Ignorance Undercuts Gene Tests' Potential
By Rick Weiss
Washington Post Staff Writer
Saturday, December 2, 2000; Page A01
URL: http://www.washingtonpost.com/wp-dyn/articles/A3506-2000Nov29.html
Date accessed: January 7, 2001
Jim Graham, a western New York assembly line worker, was 35 when he learned that his lifelong breathing problems were caused not by asthma, but by a genetic disease that gradually stiffens patients' lungs and robs them of their ability to breathe.
His death just a year and a half later from the inherited syndrome shook family members, many of whom also suffered from respiratory problems. Might some of them carry the deadly gene, too?
Graham's sister, Terri Seargent of Wilmington, N.C., was one of the few who did not worry. "This disease only affects the males of the family," she recalls her brother's doctor saying.
But that information was wrong--women can get the disease--as were other details about the disease, called alpha-1 antitrypsin deficiency.
And when a specialist finally recognized that Seargent might indeed have the ailment, he made a mistake of another kind: He ordered the genetic test without warning her about its potential consequences, a serious omission given the potential ramifications.
"I received no counseling," said Seargent, who did in fact end up testing positive for the gene. "No information that it would go in my record and could ruin my chances of getting health insurance."
Seargent's story highlights a burgeoning problem in the newly dawning age of molecular medicine: Hundreds of genetic tests are available today, thanks to the gradual unveiling of the human genetic code, and doctors are ordering them in ever increasing numbers. Yet surveys confirm that most doctors and other health care professionals understand woefully little about genetics or genetic tests.
They don't know who should get tested. They don't know which tests are most useful. And they fail miserably at interpreting and communicating genetic test results, wrongly reassuring people at risk and scaring people who have little to fear.
As a result, some people are not getting the preventive care they should. Others are being advised to pursue unnecessary follow-up tests or perhaps even surgeries, and entire families are more confused or afraid than they were without the technology.
"We see this all the time," said Mary-Claire King, a research geneticist at the University of Washington. In one recent example, she said, a woman with breast cancer came into a local clinic. She tested positive for a mutation in the BRCA-1 gene, which can cause breast and ovarian cancer.
"Her physician said, 'Your daughters don't have to worry, and you don't have to worry about ovarian cancer because your family doesn't have a history of breast cancer,' " King said.
But that was simply wrong, she said. Even without a family history of disease, the daughters are at increased risk. What's more, King said, the doctor did not do a full three-generation family history, the only way to know whether the family has been free of cancer.
"What good does it do to have all the molecular genetics at your disposal," King asked, if the doctor is going to draw the wrong conclusions anyway?
Genetic tests are available for more than 400 diseases, and tests for more than 330 others are under development, according to GeneTests, a Seattle-based genetic testing resource. More than 175,000 genetic tests were performed in 1996 alone, the last year for which estimates exist, reflecting three consecutive years of 30 percent annual increases.
No agency or organization keeps tabs on how many genetic test results are wrongly conveyed or interpreted. But genetic counselors and researchers who have conducted studies on the topic say the problem is big and getting bigger.
A study of doctors who gave patients a genetic test for inherited colon cancer found that nearly one-fifth of the 177 people tested were not at risk of the disease so should not have been tested, and only one-fifth of the group received genetic counseling before the test. Most disturbing, doctors misinterpreted the results in nearly one-third of the cases, leading some patients to believe wrongly they did not need to get potentially lifesaving colon exams.
A Georgetown University study of 1,958 health care professionals published earlier this year found that 70 percent of providers had discussed genetics with their patients and 30 percent had provided genetic counseling--but less than 10 percent felt confident they were performing those services well.
Johns Hopkins University researchers found that only one-quarter of medical school students and less than one-third of physicians could calculate a genetic test's "positive predictive value"--a basic function that tells how likely someone who tests positive will get the disease.
"They're going to have a very hard time explaining to people the probabilistic value of this test if they can't figure it out for themselves," said Gail Geller, one of the study's leaders.
Genetic tests have already tripped ethics alarms because they could be used by employers and health insurers to discriminate against people who are healthy, but whose genes put them at increased risk of disease. Professional organizations and Congress have begun to act to prevent such abuses.
But far less attention has been paid to the more difficult challenges of educating health care professionals about genetics--and teaching them how to talk to people about their genes.
"As complicated as the laws are on discrimination in the workplace and health insurance, still they are laws and society will work through that," said Nancy Wexler, a professor of neuropsychology at Columbia Presbyterian Medical School in New York and president of the Hereditary Disease Foundation.
"But the gut psychological issues, the potential emotional burdens of genetic information, are so much more difficult," Wexler said. "If the information sends you through the window to the Hudson River below, then it won't matter if you were going to be discriminated against."
Unfortunately, experts said, researchers are just starting to study how to communicate genetic information. That means most people getting genetic tests are pioneers on an uncharted voyage of self-revelation.
"The truth is, we don't know how various kinds of people respond and react to genetic information," said Karen H. Rothenberg, dean of the University of Maryland School of Law and an expert in the ethical, legal and social issues raised by genetic testing.
"And it depends on the context. Having insurance or not makes a difference. Married or not married makes a difference. Giving a woman information about breast cancer risk is different at age 40 than at age 70."
It doesn't help that the public is mostly ill informed about genetics. Surveys indicate that perhaps one-quarter of Americans have even a rudimentary understanding of what a gene is. Several studies have shown that even when test results are communicated accurately, people are apt to misconstrue them.
"People come in saying, 'Oh my baby's going to have spina bifida!' when in fact the test had only found that they were at moderately increased risk, like 5 percent," said Wendy Uhlmann, a genetic counselor at the University of Michigan who has patched up many a bad situation caused by misinterpreted results. "Others come in and don't even know they were tested."
People do especially poorly when it comes to calculating their risk of getting a genetic disease, such as inherited cancer.
In one study of risk perception, 200 women whose family histories placed them at relatively low risk of breast cancer were asked to assess their odds of getting the disease, on a scale of 1 to 100. Almost 90 percent overestimated their risk by at least 10 points.
Counseling helps, but only so much. In one study of 282 women with family patterns of inherited breast cancer, the percentage of women with an accurate perception of their own risk went up after counseling to a modest 31 percent from a baseline of 9 percent. One year later, the percentage of women with a correct assessment of their risk had dropped again by half, suggesting that in the absence of further counseling women reverted to their old, inaccurate perceptions.
"We're going to have to learn how to convey that information more effectively than we currently do," said Francis Collins, director of the National Human Genome Research Institute and chief of the international Human Genome Project.
Exaggerated fears of getting a genetic disease motivate many people to get unnecessary tests, according to a 1999 research report. At the same time, people consistently underestimate the potential drawbacks of getting genetic tests.
Many, for example, underestimate the odds of getting a false result (most gene tests are not regulated by the Food and Drug Administration and, unlike other blood tests, there is no nationwide proficiency testing for gene tests). Many are unaware of the psychological anxiety or insurance problems that can follow.
It is into this vast sea of public misperception that doctors are now beginning to wade, hobbled by their own lack of training.
Doctors can be taught the science of genetics, of course, but scientific education won't solve the whole problem of how to talk about genes and genetic tests. People get very emotional about their genes, and emotions are notoriously unimpressed by facts.
Virtually every genetic counselor has a raft of war stories in which clients collapse in tears, slip into depression or even contemplate suicide upon learning something of their genetic makeup. Blame is often heaped on one branch of the family or another--and sometimes on the counselor.
In one case several years ago, the husband of a woman getting a genetic test pulled a gun on the counselor. The test had incidentally revealed, to his surprise, that he was not the father of his child.
Even happy test results do not guarantee happy endings. Uhlmann, the Michigan genetic counselor, recalls testing a man in his thirties who had lived his life believing he had inherited his parent's gene for Huntington's disease. The brain disorder causes senility in middle age and has a 50 percent chance of being passed to each child.
"He had really lived life at the edge--partied hard, drank a lot and didn't pay attention to finances or if he hurt someone," said Uhlmann, past president of the National Society of Genetic Counselors. When the test came back negative, he became very depressed.
"He said something like, 'Wow. I thought I was a victim but now I'm just a jerk.' "
For some, the gravity of genetic testing doesn't hit home until they learn that the results are ready.
"First they want the appointment for a test as soon as they can get in. 'Tomorrow, tomorrow!' " Uhlmann said. "Then all of a sudden they are canceling and rescheduling the appointment for results. There are some who more than two years later have still not come in for their results."
All this strife might be manageable if it affected only the person being tested, but genetics is a family affair. A single genetic test result can quickly snowball into a crisis for dozens of relatives, as amply demonstrated by the convoluted tale that recently unfolded in the Washington area.
It started about five months ago, when a 47-year-old woman (who does not want her family identified) got a genetic test because her aunt had died of ovarian cancer and her mother had been diagnosed with fallopian tube cancer.
The test showed she had inherited a mutation in the BRCA-2 gene, which can cause breast and ovarian cancers, so she quickly had her ovaries removed. In a controversial act that some doctors recommend and others do not, she recently had surgery to remove both of her healthy but at-risk breasts.
That was the end of her worries, but just the beginning of a chain reaction of troubles for the rest of the family.
The woman told her cousin, 54, about the results. She also decided to get tested; the results were negative, but a couple of months later she learned that benign cysts in her ovaries had begun to grow. Despite reassuring gene test results, that news--arriving on top of her aunt's and cousin's problems--was scary enough to convince her to have her ovaries removed, too.
An aunt, in her seventies, decided to get tested, out of concern that her daughters, ages 48 and 45, might have inherited the bad gene from her. She tested positive, so the daughters recently got tested. Both came up positive, and both are scheduled to have their ovaries removed.
Meanwhile, another cousin of the woman who first was tested decided to take the test. The result was positive. Now that cousin's sister is scheduled to get tested, although she wonders if she should even bother. She feels fairly certain that, given the family history, she wants her ovaries removed no matter what--and probably wouldn't get a prophylactic mastectomy in any case.
The story gets even more complicated. BRCA-2 mutations in men are associated with increased odds of getting prostate cancer. So the uncle of the woman who is about to get tested decided to get tested.
"Guess what?" the woman said. "Positive." The uncle has four daughters in their thirties, each of whom might have inherited the gene from him, some of them married with daughters. "Now they're all waiting for their test results."
In some respects, these frightening genetic revelations have had a positive effect, the woman said. Beyond the benefit of revealing hidden risks, "it has pulled people closer, and everyone is talking and sharing and checking in."
But it has also caused familial stress and strife. "I have cousins who wish we never found all this out," the woman said. "One cousin terminated the [genetic counseling] interview because she just did not want to hear any more."
Several family members were especially horrified by her cousin's decision to get a mastectomy. "It just seemed too radical," she said.
Genetic testing can become even more problematic in families that are not so close to begin with. Unfortunately for those venturing into this emotional minefield, the ethics of when to share results with family members are still under construction.
If a family member does not tell an estranged relative about a family-wide risk for a preventable disease, is a doctor ethically obliged to pass that information along? Or would that be a violation of the first patient's confidentiality?
The stakes are high, Rothenberg said. "Once you give someone information, you can never take it away. It cannot be reversed and it will never leave their brain."
Given the weight of that responsibility, who is qualified to give advice about genetic tests and interpret results?
Genetic counselors have the best training, experts agree, but there are far too few to do the job. While new genetics-rich curricula for medical students promise to usher in a generation of more savvy doctors, medical economics may preclude physicians from being ideal sources of such information and counseling. The work requires enormous investments of time to research the genetics of specific diseases, take detailed family histories and answer clients' countless questions.
"The dirty secret here is that most things genetic are really time-intensive, and every study agrees that you can't make a lot of money talking to people," said Alan Guttmacher, senior clinical adviser to the director of the National Human Genome Research Institute.
Guttmacher and Collins, the institute's director, are among many in the field who believe that specially trained nurses may be a big part of the solution. "Nurses are used to dealing with medical facts and the social and psychological impacts of those facts," Collins said.
New technological tools will also help professionals and the public. A consortium of professional organizations is developing a seal-of- approval system for genetics Web sites that meet minimal standards for accuracy.
Interactive video programs that can be watched at home are under development. Researchers are testing whether people can be adequately counseled via videophone conference calls with experts at major medical centers.
Still, experts said, with so many in the field still learning their art, perhaps the most important lesson is that a glimpse of one's genes is not for everyone. It's a point that may be hard to remember as gene testers ramp up their advertising to doctors and even directly to clients with "informational" Web sites.
"There is going to be this pressure: 'There's a test, let's order it,' " Uhlmann said. "But just because we have a test doesn't mean you ought to use it. You need to make sure the patient is informed about the ups and downs of taking that test."
A federal advisory committee on genetic testing agrees. High on its list of recommendations released this past summer is that most people who are about to get a predictive genetic test--even on the advice of a doctor or as part of a hospital stay--should first have to sign an informed-consent form such as those that volunteers in risky medical experiments must sign.
Committee members said the proposal reflects the often overlooked reality that for now, at least, people who opt to learn the secrets of their genes are, in effect, subjects in an experiment.
It is a grand experiment, and generally a well-intentioned one. Its lofty goals are to learn how to glean meaning from people's genes and to communicate that meaning in a way that is accurate, sensitive and on balance helpful.
But it is still an experiment, experts said. And rare is the experiment in science that is not preceded by failures.
Genes are made of DNA, a long, double-stranded molecule. Each strand is made of a series of four chemical subunits, abbreviated A, T, C and G. The order in which the subunits are linked together provides the "code" used by the cell to make proteins. Mutations in the code cause diseases.
Four ways to look for mutations
After a patient's blood or tissue sample is shipped to a specialized laboratory, technicians chemically extract DNA from the sample's cells. Mutations are then looked for in the following ways:
1. A gene's sequence of A's, T's, C's and G's is read to find a "spelling error" that may cause the cell to make the wrong protein.
OR
2. A probe chemically binds to a mutant sequence and "lights up" to indicate a mutation.
OR
3. Pieces of DNA are placed in a gelatin with a mild electric current running through it. Any mutation will change the electrical charge or shape of the DNA, and thus change the rate at which DNA moves through the gelatin in response to the current.
OR
4. The DNA is placed in a machine that "reads" the code contained in a gene and follows those genetic instructions to make a protein, just as a cell would do. The protein is then examined to see if it is normal.
SOURCE: National Human Genome Research Institute