New DNA reader to bring genetics to clinics

NEW YORK (Reuters) - A new DNA reader could bring genetics to medical clinics.

After years of predictions that the "$1,000 genome" -- a read-out of a person's complete genetic information for about the cost of a dental crown -- was just around the corner, a U.S. company is announcing Tuesday that it has achieved that milestone and taken the technology several steps ahead.

The new genome-sequencing machine from Ion Torrent, a division of Life Technologies Corp., in Guilford, Connecticut, is 1,000 times more powerful than existing technology, says CEO and chairman Jonathan Rothberg.

Taking up about as much space as an office printer, it can sequence an entire genome in a single day rather than six to eight weeks required only a few years ago. The new sequencer, says cardiologist Eric Topol, chief academic officer of private California hospital and doctor network Scripps Health, "represents an exceptional advance and can change medicine."

Ion Torrent will sell the tabletop machine, called the Ion Proton Sequencer, for $99,000 to $149,000, making it affordable for large medical practices or clinics; existing sequencers cost up to $750,000. The computer chip and biochemicals to sequence a genome will cost $1,000, compared to, for example, $3,000 to test for mutations just in the BRCA genes that raise the risk of breast and ovarian cancer and $5,000 for a complete genome sequencing by Ion Torrent competitor Illumina Inc.

For a graphic on the shrinking cost of genome sequencing, see: http://link.reuters.com/xys85s

For now, Rothberg expects research labs to be his main customers, using Proton to obtain the complete genome sequence of people with cancer or autism, for instance, and thereby elucidate a disease's underlying genetic causes as well as possible ways to treat it. The company has signed on Baylor College of Medicine, Yale School of Medicine and the Broad Institute as its first customers.

Other scientists and physicians, however, say the long-awaited arrival of the $1,000 genome opens the door to widespread whole-genome sequencing even of people who are not ill. And that raises ethical, legal, and medical issues that experts are only beginning to grapple with.

"I'm a big proponent of bringing genetics into the clinic," says Thomas Quertermous, chief of the division of cardiovascular medicine at Stanford University and an expert in the genetics of heart disease. "But it has to be done in a timely way, and not before its time."

Babies might be first in line for whole-genome sequencing. Every state requires newborns to be screened for at least 29 genetic diseases.

"If the cost of whole-genome sequencing gets sufficiently low, you could sequence all the genes in a newborn" for less than the individual tests and follow-ups required when one comes back positive, says Richard Lifton, chairman of the genetics department at Yale University. "I'm increasingly confident that's going to happen. But we need to be careful how we utilize this information. Do you tell a newborn's parents his apoE status" -- that is, whether he has the form of a gene that raises the risk of Alzheimer's disease?

The cost of whole-genome sequencing will continue to plummet. Lifton foresees a "zero-dollar genome," making it likely that "we will just do it as part of routine clinical care" for children and adults. A Yale team led by Murat Gunel has already used partial genome sequencing of the 1.5% of the genome, called the exome, that codes for proteins to determine the cause of a mysterious and still unnamed genetic disease that results in severe brain malformations.

Because no genes had been identified as causing the malformation, it was not possible to do a standard genetic test, which reveals whether a particular gene is normal or mutated. But exome sequencing showed that a previously unknown gene on chromosome 19 is responsible, he and colleagues reported in 2010. "The new Proton instrument is a big step up," says Lifton. "It promises to markedly increase the speed and reduce the cost of genome-level sequencing."

TSUNAMI OF DATA

The discovery of the mutation behind the mysterious genetic disorder demonstrated the advantage of whole-genome sequencing compared to single-gene tests, as scientists can't test for a gene they don't know exists. Beyond such uses, say experts, whole-genome sequencing might not be the medical miracle that proponents forecast.

One problem is that the costs only start with the actual sequencing. "The cost of understanding the sequence will be much, much higher," says bioethicist Hank Greely of Stanford University. He participated in a 2010 project that sequenced the full genome of Stanford bioengineer Stephen Quake. The sequencing cost $48,000.

But because it found 2.6 million DNA misspellings and 752 other genetic glitches, says Greely, "it took a few hundred thousand dollars worth of labor from Ph.D. students and faculty working 4,000 to 5,000 hours to understand what the sequence meant" -- that Quake had a higher-than-average risk of sudden cardiac death, a lower risk of Alzheimer's, and a higher risk of prostate cancer.

Another challenge is that whole-genome sequencing generates a tsunami of data. It would take a genetic counselor some five hours to explain what a typical genome means, further adding to the true cost. The United States has about 2,500 genetic counselors, not nearly enough to meet the need if whole-genome sequencing becomes widespread. Might doctors take up the slack? "Surveys show that 90 percent of patients trust their physician to explain genomics data to them," says Scripps' Topol. "And 90 percent of physicians say they don't feel comfortable with genomics data."

Although many bioethicists focus on the psychological harm patients might suffer when DNA tests show an elevated risk of cancer, diabetes, Parkinson's, and other diseases, genomics information could also threaten patients' physical health if it is misconstrued. A woman whose DNA sequencing shows she does not carry BRCA mutations that raise her risk of breast cancer "might say, great, I don't need mammograms," says Stanford's Greely. "But a negative BRCA test reduces her risk of breast cancer from 12% to 11.96%. My dread is less that patients will be damaged psychologically and more that they will misunderstand (genome sequence data) and do stupid things."

Unlike tests that detect glitches in genes that a patient or physician asks to have checked (those that raise the risk of, say, colon cancer if that disease runs in the family), and unlike the dozens of genes that "personal genetics" companies test for, whole-genome sequencing reveals every bit of information the genome contains about diseases or traits.

Given the ubiquity of mutations, everyone carries genes that predispose them to more than one serious or lethal disease. Bioethicists are only beginning to study how that knowledge might affect someone's decisions, from marrying or having children to saving for retirement.

Another challenge is that although a person's genome doesn't change, its meaning will. As scientists uncover more DNA variants that protect against disease and variants that make it more likely, a genome sequence that meant one thing in 2012 will have a different meaning in 2013, not to mention 2020.

A DNA variant that was once thought to be dangerous "might turn out to be benign if countered by another," says Greely. "Whose responsibility will it be to tell you that, years later?" Today's DNA testing companies offer subscriptions that give customers regular updates like that.

Geneticists are also still struggling with the fact that most of the risk genes raise the likelihood that the person will develop the disease only slightly. "The bottom line is, the effect size is so small it's virtually insignificant clinically," says Quertermous. "So how should doctors incorporate that knowledge into their armamentarium? They won't be able to look at 6 billion data bits" -- the amount in a whole-genome scan -- "and evaluate what it means for patients."

Knowing a patient's whole-genome sequence, even if it raises the risk of diseases by only a few percent, might lead malpractice-wary doctors to order follow-up tests. If someone's genome suggests an elevated risk of heart disease, for instance, a physician might feel compelled to order regular cardiac CT angiograms, which cost $1,500 or more.

That would not only raise health-care costs, but might put patients through a physically and psychologically onerous ordeal unnecessarily. "There is no evidence that 'positive' (DNA) tests, based only on the screening for common genetic variations, will justify a specific medical follow-up and procure a medical benefit to individuals," argues geneticist Thierry Frebourg of University Hospital in Rouen, France in a commentary in an upcoming issue of the European Journal of Human Genetics. Instead, whole-genome sequencing might join the ranks of diagnostics, such as PSA tests for prostate cancer, that cost tens of millions of dollars a year but do not benefit patients, let alone save lives.

INEFFECTIVE DRUGS

Full-genome sequencing could provide real benefits in determining which patients will benefit from a drug. For instance, only half the hepatitis C patients who take Pegasys, a $50,000-a-year drug from Roche Holding AG's Genentech, and half the rheumatoid arthritis patients who take $26,000-a-year Enbrel from Amgen Inc and Pfizer Inc , benefit from them, notes Scripps' Topol, who analyzes the potential benefits of genomic medicine in his upcoming book, The Creative Destruction of Medicine.

Using genomic data to identify which patients will and will not benefit could save patients and insurers tens of billions of dollars a year now spent on ineffective drugs.

If genetic information causes patients to take better care of themselves -- eating more healthfully if they carry genes that raise the risk of diabetes or heart disease, for instance -- they can improve health. One 2010 study found that of people who bought direct-to-consumer genetic testing by companies such as 23andme, 34% said the results made them more careful about their diet and 14% exercised more.

Others incorrectly see DNA as destiny, and interpret an increased genetic risk of, say, obesity as a license to overeat, thinking they are fated to be fat. "Good" genes might lead to equally dangerous behavior. "A patient with hypertension might be told by his doctor, 'I've looked at your DNA and you're clean!'," says Stanford's Quertermous. "He might think, great, I don't need to check my blood pressure anymore or even take my medication."

As the science advances, however, the value of whole-genome sequencing to patients will grow. The common DNA variants that have been identified "account for only a small part of the heritability of disease," says Kari Stefansson, founder, chairman, and CEO of deCode Genetics of Reykjavik, Iceland.

"The expectation is that a significant part of the missing heritability lies in rare variants, and to find those you have to do whole-genome sequencing." deCode is sequencing the complete genomes of 3,750 Icelanders, and has so far identified rare variants with large effects on the risk of ovarian cancer, glioma, gout, and heart conditions that require a pacemaker. Those discoveries would have been difficult or impossible without whole-genome sequencing.

Whole-genome sequencing also promises to address one of the most troubling problems with current DNA tests, which probe some of the 1,500 or so genes that have been associated with disease out of a total of 22,000 human genes. But scientists do not know how disease risk is raised or lowered by "moderator genes," which affect other genes. "Do we know how combinations of genes affect risk?" Stanford's Quertermous asks. "The answer is completely no." As a result, the disease risk that is calculated from current genetic tests might be inaccurate. With millions of whole-genome sequences, biologists believe, they can begin to work out those crucial combined effects.

One upcoming study shows how important gene combinations can be. In research scheduled for publication in the journal Human Molecular Genetics, scientists led by Charis Eng of the Cleveland Clinic examined the incidence of breast, thyroid, and other cancers in patients carrying a mutation in a gene called PTEN. Such mutations are typically interpreted as raising the risk of cancer. But Eng found that the presence or absence of mutations in another gene, called SDHx, can alter that risk.

"Current genetic testing, which looks at only a few genes, is like trying to forecast the stock market by looking at just 26 stocks," says Eng of the Cleveland Clinic. Such limited genetic data can be misleading.

In a separate study of 44 patients, scheduled for publication in the European Journal of Human Genetics, Eng and colleagues find that family medical history assessed the risk of breast, colon and prostate cancer more accurately than DNA sequencing. For instance, family history correctly classified eight women as being at high risk for breast cancer. But only one of the eight was so classified by DNA. "For now, family health history is a better predictor of cancer risk than genomic testing, which looks at too few genes," Eng says.

Because whole-genome sequencing is not yet being marketed to consumers, the U.S. Food and Drug Administration has not taken a position on it. But it is concerned by existing tests that are sold directly to the public by Navigenics, Pathway Genomics and 23andme, and has invited companies that sell them to meet with agency officials to work out ways "to provide consumers with accurate, reliable kits," says FDA spokeswoman Erica Jefferson.

Until then, the companies are prohibited from marketing the tests to the public. "Manufacturers have not provided scientific evidence about the accuracy and reliability of their tests, which can lead to incorrect treatment decisions with serious health consequences," says Jefferson. "The risk of getting a disease depends on a set of complex interactions," so "even people with the same genetic make-up may have different risks of disease."

Gene-sequencing companies understand the challenges.

"Each genome has probably 24,000 mutations that we can understand," says Ion Torrent's Rothberg. "But there are probably 400 that have never been seen before" and whose significance for health is an enigma. Ion Torrent is working on algorithms to determine the medical significance of the millions of DNA glitches that will be found in every genome.

Companies such as Personalis, of Palo Alto, California, have sprung up to determine the medical significance of whole-genome sequences. That will take years.

"We recognize this is just the beginning," Rothberg says.

Read more »

Posted in: HEALTH

Aspirin guidelines need overhaul, researchers say

NEW YORK (Reuters Health) - Healthy people shouldn't be taking aspirin to prevent heart disease, researchers say in a new report that casts doubt on recommendations from U.S. health officials.

Medical guidelines currently urge people to take low doses of the drug if they are at high risk of heart disease but have never had any symptoms, or if they have already suffered a heart attack.

But the first piece of advice, known as primary prevention, has come under attack from more and more doctors because aspirin therapy can also be harmful.

"What we need to focus on is lifestyle, smoking cessation, and statin and blood pressure medications," said Dr. Kausik Ray, who studies heart disease prevention at St. George's University of London and led the new work. "I don't recommend aspirin."

Ray and his colleagues took a fresh look at nine previous trials of aspirin use in people who had never had chest pain or other symptoms of an ailing heart. They also looked for signs that the medication might stave off cancer, which some research has suggested.

Based on more than 100,000 men and women followed for an average of six years, there was no sign aspirin prevented fatal heart attacks. But it did cause a tiny drop in non-fatal heart attacks.

Among people taking placebo pills without active ingredients, 1.7 percent had a heart attack and survived, compared to 1.3 percent of people on aspirin.

That means 162 people would have to be treated for six years to avert just one non-fatal heart attack, the researchers write in the Archives of Internal Medicine.

There was no difference in fatal heart attacks or cancer deaths, and overall death rates were 3.8 percent in both groups. However, there was a clear harm from taking the drug, which can be bought for pennies at any pharmacy.

"The flipside is, there is a 30-percent increased risk of bleeding and these are not trivial bleeds," Ray told Reuters Health.

The rate of serious bleeding -- say, from a stomach ulcer -- was 10.1 percent among people on aspirin and 9.6 percent in the placebo group.

'A NET HARM'

Even among people at high baseline risk, Ray said, "there is never a net benefit."

For every two cases of heart disease and stroke prevented by aspirin, there were more than three cases of serious bleeding.

"It is actually not net benefit, it is a net harm," Ray said, adding that the findings were the same for men and women.

Other teams of scientists have recently analyzed the same data Ray looked at, and one interpreted the results in favor of aspirin.

Currently, U.S. guidelines all recommend aspirin for primary prevention as long as the benefits outweigh the harms, an equation that depends on baseline risk. This advice is backed by an editorial accompanying the new report.

However, even for people at high risk, not all researchers think aspirin is worth it.

In November, for instance, Dutch researchers reported that 50 women at high risk for heart disease would need to take aspirin for 10 years to see a net benefit for one.

Based on the latest findings, Ray's team concludes, "it is perhaps timely to reappraise existing guidelines for aspirin use in primary prevention."

SOURCE: http://bit.ly/7qXyI Archives of Internal Medicine.

Read more »

Posted in: HEALTH

Statin use tied to more diabetes in women

NEW YORK (Reuters Health) - Cholesterol-lowering drugs may be linked to an increased risk of diabetes, according to a new study of middle-aged and older women.

But researchers said that shouldn't dissuade people with heart disease -- or at risk of it -- from taking so-called statins.

Instead, statin users should try to reduce their risk of diabetes in other ways, such as by losing weight, and should have their blood sugar regularly monitored, they said.

"The conclusion still stands that overall, those people who've got existing heart disease or have had previous strokes, they still would get vast benefits from statins," as would those at high risk for heart disease, said Naveed Sattar, a metabolism and diabetes researcher at the University of Glasgow, UK.

Instead, the finding "may make us a bit more cautious about putting statins in the water, for example," Sattar, who wasn't involved in the new study, told Reuters Health.

In other words, not all people with few heart risks should be taking the drugs, as some researchers have suggested, because they aren't side effect-free.

For their report, Dr. Yunsheng Ma of the University of Massachusetts Medical School in Worchester and his colleagues used data from the Women's Health Initiative, including more than 150,000 diabetes-free women in their 50s, 60s and 70s.

As part of that larger trial, some of the women were prescribed diet changes or took daily hormone therapy or vitamins, while others weren't told to change their diet or lifestyle.

At the start of the study in the mid-1990s, women filled out health questionnaires that included whether or not they were taking statins, as well as information on other diabetes risks, such as weight and activity levels. The researchers then followed participants for six to seven years, on average, and tracked how many of them were diagnosed with diabetes.

In total, just over 10,200 women developed diabetes. Ma's team found that the women who reported using any kind of statin at the start of the study -- about one in 14 of the participants -- were 48 percent more likely to be diagnosed with diabetes than those not taking statins.

That was after considering other known diabetes risks, the researchers reported Monday in the Archives of Internal Medicine.About one-quarter of adults age 45 and older in the United States now take statins -- which run anywhere from $11 to over $200 per month -- to lower their cholesterol and heart disease risks.

Previous studies, mostly in men, have suggested a smaller, 10-to-12-percent increase in diabetes among statin users, according to Sattar.

Those numbers may be more accurate because they come from trials in which participants were randomly assigned to take a statin or not, which can better account for possible differences in groups of patients, he added.

What's more, this type of "observational" study can't prove cause-and-effect.

Still, "broadly speaking, this kind of confirms that stains may well increase diabetes risk," Sattar said. Why that's the case isn't totally clear, he said, but statins' effects on the muscles and liver may lead the body to make slightly more sugar than it normally would, or cause users to exercise a bit less.

'A VERY FAIR TRADE-OFF'

Dr. David Jenkins, a nutrition and chronic disease researcher from the University of Toronto, said the medical community has accepted an increased risk of diabetes with statins as "a very fair trade-off," since statins lower the risk of heart disease, the primary concern related to diabetes.

Still, the findings highlight the importance of monitoring risks for diabetes, including blood sugar levels, and encouraging patients who are on the drugs to try to eat better and be physically active, researchers said.

"Statins will always be with us, they will always be valuable, and we will always prescribe them," Jenkins, who wasn't tied to the new research, told Reuters Health. But, "Statins, brilliant as they are, haven't actually completely precluded the use of changing one's diet and one's lifestyle."

Ma told Reuters Health that there's a need for future studies to evaluate both the risks and benefits of statins for people of different ages and genders, with and without heart disease. For some with high cholesterol, he said, a smart choice may be starting out with changes in diet and lifestyle, before going straight to a statin.

"Each person deserves a careful risk versus benefit assessment," agreed his co-author, Annie Culver, from the Mayo Clinic in Rochester, Minnesota.

Then, she told Reuters Health, "Once (you) receive the statins, don't abandon the idea of making lifestyle changes."

SOURCE: http://bit.ly/fO01ME Archives of Internal Medicine, online.

Read more »

Posted in: HEALTH

Acupuncture little better than 'sham' for migraine

NEW YORK (Reuters Health) - Traditional Chinese acupuncture seems little better than a "sham" version of the procedure when it comes to preventing migraines, a study published Monday suggests.

The findings, reported in the Canadian Medical Association Journal, add to a pattern commonly seen in studies on acupuncture and migraines.

Many have found that people with migraines can get relief from acupuncture. But often, "true" acupuncture has worked no better than "sham" acupuncture -- where the needles are inserted only to a superficial depth in the skin, or into sites that are not considered acupuncture points in traditional medicine.

That raises the question of whether acupuncture works by "non-specific" effects, according to the researchers on the new study, led by Dr. Ying Li of Chengdu University of Traditional Chinese Medicine in China.

That is, some people might feel better because they expect to, or because of the personal attention from the acupuncturist.

But other experts said that the findings do not mean that acupuncture offers nothing more than a "placebo effect" for migraine sufferers.

For the study, Li's team recruited 480 adults who had migraines at least twice a month.

They randomly assigned people to one of four groups: In three, patients were given one of three different types of acupuncture that focused on traditional points, with electrical stimulation added to the needling; the fourth group received a sham version.

In the sham group, needles were inserted in the skin at non-traditional sites, with electrical stimulation. But the needles were not manipulated to create a so-called "de qi" sensation.

Patients in all four groups were offered 20 acupuncture sessions over four weeks.

In the month after treatment ended, migraine sufferers in all four groups were reporting fewer headache days, Li's team found.

On average, they had migraine pain on about three days out of the month -- down from around six days at the study's start.

In the third month after treatment, the "real" acupuncture groups were doing slightly better, while the sham group held steady at around three headache days. But the advantage was "clinically minor," according to Li's team, who did not respond to requests for comment.

'SHAM' MAY HAVE REAL EFFECTS

So does that mean acupuncture's benefits are all in your head?

No, according to Dr. Albrecht Molsberger, of Ruhr University Bochum in Germany, who wrote an editorial published with the study.

The problem, he told Reuters Health by email, is that sham acupuncture is not a true placebo -- and may have real physiological effects.

According to traditional Chinese medicine, acupuncture eases pain by stimulating certain points on the skin believed to affect the flow of energy, or "qi" (pronounced "chee"), through the body.

But some modern research suggests that the needle stimulation triggers the release of pain- and inflammation-fighting chemicals in the body, even if it doesn't strictly follow traditional principles.

"The sham acupuncture effect is so strong and long lasting, that this suggests that other factors, like the stimulation of cytokines or endorphins, are important too," Molsberger said.

And even though real acupuncture has not clearly beaten the sham version, it has outperformed standard migraine treatments in some studies.

A recent research review looked at four clinical trials that tested acupuncture against medications proven to prevent migraine attacks. Overall, acupuncture patients reported somewhat fewer migraines in the couple months after treatment, with fewer side effects.

Dr. Jongbae J. Park, who directs Asian Medicine & Acupuncture Research at the University of North Carolina at Chapel Hill School of Medicine, agreed that the sham in this study was not a true placebo.

"In my mind, it's far from being a true 'control,'" Park said in an interview.

In fact, Park said, the issue with acupuncture research in general is that sham procedures vary from study to study.

Researchers need to settle on a form of true placebo that is used consistently, according to Park -- who acknowledged that questions about acupuncture's effectiveness remain, and further studies are needed.

But based on research overall, acupuncture "should be an option" for treating migraines, said Molsberger, who is also president of Forschungsgruppe Akupunktur, which profits by offering acupuncture training.

Acupuncture is considered a generally low-risk procedure, with side effects like bruising at the needle site. The cost can vary widely -- and may or may not be covered by insurance -- but a session would typically start around $100.

At his center, Park said a typical migraine patient might start with six weekly sessions, and then come monthly, tapering down to once every six months. But the acupuncture sessions would also involve "whole-person" care, with advice on diet, sleep and other lifestyle habits.

There are, of course, other ways to tackle migraines. Several types of medications can prevent attacks, including a group of drugs known as triptans, certain antidepressants, high blood pressure drugs and anti-seizure medications.

Another non-drug option is biofeedback, in which people learn to control the physical responses to stress, like muscle tension -- which may help head off or ease migraine pain.

SOURCE: http://bit.ly/wdot9I Canadian Medical Association Journal, online.

Read more »

Posted in: HEALTH