R esults of Family Tree DNA, a genetic testing company, helped Lara Diamond find a branch of her family she thought had been lost in the Holocaust. Those results of 2012 brought dozens of new people into your life.
Eager to find more relatives, Diamond, now 42, a professional genealogist in Baltimore, decided to try out all the companies that offer gene-DNA testing to see what else he could do. to learn. The results of one of them, 23andMe, hit her with a completely different type of life-changing knowledge: a high risk of bad cancer.
Examining the health and trait reports provided by the company, Diamond came to the blocked reports, which contain information on genetic variants that increase the risk of developing bad cancer, Alzheimer's disease or Parkinson's. Customers have to choose to "unlock" that information, as it can bring disruptive news.
Diamond considered his family history. "Because we have Alzheimer's and Parkinson's in my family, I said, OK, I'm going to think about that But we do not have bad cancer, so I'm going to open this thing BRCA & # 39 ; & # 39; he says, referring to the family of genes related to bad cancer.
To his surprise, Diamond learned that he has a variant in his DNA that alters an amino acid in the BRCA2 protein, putting it on high risk of the disease. "A small stupid mutation. An amino acid And it changes your whole life. "
The next morning she called her doctor, who sent her to a genetic counselor, and the counselor ordered a DNA confirmation test from a certified laboratory to perform diagnostic medical tests. He also had a mammogram, an MRI, an ultrasound, and blood tests to detect bad, ovarian, and pancreatic cancer, because his variant increases the risk for all three.The magnetic resonance revealed a small spot of cancer inside his bad, too small for mammography to detect it.She decided to have a double mastectomy.
Genetic tests became generalized
Your doctors urge you to also have your ovaries and fallopian tubes removed to prevent ovarian cancer. "I'm not ready to do that yet," says Diamond.
Diamond was more interested in what his genes might reveal about his family history, not the health information they have. But millions of genetic testing clients want to know their medical future. Although most consumer genetic testing companies collect data on thousands of genetic variants that can have an impact on health, companies like 23andMe can only give limited information about genetic risks to health. The company reports focus mainly on ancestors or basic physical traits ( SN: 5/26/18, p.20 ).
Then, the market has devised an alternative solution: Consumers who want to know about their risks for diabetes or several other diseases can turn to third-party services to badyze the raw DNA results generated by the test companies. However, new research suggests that some of the answers people find through these third-party services are incorrect and could prevent people from listening to their doctors or genetic counselors. That is, if the person bothers to see one.
The market responds
Diamond got its health-related results in 2013, just before the US Food and Drug Administration. UU I told 23andMe to stop providing health information to consumers. The company had to prove to the FDA that the information it provides is accurate and communicated in an easy to understand manner. In 2017, 23andMe obtained the approval to re-add reports slowly for certain health conditions.
Most recently, in March, the FDA granted approval for the company to inform clients if they have one of the three genetic variants in BRCA1 and BRCA2 genes . Those three variants are responsible for about 74 percent of hereditary bad cancers among people of Ashkenazi Jewish descent. Less than 0.1 percent of people of other ethnicities have these variants.
It offers information on only three variants, when there are thousands in the two genes that increase the risk of bad and ovarian cancer, as well as melanoma, prostate and pancreatic cancer. it's problematic, say healthcare providers, bad cancer advocacy groups and others.
A small stupid mutation. An amino acid And change your whole life.
– Lara Diamond
With only a partial list of the variants convened, examiners who do not have one of those variants can misinterpret the results, concerns Lisa. Schlager, vice president of community affairs and public policy of FORCE, a group of information and hereditary support on bad cancer.
People who do not have one of the variants can say: "I do not have a genetic risk that predisposes me". to cancer I'm sure, "says Schlager." But that's not absolutely right; you are only negative for three of thousands of possible mutations. So, our concern is that the public does not understand the limitations. "
However, Schlager and others admit that allowing companies like 23andMe to provide information approved by the FDA and explain the results, although incomplete, may be the lesser of two. evils
"There is a kind of underworld that has been going on since the FDA stopped 23andMe from interpreting these results and giving them to people," says Schlager.At a small fee, third-party badysis services are ready to offer the interpretation that the test companies choose not to provide, or are not allowed to provide according to FDA standards, These services include Promethease, an early market participant in gross consumer data badysis, along with Genetic Genie, LiveWello and many, many others.
That's possible because customers of direct consumer DNA testing services like 23andMe, AncestryDNA and Family Tree DNA can download your raw DNA data to be sent to third-party badytics sites or applications. These raw data consist of a list of points, known as SNPs (pronounced "snips"), where the customer's DNA varies. Some third-party badysis services will also badyze a broader range of information, data on regions of protein coding, called exome. Genos is a test company that provides raw data in the exome.
Helix, a test company that provides "exome plus" data, has partner applications that customers can buy to badyze limited sets of their data. (Or, for $ 499, you can download all your raw data). So far, very few of the third-party badysis services are configured to process data from the whole book of genetic instructions or genome.
To write their reports, Promethease and others find scientific studies that mention the genetic variants a client performs and makes inferences about the health risks of carrying those variants. "It has been an absolute nightmare," says Schlager. Consumers do not understand the information and often react in an exaggerated way.
Devil in the data
In the Facebook groups for people with BRCA mutations Diamond, who is a FORCE volunteer, often encounters people who are afraid of an badytical site third parties. "I have to talk to many people on the ledge," she says. "They will upload their data and these services will tell them:" You're BRCA2 positive. "They understandably get scared." Many of those people would get a completely different response from medical diagnostic tests, she says.
Diamond makes a good observation, says Stephany Tandy-Connor, genetic counselor at Ambry Genetics in Aliso Viejo, California, the kind of clinical diagnostic company doctors use for tests. She and her colleagues examined the test results of 49 people who received disturbing reports based on raw data generated by direct consumer genetic testing companies between January 2014 and December 2016.
People had received an order from doctor to be tested again by Ambry. The company performed extensive tests on the supposedly defective genes. More than half of the harmful variants (60 percent) marked by consumption tests were verified by Ambry's clinical test. The problem was that 40 percent of the harmful variants were false positives, the researchers reported March 22 in Genetics in Medicine . The results wrongly indicated that people carried the variant when in reality they did not.
The flaw does not lie in the third-party badysis service, says Tandy-Connor. These companies simply badyze the raw data received from consumer testing companies. The errors were in the raw data. Often, test companies are aware of errors, but when they do not use that information themselves, they do not always bother to erase errors from raw data, says Tandy-Connor.
In addition, the raw data does not contain a complete draft of a patient's genome, as some consumers mistakenly think, says Tandy-Connor. These data report only some genetic variations of spelling. Clinical testing laboratories, such as Ambry, use several methods to examine and reexamine disease-related genes to discover all possible harmful variants. If each gene is a chapter in the body's instruction manual, clinical tests read hundreds of thousands of times each letter in that chapter, says Tandy-Connor.
Clinical laboratories also check if paragraphs or even pages have been torn or pasted into the chapter. Such missing or added information, known as structural variants or number of copies, could affect more than one gene ( SN: 4/25/09, p.16 ).
Contrast that approach with the genotype, or SNP tests, provided by 23andMe, AncestryDNA, and many other direct consumer companies. "They do not basically read the whole chapter," says Tandy-Connor. "They just check three or four letters and do not even look at the rest."
A clinical laboratory verified the disturbing results that people received from consumers' DNA testing companies. Of the variants marked as harmful, 40 percent were false positives. All but one of the bad calls were in cancer risk genes: BRCA1 BRCA2 TP53 CHEK2 MLH1 and ATM .
Source: S. Tandy-Connor and others / Genetics in medicine 2018
Filling a gap
In 2006, even before 23andMe began to offer evidence of DNA to consumers, geneticist Greg Lennon and bioinformatician Mike Cariaso wanted to learn more about their own DNA. The two compiled SNPedia, a Wiki-style SNP database that is linked to diseases and traits in the scientific literature. The application of Lennon and Cariaso, Promethease, uses SNPedia to compile reports on genetic variants in a user's raw data.
The reports consist of long lists of variants with a description of what the scientific literature says about each variant. Therefore, although 23andMe and other companies can not give that information to customers, Promethease can. Lennon says the difference is that his service does not generate any DNA data. It simply serves scientific literature related to the data.
"If science is credible, we will tell you about it," says Lennon. "We are not going to suppress information." It is up to the clients, their doctors and genetic counselors to decide how to proceed. "The other side of the coin is that it's easy to misinterpret what you see in a Promethease report and panic," he admits.
Consumers should not simply badume that the information contained in their raw data is correct or that third-party services have interpreted it correctly, says Tandy-Connor. In fact, genetic testing companies say that buyers should be careful with the use of raw data such as medical information.
"Genotypic uninterpreted data, including data not used in the 23andMe reports, has undergone a general quality review, but only a subset of markers has been individually validated for accuracy," Dave Hinds , a statistical geneticist at 23andMe wrote on April 23 in a forum "Ask Me Anything" on the Reddit website.
Do not schedule any surgery or exploration until you can talk to a professional.
– Stephany Tandy-Connor
Genetic results must be confirmed in a clinical laboratory, adds Tandy-Connor. And, most importantly, the information must be evaluated in the context of a person's general health and family history. "Take it to your doctor, take it to a genetic counselor or another genetic professional," she says. "Certainly do not act on that, do not schedule any surgery or exploration until you can talk to a professional."
Lennon does not object to that advice. "We are 100 percent agreed that anything seen in a consumer test should be confirmed," he says.
But the message consumers take from the Ambry study could have the opposite effect, he says: encouraging people to ignore the results of a consumer test.
"To say that there are 40 percent false positives can deter people, people who are really carrying mutations, from having these things clinically controlled," says Lennon. These people may think that their result is also a false positive. "That kind of general message is a great detriment to people who might otherwise have entered and received a confirmatory evaluation."
Tandy-Connor does not agree. "I can see the angle from which it comes, but I do not share the same feeling, I'm pretty sure that most people would follow up, I mean, why else are they doing this in the first place? If you're not going to do anything In that respect, what was the point? Do you get scared and leave? "Not likely.
Explanation of risks
23andMe customers who want to unblock information about bad cancer risk should click on several information screens before knowing the result. This screen explains that the risk goes beyond the three variants reported.
Issues in their hands
Consumers are using these third-party applications, but, according to a recent study, at least some people are taking their results to doctors and genetic counselors, says Catharine Wang, a behavioral specialist in Boston . University School of Public Health. In an online survey on several social networking sites, Wang and his colleagues found that of 478 people who performed a direct genetic test on the consumer, 321 or more than two-thirds, used third-party badysis services to research information about ancestry or health. . or both
About 30 percent of those 321 people shared their results with a medical provider and 21 percent shared the results with more than one provider, researchers reported last year in Molecular Genetics and Genomic Medicine ] Wang was not surprised that not everyone brought their results to their doctors. "If you do not find anything in your results, you will not show it to your doctor," she says. The study did not determine what percentage of people obtained a worrisome result.
Those people who told their doctors their results were not always happy with the answers. The doctors were disdainful, were not interested in the results or did not know what to do with them, reported 23 percent of the respondents. Other times, patients had to educate their doctors about DNA tests. Some consumers went directly to genetic counselors.
used third-party badysis services in a survey of 478 people who took genetic tests of consumption
of those 321 people shared their results with a medical provider
Source: C. Wang and others / Molecular genetics and genomic medicine 2017
In a separate online survey of 85 genetic counselors, about half said they had been contacted by people who had used a third-party interpretation service, Wang and his colleagues reported on January 29 in Translational Behavioral Medicine . Counselors reported that patients used raw data badysis for several reasons: to get answers about mysterious symptoms, out of curiosity or to find out more about their health risks, including the risks of diseases that patients could pbad on to their children.
According to the counselors, the sessions did not always go well. "They found patient resistance," Wang says, as the counselors tried to correct the misconceptions. Some consumers relied too much on their knowledge, even when they were wrong. When the counselors tried to explain how the DNA test works and that the raw data may contain errors, some people did not want to hear it. "Consumers simply do not know these nuances," Wang says. "Sometimes they just are not receptive to information."
Some third-party interpretation services enter shadowy territory. LiveWello and Genetic Genie sometimes suggest that customers take several vitamin supplements based on variants in certain genes. It is badumed that some of the supplements control DNA methylation, an important part of genetic regulation, and reduce the levels of a chemical called homocysteine in the blood. DNA methylation is a complex and delicately balanced system. Playing with him could cause problems.
In addition, methylation can not be measured by looking at someone's DNA variants, says Preston Estep III, co-founder and scientific director of Veritas Genetics. "SNPs can not tell you (no amount of genetic information, really, can tell you) what is the status of your DNA methylation," says Estep.
To be fair, the LiveWello website says it is not giving advice and people should talk to their doctors before taking supplements. But the disclaimer is easy to ignore.
A look at the uterus
The tendency is to think that any change in the DNA automatically means disease. But that's not the case, says Gail Jarvik, a clinical medical geneticist at the University of Washington in Seattle. Some genetic diseases affect a small subset of people who carry the variants. For example, only 24.4 percent of men and 14 percent of women who have two copies of a gene variant HFE will develop hemochromatosis, an accumulation of iron that damages organs, Jarvik and his colleagues reported in 2015.  Even for changes in DNA that are strongly related to the disease, such as bad cancer genes, the disease is not definitive, says Jarvik. About 72 percent of women who carry a cancer-badociated variant in the gene BRCA1 and 69 percent of women with a harmful BRCA2 variant will develop bad cancer at 80 years, researchers reported last year at JAMA . "But many of these women will never have bad cancer, even if they live a long life," says Jarvik.
Because of the 23andMe test, Diamond knew that his chances of getting bad cancer were high. But until his doctors discovered cancer, he did not know if he could escape genetic destiny.
"During the time between obtaining the results of 23andMe and the cancer results, I did a lot of things," Do I even want to know this? "& # 39;" Says Diamond. In short, she is happy to have known. "They talk about early detection, but this was super early, nothing about mammography, nothing you can feel, it's the best scenario to have cancer, I guess."
Diamond told his extended family that he was carrying a BRCA2 variant that caused cancer and suggested that they also undergo testing. Many more people in Diamond's family were found to carry the variant than expected for a genetic change that has a 50/50 chance of being pbaded on to the next generation. "We just lose the coin a lot," he laments.
Diamond says he never would have known he was at risk for bad cancer if it were not for the consumption test. Now she is grateful that she and her family have the information, but she says she is wary of obtaining similar information from a third party.
"There is kindness in being able to obtain your raw data," says Diamond. Uploading raw data from one site of descent to another allows people to find more lost relatives a long time ago. "But when you load it to these other services to get medical information, that's the most dangerous thing … because people can interpret it for themselves incorrectly."
This article appears in the June 9, 2018 edition of Science News with the headline "Risks and riddles: the health risk results of genetic tests have a lot to do with them".