Combining the power of advanced math with tests commonly used to measure
blood sugar, scientists from Harvard Medical School
By factoring in the age of each patient¹s red blood cells, the new method
offers a more precise, individualized gauge of three-month blood sugar
averages and reduces in half the error rate of the most commonly used ‹
but sometimes inaccurate ‹ test known as A1C. Findings of the study are
described Oct. 5 in Science Translational Medicine
"What we currently deem the gold standard for estimating average blood
glucose is nowhere as precise as it should be," said senior investigator
John Higgins, an associate professor of systems biology at HMS and a
clinical pathologist at Massachusetts General Hospital. "Our study not
only pinpoints the root of the inaccuracy but also offers a way to get
around it."
The A1C test led to notable off-target estimates in about a third of more
than 200 patients whose test results were analyzed as part of the
research. The team found these inaccuracies stemmed entirely from
individual variations in the life span of a person¹s red blood cells.
In a final step, the scientists calculated new, age-adjusted estimates and
tested their predictive accuracy by comparing them to actual blood sugar
levels measured directly via continuous glucose monitors ‹ wearable
devices that read a person¹s blood sugar every five minutes.
Incorporating the new model into existing tests, the researchers said,
could lead to more precise diagnosis, monitoring and better-tailored
treatments.
Estimating a person¹s three-month blood sugar average is the best
indicator of disease control and the most accurate predictor of looming
complications, according to experts. Persistently elevated blood sugar
can, over time, damage the heart, brain, kidneys, eyes, nerves and other
organs.
Because blood sugar varies by the hour and even by the minute, capturing
"an average" to account for fluctuations over an extended period is a far
better indicator of disease status than taking a "snapshot" measurement at
one time.
To estimate blood sugar averages, physicians use the A1C test as a proxy.
The A1C measures so-called glycated hemoglobin ‹ the amount of sugar
soaked up by red blood cells over an extended period of time.
The test, however, is somewhat imprecise. As little as 15 milligrams of
glucose per deciliter of blood could signal the difference between high
normal values in a person without diabetes and low abnormal values in
someone with the disease. The A1C test can lead to identical readings for
people with average blood sugar levels that differ by as much as 60 mg/dl.
At the same time, people with similar blood sugar levels can end up having
widely divergent results. Researchers are not sure what fuels this
discrepancy, but the age of red blood cells has recently emerged as a
prime suspect.
"Like a water-soaked sponge that¹s been sitting on the kitchen sink for
days, older red blood cells tend to have absorbed more glucose, while
newly produced red blood cells have less because they haven¹t been around
as long," Higgins said.
Thus, the researchers said, two people with the same amount of sugar in
their blood but could end up with different results on their A1C test
depending on the average lifespan of their red blood cells.
To eliminate the influence of age-related variation, the HMS team
developed a formula that factors in the life span of a person's red blood
cells. The formula is based on several values, including directly measured
glucose levels, and, crucially, on earlier findings by Higgins' team
showing that in each person, the lifespan of red blood cells is tightly
regulated, within 1 percent or so. Next, researchers compared the
age-adjusted blood sugar estimates to estimates derived from the standard
A1C test and then to readouts of glucose levels measured directly by
continuous glucose monitors.
The standard A1C test provided values that were significantly off target ‹
by 15 mg/dl or more ‹ in one out of three patients. By factoring in red
blood cell age, however, the scientists reduced the error rate to 1 in 10.
For example, using the standard A1c test, one patient's glycated
hemoglobin levels measured at 8.1 percent, leading to an estimated blood
sugar level of 186 mg/dl. When the researchers factored in the person's
red blood cell age ‹ 45 days ‹ the estimate went up to 209 mg/dl. Compared
with the actual glucose levels measured by a continuous glucose monitor ‹
210mg/dl ‹ the age-adjusted estimate was off by a mere point. By contrast,
the standard estimate was off by 24 points.
Incorporating the age-adjusted formula into current A1C testing approaches
would significantly boost the accuracy of glucose estimates, the
researchers said. Under the new model, patients could wear a glucose
monitor for a few weeks to have their blood sugar tracked as a baseline,
also allowing physicians to calculate the average age of a person¹s red
blood cells before having the monitor removed.
"Physicians treating recently diagnosed patients would immediately know
what a patient¹s red blood cell age is," Higgins said. "The patient's test
results can then be adjusted to factor in the red blood cell age and get a
result that more accurately reflects the actual levels of blood sugar,
allowing them to tailor treatment accordingly."
### Roy Malka and David M. Nathan were co-investigators on the study.
The work was supported by the National Institutes of Health under grant
number DP2DK098087 and by a research grant from Abbott Diagnostics, a
manufacturer of diagnostic and laboratory equipment.
The authors have a patent application pending related to findings from
this study.
Science Translational Medicine
Journal
News Release