Biomarker Profiling by Nuclear Magnetic Resonance Spectroscopy for the Prediction of All-Cause Mortality: An Observational Study of 17,345 Persons

Early identification of ambulatory persons at high short-term risk of death could benefit targeted prevention. To identify biomarkers for all-cause mortality and enhance risk prediction, we conducted high-throughput profiling of blood specimens in two large population-based cohorts. 106 candidate bi...

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Published in:PLoS medicine Vol. 11; no. 2; p. e1001606
Main Authors: Fischer, Krista, Kettunen, Johannes, Würtz, Peter, Haller, Toomas, Havulinna, Aki S., Kangas, Antti J., Soininen, Pasi, Esko, Tõnu, Tammesoo, Mari-Liis, Mägi, Reedik, Smit, Steven, Palotie, Aarno, Ripatti, Samuli, Salomaa, Veikko, Ala-Korpela, Mika, Perola, Markus, Metspalu, Andres
Format: Journal Article
Language:English
Published: United States Public Library of Science 01.02.2014
Public Library of Science (PLoS)
Subjects:
Adolescent
Adult
Aged
Aged, 80 and over
Biological markers
Biological Specimen Banks
Biology
Biomarkers - blood
Cause of Death
Cholesterol
Citric Acid - blood
Estonia - epidemiology
Female
Finland
Finland - epidemiology
Health risk assessment
High-Throughput Screening Assays - methods
Humans
Kaplan-Meier Estimate
Lipoproteins, LDL - blood
Magnetic Resonance Spectroscopy
Male
Medicine
Middle Aged
Mortality
NMR
Nuclear magnetic resonance
Nuclear magnetic resonance spectroscopy
Orosomucoid - analysis
Particle Size
Physiological aspects
Predictive Value of Tests
Prognosis
Proportional Hazards Models
Reproducibility of Results
Risk Assessment
Risk Factors
Serum Albumin - analysis
Serum Albumin, Human
Studies
Time Factors
United Kingdom
United States
Young Adult
Finland
Estonia
United States
United Kingdom
ISSN:1549-1676, 1549-1277, 1549-1676
Online Access:Get full text
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Summary:Early identification of ambulatory persons at high short-term risk of death could benefit targeted prevention. To identify biomarkers for all-cause mortality and enhance risk prediction, we conducted high-throughput profiling of blood specimens in two large population-based cohorts. 106 candidate biomarkers were quantified by nuclear magnetic resonance spectroscopy of non-fasting plasma samples from a random subset of the Estonian Biobank (n = 9,842; age range 18-103 y; 508 deaths during a median of 5.4 y of follow-up). Biomarkers for all-cause mortality were examined using stepwise proportional hazards models. Significant biomarkers were validated and incremental predictive utility assessed in a population-based cohort from Finland (n = 7,503; 176 deaths during 5 y of follow-up). Four circulating biomarkers predicted the risk of all-cause mortality among participants from the Estonian Biobank after adjusting for conventional risk factors: alpha-1-acid glycoprotein (hazard ratio [HR] 1.67 per 1-standard deviation increment, 95% CI 1.53-1.82, p = 5×10⁻³¹), albumin (HR 0.70, 95% CI 0.65-0.76, p = 2×10⁻¹⁸), very-low-density lipoprotein particle size (HR 0.69, 95% CI 0.62-0.77, p = 3×10⁻¹²), and citrate (HR 1.33, 95% CI 1.21-1.45, p = 5×10⁻¹⁰). All four biomarkers were predictive of cardiovascular mortality, as well as death from cancer and other nonvascular diseases. One in five participants in the Estonian Biobank cohort with a biomarker summary score within the highest percentile died during the first year of follow-up, indicating prominent systemic reflections of frailty. The biomarker associations all replicated in the Finnish validation cohort. Including the four biomarkers in a risk prediction score improved risk assessment for 5-y mortality (increase in C-statistics 0.031, p = 0.01; continuous reclassification improvement 26.3%, p = 0.001). Biomarker associations with cardiovascular, nonvascular, and cancer mortality suggest novel systemic connectivities across seemingly disparate morbidities. The biomarker profiling improved prediction of the short-term risk of death from all causes above established risk factors. Further investigations are needed to clarify the biological mechanisms and the utility of these biomarkers for guiding screening and prevention.
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PW AJK PS and MAK are shareholders of Brainshake Ltd., a startup company offering NMR-based metabolite profiling. All other authors declare that no competing interests exist.
These authors are joint senior authors on this work.
Conceived and designed the experiments: KF JK PW VS MAK MP AM. Performed the experiments: AJK PS MAK. Analyzed the data: KF JK PW. Contributed reagents/materials/analysis tools: TH ASH AJK TE RM SR. Wrote the first draft of the manuscript: KF JK PW. Contributed to the writing of the manuscript: KF JK PW TH ASH VS. ICMJE criteria for authorship read and met: KF JK PW TH ASH AJK PS TE MLT RM SS AP SR VS MAK MP AM. Agree with manuscript results and conclusions: KF JK PW TH ASH AJK PS TE MLT RM SS AP SR VS MAK MP AM. Enrolled patients: MLT SS AP VS MP AM.
ISSN:1549-1676
1549-1277
1549-1676
DOI:10.1371/journal.pmed.1001606