Julie Kennerly-Shah and Summit Shah.
Julie Kennerly-Shah and Summit Shah were dating back in 2016 when they decided to buy kits from 23andMe, the popular consumer DNA health and ancestry company. Like many customers, they were doing it to learn more about their heritage, but also to see if there were any health insights they could act on.
When they got their results a few weeks later, they mostly used the reports to tease each other about traits like who was more likely to have body odor or wet earwax.
“It was kind of fun to joke around with each other and say that I don’t need to shower, or you need to shower more frequently,” said Shah.
But they also exported their data to Promethease.com, a third-party DNA analysis company that links detected genes in a person’s DNA report to published research about those genes, then summarizes the potential medical implications of those genes. Kennerly-Shah, a pharmacist, and Shah, a doctor, were in fact more eager to see what results Promethease would turn up, as they were both medical professionals who felt they could parse the more complicated ― but unvalidated ― genetic reports that turned up.
The initial reports weren’t very interesting, but the site promised to provide new insights over time as they added more research to their database. And in January 2018, when the couple, now newlyweds, logged back into Promethease.com, they were shocked to see a new notification on Kennerley’s dashboard: She had a gene mutation linked to Lynch syndrome, a rare genetic condition that gives people an over 80 percent risk of developing colon cancer and women a 71 percent risk of endometrial cancer. She also had a higher risk of familial hypertrophic cardiomyopathy, which is a genetic heart disease that increases the risk of arrhythmias and sudden death, even in people with no symptoms.
The couple was terrified.
They were in the middle of a medical mission trip in Malawi when they got the result and felt helpless that they couldn’t see a genetic counselor right away. While both conditions are serious, Kennerly-Shah and Shah were most concerned about Lynch syndrome. Kennerly-Shah was very familiar with this devastating genetic condition — she worked at the James Cancer Hospital in Ohio, which is currently doing a genetic study with colon cancer patients and their families to see if families with multiple cases of colon cancer may have the condition.
“Our first reaction was to dive in to being the pharmacist and physician and looking up as much research as we could find — not only on Lynch syndrome but the reliability of genetic testing in general,” said Kennerly-Shah. “Summit was probably more scared than I was, and I think that probably increased my anxiety.”
Kennerly-Shah and Shah began to make new plans. They might have to start a family earlier than they wanted ― hysterectomies are often recommended as a preventive measure for women with Lynch syndrome. And they’d likely have to achieve pregnancy through IVF treatments, which could ensure they only implanted embryos that did not carry the mutation.
This story has a happy, if somewhat nerve-wracking ending: Acting on the advice of colleagues, when Kennerly-Shah got back to the U.S., she immediately scheduled an appointment with a genetic counselor at The Ohio State University Wexner Medical Center to do tests with genetic companies that specialize in cancer and heart disease analysis to confirm that she was at risk for Lynch syndrome.
When the results came back, Kennerly-Shah was in the clear. She did not have genetic mutations linked to either condition, and she and her husband could resume their life planning as a young, healthy couple.
But their story demonstrates both the risks and benefits of direct-to-consumer genetic testing for health purposes. While advocates for these tests say they can give people more control over their own treatment and empower patients to advocate for themselves in medical settings, Kennerly-Shah experienced unnecessary fear and anxiety over results that turned out to be false positives. And experts fear that people who get results like Kennerly-Shah’s may take the results to doctors who could recommend invasive treatments without confirming the condition in clinical tests.
23andMe, the only direct-to-consumer genetic test authorized by the FDA to offer reports on genetic risk, claims to have more than 2 million customers. Only a fraction of these customers upload their genetic report to Promethease (its founders said in a past interview that the site generated up to 500 reports a day), and there is no data on how many customers take action based on what they find.
A doctor would have never ordered a cancer or heart disease genetic screening panel for someone like Kennerly-Shah, who had no symptoms and no family history of the disease, if it hadn’t been for her Promethease.com results.
“If their doctor wanted to order this test, they couldn’t do it,” said Dr. Ellen Wright Clayton, a genomics and ethics researcher at Vanderbilt University who was not involved in Kennerly-Shah’s care. “But the question that you could ask is, if this is a test that we don’t think is medically appropriate in general practice, why should … the healthcare system have to pay for a follow up? That’s part of what we’re talking about here.”
In general, these direct-to-consumer DNA test results are so compelling that they can’t reasonably be ignored by conscientious doctors, so they typically set off a cascade of medical interventions — such as additional testing — with no guarantee that health insurance coverage will pay for anything. Because of the results from Promethease, for example, Kennerly-Shah had to pay $250 out of pocket for in-depth testing to confirm the results.
And that’s a best-case scenario. The results of these direct-to-consumer tests could prompt less research-driven doctors to recommend invasive preventive treatments that would have been completely unnecessary.
Dr. Amanda Toland, a cancer and genetics researcher and member of the care team that reviewed Kennerly-Shah’s case, is concerned that a more aggressive doctor, or a doctor who isn’t well-versed in genetic research, could have recommended a hysterectomy or similarly invasive medical treatment simply based on the results of a patient’s direct-to-consumer analysis.
For instance, when doctors were first learning how mutations on the genes BRCA 1 and BRCA 2 might contribute to higher risk of breast and ovarian cancer, she did hear of women getting preventive mastectomies even though their genetic analysis results were inconclusive or showed no association with disease.
Doctors could say, “OK, if you have this mutation, you can think about having your ovaries out and we need to get you doing these screenings,” Toland said. “You could have complications from any types of those things. It’s scary. It’s very scary.”
The Trouble With At-Home Genetic Testing: False Positives
Kennerly-Shah and Shah waded into unregulated waters by uploading their data to Promethease.com, a site that FDA hasn’t cleared to offer genetic services. 23andMe, which is currently the only direct-to-consumer genetic test authorized to report on health risks, also started off offering unregulated genetic screening.
In 2008, 23andMe started offering people genetic testing for $999 (a relative bargain at the time), and the company’s founders weren’t shy about suggesting it had the potential to save lives. But the Food and Drug Administration decided in 2010 that the DNA testing kits amounted to a medical device, and that 23andMe and other companies needed to apply for approval before marketing the service. Then, in 2013, the FDA banned 23andMe outright from selling the health analysis component of their DNA tests. It wasn’t until 2017 that 23andMe won regulatory approval for health risk reports on 10 diseases.
Part of the service’s appeal has been the way it removes the barrier to entry for accessing one’s own genetic data. A popular perspective, evoked even by Shah in the aftermath of their scare, is the idea that genetic testing should be available to the consumer. In other words, we own the rights to our own genes and have a right to access this information and use it for as many screening tests as we want.
This ethos ignores some of the shortcomings of consumer-facing genetic data companies that clinical, professional-grade services do not have. Promethease.com does not share information with its customers on their rate of false positive results. In fact, neither does 23andMe.
Scientists at Ambry Genetics, a clinical diagnostics company, found that when they ran clinical-grade tests to confirm the results from direct-to-consumer testing and analysis on 49 patients, 40 percent of the direct-to-consumer results were actually false positives. A spokesman for 23andMe noted, however, that the genetic variants Ambry ran from 23andMe were accurate.
Anecdotally, doctors are also confirming false positives in patients who come to their office with test results in hand. For example, Toland said that in addition to Kennerly-Shah, her center saw two other patients trying to confirm serious disease risks they had found on direct-to-consumer genetic testing that month. All three of them turned out to be false positives.
When asked about this issue, the commercial facilities are quick to recast their role as informational rather than clinical ― a departure from the Silicon Valley premise that more data means more actionable insight.
A spokesman for 23andMe said the company doesn’t recommend or endorse sending your genetic data to third-party sites for health analysis, as the company’s research on raw genotype data has not been completely validated for accuracy. However, 23andMe makes the data available for export because the company believes that people have a right to their own genetic data.
Greg Lennon, a spokesman for Promethease, called the company a “literature retrieval service” and emphasized that it doesn’t generate or edit any data that consumers upload from 23andMe.
This kind of “caveat emptor” language is par for the course for companies that want to minimize their liability. But companies don’t sufficiently warn consumers ― patients, really ― about the expensive and emotional “wild goose chase” that these test results can trigger, says Clayton.
In a conversation with Shah about false positives on a Promethease-moderated Reddit thread, an unnamed company spokesperson denied responsibility for this issue.
“Most of these DTC test results are not clinically validated, and while the data from them can be quite informative, it’s a caveat emptor world, and before a user got their data, they checked quite a few online ‘boxes’ acknowledging they understood this.”
But the company went on to say they were collecting data on errors.
“We are indeed collecting data on false positives (and false negatives) and sharing it when it’s reliable,” the spokesman told Shah.