Biomarker profiling by nuclear magnetic resonance spectroscopy for the prediction of all-cause mortality: an observational study of 17,345 persons

Krista Fischer, Johannes Kettunen, Peter Würtz, Toomas Haller, Aki S Havulinna, Antti J Kangas, Pasi Soininen, Tõnu Esko, Mari-Liis Tammesoo, Reedik Mägi, Steven Smit, Aarno Palotie, Samuli Ripatti, Veikko Salomaa, Mika Ala-Korpela, Markus Perola, Andres Metspalu

Research output: Contribution to journalArticle (Academic Journal)peer-review

175 Citations (Scopus)


BACKGROUND: 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.

METHODS AND FINDINGS: 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).

CONCLUSIONS: 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.

Original languageEnglish
Pages (from-to)e1001606
JournalPLoS Medicine
Issue number2
Publication statusPublished - Feb 2014


  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Biological Specimen Banks
  • Biomarkers
  • Cause of Death
  • Citric Acid
  • Estonia
  • Female
  • Finland
  • High-Throughput Screening Assays
  • Humans
  • Kaplan-Meier Estimate
  • Lipoproteins, LDL
  • Magnetic Resonance Spectroscopy
  • Male
  • Middle Aged
  • Orosomucoid
  • Particle Size
  • Predictive Value of Tests
  • Prognosis
  • Proportional Hazards Models
  • Reproducibility of Results
  • Risk Assessment
  • Risk Factors
  • Serum Albumin
  • Time Factors
  • Young Adult

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