Daily Archives: March 11, 2014

Genome-Wide Association Studies (GWAS)
Video made for Mr.O #39;Malley #39;s Honors Bio Class. May or may not be my last video.

By: Ricky Wong

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Genome-Wide Association Studies (GWAS) - Video

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Current technology for sequencing a person's whole genome does not always capture data on key genes.

Sequencing a persons entire genome can reveal potentially life-saving information about the presence of mutations associated with diseases. But there are drawbacks a study published this week finds that current sequencing technology does not always capture the complete genome, and illustrates the challenges of interpreting what the results mean for an individual patient1.

There are many steps that have to be worked out to ensure that we gain the most health-care benefit, says William Feero, a physician at the Maine Dartmouth Family Medicine Residency in Fairfield, Maine, who was not involved in the study.

Researchers at Stanford University in California, examined whether a whole-genome scan could identify disease risks in healthy people a use of the technology that is within financial reach as the cost of sequencing drops.

The team of doctors, genetic counsellors and scientists report today in the Journal of the American Medical Association that it sequenced the whole genomes of 12 people with no diagnosed genetic diseases, looking for genetic mutations that might cause disease. Every patient was found to have 26 such mutations, and one woman found out that she carried a mutation in the gene BRCA1, which is linked to greater risk of ovarian and breast cancer. She opted to have her ovaries removed as a result.

But the researchers, led by cardiologists Euan Ashley and Thomas Quertermous, also found that between the two genome sequencing services they used Illumina, based in San Diego, California, and Complete Genomics, based in Mountain View, California 1019% of genes known to be linked to disease were not adequately sequenced. So doctors might have missed finding harmful mutations in these genes. The two services also disagreed two-thirds of the time about the presence of a particularly worrisome type of mutation the addition or deletion of parts of genes linked to disease.

Deciding what these results meant for patients was not easy. The study clinicians often disagreed about what patients should do in light of the findings about their genomes for instance, whether a particular mutation meant that the patient should undergo further testing.

Were very excited about the idea that genome sequencing can transform medicine, Ashley says. We need to apply some tough love and be really honest about what we can be confident about with this technology and what still needs a bit of work.

On the bright side, the researchers found that the cost of whole-genome sequencing was lower than they expected. Ashley estimates it costs about US$11,000 to sequence one persons genome and interpret the data. Follow-up testing for people in the study cost less than $1,000 per person, indicating that the adoption of whole-genome sequencing is not unleashing a flood of expensive downstream procedures.

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Genome sequencing stumbles towards the clinic

hide captionInterpreting the results from a genome scan takes a lot of people time. And the databases used to interpret the results aren't infallible.

Interpreting the results from a genome scan takes a lot of people time. And the databases used to interpret the results aren't infallible.

For more than a decade scientists have been saying that a genomic revolution will transform medicine, making it possible to scan all of a person's DNA to predict risk and customize medical care.

Well, we've got the machines. Where's the revolution?

Getting closer, say researchers at Stanford University, who tested the technology on 12 people. But not quite ready for every doctor's office.

""We were witness to the birth of this idea, and now we feel like we have an unruly teenager on our hands," says Dr. Euan Ashley, an associate professor of medicine and genetics at Stanford, and an author of the study. "It's going to take some tough love."

The study was published Tuesday in JAMA, the journal of the American Medical Association.

Whole-genome scanning uses machines to plow through all of a person's DNA looking for variations that could be associated with disease. Though until now it's been used rarely for diagnosing patients, it's becoming increasingly fast and affordable. Machines are now able to run a whole-genome scan in a day or two, at a cost of just a few thousand dollars.

Quick and affordable, maybe, but not necessarily accurate.

When the Stanford researchers compared whole-genome scans done on two different machines, they found that the results matched up just one-third of the time for genetic variants that could signal a risk of inherited disease.

Excerpt from:
Whole Genome Scans Aren't Quite Ready For Your Doctor's Office

PUBLIC RELEASE DATE:

11-Mar-2014

Contact: Krista Conger kristac@stanford.edu 650-725-5371 Stanford University Medical Center

STANFORD, Calif. Whole-genome sequencing has been touted as a game-changer in personalized medicine. Clinicians can identify increases in disease risk for specific patients, as well as their responsiveness to certain drugs, by determining the sequence of the billions of building blocks, called nucleotides, that make up their DNA.

Now, researchers at the Stanford University School of Medicine have discovered that although life-changing discoveries can be made, significant challenges must be overcome before whole-genome sequencing can be routinely clinically useful. In particular, they found that individual risk determination would benefit from a degree of improved sequencing accuracy in disease-associated genes. Furthermore, up to 100 hours of manual assessment by professional genetic counselors or informatics specialists is required for detailed genome analysis.

Although the technique was once prohibitively expensive, plummeting costs have been widely expected to rapidly usher whole-genome sequencing into the arena of mainstream health care. However, the researchers' findings indicate that clinical advances from whole-genome sequencing are, at least in the near future, likely to be significantly more expensive and labor-intensive than some patients and clinicians may have been led to believe.

"We need to be very honest about what we can and cannot do at this point in time," said Euan Ashley, MD, associate professor of medicine and of genetics, one of three senior authors of the paper. "It's clear that if we sequence enough cases, we can change someone's life. But with this opportunity comes the responsibility to do this right. Our hope is that the identification of specific hurdles will allow researchers in this field to focus their efforts on overcoming them to make this technique clinically useful."

The paper will be published March 12 in the Journal of the American Medical Association. Michael Snyder, PhD, professor and chair of genetics, and Thomas Quertermous, MD, professor of medicine, also share senior authorship of the paper. Postdoctoral scholar and cardiology fellow Frederick Dewey, MD, genetic counselor Megan Grove, CGC, and postdoctoral scholar Cuiping Pan, PhD, share lead authorship of the paper.

The researchers analyzed the whole genomes of 12 healthy people and took note of the degree of sequencing accuracy necessary to make clinical decisions in individuals, the time it took to manually analyze each person's results and the projected costs of recommended follow-up medical tests.

"This has been an important project for the Stanford team for a number of reasons, not the least of which is that it represents the initial genetics effort to make use of the Stanford GenePool Biobank," said Quertermous, the William G. Irwin Professor in Cardiovascular Medicine. GenePool was recently launched to promote genomic research in a clinical setting and to improve patient care; the 12 people in the study were the first participants in the effort.

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Whole-genome sequencing for clinical use faces many challenges, Stanford study finds

PUBLIC RELEASE DATE:

11-Mar-2014

Contact: Krista Conger kristac@stanford.edu 650-725-5271 The JAMA Network Journals

In an exploratory study involving 12 adults, the use of whole-genome sequencing (WGS) was associated with incomplete coverage of inherited-disease genes, low reproducibility of detection of genetic variation with the highest potential clinical effects, and uncertainty about clinically reportable findings, although in certain cases WGS will identify genetic variants warranting early medical intervention, according to a study in the March 12 issue of JAMA.

As technical barriers to human DNA sequencing decrease and costs approach $1,000, whole-genome sequencing (WGS) is increasingly being used in clinical medicine. Sequencing can successfully aid clinical diagnosis and reveal the genetic basis of rare familial diseases. Regardless of context, even in apparently healthy individuals, WGS is expected to uncover genetic findings of potential clinical importance. However, comprehensive clinical interpretation and reporting of clinically significant findings are seldom performed, according to background information in the article. The technical sensitivity and reproducibility of clinical genetic findings using sequencing and the clinical opportunities and costs associated with discovery and reporting of these and other clinical findings remain undefined.

Frederick E. Dewey, M.D., of the Stanford Center for Inherited Cardiovascular Disease, Stanford, Calif., and colleagues recruited 12 volunteer adult participants who underwent WGS between November 2011 and March 2012. A multidisciplinary team reviewed all potentially reportable genetic findings. Five physicians proposed initial clinical follow-up based on the genetic findings.

The researchers found that the use of WGS was associated with incomplete coverage of inherited-disease genes (important parts of the genome for diseases that run in families are not as easy to read as other regions); there was low reproducibility of detection of genetic variation with the highest potential clinical effects (disagreement around the types of variation particularly important for disease); and there was uncertainty about clinically reportable WGS findings (experts disagree on which findings are most meaningful). Two to 6 personal disease-risk findings were discovered in each participant. Physician review of sequencing findings prompted consideration of a median (midpoint) of 1 to 3 initial diagnostic tests and referrals per participant.

The authors write that their clinical experience with this technology illustrates several challenges to clinical adoption of WGS, including that although analytical validity of WGS is improving, technical challenges to sensitive and accurate assessment of individual genetic variation remain. In addition, the human resource needs for full clinical interpretation of WGS data remains considerable, and much uncertainty remains in classification of potentially disease-causing genetic variants.

"These issues should be considered when determining the role of WGS in clinical medicine."

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Examining potential of clinical applications of whole-genome sequencing