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Effect of analytical error on the assessment of cardiac risk by the high-sensitivity C-reactive protein and lipid
1Department of Clinical Chemistry Development, Beckman Coulter Inc., 200 S. Kraemer, Brea, CA 92821, USA. Jsmiddleton@beckman.com
Insights
Assay imprecision in cardiac risk markers like HDL-cholesterol (HDLC) significantly impacts cardiovascular disease risk assessment. Multiple HDLC measurements can improve accuracy, especially with specific assay methods, reducing misclassifications.
Area of Science:
- Clinical Chemistry
- Cardiovascular Diagnostics
- Biomarker Analysis
Background:
- High-sensitivity C-reactive protein (hsCRP) is a recognized serum marker for cardiac risk.
- Combining hsCRP with lipid screening enhances clinical utility for cardiovascular risk assessment.
- Assay imprecision of hsCRP, HDL-cholesterol (HDLC), and total cholesterol (TC) affects risk evaluation.
Purpose of the Study:
- To evaluate the impact of hsCRP, HDLC, and TC assay imprecision on cardiac risk assessment.
- To quantify variations in cardiovascular disease risk estimates due to laboratory test variability.
- To assess the utility of Monte Carlo simulations in understanding analytical variation's clinical impact.
Main Methods:
- Cardiac risk assessment was simulated using specialized software (Visual Basic for Applications in Excel).
- Monte Carlo simulations were employed, using assay standard deviation estimates from CAP surveys and literature.
- Analyte concentrations represented true patient marker values, with simulations incorporating assay imprecision.
Main Results:
- Assay imprecision led to clinically significant variations in risk distributions.
- Relative risks for cardiovascular disease varied up to 6-fold under different imprecision levels.
- Underestimation or overestimation of true relative risks by over 25% occurred in 3-11% of cases depending on imprecision.
Conclusions:
- Monte Carlo simulation is a valuable tool for assessing analytical variation's impact on clinical decisions.
- Multiple HDLC measurements can mitigate misclassifications caused by assay imprecision, particularly for specific assay methods.
- HDLC contributes the largest error component to relative risk estimates; TC and hsCRP assay replication is less critical under typical performance conditions.
Background:
Several prospective epidemiologic studies have demonstrated that high-sensitivity C-reactive protein (hsCRP) is an effective serum marker for cardiac risk assessment. When hsCRP is considered in conjunction with traditional lipid screening, its clinical utility is further increased. In this report, hsCRP, HDL-cholesterol (HDLC), and total cholesterol (TC) assay imprecision is evaluated in terms of the impact on the cardiac risk assessment process.
Methods:
Cardiac risk assessment events were simulated using software written in Visual Basic for Applications with Microsoft Excel. Representative sets of analyte concentrations were used for true patient cardiac marker values. Monte Carlo simulations about the marker values were run using assay SD estimates based on College of American Pathologists surveys and journal articles.
Results:
Risk distributions for reasonable assay imprecision showed clinically significant variation. Estimated relative risks of cardiovascular disease using the Ridker-Rifai quintile model varied by as much as 2.5-, 3.5-, and 6-fold for conditions of low, medium, and high laboratory test imprecision, respectively. The true relative risks were underestimated by >25% in 3%, 6.7%, and 10.5% of cases under conditions of low, medium, and high laboratory test imprecision, respectively, and overestimated by >25% in 4.4%, 8.5%, and 11.1% of cases under those conditions.
Conclusions:
Use of the Monte Carlo simulation method as a tool to assess the impact of analytical variation on the clinical decision-making process is valuable. From this analysis, it is shown that multiple measurements of HDLC may reduce misclassifications that result from assay imprecision. This is most important when using HDLC assays that include sample preparation with 500 000 molecular weight dextran sulfate. For these assays the total assay method SDs are higher than for other assay methods. In addition, as demonstrated by a propagation of error analysis, HDLC has the largest component of overall error in the relative risk estimate. Under conditions of typical TC and hsCRP assay performance, replication of these assays is less important.
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