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Researchers in Finland have discovered four biomarkers in blood that appear to accurately identify individuals at high-risk of death in the short term 

Will there be demand for a medical laboratory test that can help pathologists accurately predict the probability of death within five years for an individual? New research emerging from Europe suggests that such a diagnostic assay may be feasible.

More remarkable, this clinical laboratory test may be as simple as testing for the concentration of four biomarkers in blood. In combination, these biomarkers indicate the status of metabolism in all humans that can possibly predict when an individual will die. According to researchers, their relative amounts are crucial to determining if an individual is at high risk for death within five years.

Finnish Researchers Close to Developing a Diagnostic Test

These discoveries emerged from a 10-year study conducted in Finland by the global Computational Medicine Research Group, University of Oulu, and the University of Eastern Finland (UEF).

mika ala korpela phd

Mika Ala-Korpela, Ph.D. (pictured above), was one of the lead researchers of a study that determined that four biomarkers in blood could be accurate predictors of death within five years. The study was done in Finland by a team at the Computional Medicine Institute. (Photo copyright the Computational Medicine Institute.)

Biomarker Score in Top 20% Marked Subjects for Death within 5 Years

The study was published in the journal PLOS Medicine in February 25, 2014. It was titled: “Biomarker Profiling by Nuclear Magnetic Resonance Spectroscopy for the Prediction of All-Cause Mortality: An Observational Study of 17,345 Persons.”  It involved 17,345 Finish and Estonian subjects. A team of Computational Medicine researchers was led by University of Oulu Professor Mika Ala-Korpela, Ph.D., and UEF Assistant Professor Pasi Soinien, Ph.D., who heads the university’s Nuclear Magnetic Resonance (NMR) Metabolomics Laboratory.

The researchers measured 106 biomarkers in blood samples of subjects using NMR spectroscopy. Following up, they examined health records of both the Estonian Biobank and FINRISK cohorts and identified 684 subjects, ages 18 to 103 years, who had died over the next 5.4 years. The majority of these deaths were from heart disease, cancer and other life-threatening diseases.

Using statistical analysis, researchers searched for links between the levels of different biomarkers in the blood and people’s short-term risk of dying. They also factored in other health issues that might contribute to the onset of life-threatening diseases. These variables included age, weight; tobacco and alcohol use; cholesterol level; and history of diabetes, cancer, and heart disease, noted study authors.

Just Four Biomarkers Seem to Accurately Predict Short-term Death

Notably, it is the levels of four biomarkers that appeared to accurately predict short-term death. Those biomarkers are:

Individuals with scores in the top 20% had a risk of dying within five years. This was 19 times greater than that of individuals with a score in the bottom 20%—288 versus 15 deaths.

Biomarkers Trumped Other Health Risks in Predicting Death 

“Out of all available risk factors, the biomarker summary score was the strongest predictor of all-cause mortality in the Estonian Biobank cohort,” wrote the authors of the study. They noted that persons with a very high biomarker score were associated with substantially higher mortality rates than those with average biomarker levels. Additionally, hazard estimates were similar in analyses limited to individuals without prevalent diabetes, cardiovascular disease, or cancer.

Pathologists and clinical laboratory managers are likely to recognize the fact that the four biomarkers associated with mortality are implicated in various pathophysiological mechanisms. These include inflammation, fluid imbalance, lipoprotein metabolism, and metabolic homeostasis, as explained by the study authors.

Alpha-1-Acid Glycoprotein Identified as Strongest Risk Factor

The acute phase protein alpha-1-acid glycoprotein is elevated in response to infection and inflammation. Plasma levels of alpha-1-acid glycoprotein have been associated with all-cause mortality in elderly persons, as well as cardiovascular mortality and prognosis of certain cancers, they noted. “Here, alpha-1-acid glycoprotein was the strongest multivariate predictor of the risk of death from all causes,” the authors wrote. They further noted that alpha-1-acid glycoprotein additionally influenced the association of several VLDL lipid measures.

They pointed out that low levels of plasma albumin—a marker of liver and kidney function, nutritional status, and inflammation—is associated with increased mortality from vascular, nonvascular, and cancer causes. The strong inverse association of albumin with short-term risk of death may, therefore, be considered as a positive control in the biomarker discovery.

VLDL Particle Risk Intensified by Alpha-1-Acid Glycoprotein Level

Triglyceride-mediated lipoprotein metabolism is recognized as a risk factor for cardiovascular disease, and average size of VLDL particles may be an overall indicator of triglyceride metabolism.

“In this study, VLDL particle size was inversely associated with risk of death, and the association became stronger when alpha-1-acid glycoprotein was included in the multivariate model, which might indicate a combined effect of perturbed triglyceride metabolism and low-grade inflammation,” wrote the study authors. They pointed out that this finding is supported by genetic evidence.

Study Identifies Citrate as a Mortality Risk Factor for First Time

Citrate—which acts as a chelator to modulate calcium, magnesium, and zinc ion concentrations—exhibits anticoagulating properties and is an intermediate in the citric acid cycle, making it central to energy metabolism. While not previously implicated as a biomarker for mortality, increased citrate was associated with increased risk of cardiovascular death and cancer death among Estonian participants, continued the study authors.

Additionally, they called attention to a recent molecular profiling study, published in the journal Science. This study indicated that citric acid cycle deviations, including elevated citrate levels, were predictive of death from sepsis in hospital settings.

What This Study Means

“Identifying individuals who are at high risk [of death] using these biomarkers might help to target preventative medical treatments to those with the greatest need,” wrote the PLOS Medicine Editor Cosetta Minelli, Ph.D., of the Imperial College London.

She cautioned, however, “As an observational study, it provides evidence of only a correlation between a biomarker score and ill health. It does not identify any underlying causes. Other factors, not detectable by NMR spectroscopy, might be the true cause of serious health problems and would provide a more accurate assessment of risk.” Minelli suggested that more research is needed to determine whether testing for these biomarkers would provide clinical benefit.

While this study may not be conclusive, its implications cannot be ignored. Further research is needed to verify the results and develop appropriate treatments to prevent early death. The potential of such a clinical laboratory test would place pathology groups in the unique position of identifying patients at high-risk of early death. It would also add another medical laboratory test to those physicians routinely order to determine health status of patients.

—by Patricia Kirk

Related Information:

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

An Integrated Clinico-Metabolomic Model Improves Prediction of Death in Sepsis

Biomarked for Death—Four Blood Proteins Can Predict Early Demise

Blood Test Accurately Predicts Risk Of Death: Clues Found In 4 Biomarkers In Blood

The UT’s Estonian Genome Center and Finnish researchers discovered novel blood biomarkers related to mortality