October 17, 2006

Transparency in Home (Direct to Consumer) Genetic Testing: Of Cloned Cats and Fetal Sex Predictors

Contributing Editor Ricki Lewis has been looking hard at direct to consumer genetic testing. And cloned cats.:
It was with mixed feelings that I learned of the demise of Genetic Savings & Clone, the Sausalito, CA company that was "the world's leader in the cloning of exceptional pets", as if every strip mall has such an outlet. Founded in 2000 by a billionaire seeking to clone his beloved Missy, of humble mongrel origins, the company intended to eventually clone other members of Canis familiaris for $100,000, and Felis familiaris for $50,000. They succeeded with cats, with a recent price reduction to drum up business.

Animal rights activists protested pet cloning, but a less publicized aim made sense to me - funding research that uses animal embryos at Texas A&M University. If a billionaire's desire to recreate his mutt could support basic research, that's ok, for such research has shed light on causes of recurrent pregnancy loss in humans, among other things. (For the record, I own 6 cats of the uncloned variety, and look forward to being an old crone with 83 of the creatures someday, the more genetically diverse, the better.)

The saga of the recent demise of another genetics-based company offering a direct-to-consumer (DTC) service had more serious repercussions. The saga of Baby Gender Mentor provides a case study of how consumers can be deceived by lists of relevant-sounding scientific articles paired with outrageous claims. It is yet another example of the need for regulation of DTC testing. The emerging buzzword is transparency -- to consumer and health care professional alike as to what exactly a test is testing, and what it means (Lewis).

"Gender Disappointment"

"When I was a resident, the first question in the delivery room was 'is it a boy or a girl?' Nowadays people know that." So began a riveting talk by Diana Bianchi, professor of pediatrics, obstetrics, and gynecology at Tufts University, at the annual meeting of the American Society of Human Genetics in New Orleans October 8-13. Bianchi was referring to the routine use of ultrasound and prenatal tests that reveal fetal gender. She is one of the pioneers of the technology of separating cell-free fetal (cff) DNA from the maternal circulation for use in probing for telltale sequences - such as the SRY gene that heralds a Y chromosome and mutations that cause inherited disease.

Detecting cff DNA grew out of the observation that it's common for a few fetal cells to persist in a woman's circulation, even when that fetus has passed voting age. Sometimes a woman's immune system tunes into those stowaway cells in middle age, causing what looks like an autoimmune attack. As long ago as 1893, doctors reported finding placental cells in the lungs of women who had died while pregnant. Then in 1969, researchers detected Y chromosomes in the nuclei of white blood cells circulating in pregnant women. A 1977 study identified fetal blood cells in 40 to 70 percent of a large sample of pregnant women by the third trimester. In the 1990s Dennis Lo, now at the Chinese University of Hong Kong, and his colleagues took the field in a different direction by amplifying SRY in the maternal circulation - free of cells and not even wrapped up into chromosomes -- and estimated that 3-6% of such DNA in a pregnant woman's plasma is from the fetus (Lo).

Spotting SRY in a mom-to-be's blood is valuable information, because the only way she could be harboring such a macho gene is if she's also harboring a son. By inference, if SRY isn't there, and the pregnancy test strip says "yes", she's carrying a girl. That SRY is a powerful gene, because gender selection is a big market, from individual families wishing to end a string of same-sex births, to entire societies where the fair sex is disappearing (Bhat). The website www.in-gender.com, which is a guide to methods of upping the odds of conceiving, detecting, or banishing an XX or an XY, has a heading for "gender disappointment", with several links to support groups for those enduring this tragedy.

An at-home test called Baby Gender Mentor, from Acu-Gen Biolab, Inc. of Lowell, Mass., offered a test that can purportedly tell gender as early as the 5th week of pregnancy. It cost $25 to submit a blood sample, and $250 to have it processed in a laboratory. The company's website (BabyGenderMentor.com, although the test is unavailable for now) has an impressive bibliography. But like the publication lists at nutrigenetics websites, this one requires some reading-between-the-lines to figure out what the company is actually offering, and how the test has fared as a DTC product. None of the references by themselves validate the Baby Gender Mentor test, but a consumer not accustomed to reading Clinical Chemistry might assume the jargon sounds about right and that the test has passed muster in clinical trials. The situation is about as transparent as mud.

The Acu-Gen website lists 42 scientific papers and patents, most of which detail nuances of PCR, such as blocking repeats to ensure that one is hauling out unique DNA sequences. One paper addresses Y-specific sequences, 3 address cff DNA, and 3 combine the topics, discussing use of PCR to amplify some of that lovely cff DNA. Since Acu-Gen is offering results on samples from weeks 5 through 8, they aren't even targeting fetal material, but embryonic material. But forget Bio 101 for now. I tried to infer just what the heck their test amplifies, which was a little like playing a game of Clue.

My first tip came from the wording that consistently refers to "fetal genetic materials". The plural had to mean RNA, the only other nucleic acid besides DNA. It turns out that two tests are performed on each sample. This is probably because in the absence of the telltale SRY, a daughter's DNA would look just like mom's, unless some marker of embryonic or fetal existence is probed too. Tip #2: what's a gene that's expressed only in an embryo or fetus? My best guess: embryonic or fetal hemoglobin. Haul out some epsilon or gamma globin chains, and you've got a lurking embryo or fetus. (Theoretically one could test for a gene variant known to come only from the father, but that would be much too labor-intensive and not always informative, especially if mom and dad are from the same ethnic group.) What Baby Gender Mentor actually tests for is proprietary, and the company claims it hasn't published clinical trial data because they are awaiting patent protection (Kaiser 2005). So stay tuned.

What drew attention to Baby Gender Mentor, both to consumers and scientists, wasn't the list of publications, but rather the unscientific-sounding claims. In earlier renditions of the website, before mistakes started cropping up, the company claimed 99.9% accuracy, and that they offered a test "superior to any other gender test on the market" - which Bianchi pointed out was news to geneticists. Most convincing to consumers was the offer of a 200% return on one's investment should appearance at birth contradict the company's prediction of gender. It was, I think, a smart marketing strategy: simply charge enough to offset the payback for any errors, all the while creating an aura of confidence. Many fell for it. But then the publicity backfired.

First came a spot on the Today Show that, while perhaps not as offensive as the "who's the daddy" reveals on Jerry Springer, was still an entrant in the bad taste hall of fame. A pregnant woman with two daughters had the gender of her third child-to-be revealed on air by a company representative. The verdict - yet another XX - was greeted with a glum "another one" from the woman, before she muttered a subdued "a third is great" (Kaiser 2005). Newspapers, NPR, and local TV and radio stations picked up the story. More distressing was an ABC Action News in Tampa Florida report on a woman whose husband was serving in Afghanistan. She was told the fetus had a lethal extra chromosome 18, detectable somehow by her sample having excess DNA. The child was born healthy. Then cases began to accrue of ultrasounds inconsistent with Baby Gender Mentor predictions. This led to women undergoing the risk of invasive prenatal diagnosis procedures to straighten the contradiction out.

Bianchi, a vocal supporter of regulation of DTC genetic tests, wasn't surprised as the mismatches began to accumulate, because studies that she had participated in and were listed in the Acu-Gen bibliography had shown that detecting cff DNA is not nearly as far along as Acu-Gen would have a consumer believe, with their claims of "unsurpassed sensitivity." In that study, samples from 20 women 10-20 weeks pregnant were divided in 5, and sent to 5 different labs for analysis of total DNA and presence of SRY (Johnson). All but 4 of the 100 samples were assigned the correct gender - not quite the 99.9% that Acu-Gen claimed. Acu-Gen's technique, whatever that might be, would be expected to be even less accurate because levels of embryonic cell-free DNA are lower than fetal levels.

The latest incarnation of Acu-Gen's website oozes disclaimers, yet still reads "The test is able to identify the presence of fetal genetic materials often as early as five weeks after conception" - the company president still unaware of the distinction between embryo and fetus. The disclaimers warn anyone who's ever had an abortion, miscarriage, transfusion, or IVF, or is less than 8 weeks pregnant, that results may be "inconclusive". And instead of admitting to mistakes, the company oft evokes the "vanishing twin" excuse - that the detected gender was indeed present as part of a twosome, but died. It happens.

The current status of Acu-Gen and Baby Gender Mentor is somewhat unclear. The company president told NPR that the test was going on hiatus for a year while data accumulate. PregnancyStore.com, a marketer of Baby Gender Mentor, offers testimonial after testimonial, along with decidedly unscientific language in broken English, and at the end simply states, "Sorry. We are temporarily out of stock of the Baby Gender Mentor". Meanwhile, a class action lawsuit has been filed against Acu-Gen.

A Sea Change?

Baby Gender Mentor may, however, go down in history as contributing to the wake-up call to the agencies that should, and could, protect consumers against genetic tests being marketed when they are not quite ready for prime time. FDA hasn't regulated the test because it isn't a kit, and it doesn't address a disease or "condition" such as pregnancy. Nor is fetal (or embryonic) gender testing under the purvue of the Centers for Medicare and Medicaid Services (CMS), which enforce the Clinical Laboratory Improvement Amendments (CLIA), which currently ignore genetic tests as a specialty worth regulating. And the FTC has apparently not gone after the claims that are at odds with scientific evidence.

But change is in the air. The American Society of Human Genetics is currently drafting a position statement concerning DTC genetic tests. Rather than objecting to them across the board, the society will suggest that in some circumstances, they could be valuable, but that they all must be regulated and that they all must adhere to a policy of transparency.

Legislation is in the works too. Barack Obama (D-Ill) introduced a bill (the Genomics and Personalized Medicine Act of 2006) on August 3 that provides specific guidelines for the development and dissemination of genetic tests. The bill asks that CLIA embrace genetic testing, calls for guidelines for health professionals who may not be that familiar with genetics and genomics, and for Health and Human Services to develop risk-based protocols to review all tests.

Across the pond, the Special Non-invasive Advances in Fetal and Neonatal Evaluation (SAFE) network is a 19-nation effort to create partnerships that promote the development and use of routine non-invasive prenatal diagnostic and neonatal screening tests (http://www.safenoe.org/cocoon/safeorg/). The 5-year program began in March 2004, and includes among its objectives monitoring use of fetal DNA and RNA for detecting genetic disorders.

These new efforts focus on genetic testing for disease, but the experience with Baby Gender Mentor reveals what can go wrong when errors of intentional omission - that is, not including references to clinical trials of whether tests can work in a DTC format without causing harm - mislead consumers. For the downside of Baby Gender Mentor may be more serious than "gender disappointment." It may mean unnecessary invasive testing, mistaken termination of pregnancies predicted to be male in families with known X-linked conditions, and last but not least, the tainting of a technology that has been more than a decade in the making and will likely soon revolutionize prenatal testing - legitimately.

In the meantime, if anyone tries to sell you a cloned cat whose gender you can select, head the other way.

Ricki Lewis

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