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There are only about 100 biomarkers in routine clinical use // Thousands of biomarkers are proposed and rejected every year // Why does the hunt take science in circles?

The Problem With Biomarkers

By Anita Slomski // Fall 2012
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Justin Gabbard

In June, The New York Times Magazine touted Eva Redei’s discovery—of 18 genetic markers in the blood that appear to identify major depression and anxiety in adolescents—as an innovation “that will change your tomorrow.” It could certainly help solve an acute problem. Only a quarter of depressed and anxious young people get treated, many self-medicate with drugs and alcohol, and suicide is all too common.

“Adolescents must overcome horrendous hurdles just to be diagnosed,” says Redei, professor of psychiatry, behavioral sciences and physiology at Northwestern University’s Feinberg School of Medicine. “Parents have to recognize signs of depression, and teens have to be willing to talk about it—and adolescents aren’t communicative. They’re also dealing with significant peer pressure and having to make major decisions about their lives.” A blood test could ease the stigma of depression by objectively diagnosing the disease, says Redei.

But translating her findings, 12 years in the making, into a diagnostic test could take several more years, might cost hundreds of thousands of dollars, and may never happen. Yet she and many other scientists continue their quest for biological clues—often in the form of changes in blood, urine or body tissues—that signal the risk or presence of disease. Such “biomarkers” are at the root of every routine screening or diagnostic test. Fasting glucose is a biomarker for diabetes, high readings for cholesterol or blood pressure indicate an elevated risk of cardiovascular disease, and liver enzymes that spill into the blood suggest liver disease.

All of those biomarkers, however, are fairly blunt tools, and science has long been anticipating much more sensitive measurements. In the wake of the Human Genome Project and other advances in molecular biology—and with technology now able to quantify thousands of changes involving proteins, enzymes, DNA, RNA and antibodies—there have been more than 150,000 published papers heralding thousands of new biomarkers. Yet there are only about 100 biomarkers in routine use, and many have been around for decades. “In cancer, there are about 3,000 papers every year proposing biomarkers,” says John Ioannidis, director of the Stanford Prevention Research Center. “But we use only about a dozen—because all the others either have failed or have not yet shown they’re really helpful.”

And recently, even some long-established biomarkers have been discredited. In separate announcements this year, the U.S. Preventive Services Task Force recommended against PSA testing, which measures levels of prostate-specific antigen in the blood, for routine screening of prostate cancer, and said that women without symptoms should no longer get the cancer antigen-125 (CA-125) blood test, which detects a protein that ovarian cancer cells produce. The task force said the tests weren’t sensitive or specific enough to distinguish between aggressive cancer and benign changes.

That judgment has been controversial, with many physicians and patients insisting the tests often lead to early, lifesaving cancer detection. And the search for valuable new biomarkers continues for good reason—because effective finds can do a world of good. After the HIV virus was discovered in 1982, scientists worked with unprecedented speed and funding to come up with an HIV antibody blood test just two years later. That was an invaluable step in controlling the spread of AIDS, in part by preventing HIV-infected donors from contaminating the global blood supply. And the test let people know they were at risk well before they had symptoms—early enough to benefit from the effective treatments that eventually arrived.

To facilitate the hunt for the next great biomarker, a few nonprofit organizations have established collaborative research networks, while other scientists are urging higher standards in biomarker research. Further advances in technology should also help. But it may take all of these developments, and more, to reverse the recent pattern of disappointment.

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Trouble Signs

Researchers are taking two paths toward the same goal: a blood test for depression.


1. “Comparison of Effect Sizes Associated with Biomarkers Reported in Highly Cited Individual Articles and in Subsequent Meta-Analyses,” by John P.A. Ioannidis and Orestis A. Panagiotou, JAMA, June 1, 2011. Highly promising initial biomarker studies appearing in scientific journals often turn out to have exaggerated associations to disease, according to these researchers, who urge greater skepticism in interpreting published reports and higher standards for claiming biomarker success.

2. “So, You Want to Look for Biomarkers,” by Joshua LaBaer, Journal of Proteome Research, June 2005. Biomarker researcher LaBaer outlines the basic rules for discovering clinically useful biomarkers, including understanding the consequences of being wrong, such as developing a biomarker that is so sensitive it generates unacceptable false-positive results.

3.“Bias as a Threat to the Validity of Cancer Molecular-Marker Research,” by David F. Ransohoff, Nature Reviews Cancer, February 2005. Researchers can unwittingly compromise the specimens they are analyzing for possible biomarkers, making their discoveries impossible to validate. Ransohoff explains how bias occurs in biomarker research and how to avoid it.

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