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      C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis

      The Emerging Risk Factors Collaboration

      Lancet

      Lancet Publishing Group

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          Summary

          Background

          Associations of C-reactive protein (CRP) concentration with risk of major diseases can best be assessed by long-term prospective follow-up of large numbers of people. We assessed the associations of CRP concentration with risk of vascular and non-vascular outcomes under different circumstances.

          Methods

          We meta-analysed individual records of 160 309 people without a history of vascular disease (ie, 1·31 million person-years at risk, 27 769 fatal or non-fatal disease outcomes) from 54 long-term prospective studies. Within-study regression analyses were adjusted for within-person variation in risk factor levels.

          Results

          Log e CRP concentration was linearly associated with several conventional risk factors and inflammatory markers, and nearly log-linearly with the risk of ischaemic vascular disease and non-vascular mortality. Risk ratios (RRs) for coronary heart disease per 1-SD higher log e CRP concentration (three-fold higher) were 1·63 (95% CI 1·51–1·76) when initially adjusted for age and sex only, and 1·37 (1·27–1·48) when adjusted further for conventional risk factors; 1·44 (1·32–1·57) and 1·27 (1·15–1·40) for ischaemic stroke; 1·71 (1·53–1·91) and 1·55 (1·37–1·76) for vascular mortality; and 1·55 (1·41–1·69) and 1·54 (1·40–1·68) for non-vascular mortality. RRs were largely unchanged after exclusion of smokers or initial follow-up. After further adjustment for fibrinogen, the corresponding RRs were 1·23 (1·07–1·42) for coronary heart disease; 1·32 (1·18–1·49) for ischaemic stroke; 1·34 (1·18–1·52) for vascular mortality; and 1·34 (1·20–1·50) for non-vascular mortality.

          Interpretation

          CRP concentration has continuous associations with the risk of coronary heart disease, ischaemic stroke, vascular mortality, and death from several cancers and lung disease that are each of broadly similar size. The relevance of CRP to such a range of disorders is unclear. Associations with ischaemic vascular disease depend considerably on conventional risk factors and other markers of inflammation.

          Funding

          British Heart Foundation, UK Medical Research Council, BUPA Foundation, and GlaxoSmithKline.

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          Most cited references 50

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          Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge.

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            Inflammation, atherosclerosis, and coronary artery disease.

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              Evaluating the added predictive ability of a new marker: from area under the ROC curve to reclassification and beyond.

              Identification of key factors associated with the risk of developing cardiovascular disease and quantification of this risk using multivariable prediction algorithms are among the major advances made in preventive cardiology and cardiovascular epidemiology in the 20th century. The ongoing discovery of new risk markers by scientists presents opportunities and challenges for statisticians and clinicians to evaluate these biomarkers and to develop new risk formulations that incorporate them. One of the key questions is how best to assess and quantify the improvement in risk prediction offered by these new models. Demonstration of a statistically significant association of a new biomarker with cardiovascular risk is not enough. Some researchers have advanced that the improvement in the area under the receiver-operating-characteristic curve (AUC) should be the main criterion, whereas others argue that better measures of performance of prediction models are needed. In this paper, we address this question by introducing two new measures, one based on integrated sensitivity and specificity and the other on reclassification tables. These new measures offer incremental information over the AUC. We discuss the properties of these new measures and contrast them with the AUC. We also develop simple asymptotic tests of significance. We illustrate the use of these measures with an example from the Framingham Heart Study. We propose that scientists consider these types of measures in addition to the AUC when assessing the performance of newer biomarkers.
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                Author and article information

                Author notes
                [‡]

                Members listed at end of paper

                Journal
                Lancet
                Lancet
                Lancet
                Lancet Publishing Group
                0140-6736
                1474-547X
                9 January 2010
                9 January 2010
                : 375
                : 9709
                : 132-140
                3162187 20031199 LANCET61717 10.1016/S0140-6736(09)61717-7
                © 2010 Elsevier Ltd. All rights reserved.

                This document may be redistributed and reused, subject to certain conditions.

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                Medicine

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