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UK invests in DNA testing research

Posted in Diagnostic testing, Scientific research by Matt at WelcometoIllinois on May 13, 2009

The Times is reporting that the UK’s Medical Research Council (MRC) is investing £7m in a national network of centres dedicated to DNA testing research, including the use of DNA testing for the prenatal diagnosis of Down’s syndrome.

Projects include genetic sequencing for transplant matching, “identifying inherited genetic mutations that can cause breast cancer, colon cancer and kidney and eye disorders”, and “studying the genetic factors that contribute to mental illnesses, and infectious diseases such as malaria and the antibiotic-resistant bacteria Clostridium difficile.”

As far as Down’s syndrome is concerned, a “project at the Cambridge hub will evaluate methods of testing the blood of pregnant women for foetal DNA. This could potentially allow prenatal diagnosis of Down’s syndrome without amniocentesis, an invasive test that can cause miscarriage,” The Times reports.

I’ve written about DNA testing for prenatal diagnosis of Down’s syndrome before. In particular Sequenom appeared to making good progress but has subsequently admitted that the data was mishandled by employees.

The use of DNA chips in diagnostic testing

Posted in Diagnostic testing, Scientific research by Matt at WelcometoIllinois on December 1, 2008

I previously wrote about the use of “‘microarrays’ or gene chips in the genetic testing process and a new DNA test called array comparative genomic hybridization (aCGH). MIT Technology Review has an overview of the technology.

The DNA chip used in the study performs a process known as array comparative genomic hybridization (aCGH), which involves looking for an abnormal number of copies of particular segments of DNA. Normally, humans have two copies of each segment. Having extra or missing copies can result in serious medical problems. Each DNA chip contains hundreds of single-stranded DNA segments, each embedded in a piece of glass at a precise location. The researchers then add single-stranded, fetal DNA segments, usually taken from amniotic fluid. These strands are labeled red. Single-stranded DNA reference segments, which act as a control group and are labeled green, are also added to the chip. Once the fetal and control strands are bound with the embedded DNA, the arrangement of colors on the chip is imaged and analyzed by a computer.

“Basically we measured the color signal intensity,” said [Sau Wai Cheung, director of Baylor College of Medicine’s Cytogenetics Laboratory]. If the fetus has an extra copy of a particular segment of DNA, then the spot on the chip that corresponds to that DNA segment will appear more red than green. If the fetus is missing a DNA segment, the corresponding spot on the chip will appear more green than red. And if the fetus has the correct number of copies of the DNA segment, then the spot should appear yellow.

To put this in some context:

“The process normally used for prenatal diagnosis is karyotyping, which looks at the overall size and shape of chromosomes to identify problems. [Cheung] says the new research shows that DNA chips can reliably detect far smaller chromosomal abnormalities than karyotyping allows. And while these abnormalities may be small in size, they can have a big impact. “A lot of the diseases that we tested for [in this study] cause mental delays and problems with physical development,” said Cheung. Angelman syndrome, for example, can result in significant developmental problems and seizures.”

The study at Baylor included 300 cases and identified seven cases where the aCGH results provided new information about the risk of disease, “including two cases that would otherwise have been missed”. On the downside still requires an invasive testing procedure and has not been widely studied at this stage.

In fact, I previously mentioned the technique in the context of a warning from Leslie G. Biesecker of the federal government’s National Human Genome Research Institute, that the tests do not provide enough information to know whether genetic abnormalities will actual cause a disorder, or how severe the effects might be.

The MIT Technology Review story raises the same issue, as Diana Bianchi, professor of pediatrics, obstetrics, and gynecology at Tufts University School of Medicine and the editor in chief of Prenatal Diagnostics (which published details of the Baylor study): “The downside of aCGH is you pick up these copy-number variants that may or may not have clinical significance, and in the worst case [the impact] may be unknown.”

The reports adds: “Knowing that an unborn child has genetic abnormalities but not knowing how those might affect the child’s development could leave many parents scared and confused, Bianchi says.”

Of course that is the exact same issue that impact parents receiving screening and diagnostic test results today, but no one seems to bother about that.

DNA testing techniques prompt wider debate

Posted in Diagnostic testing, Scientific research by Matt at WelcometoIllinois on October 29, 2008

I wrote yesterday about the importance of accuracy in ante-natal testing for chromosome abnormalities such as Down’s syndrome, noting that I am in favour of new non-invasive DNA testing currently being developed.

On the subject of those DNA testing procedures I previously wrote that “While the development of more accurate testing procedures is to be welcomed in terms of reducing false-positives and false-negatives, I believe they also provide an opportunity for wider debate on the accepted wisdom that it is acceptable to prenatally diagnose Down’s syndrome in the first place.”

It is in that context that this article in the Washington Post makes for interesting reading, covering as it does a new DNA test called comparative genomic hybridization that uses “‘microarrays’ or gene chips to search for dozens of less common, often more severe syndromes caused by subtle deletions or additions of genetic material that standard genetic analysis misses.”

As the article indicates, the development of this technique, which can detect about 150 known genetic disorders, raises both hope and concern:

Some worry that the technique could be used to hunt for the rapidly growing list of genetic markers that merely signal an increased risk for cancer, diabetes, mental illness, obesity, addiction and other conditions later in life. Someday, similar tests could perhaps even vet fetuses for traits associated with beauty, personality or intelligence.

It is easy to dismiss such concerns as exaggeration. Less so the fact that the tests are already being promoted by two labs – the report mentions Baylor College of Medicine and Signature Genomic Laboratories – before a a $3.3m federally funded study evaluating the technology in 4,000 pregnancies led by  Ronald J. Wapner of Columbia University, has been completed.

Then there is the fact that the results do not necessarily provide parents with enough information for them to make an informed decision. The report quotes Leslie G. Biesecker of the federal government’s National Human Genome Research Institute:

“There’s a lot of variation down in the DNA that as far as anyone knows today not only doesn’t cause any disease or syndrome, but doesn’t have any consequence whatsoever. They are part of what make us different,” Biesecker said. “The trick is, you have to distinguish whether it’s going to cause any disorder. We’re not there yet.”

Even if the abnormalities detected are in a region of DNA clearly associated with a known syndrome, it is often unclear how severely affected the child would be. Missing DNA almost always causes a syndrome. But extra DNA in the same area may or may not, or may cause a mild version. Many of the syndromes can range from devastating to barely noticeable.

“We’re opening up a huge can of worms,” said Caroline Ogilvie of the Guy’s and St. Thomas’ NHS Foundation Trust in London. “More information is not always a good thing.”

“Put yourself in the place of a woman who is carrying a baby she wants,” said Jan Friedman of the University of British Columbia. “You find something that may or may not be abnormal. If it’s abnormal it may be very bad, or it may be normal. She doesn’t know what to do about it. If she continues a pregnancy, it may be a serious abnormality. If she terminates a pregnancy, she may be terminating a normal baby.”

While I am not naive enough to believe that society can reverse the trend towards increased ante-natal screening I still think there is room for debate about why it is done. Ironically it is the development of easier and more broadly-applicable tests that provides the best hope that the debate will take place.

“I don’t really see her as any different”

Posted in Attitudes to disability by Matt at WelcometoIllinois on September 23, 2009

Check out this video of Kelly Fitzgerald, one of only two people in New Zealand with Down’s syndrome that have their full driver’s license. It is really inspirational to see how independent and confident she is. Congratulations to Kelly, and also her parents for the way they have raised her.

Her Mum, Edna, has written a book, and says: “We never made any excuses for her… if she could do it, we just encouraged her. I’m pretty proud of her but I’m proud of all the kids and I don’t really see her as any different.”

UK NHS developing non-invasive diagnosis tests

Posted in Diagnostic testing, Genetics, Scientific research, Screening by Matt at WelcometoIllinois on August 9, 2009

The Guardian reports that the UK’s National Health Service has begun a program to develop non-invasive blood tests that will reduce the risk of ante-natal testing for a number of conditions, including Down’s syndrome.

I’ve written about non-invasive diagnostic tests a number of times, including the news that the UK’s Medical Research Council (MRC) is investing £7m in a national network of centres dedicated to DNA testing research.

The latest new concerns a £2m grant from UK National Institute for Health Research (NIHR) to a study entitled Reliable Accurate Prenatal non-Invasive Diagnosis (RAPID), which will run for 5 years from April 2009 and test non-invasive alternatives to amniocentesis and CVS.

Specifically the program will investigate the use of circulating cell-free fetal nucleicacid (cffNA) technology for non-invasive prenatal diagnosis (NIPD).

Interestingly, the Guardian reports, and this report (PDF) from the working group considering the potential use of NIPD confirms, that tests based on the analysis of cffNA have been available as a service to hospital trusts since 2001 for “rhesus negative women whose baby is at high risk of having potentially fatal anaemia or jaundice.”

However, the potential use of cffNA as part of the national screening programme is a different matter – one that could potentially increase the accuracy of ante-natal testing for genetic abnormalities and other conditions, but also one that raises significant practical and ethical concerns.

These concerns were not lost on the working group investigating the increased use of cffDNA. The working group report suggests that the national implementation of cffNA for Down’s syndrome screening could be possible in five years but also notes that “a possible consequence of increased testing is more terminations, which could in turn result in increased social pressure to terminate, particularly if the diagnosed conditions were to become rarer in society resulting in a decline of support services.”

The working group report adds:

“It is therefore important to ensure that policies in this area are genuinely motivated by concern for parental autonomy, rather than any sense of reducing financial and social ‘burden’, and that the experiences of disabled people and their families be fairly reflected when framing policy and educational materials.”

In particular, given blood tests are a routine part of any pregnancy, the working group reports that it will be important to ensure that any NIPD tests are not taken lightly.

“If cffNA tests were made available to all pregnant women early in pregnancy as a replacement technology, there would be a need to move towards the rigorous informed consent model commonly used for diagnostic testing, where an active decision is made following discussion with a health care professional.”

Stop me if you think you’ve heard this one before

Posted in Media, Politics by Matt at WelcometoIllinois on February 24, 2009

The Washington Post has published an interesting story about the implications of new non-invasive testing techniques.

However, the story is pretty much a re-hash of the issues discussed in this article in the same paper in October 2006, which I covered here.

A clue as to why the story has been rehashed comes from the fact that funding for the Prenatally and Postnatally Diagnosed Conditions Awareness Act, which was approved in September.

“The new tests for Down syndrome come as advocates pressure Congress to fund a law passed last year aimed at ensuring that couples get accurate information about genetic conditions and at providing support for women who decide to keep their affected children or put them up for adoption.

“These tests make this all the more important,” said Madeleine Will of the National Down Syndrome Society, which is seeking $25 million over five years to implement the legislation. Society members are gathering in Washington this week to lobby on this and related issues. “

Accepted, or patronised?

Posted in Ability, Attitudes to disability by Matt at WelcometoIllinois on February 6, 2009

“Patrick Thibodeau, who has Down Syndrome, trotted onto the floor Tuesday night for the team’s final home game of the season. When the time came to shoot, he nailed a 3-pointer for the second basket of the game. He hit another at the final buzzer,” reported USA Today earlier this week.

It sounds like a heart-warming tale of a young man overcoming disability with real achievement. Add in the fact that his father, the team’s statistician, “was released from a hospital early – he suffered a stroke two weeks ago – so he could witness the event” and its no wonder the TV news was all over it.

However, this report of the same story from disabilityscoop paints a slightly different picture:

“Patrick Thibodeau attended all the practices and all the games. But until this week, the high school senior with Down syndrome had done little more than fill water bottles and cheer on the sidelines during his high school basketball team’s games.”

As Amy Silverman at Girl in a Party Hat writes:

“I looked hard at that kid with Down syndrome on that Today Show segment about high school basketball and thought, Man, I hate this story. A lot. The kid filled water bottles for what, 9 years, so they gave him a few minutes on the court.”

I had a similar feeling myself when I read this report about a woman with Down’s syndrome being made manager of a coffee shop. Sort of:

“Staff tweaked the job description to suit Natalie, whose schedules now expands to five days a week from three. Instead of doing paperwork, she’ll be in charge of greeting customers and serving tables.”

Not to diminish the achievements of these individuals, but both stories indicate that they are being more than a little patronised.

As Maya at Everything Happens for a reason writes:

“The water bottle and the nine years part made me sad. And of course it made me sad that this kid couldn’t play basketball and score a basket and just be like everyone else, that it had to be some grand, big thing that he got to play in a game and all because he has Down syndrome… I want our kids to be included and recognized, but not as charity cases. I want Leo to fit in because he does, not because someone feels sorry for him.”

Or as Dan Olmsted of Age of Autism writes:

“If the kid can play, let him play, not pick up sweaty towels. Don’t make inclusion on the court or on the field a ‘very special,’ made-for-TV story. Make it typical.”

Or maybe we’re all just too cynical. As Libby at Blessings and Glory writes:

“Charlie and I cheered (and I cried a bit.) I pray that our local high school students will be as accepting of our Charlie.”

And I watched the video myself and when Patrick’s Dad says of his first basket “I knew that was Patrick, especially when it went in. Best feeling you could ever have in your life. Just become a parent and you’ll find out why” you can see he couldn’t be prouder.

And I don’t know because the last thing I want is for G to be patronised but maybe if someone went out of their way to make G welcome and involved him in their team, or their workplace, and made him feel accepted, and gave him a chance to shine – even for a moment – then how could I begrudge that?

But its nice to know that I am not alone in feeling a bit sad about that too.

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Non-invasive Down’s syndrome tests make progress

Posted in Diagnostic testing, Scientific research, Screening by Matt at WelcometoIllinois on January 29, 2009

Genetic analysis company Sequenom has announced that it is making progress towards commercialising its non-invasive test for Down’s syndrome and other chromosomal abnormalities.

Based on an expanded sample of 858 tests “the Sequenom SEQureDx RNA-based technology demonstrated a 100% positive predictive value (PPV) and a 99.9% negative predictive value (NPV).”

As The Street notes, that last figure indicates that the company is no longer able to repeat its
previous claim to no false positives.

“Until today, Sequenom’s test had a 100% detection rate for Down syndrome and a 0% false positive rate when used in just under 400 pregnant women — a perfect record. While Wednesday’s disclosure of one false positive test in more than 858 total samples mars that flawless performance, Sequenom CEO Harry Stylli says an overall false positive rate of one-tenth of 1% is significantly better than current prenatal screening methods for Down syndrome, which can have a false positive rate of around 5%.”

UPDATE – It turns out the test results were wrong – UPDATE

According to The Street, the test works like this:

“The Sequenom test relies on new technology that can detect minute amounts of fetal RNA in a mother’s bloodstream. Using a small sample of blood taken from the mother, Sequenom isolates fetal RNA [ribonucleic acid] and determines whether there are two copies of chromosome 21 (a healthy baby) or an extra copy of the chromosome, which would indicate Down syndrome.”

Sequenom is coming to make its test available in the US in June, although as Xconomy reports “The medical audience will demand evidence published in peer-reviewed journals, and loads of it, before they give their full stamp of approval.”

Detailed results should be published in peer-reviewed journal in mid-2009, according to the company. Recommendation from American College of Obstetricians and Gynecologists will likely not come until 2010 or 2011, at the earliest.

Sequenom is not the only company developing new non-invasive testing techniques. I previously wrote about similar testing technology under development at Stanford University being licensed to a company called Fluidigm.

A company called Artemis Health has also acquired a license from Stanford University to develop cell-free fetal DNA prenatal diagnostic tests.

Meanwhile a company called Lenetix announced that it is making progress with maternal serum test developed at the University of Vermont that make use of methylation-sensitive amplification (MSA) of fetal nucleic acid markers.

The genetics of Down’s syndrome in 60 minutes

Posted in Genetics, Statistics by Matt at WelcometoIllinois on December 19, 2008

I’ve been meaning to write a quick post on the genetics of Down’s syndrome for some time, but I haven’t got round to it. I wanted to write about as a record for any visitors looking for info about genetics, but also in the hope that it will help me understand/remember it. Thinking about G’s karyotype results has spurred me on, so I’m going to bash this out as quick as I can.

There are three types of Down’s syndrome:

  • Regular trisomy 21
  • Translocation
  • Mosaic
  • But first, the basics:

    The human body is a collection of cells. Each cell contains a collection of genes. Genes are made of of DNA. Chromosomes are groups of genes. There are 46 chromosome in 23 pairs in all cells (apart from the sperm and egg cells, which have 23 chromosomes each). One pair comes from the mother, the other from the father. Each chromosome has two sections, known as the ‘long arm’ and the ‘short arm’ (this bit is relevant to translocation). The body grows by creating new cells. In order to do this a copy of the chromosomes in each cell is produced, before the cell splits in two with a set of chromosomes in each of the new cells. This is called mitosis. Egg and sperm cells divide using a different process called meiosis, but we don’t need to bother with that now.

    Regular Trisomy 21
    About 94% of people with Down’s syndrome have trisomy 21, which means they have an extra chromosome (No 21) in every cell, making 47 chromosomes per cell in all. This occurs due to unusual cell division, the cause of which is unknown. The extra chromosome comes from an egg cell or sperm cell which is produced with 24 chromosomes rather than the usual 23.

    Karyotype for regular trisomy 21

    down_syndrome_karyotype
    Source: Wikimedia commons/Human Genome project.

    Why does this happen?

    No one knows. It is not hereditary – the production of the abnormal egg or sperm cell just happens. Mothers over the age of 35 are more likely to have a baby with Down’s syndrome. One theory for this is that all women have eggs with 24 chromosomes but the body uses the normal egg cells first. Another theory is that the older a woman is, the harder her body works to ensure that the baby is not miscarried. There is some debate over whether the age of the father has an impact, given that men produce new sperm throughout their lives, whereas women start making their egg cells while they themselves are still in utero, however recent research indicates that the age of the father is significant.

    Translocation
    About 4% of people with Down’s syndrome have translocation, which means that they have an extra part of chromosome 21 attached to another chromosome (either 13, 14, 15, or 22). Translocation occurs when the small arms (see basics above) of chromosome 21 and another chromosome break off and the two long arms join together. There is an extra copy of a large part of chromosome 21 so the effect of translocation Down’s syndrome is no different from trisomy 21.

    Why does this happen?

    In two-thirds of cases this translocation occurs during the formation of the egg or sperm cell. No one knows why. When the egg or sperm cell fuses with a regular sperm or egg cell one of the created 46 chromsomes will have an extra bit of chromosome 21 attached to it, which acts as a single chromosome in cell division, and all cells therefore have an extra chromosome 21.

    In one-third of cases the translocation is inherited from one of the parents who has two number 21 chromosomes in each cell, one of which is attached to another chromosome. The parent does not have any traces of Down’s syndrome as they have the correct amount of genetic material (balanced translocation), however it is possible for their egg or sperm cells to pass on both the translocated chromosome 21 material and the free chromosome 21, resulting in their baby having Down’s syndrome.

    The age of the parents is not a factor in translocation.

    Mosaic
    About 2% of people with Down’s syndrome have mosaicism, which means they have an extra chromosome 21 in only some of their cells. Depending on how many cells are trisomic, and which ones, a person with mosaic Down’s syndrome may be less affected physically and mentally than those with regular trisomy 21 and translocation.

    Why does this happen?

    No one knows. Mosaicism occurs after conception. As the cells divide and multiply in one cell with 46 chromosomes the pair of 21 chromosomes fails to separate (nondisjunction). This cell divides into one cell with 47 chromosomes (and an extra copy of chromosome 21) and one with 45 chromosomes (which does not survive). The cell with 47 chromosomes survives and continues to divide , producing further trisomic cells alongside the other ordinary cells. The age of the parents is not a factor in mosaicism.

    (For more on mosaic Down’s syndrome see this post)

    Like I say, this is not meant to be authoritative, and I’m sure I’ve missed out a lot of details. I’ve certainly identified a couple of areas to follow up on, such as balanced translocation and nondisjunction, while I haven’t even mentioned partial translocation (which I don’t understand at all). I’ll come back to these another day as I’ve exceeded my hour already.

    For a more detailed look at the genetics of Down’s syndrome try this article from the Down’s Syndrome Association, which was my main source of information. I’ll link to further articles later.

    Amendement 51 rejected

    Posted in Politics, Support services by Matt at WelcometoIllinois on November 5, 2008

    Sometime ago I asked the question “Would you pay more tax to help disabled?” in relation to Colorado’s proposed sales tax increase to fund disability services.

    For Coloradans it seems the answer was ultimately “no”. This report in the gloriously named Steamboat Pilot & Today states that they voted against Amendment 51 by ratio of nearly 2-to-1.

    The report blames economic conditions for the result.

      “The economy was the issue,” said Marjio Rymer of ARC of Colorado and chairwoman of the coalition to End the Developmental Disability Wait List. “We couldn’t have predicted the fall of the world economy, but we will be back.”

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