2012年9月1日土曜日

出生前診断 MaterniT21(+) test

血液より、精度が高い出生前診断の受診ができるようだ。
 妊婦の血液だけで、胎児にダウン症などの染色体異常があるかを99%の
精度で調べる米国の会社が開発した新型の出生前診断を、国内の2病院が
来月から試験的に開始することが分かった。流産の危険があった従来の
検査に比べ、安全に調べることができる一方、異常が見つかれば安易な
人工妊娠中絶にもつながることから、カウンセリング体制の整備などが
課題になりそうだ。

9月以降に導入する方針の施設
・臨床研究が目的。
 35才以上の妊婦で、費用は21万円程度を予定
 日本人の検査精度調査、専門医によるカウンセリングのあり方を検証。
・国立成育医療研究センター
・昭和大
・東京慈恵会医大
・東大
・横浜市立大

MaterniT21
・シーケノム社製
・妊婦から採血し、血液中にわずかに漂う胎児のDNAを集めて、遺伝子の
 配列を調べる。23対ある染色体のうち、ダウン症の特徴である21番染色
 体が通常より1本多いかどうかを判定する。
・精度は99%とされる。
・13番、18番の染色体異常についても高精度で検出可能。
・米国では235ドル(?)。
・前に販売したSEQureDxが、2008-2009年に、検査結果を操作したことで、
 関与した役員らは、後に、証券詐欺として有罪判決を受けている。
 また、株主による集団訴訟で、1400万ドル支払った経緯がある。

日本ダウン症協会
・安易にこの検査が行われることがないよう、必ず専門医によるカウンセ
 リングを伴うことなどを求める意見書を提出。

出生前診断の種類と検査時期
MaterniT21+検査     10週頃~
絨毛検査        10週~11週頃 流産の可能性が高い
母体血清マーカー    初期11週~13週頃、中期15週~21週頃 精度が劣る
羊水検査        15週~21週頃 流産の可能性がある
エコー検査       項部浮腫(NT)10週~14週、他18週~28週頃
トリプルマーカーテスト 14週~18週頃 精度が劣る

MaterniT21(+) testは、米国では、235ドルとの説もあるが、日本の医療
施設にかかると2625ドル(1ドル80円換算)が必要で、その上、臨床試験。
検査もMaterniT21なのかMaterniT21+なのかも不明。
安易な受診を減らすことが目的だろうが、35才以上で、富裕層と言う条件
になると、臨床試験として成立するかは別な話と思う。

MaterniT21 test精度
・日本の報道では、99%。
・米国の報道では、90-95%。98.6%説(Genetics)あり。
  212陽性サンプル中、209サンプルを陽性と判定。
 擬陽性率が0.2%。
  1471陰性試料中、3試料を陽性と判定。
 判定不可が0.8%
  1696中13が判定できなかった。
 13番、18番の染色体異常についての精度は未確定。

MaterniT21+
・13番、18番の染色体異常についての精度は高精度の検出が可能。

日本の報道と米国の報道には差異があり、何か意図があったのだろうか。
出生前診断では、現実的な問題と倫理的な問題が相変わらず問われる。

出生前診断の検査は、Sequenomだけでなく、Verinata Healthも販売する
とのこと。出生前診断市場が立ち上がるようだ。

技術の発達により、特定の先天性疾患から、ガン、糖尿病等の疾患関連
遺伝子まで検査できるようになるかもしれない。
そうなると、さらに、難しい倫理的な問題に発展しそうだ。

胎児エコー検査 染色体異常も推定可能エコー検査 ICが必要
遺伝子検査ビジネス
Legitimate Rape


Insidermedicine In 60 - October 20, 2011


---ダウン症の出生前診断:来月から妊婦血液検査を試行---
毎日新聞 2012年08月29日 11時57分(最終更新 08月29日 12時18分)
http://mainichi.jp/select/news/20120829k0000e040200000c.html

 妊婦の血液だけで、胎児にダウン症などの染色体異常があるかを99%の精度で調べる米国の会社が開発した新型の出生前診断を、国内の2病院が来月から試験的に開始することが分かった。流産の危険があった従来の検査に比べ、安全に調べることができる一方、異常が見つかれば安易な人工妊娠中絶にもつながることから、カウンセリング体制の整備などが課題になりそうだ。
 検査を始めるのは国立成育医療研究センター(東京)と昭和大学病院(同)で、いずれも臨床研究として行う。対象は高齢出産となる35歳以上の妊婦で、費用は21万円程度を予定している。日本人での検査の精度を調べるとともに、専門医によるカウンセリングのあり方を検証し、この検査が国内に普及した場合の課題やモデルケースを探る。
 検査は米国の検査会社「シーケノム」が昨秋米国で始めた。妊婦から採血し、血液中にわずかに漂う胎児のDNAを集めて、遺伝子の配列を調べる仕組みだ。23対ある染色体のうち、ダウン症の特徴である21番染色体が通常より1本多いかどうかを判定する。精度は99%とされており、他に発生頻度が比較的高い二つの染色体異常についても高精度で検出可能という。
 検査は米国の検査会社「シーケノム」が昨秋米国で始めた。妊婦から採血し、血液中にわずかに漂う胎児のDNAを集めて、23対ある人間の染色体のうちダウン症の特徴である21番染色体が通常より1本多いかどうかを判定する。精度は99%とされており、妊娠10週ごろから可能。他に発生頻度が比較的高い二つの染色体異常についても高精度で検出できるという。
 現在行われている出生前診断は数種類あるが、採血だけで胎児の遺伝子を直接調べられるものはない。例えば「羊水検査」は胎児の遺伝子を調べられるが、妊婦の腹部に針を刺して羊水を抜くため、0.5%程度流産のリスクがある。一方、「母体血清マーカー検査」は採血だけですむが、精度が低く、異常があるかを確実に知るためには羊水検査が必要になる。このため、流産のリスクがなく染色体異常を高精度で調べられるシーケノム社の検査に対し、世界中から注目が集まっていた。
 一方、検査が普及すれば中絶を選ぶ夫婦が増える可能性がある。日本ダウン症協会(玉井邦夫理事長)は27日、日本産科婦人科学会に対し、安易にこの検査が行われることがないよう、必ず専門医によるカウンセリングを伴うことなどを求める意見書を提出した。【斎藤広子】


---妊婦の血液でダウン症診断 5施設で9月以降導入 中絶大幅増の懸念も---
2012.8.29 11:24
http://sankei.jp.msn.com/life/news/120829/bdy12082911260002-n1.htm

 妊婦の血液を調べるだけで、胎児にダウン症などの染色体異常があるかどうかがほぼ確実に分かる新しい出生前診断を、国立成育医療研究センター(東京)など5施設で9月以降に導入する方針であることが29日、分かった。
 妊婦の腹部に細い針を刺して羊水を採取する従来の方法に比べて極めて安全にできるが、簡単に検査ができるため、異常が発見された際の人工妊娠中絶が大幅に増える懸念もある。
 そのため日本産科婦人科学会などでは、専門医やカウンセラーなどの体制が整備された医療機関で先行的に行い、有用性や問題点などを分析していく方針。導入を検討している病院の医師らは31日にも研究組織を立ち上げ、検査を行う際の共通のルールを作る。
 関係者によると、導入を検討しているのは、同センターと昭和大(同)、東京慈恵会医大、東大、横浜市立大。高齢出産だったり、以前にダウン症の子供を出産していたりするなど、染色体異常のリスクが高い妊婦で検査希望者が対象になる。保険がきかず、費用は20万円程度になる。
 検査は妊娠10週目以降から可能で、妊婦の血液中に含まれるわずかな胎児のDNA型を調べ、99%の精度で異常が分かるという。
 日本産科婦人科学会副理事長の岡井崇昭和大教授は「これまでに比べて検査時のリスクが格段に小さくなるが、乱用されれば問題も出てくる。どう行っていけばいいか、しっかり検討したい」としている。
 一方、日本ダウン症協会の水戸川真由美理事は「出生前診断が胎児のふるい分けとして一般化したり、安易に行われることは断固反対。検査に対する基本的な考え方をしっかりと明示してほしい」と述べた。


---出生前診断で「胎児に異常」、10年前と比べ中絶倍増---
2012年4月5日7時47分
http://www.asahi.com/science/update/0405/TKY201204040916.html

  出生前診断で胎児の異常が分かったことを理由にした中絶が2005~09年の5年間で少なくとも6千件と推定され、10年前の同期間より倍増していることが、日本産婦人科医会の調査でわかった。高齢出産の増加や簡易な遺伝子検査法の登場で今後、十分な説明を受けずに中絶を選ぶ夫婦が増える可能性もあるとして、日本産科婦人科学会は遺伝子検査の指針作りに乗り出した。
 同医会所属の約330施設を対象に中絶の実態を調べ、平原史樹・横浜市立大教授(産婦人科)がまとめた。年により回答率にばらつきがあるため、5年単位で傾向を分析した。この結果、ダウン症、水頭症などを理由に中絶したとみられるのは、1985~89年は約800件だったのが、95~99年は約3千件、05~09年は約6千件と急増していた。
 日本では、70年代から胎児の異常を調べる羊水検査やエコー検査、90年代から母体血清マーカー検査が広がった。35歳以上の高齢出産の増加で、出生前診断を受ける人は増えている。妊婦健診で使われるエコーも精度が上がり、染色体異常の可能性を示す首の後ろのむくみの厚さや臓器の奇形もわかるようになった。


---ccfDNA検査とは---
20120829
http://www.prenatal-diagnosis.info/pd_hikaku/ccfdna%E6%A4%9C%E6%9F%BB.html

ccfDNAとは、Circulating cell-free DNA(循環細胞フリーDNA)の略です。
ccffDNAという場合もありますが、これはCirculating cell-free fetal DNA(循環細胞フリー胎児DNA)の略です。
妊婦さんの血液中にごく僅か循環している胎児のDNA断片を分析する検査です。

母体血中NRBC検査が胎児の細胞を分析するのに対し、ccfDNA検査は、細胞が破壊されて出てきたDNAの断片を分析します。

アメリカで、Sequenom社がMaterniT21 testという名称で検査サービスを開始しました。

■具体的な検査方法
妊婦さんから採血によって血液を取ります。
その後、DNA断片を分離します。
分離したDNAの中には、妊婦さん由来のものと胎児由来のものが混在しています。
胎児由来のものは、ごくわずかです。

■検査可能な時期は
10週目から検査可能です。

■結果が分かるまでの日数は
10日間程度です。

■検査費用は
アメリカでは、検査費用が保険により支払われるため、自己負担としては235ドル程度となるようです。

■ccfDNA検査で何が分かるのか
21トリソミー(ダウン症候群)が分かります。

■ccfDNA検査の精度
1,696検体の精度検査研究の結果

212件トリソミー21のうち、210件を検出
99.1% sensitivity(敏感度)・・・病気を発見する能力 (95% CI: 96.3-99.8%)
99.9% specificity(特異度)・・・非病人を病気だと誤診しない能力 (95% CI: 99.6-99.9%)

DNA Sequencing of Maternal Plasma to Detect Down Syndrome: An International Clinical Validation
Genet Med. 2011 Nov;13(11)

■ccfDNA検査のメリット
・妊婦さんの採血だけで済むため、検査による流産のリスクはありません。
・妊娠10週目から検査可能です。
・21トリソミーの確定ができます。

■ccfDNA検査のデメリット
・21トリソミー以外の染色体異常は検出できません。
・発見できない可能性があります。
・現状、アメリカでしか検査を行うことができません。


---Fetal gene screening comes to market---
Published online 25 October 2011
http://www.nature.com/news/2011/111025/full/478440a.html

Non-invasive procedure could make prenatal testing easier, but it comes with ethical problems.

Until last week, scrutinizing a fetus's DNA for indications of genetic abnormalities meant tapping into the mother's womb with a needle. Now there's a test that can do it using a small sample of the mother's blood. MaterniT21, a Down's syndrome test that Sequenom of San Diego, California, launched in major centres across the United States on 17 October, is the first of several such tests expected on the market in the next year. It signals the arrival of a long-anticipated era of non-invasive prenatal genetic screening, with its attendant benefits and ethical complications.

With the technology in place to sequence the fetal DNA carried in a pregnant woman's bloodstream, geneticists predict the list of conditions that can be detected by non-invasive means will grow rapidly. Another company, Gene Security Network of Redwood City, California, says its forthcoming test will also check for other genetic abnormalities, and Sequenom is studying the feasibility of expanding its test.

"There's every reason to think that in the future you'll be able to extract an enormous amount of information from that sequencing data," says Peter Benn, director of the Diagnostic Human Genetics Laboratories at the University of Connecticut Health Center in Farmington.

Sequenom's test sequences 36-base-pair fragments of DNA to identify sections from chromosome 21. Normally, the chromosome contributes 1.35% of the total maternal and fetal DNA in the mother's blood. An overabundance of this material indicates the genetic abnormality that marks Down's syndrome.

Sequenom is marketing its test as an add-on to current screening methods, which estimate the chance that a woman is carrying a fetus with Down's syndrome from ultrasound results and protein markers in the blood. Such non-genetic screening can detect 90-95% of Down's syndrome cases, but falsely indicates that up to 5% of women are carrying a baby affected by the condition. Sequenom's test could be taken after a positive screening result to help a woman decide whether to undergo amniocentesis, a test that extracts amniotic fluid with a needle and carries a small risk of miscarriage. A study published this month, and paid for by Sequenom, found that the company's test has a false positive rate of 0.2%.

It could spare some women from having amniocentesis after a false-positive screening result. But Benn says that the test will also pose difficulties. For instance, because it would take 8-10 days to get the results of Sequenom's test, if a woman did still opt for amniocentesis, and the result confirms that the baby has Down's syndrome, there would be little time left to decide whether to terminate the pregnancy. And some women who test positive on MaterniT21 will probably choose to terminate pregnancies immediately rather than have amniocentesis.

"Inserting this new test in the way that Sequenom is proposing is very difficult, from the patient perspective, and difficult for physicians and counsellors to manage," Benn says.

Ethicists also caution that using such easy screening methods ever earlier in pregnancy might worsen the gender imbalance seen in countries such as China and India. And if it becomes routine to check for many different kinds of genetic abnormalities, ethicists predict that more couples may face the quandary of whether to carry an 'unhealthy' fetus to term.

"The idea that couples have choices about whether to continue their pregnancies may become strained because parents may be seen as irresponsible for allowing 'defective' pregnancies to go to term," says Mildred Cho, an ethicist at Stanford University in Palo Alto, California. Other ethicists worry that fears of eugenics will be raised if testing can be done for less-serious conditions.

Sequenom is solely focused on developing tests for conditions that are already part of prenatal screening programmes, says Mathias Ehrich, the company's senior director for research and development diagnostics. "We do not want to invent new applications. Our focus is on making existing clinical applications safer," he says. "I don't think that we are in a position to say that we should determine what hair colour the baby has."


---A Less Risky Down Syndrome Test Is Developed---
By ANDREW POLLACK
Published: October 17, 2011
http://www.nytimes.com/2011/10/18/business/sequenom-test-for-down-syndrome-raises-hopes-and-questions.html?pagewanted=all

New tests are coming to market that can detect Down syndrome in a fetus using a sample of the mother’s blood, potentially reducing the need for riskier invasive tests while also stirring ethical concerns.

 Researchers say the new tests may not be reliable enough yet to replace amniocentesis or chorionic villus sampling, two invasive techniques that carry a slight risk of inducing a miscarriage. But they may lower the numbers of women who undergo those tests but then learn their fetus is normal.

“You will have dramatically fewer procedures,” said Dr. Stephen A. Brown, an associate professor of obstetrics and gynecology at the University of Vermont who has no financial relationship with any of the companies. “It’s a game-changer.”

The first new test, which analyzes fetal DNA in the mother’s blood, is being offered in 20 major cities starting Monday by Sequenom, a biotechnology company in San Diego whose previous work on a Down syndrome test had been marred by a scandal over manipulating data that resulted in the firings of top officials.

The results of a study published online Monday by the journal Genetics in Medicine showed that Sequenom’s new test picked up 98.6 percent of Down syndrome cases.

The false-positive rate - when the test incorrectly said that a baby would have Down syndrome - was 0.2 percent.

“It’s better than anything by far that we’ve ever seen in testing for Down syndrome noninvasively,” said Jacob A. Canick, a professor of pathology at Brown University and the senior author of the study.

The test can be used as early as 10 weeks into a pregnancy, though half of the samples tested in the study were from the second trimester, meaning 15 weeks or more.

Another company, Verinata Health, has said it would introduce a similar test in early 2012. Gene Security Network hopes to have a test ready later in 2012.

Sequenom’s test, called MaterniT21, would be ordered by doctors, not directly by consumers. All samples will be sent to Sequenom’s laboratory for analysis. The test is expected to cost about $1,900, about as much as amniocentesis.

The company said that privately insured women would have to pay $235 out of pocket, with the company assuming the risk of getting insurers to pay the rest. It is not clear how willing insurers will be to cover this test.

Sequenom’s test has not been approved by the Food and Drug Administration. The agency has typically not regulated tests that are offered by a single laboratory, although it has said it might start doing so. In New York, the test will not be available immediately because the state has its own approval process.

Similar techniques are already being used to determine the gender of the fetus and paternity. Some people worry that use of such tests early will lead to more abortion of fetuses with minor abnormalities, the wrong sex or an undesired father.

“The number of American women who will have to grapple with this information prenatally will substantially increase,” said Dr. Brian G. Skotko of the Down syndrome program at Children’s Hospital Boston. His sister has Down syndrome, he said, and he pointed out that these tests could encourage more people to end their pregnancies, causing a decline in the numbers of people with the condition and leading to diminished support for them.

Down syndrome is marked by mild to moderate mental retardation, unusual facial characteristics and various health problems. Most cases occur because a person has three copies of chromosome 21 instead of the usual two.

Many pregnant women undergo preliminary screening using either ultrasound or tests for proteins in the mother’s blood, or both. Those deemed at high risk from that screening or because of their age are then offered an invasive test, in which fetal cells are extracted from the womb.

The existing screening tests have a false positive rate as high as 5 percent. The result is that the vast majority of women who undergo an invasive test have a normal baby.

Sequenom said the test was meant for the 750,000 women a year in the United States who are deemed to be at high risk after initial screening. Women who test negative on the new test may feel comfortable skipping the invasive procedure, researchers said.

However, women who test positive would still be advised to undergo the more definitive invasive tests before terminating a pregnancy. “We don’t feel it’s appropriate to act or make decisions” based solely on the Sequenom test, Dr. Canick said.

Sequenom executives also said they hoped the test would be used by women who choose not to undergo invasive tests because of the risk of miscarriage.

The test has some shortcomings. At least for now, it does not detect other chromosomal abnormalities, including some rare forms of Down syndrome not caused by the triple chromosome.

Down syndrome “only represents 50 percent of all the chromosomal abnormalities that you would identify through amniocentesis or C.V.S.,” said Peter Benn, professor of genetics and developmental biology at the University of Connecticut.

Another drawback, Dr. Benn said, would be the estimated wait for test results that could take up to two weeks, delaying amniocentesis and leaving less time to terminate a pregnancy.

Sequenom could also face heightened skepticism because of its past problems. The company was preparing to introduce another prenatal Down syndrome test in 2009 when it abruptly announced that the data it had promoted to investors could no longer be trusted.

It turned out that a top research official had known which samples were positive and negative and had told subordinates to adjust the parameters of the test to improve its accuracy.

Five executives, including the chief executive and the research official, were fired. The research official, Elizabeth A. Dragon, pleaded guilty to conspiracy to commit securities fraud. (She died this February, before sentencing.)

Sequenom’s stock, which had been over $25 early in 2009, collapsed after the scandal. On Monday it rose 24 cents to close at $5.56.

With a new testing technique and new management, Sequenom is trying to establish credibility by having the results of its study published Monday in the medical journal. The company paid for the study and some authors of the paper are employees. Dr. Canick and the other lead investigator were paid consultants to Sequenom, but ended those relationships when the study started.

The study used blood samples from pregnant women who were about to undergo an invasive test.

The Sequenom test correctly identified 209 of the 212 Down syndrome samples, a rate of 98.6 percent. It incorrectly characterized three of 1,471 negative samples as showing Down syndrome. The test could not determine any answer for 13 pregnancies, or about 0.8 percent of cases.

The test counts small fragments of DNA in the mother’s blood. While most of this DNA is from the mother, some is from the fetus. Sequenom uses high-speed gene sequencers to determine the sequence of millions of the fragments. Using knowledge of the human genome, it determines which chromosome each fragment comes from. If the fetus has three copies of chromosome 21, there will be more than the expected number of fragments coming from chromosome 21.

One of the first papers on this approach was published in 2008 by Stephen Quake, a professor of bioengineering and applied physics at Stanford. Verinata has the rights to his discoveries, setting up a potential patent battle with Sequenom.

Professor Quake said that by increasing the number of fragments counted, it would be possible to prenatally diagnose abnormalities that do not involve entire extra chromosomes, even single mutations that cause diseases like cystic fibrosis.

Gene Security Network and another company, Tandem Diagnostics, are developing tests using somewhat different genetic analysis techniques. Other researchers are trying to use intact fetal cells, as opposed to DNA fragments. But such cells are extremely rare in the mother’s blood.


---Trisomy 21 - Prenatal Genetic Testing, Cystic Fibrosis Test & Trisomy 21 Test | Sequenom Center for Molecular Medicine---
2012年8月29日
http://www.sequenomcmm.com/home/patients/trisomy-21/

What Is Trisomy 21?
Trisomy 21 is the most common cause of Down syndrome. Down syndrome is a condition in which extra genetic material causes delays in the way a child develops, both mentally and physically. Not everyone with Down syndrome is affected in the same way, and there is no way to determine before birth how a child may be affected.

Down syndrome affects about 1 in every 800 babies. Approximately 5000 babies with Down syndrome are born each year. It is the most common chromosomal variation. The risk to have a child with Down syndrome does increase with the mother’s age, but mothers of all ages can have a child with Down syndrome.

Down syndrome is most often caused by extra genetic information from chromosome 21. It is important to know that most cases of Down syndrome are not inherited. In fact, most cases of Down syndrome happen randomly by chance.

Why Prenatal Screening For Trisomy 21 Is Important…

Prenatal screening tests help identify women who have an increased risk of having a baby with certain birth defects or chromosomal variations. The American College of Obstetricians and Gynecologists (ACOG) recommends that all pregnant women be offered a screening test for Down syndrome, regardless of the mother’s age. Your doctor may also recommend screening for Down syndrome if you have other risk factors such as a family history of Down syndrome. Prenatal screening for Trisomy 21 can help determine whether your baby has Down syndrome. Knowing the risk of Down syndrome can help you, your family and your healthcare provider make informed decisions about your pregnancy.

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