Response by Welsh et al to Letter Regarding Article, “Comparison of Conventional Lipoprotein Tests and Apolipoproteins in the Prediction of Cardiovascular Disease”
Authors: Paul Welsh, Claire Welsh, Jill Pell, Naveed Sattar
Journal: Circulation (2019)

We thank Professor Sniderman and colleagues for their interest and recognize their contributions on this issue.We considered the evidence in an agnostic manner and maintain that our conclusion is consistent with existing literature. 1 The Emerging Risk Factors Collaboration analyzed the predictive power of apolipoproteins in a wide range of harmonized cohorts.They concluded, "none of the following measures were superior to total cholesterol and HDL-C when they replaced traditional cholesterol measurements in risk prediction scores: the total cholesterol:HDL-C ratio; non-HDL-C; the linear combination of apolipoprotein B and A-I; or the apolipoprotein B:A-I ratio." 2 Many national guidelines do not support the widespread use of apolipoproteins in primary prevention, as the correspondents are aware. 3Discrepancies between guidelines speak to the need for additional convincing evidence.The UK Biobank data help in that regard.Sniderman and colleagues argue that "If the authors' analysis and reasoning are correct, total cholesterol and high-density lipoprotein cholesterol (HDL-C) should displace low-density lipoprotein cholesterol, non-HDL-C, and apoB in clinical care."We suggest that no displacement is necessary because in nearly every primary prevention risk calculator (the pooled cohort equation, QRISK3, SCORE [Systematic Coronary Risk Evaluation], WHO CVD [World Health Organization Cardiovascular Disease] risk charts), total cholesterol and HDL-C are the default lipid measurements.Our results simply support the status quo in primary prevention, where there is no need to measure apoB or direct low-density lipoprotein cholesterol, which incur additional cost, but have correlations of r≥0.95 with non-HDL-C.We have not said that non-HDL-C or low-density lipoprotein cholesterol should not be calculated using total cholesterol and HDL-C; these calculations are simple.Indeed, our analysis and discussion frames non-HDL-C as the standard lipid measurement in those with baseline cardiovascular disease or on a statin.We agree that the C-index is not the only tool in predictive analyses; we also report categorical net reclassification index, Akaike Information Criteria, and Bayesian Information Criteria, which support our conclusions.We agree that the C-index is heavily influenced by age, because age is the most important cardiovascular disease risk factor.If a cohort is limited in age range, this internally restricts the most important determinant of cardiovascular disease, and the C-index falls.That is not necessarily an inherent limitation of the C-index as a metric.Indeed, limiting our original analysis to those aged 60 or over (n=131 282 participants, n=3745 cardiovascular disease events) lowers the base comparator C-index of classical risk factors plus total cholesterol and HDL-C (C-index=0.6787),but addition of apoB still does not improve it (+0.0003[95% CI, -0.0003, 0.0010]).Our discordance analysis, in terms of the hazard ratio, is similar to previous studies.However, as the accompanying editorial notes, "disagreement is post hoc information." 4One needs to measure apoB in everyone to find disagreement, and