Genetic study on longevity may be flawed

When scientists announced last week that they had identified 150 genetic features that could be used to predict whether a person will live past 100, the public was intrigued (and I reported on it myself) – but fellow scientists were skeptical.

A few aspects of the study raised red flags for geneticists.

First, the impressive 77% prediction accuracy was unheard of for similar types of reports, and particularly stood out given the relatively small number of subjects for this study. The study featured more than 1,000 centenarians -- an impressive number given how rare it is for people to live this long. But most genetic studies of this type (ones that look at the entire genome to try to find associations with particular traits or diseases) need DNA data from tens or hundreds of thousands of people to reach meaningful conclusions.

There were also some methodological issues. The researchers weren’t totally consistent about the DNA-analyzing technology they used over the course of the study, reportedly because the tool they used at the beginning of the study was taken off the market midway through, so they had to switch to a comparable but not identical product.

Furthermore, genetic information from the centenarians and the younger controls was collected differently, potentially introducing errors.

The blogosphere has quickly picked up on the story since Newsweek magazine broke it July 7.  Daniel MacArthur at Genetic Future provides a technical perspective, including a graph showing one of the troubling ways that this study deviates from the usual reports of this type.

The personal genome-sequencing company 23andMe also published a blog post about the topic. The firm used its extensive genetic data of customers (including 134 who were 95 and older and 27 who were 100 and older) to test the predictive power of the reported genetic markers -- and found it to be not significantly better than random.

It’s too early to toss the study in the trash; simple follow-up experiments with standardized equipment could provide a quick answer about the truth of it. Regardless, these concerns do raise significant questions about how to ensure that good journals publish good science.

-- Rachel Bernstein

Ancestry, not just race, is important to personal medical history

Doctors often ask patients to list their race -- white, Latino, African American, Asian, Native American -- to help them provide better healthcare. They do this because loads of medical research shows that the incidence of certain diseases and treatment success can vary somewhat from race to race.

But the more important question may be: What is your genetic ancestry?

A study released Wednesday in the New England Journal of Medicine examined the accuracy of a lung function test and how race and ancestry played a role in the test's accuracy. A lung function test measures damage to the lungs caused by asthma or other disease. However, the definition of "normal" lung function is known to vary substantially by race. For example, doctors have long known that vital lung capacity (the maximum amount of air that can be expelled after maximum inhalation) is 6% to 12% lower in blacks compared with whites and Native Americans.

Researchers looked at data from more than 3,000 patients that included their lung function test results, standard information on race and additional information on genetic ancestry that was obtained through genotyping. The study found that standard race categories don't capture the extent of ancestral diversity and, thus, may limit the amount of information available to a doctor in making a diagnosis or ordering treatment. Instead, many people have a rich and diverse genetic background that does not lend itself to a simple classification, such as "white" or "Asian."

For example, when using genetic ancestry data, the study showed a strong link between African ancestry and lung function measurement in both men and women. According to the findings, for 6.4% of people in the United States who identify themselves as African American, the actual percentage of African ancestry would be 15% higher or lower than average -- a difference that would result in an incorrect estimation of lung function test, and possibly, mistakes about the severity of lung disease. About 2.1 million self-identified African Americans have asthma. But based on the study conclusions, the severity of the asthma would be misclassified in about 4% of those patients.

"When we force patients into an individual box, such as 'African American' or 'Caucasian,' we're missing a lot of genetic information," senior author of the study Dr. Esteban G. Burchard, of UC San Francisco, said in a news release. "This study provides new evidence that genetic ancestry correlates to physiological measures. With it, we're one step closer to personalized medicine."

On a more practical level, the study points to the need for improvements in measuring lung function in some people. In an editorial accompanying the paper, authors noted: "Refinements are needed for poorly represented or misrepresented populations and for persons of mixed ancestry, who represent an increasing proportion of the U.S. population."

-- Shari Roan
 
Photo: Getty Images

 

Preventing homosexuality in utero: Could we? Would we? Should we?

A workhorse drug that's been around for decades has, in recent weeks, stirred up a biomedical debate that will likely resonate with any parent who's ever asked him or herself: If I could prevent my child from being gay, would I?

Dexamethasone is a corticosteroid that has been widely used in the treatment of arthritis, of intestinal, kidney and thyroid disease, in certain kinds of cancers. It's also been prescribed to — and used by — pregnant women carrying female babies who are at genetic risk of a condition called congenital adrenal hyperplasia, or CAH.

Children born with the genetic anomaly will need a lifetime of medication to ensure their normal growth, sexual development and reproductive function. But for girls, one manifestation of CAH is evident at birth: her external genitalia will look more masculine than feminine. The resulting person used to be called a hermaphrodite. The preferred term now is intersex, a condition of gender ambiguity that can be caused by a number of different conditions.

Dexamethasone, when administered in utero, appears to correct the development of a female fetus' genitalia. As a result, it relieves parents and child of a difficult decision — to have later corrective surgery, with all of its risks.

That a parent should take it upon him or herself to "correct" a child's ambiguous gender identity is debatable enough. (The Intersex Society of North America maintains that "parents' distress must not be treated by surgery on the child.") What ignites serious controversy is a side effect of  prenatal dexamethasone — its ability to feminize, not just the external genitalia of a girl with CAH, but her internal outlook and her behavior. That is significant because among CAH's more subtle effects, according to Mount Sinai Medical Center endocrinologist Dr. Maria I. New, is that women who have it tend to be more masculine in their behavior and interests, including sexual attraction to women. New has been a leading researcher on CAH and, in an earlier practice, is reported to have prescribed dexamethasone. She and a research collaborator, Columbia University psychologist Heino F.L. Meyer-Bahlburg, has investigated at length the "psychosocial" as well as medical issues faced by those with CAH.

In short, dexamethasone seems to hold the promise not only of sparing a child a difficult and risky surgery, it may also redirect a sexual trajectory that will lead to bisexuality or lesbianism.

That, say bioethicists, is going too far. In a recent posting on the Bioethics Forum of the Hastings Center, a nonpartisan bioethics institute based in Garrison, N.Y., Alice Dreger, Ellen K. Feder and Anne Tamar-Mattis warn that treatment of the external manifestations of CAH are debaeable enough in and of themselves: But, in this case, that treatment will make it possible for some parents to take actions motivated -- at least in part -- by a desire to prevent their child from becoming a homosexual.

Dreger, Feder and Tamar-Mattis suggest that in insisting that homosexuality is not a choice but a biologically determined fact of identity, gay and lesbian rights activists may have set themselves up for medical researchers to see sexual orientation as a condition that can be "fixed." They "should be wary of claims that the innateness of homosexuality will lead to liberation," they wrote. Instead, it might "very well lead to new means of pathologization and prevention," write the bioethicists.

Also unclear is whether the use of dexamethasone by pregnant women is safe — or for that matter, effective. Neither has been demonstrated by clinical trials. The prescribing of a drug in treatment of a condition other than that for which the Food and Drug Administration has approved it — called off-label — is very common and legal. But the debatable use of dexamethasone in pregnant women has caused sufficient concern among endocrinologists that the Endocrine Society next month is expected to issue a consensus document warning physicians who prescribe prenatal dexamethasone for CAH that the treatment should be considered experimental. That imposes far greater ethical strictures on physicians: They must seek the approval of an ethics and safety review board and satisfy other conditions designed to protect a patient's rights. 

Want to know more about what researchers have learned about the bases of homosexuality, and the ethical debates that result? Here's an article on the subject from the LA Times Health section.

--Melissa Healy

Students' DNA on the curriculum at Stanford Medical School

In addition to hitting the books, students at Stanford Medical School will have the chance to study their own DNA as part of a new course being offered over the summer.

The class – Genetics 210: Genomics and Personalized Medicine – is designed to give future doctors a sense of how to deal with patients who take the type of tests currently offered by companies like Navigenics and 23andMe to predict their genetic risk for certain diseases. The tests – sold directly to consumers over the Internet – examine mutations on specific genes that are thought to make people more or less likely to develop Alzheimer’s disease, age-related macular degeneration and other conditions.

But with so much still unknown about the link between genes and disease, the tests have serious limits. That’s one of the lessons the class will offer, according to the university. Students will also learn how to analyze and interpret the test results, as well as discuss the legal and ethical issues surrounding personal genomics. (One recent development: Last week the U.S. Food and Drug Administration told the companies that the tests should be considered medical devices and must get FDA approval to remain on the market.)

Swabbing one’s cheek is not a requirement – students who feel squeamish about seeing their own genetic code can use a publicly available DNA sample instead. Also, to reduce the risk that students will submit to the test just because it’s free, the university will charge a $99 copay. These and other stipulations were recommended by a panel of scientists, clinical professors and bioethicists after a yearlong review of course.

The course still concerns some genetics watchdogs, such as Jesse Reynolds at the Center for Genetics and Society in Berkeley. The eight-week elective could lead to more widespread genetic testing among Stanford students, he writes on the center’s blog, Biopolitical Times. It could also be seen as endorsement of the controversial direct-to-consumer DNA testing industry.

But the Stanford class is not nearly as worrisome as UC Berkeley’s plan to send DNA collection kits to thousands of incoming freshmen and transfer students over the summer, Reynolds writes. The Bring Your Genes to Cal initiative was intended to give new students something meaningful to discuss in campus seminars this fall, but privacy advocates have urged the university to cancel the program.

-- Karen Kaplan

Photo: Stanford medical students will add their DNA to the curriculum this summer. Credit: Al Seib/Los Angeles Times.

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Personalized DNA testing kits should be regulated as medical devices, the FDA says

The U.S. Food and Drug Administration has decided that the personalized DNA tests sold by companies like 23andMe are medical devices subject to government regulation, and the federal agency says the tests must be vetted by regulators if they are to remain on the market.

Alberto Gutierrez, director of the Office of In Vitro Diagnostic Device Evaluation and Safety at the FDA’s Center for Device and Radiological Health, sent letters on Thursday to 23andMe, Navigenics, DeCode Genomics, Knome and Illumnia telling the companies that they should have submitted their tests to the FDA before offering them for sale to the public. According to the letters, the tests qualify as medical devices because they are:

intended for use in the diagnosis of disease or other conditions or in the cure, mitigation, treatment, or prevention of disease, or [are] intended to affect the structure or function of the body.

For instance, Gutierrez told reporters, a test might tell a woman that she has a higher-than-average risk of developing ovarian cancer, and that information might prompt her to have her ovaries removed. But the accuracy of these tests is an open question, and many genetics experts say their predictive value is dubious at best.

In the letters (which were posted on the FDA’s website Friday), Gutierrez asked the companies to take “prompt action” and schedule meetings with the FDA to find out what they should do to win regulatory approval – or to make their case that the FDA is wrong.

That’s what Navigenics intends to do, according to this post on the company’s blog:

We believe our services comply with all existing federal and state regulations, and look forward to continuing our dialogue with the FDA to ensure transparency and the optimal use of genetic information as it applies to personalized medicine.

23andMe took a similar position, arguing that people have a right to know their genetic information and that the FDA should not stand in their way.

While the companies and regulators hash things out, the test kits will be able to stay on the market (they are sold primarily to consumers via the Internet). Gutierrez said that such a drastic move would have been unfair considering that the FDA had not made its views explicit until now.

But the move is part of a recent trend at the FDA to crack down on DNA tests offered directly to consumers. Last month, the Walgreens drug store chain backed away from a plan to sell a consumer-oriented test kit made by Pathway Genomics in its stores after the agency said the kit lacked FDA approval.

-- Karen Kaplan

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Photo: This chip, which contains the DNA of a Navigenics customer, is a medical device subject to regulation from the FDA, according to the agency. Credit: Steve Yeater

Big study identifies new genes that may be involved in autism

A large international consortium of authors (including some at UCLA) have identified new genes that appear to be involved in autism somehow. The findings appear in the journal Nature.

The researchers in this big effort examined the DNA of 996 children with autism spectrum disorder plus their parents, and compared what they found with the DNA of 1,287 matched controls (who didn't have autism but were of similar ancestry, etc). They looked for differences between the two groups in places in the genome where chunks of DNA are repeated or deleted. 

Such repeats or deletions were found 20% more often in the autism group -- some of them situated at genes that, therefore, may be involved in the condition. The implicated genes appear to be involved in functions such as nerve connections and nerve growth, and others had been implicated in learning disabilities.

In some cases, the parents also had these little duplications or deletions, implying inheritance. In other cases, the kids had them but the parents did not, implying, perhaps, that they had developed in sperm or eggs that gave rise to the children.

That genes are involved in autism is not a surprise: The condition is known to run in families, and twin studies indicate inheritance. And previous studies have identified some genes. But this was the biggest autism-DNA study yet, and it adds to the list of genes that could be involved in autism.

The study doesn't produce any kind of diagnostic test, since the genes identified don't definitively predict autism, but just indicate heightened risk (some of the researchers are now working on a project to see whether the genes can help in diagnosis of new cases of autism). And they also don't explain more than a fraction of autism cases.   

Here's the Nature paper.

You can also read several news releases explaining the study in simpler terms -- for example, one from UCLA and one from Oxford University.

Here's a fact sheet about the global Autism Genome Project.

And here's a write-up at Scientific American.

--Rosie Mestel

Personal genetic test results were mixed up, company admits [Updated]

A leading personal genomics company, 23andMe, says some of its customers received the wrong test results recently because samples were incorrectly processed. Up to 96 customers were affected by the mix-up. According to the blog Genetic Future, which reported on the mix-up Monday, some customers were upset about the test results before learning that they were given the wrong information. One woman suspected her baby might have been switched in the hospital at birth.

The company, based in Mountain View, Calif., has since notified all of the customers affected and posted an announcement on its website that is accessible to customers who have accounts with the company.

This statement was released to the Los Angeles Times on Tuesday:

"We recently determined that a number of new 23andMe customer samples were incorrectly processed by our contracted lab. We want to clarify what happened with the sample errors, how it happened and what we're doing to prevent it from happening again. Providing each and every one of our customers with accurate data is 23andMe's number one priority, and we fully realize the gravity of this incident.

Up to 96 customers may have received and viewed data that was not their own. Upon learning of the mix-ups, we immediately identified all customers potentially affected, notified them of the problem and removed the data from their accounts. The lab is now concurrently conducting an investigation and re-processing the samples of the affected customers and their accurate results will be posted early next week. We expect the investigation will be complete over the next several days and we will provide further details when we have them.

We are currently putting additional procedures in place that will add an extra layer of safeguards to help assure that similar incidents do not occur in the future. We are deliberating on a process that would include removing manual steps at the lab, completely automating the sample analyses, and implementing further checks of the data before it gets loaded into customer accounts. Please be assured that our testing laboratory's processes comply with strict professional, regulatory, and corporate quality assurance standards for ensuring that all laboratory test results are accurate. The laboratory will adopt corrective action as warranted based on the findings of the investigation.

The science behind 23andMe's personal genetics service remains proven and sound. We recognize that this is a very serious issue and your trust is of the utmost importance. We hope that this helps clarify what has happened and what we are doing to prevent these problems in the future. Please contact me at khomenko@23andme.com if you have any further questions. We appreciate your comments and feedback."

Although lab mistakes are certainly not uncommon, the experience is a reminder that the field of personal gene testing is new and untested. Genetics experts are not sold on the value of personal gene testing, although medicine is moving swiftly toward a personalized approach and gene testing will, someday, be routine. Labs need to redouble their efforts to minimize potentially devastating mistakes.

[Updated at 1:29 p.m.: This statement was released by 23andMe:

We recently determined that a number of new 23andMe customer samples were incorrectly processed by our contracted lab. We want to clarify what happened with the sample errors, how it happened and what we’re doing to prevent it from happening again. Providing each and every one of our customers with accurate data is 23andMe’s number one priority, and we fully realize the gravity of this incident.

After a full investigation from our contracted laboratory and independent confirmation by 23andMe, we have found that the processing mistake was caused by human error and the incorrect placement of a single 96-well plate used in processing samples.

We are uploading the correct data to impacted customers today, after again independently verifying the new results.

Both our contracted laboratory and 23andMe are adding new procedures to prevent this from happening again.  Our contracted laboratory has adjusted the mounting process for these 96-well plates and this new adjustment physically prevents any incorrect manual placement of the plates used at this step of processing.  As an additional safeguard, 23andMe will collect data regarding sex for all new customers prior to laboratory processing so an additional quality check can be conducted prior to uploading data.

We are committed to continually improving the quality of our processes.  We hope this clarifies what has happened and how we intend to prevent this from happening in the future.]

-- Shari Roan

Photo: A scanning probe microscopic image of human chromosomes. Credit: Reuters

The FDA approves new drug for Pompe disease

The Food and Drug Administration on Tuesday approved a new drug called Lumizyme for the treatment of Pompe disease, a disabling genetic disorder that is often fatal. A drug called Myozyme is available to treat the disease, but supplies have been severely restricted and it is reserved for use in children and infants with the most severe form of the disorder. Approval of Lumizyme, which is closely related to Myozyme, will make treatment available to much larger numbers of people.

Pompe disease, which affects about one in 40,000 Americans, is caused by mutations in the gene that is the blueprint for an enzyme called acid alpha-glucosidase, which is used by tissues to convert a form of sugar called glycogen into energy. If the enzyme is not working properly, glycogen builds up in tissues, especially in the heart and muscles, weakening them severely. Many different mutations have been discovered, and they vary in severity. Some mutations produce only a partial impairment in activity and the disease does not become a problem until adolescence or adulthood. In other cases, however, the enzyme does not work at all, and the disorder can be fatal at a very young age unless treated. In infants, symptoms include respiratory problems that often lead to infections, feeding problems, poor weight gain, muscle weakness, floppiness, head lag and an enlarged heart. More than half of victims also suffer enlarged tongues. In the late onset form, the primary symptom is muscle weakness leading to respiratory problems that can be fatal. The heart is usually involved, but it does not become grossly enlarged.

Myozyme, produced by Genzyme Corp. of Cambridge, Mass., is a synthetic form of alfa-glucosidase that breaks down the glycogen, easing Pompe symptoms. The company originally produced the drug in 160-liter batches, which limited the available supply so that its use had to be restricted to infants and children who were most severely affected. The company applied to the FDA to manufacture the drug in 2,000-liter batches, but the agency determined that the synthetic enzyme produced in the larger batches was slightly different from the original product. Apparently, more sugar molecules are attached to its surface. The company was thus forced to conduct clinical trials of the new form, which it chose to call Lumizyme. The safety and efficacy of the drug was demonstrated in a trial on 90 late-onset patients ages 10 to 70, and the FDA granted approval. An estimated 200 adult patients in this country are already receiving the drug on a compassionate basis, and it has already been approved in several other countries.

Because it is a protein, the drug has to be administered by infusion. The primary side effects are allergic reactions to the drug, which include hives, diarrhea, vomiting, itchy skin, skin rash and chest discomfort. The drug will carry a so-called black box warning cautioning about the possibility of severe allergic reactions. The company will undertake a post-marketing surveillance program to monitor for side effects, and the drug will be available only through a restricted distribution system to ensure that it reaches the proper patients, the FDA said.

-- Thomas H. Maugh II

How a fat cell comes to be

Look at that fat cell! Lovely, yes? Ever wonder how one forms?

Well, it just so happens that an article in the current issue of the journal Genes and Development describes how immature fat cells pass through a fleeting, previously unappreciated "intermediate-fat-cell" stage before emerging, like a butterfly from a chrysalis, into full, fatty maturity.

Well, maybe not quite like a butterfly emerging from a chrysalis. But the finding does have implications for drug development.

Scientists at the University of Pennsylvania School of Medicine found that early stage fat cells first enter an intermediate fat-cell stage. The intermediate stage is kick-started by hormones related to cortisol, the stress hormone. All kinds of changes in gene activity happen during this intermediate stage, ones that send the fat cell inexorably down the road to maturity even after the trigger has gone away.

Study author Dr. Mitchell Lazar of Penn suggests that these gene changes may offer clues to drugs that might stop the fat cells from maturing. Leads would seem to be needed, as quite a few anti-obesity candidates have not panned out. (One current hope is Qnexa, a combination of the drugs phentermine and topiramate, currently under review by the Food and Drug Administration.)

Photo credit: Dr. Mitchell A. Lazar, PhD / University of Pennsylvania School of Medicine

FDA has questions about DNA testing kit, so Walgreens backs off on selling it

Bad news for those of you eager to buy a DNA testing kit at Walgreens: The drug store chain has put off plans to carry the controversial product in its stores.

It turns out the Food and Drug Administration has some questions for the kit's manufacturer, San Diego-based Pathway Genomics. According to this story in Thusday's Los Angeles Times, the FDA's deputy director for patient safety and product quality, James Woods, is concerned that his agency hasn't approved the testing kit for sale. Woods sent Pathway Genomics a letter about the situation this week.

"If you do not believe that you are required to obtain FDA clearance or approval," Woods wrote, "please provide us for the basis for the determination."

The Insight Saliva Collection Kit was expected to sell for $20 to $30. Users would deposit some spit and send it off to a testing lab. Then they would go online to order tests that would analyze their DNA for risks for a range of disease, gauge the effectiveness of certain drugs, or check whether they are carriers for dozens of genetic disorders.

In a statement, the company implied that it could sell the products in a bricks-and-mortar store because it has been selling the same kit online for a year. But the company also stressed that it was "continuing discussions with the FDA about the regulation of personal genomic information."

Meanwhile, Walgreens decided it was safer to keep its distance from Pathway and its product "until we have further clarity on this matter," said spokesman Jim Cohn.

-- Karen Kaplan

Photo: This DNA testing kit will not be appearing on Walgreens shelves in the near future. Credit: Business Wire