Abstract
Objectives
To develop a crude screening method for detecting biomarkers which frequently exhibit a rise (or fall) in level prior to a serious event (e.g. a stroke) in patients with a chronic disease, signalling that the biomarker may have an alarm-raising or prognostic potential. The subsequent assessment of the marker’s clinical utility requires costly, difficult longitudinal studies. Therefore, initial screening of candidate-biomarkers is desirable.
Methods
The method exploits a cohort of patients with biomarkers measured at entry and with recording of first serious event during follow-up. Copying those individual records onto a common timeline where a specific event occurs on the same day (Day 0) for all patients, the baseline biomarker level, when plotted against the patient’s entry time on the revised timeline, will have a positive (negative) regression slope if biomarker levels generally rise (decline) the closer one gets to the event. As an example, we study 1,958 placebo-treated patients with stable coronary artery disease followed for nine years in the CLARICOR trial (NCT00121550), examining 11 newer biomarkers.
Results
Rising average serum levels of cardiac troponin T and of N-terminal pro-B-type natriuretic peptide were seen prior to a fatal cardiovascular outcome. C-reactive protein rose prior to non-cardiovascular death. Glomerular filtration rate, seven lipoproteins, and nine newer cardiological biomarkers did not show convincing changes.
Conclusions
For early detection of biomarkers with an alarm-raising potential in chronic diseases, we proposed the described easy procedure. Using only baseline biomarker values and clinical course of participants with coronary heart disease, we identified the same cardiovascular biomarkers as those previously found containing prognostic information using longitudinal or survival analysis.
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Research funding: This study was funded by the Copenhagen Trial Unit, Centre for Clinical Intervention Research; the original funders of the CLARICOR trial [please see references 2, 3, and 7], and The Swedish Research Council, Swedish Heart-Lung Foundation; Thuréus Foundation; Marianne and Marcus Wallenberg Foundation, Dalarna University; and Uppsala University.
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Author contributions: PW conceived the idea of the method and JH and PW reviewed, discussed, and improved the statistical rigor of the proposed methodology. PW wrote the programs used for computation of the tables and figures. JH, PW, CG, and JCJ prepared the manuscript which was subsequently reviewed by the cardiologists of the CLARICOR trial. All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
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Competing interests: Authors state no conflict of interest.
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Informed consent: Informed consent was obtained from all individuals included in the CLARICOR trial.
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Ethical approval: Ethical and regulatory approval was obtained by VEKKF01-076/99; Danish Medicines Agency 2612-975; Danish Data Protection Agency 1999-1200-174; VEK H-B-2009-015.
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Supplementary Material
The online version of this article offers supplementary Material (https://doi.org/10.1515/cclm-2021-0333).
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