU - Thomas Bolton AU - Stephen Burgess AU - Frank Dudbridge AU - Qi Guo AU - Scott C Ritchie AU - Eleni Sofianopoulou AU - David Stevens AU - John R Thompson AU - Adam S Butterworth AU - Angela Wood AU - John Danesh AU - Nilesh J Samani AU - Michael Inouye AU - Emanuele Di Angelantonio TI - Use of polygenic risk scores and other molecular markers to enhance cardiovascular risk prediction: prospective cohort study and modelling analysis AID - 10.1101/744565 DP - 2019 Jan 01 TA - bioRxiv PG - 744565 4099 - http://biorxiv.org/content/early/2019/08/22/744565.short 4100 - http://biorxiv.org/content/early/2019/08/22/744565.full AB - Background There is debate about the value of adding information on genetic and other molecular markers to conventional cardiovascular disease (CVD) risk predictors.Methods Using data on 306,654 individuals without a history of CVD from UK Biobank, we calculated measures of risk-discrimination and reclassification upon addition of polygenic risk scores (PRS) and a panel of 27 clinical biochemistry markers to a conventional risk prediction model (i.e., including age, sex, systolic blood pressure, smoking status, history of diabetes, total cholesterol and HDL cholesterol). We then modelled implications of initiating guideline-recommended statin therapy after the assessment of molecular markers for a UK primary-care setting.Findings The C-index was 0.710 (95% CI, 0.703-0.717) for a CVD prediction model containing conventional risk predictors alone. The C-index increased by similar amounts when adding information on PRS or biochemistry markers (0.011 and 0.014, respectively; P<0.001), and it increased still further (0.022; P<0.001) when information on both was combined. Among cases and controls, continuous net reclassification improvements were about 12% and 19%, respectively, when both PRS and biochemistry markers were added. If PRS and biochemistry markers were to be assessed in the entire primary care population aged 40-75, then it could help prevent one additional CVD event for every 893 individuals screened. By contrast, targeted assessment only among people at intermediate (i.e., 5-10%) 10-year CVD risk could help prevent one additional CVD event for every 233 individuals screened. This targeted strategy could help reclassify 16% of the intermediate-risk group to the high-risk (i.e., ≥10%) category, preventing 11% more CVD events than conventional risk prediction.Interpretation Adding information on both PRS and selected biochemistry markers moderately enhanced CVD predictive accuracy and could improve primary prevention of CVD. However, our modelling suggested that targeted assessment of molecular markers among individuals at intermediate-risk would be more efficient than blanket approaches.