Down syndrome

A New Era in Noninvasive Prenatal Testing.

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A new, noninvasive prenatal test is poised to change the standard of care for genetic screening. Cell-free fetal DNA (cfDNA) testing requires only a maternal blood sample, can be performed as early as 9 weeks of gestation, and outperforms standard screening tests for trisomies 21, 18, and 13 in high-risk populations. It has a sensitivity exceeding 98% and a specificity above 99.5% characteristics of Representative Noninvasive Prenatal Tests Available in the United States.).

Currently, standard screening entails testing of maternal blood samples at gestational weeks 10 to 13 or 16 to 18 (or at both points) to measure serum markers associated with common trisomies and usually an ultrasound examination, including measurement of nuchal translucency, at 11 to 13 weeks. This approach identifies more than 90% of trisomies, with a screen-positive rate of 5% in the general population. Diagnostic testing for women with positive results on screening requires either amniocentesis or chorionic villus sampling, invasive procedures that carry a risk of miscarriage. Amniocentesis, which is performed far more commonly than chorionic villus sampling, is generally delayed until after 15 weeks, with a 1-to-2-week turnaround time for results.

The use of cfDNA testing may appeal to expectant parents for many reasons: it carries no risk of miscarriage, permits earlier detection, and generally provides earlier information about a fetus’s sex. Earlier testing can reassure parents who have negative results, while offering those with abnormal results timely information to help them make difficult decisions. People who choose to continue a pregnancy after an abnormal result have additional time to prepare to deliver and care for their child.

Nevertheless, the diffusion of cfDNA testing into routine prenatal care may be occurring too quickly. Professional societies do not recommend these tests for normal-risk pregnancies because their clinical utility in the general population is not well established. Yet because the Food and Drug Administration (FDA) is not empowered to require testing companies to produce evidence of clinical utility before receiving marketing approval, companies have been free to build consumer demand for cfDNA testing by aggressively marketing the tests, emphasizing data that do not answer key questions. As a result, cfDNA testing seems to be drifting into routine practice ahead of the evidence.

Tests of cfDNA appear to be highly sensitive and specific in detecting trisomies, but two problems plague the evidence base. First, the sensitivity and specificity of the tests derive from studies done on collections of archived samples with known karyotypes that intentionally included a large proportion of specimens from women with known aneuploid fetuses. Evidence concerning the performance characteristics of the testing in the general population and for multiple gestations is limited.1 Second, cfDNA-testing companies have not reported information about their tests’ positive predictive value (PPV), and there is reason to question the tests’ performance on this measure.2 Arguably, PPV is more important than sensitivity and specificity to patients undergoing testing: it indicates the probability that a positive test result indicates a true fetal aneuploidy. Thus, PPV should be discussed in study reports and marketing materials but isn’t.

Studies of cfDNA testing have often been conducted on samples including a high percentage of specimens with known abnormal karyotypes. Prevalence rates for Down’s syndrome in the samples are as high as 1 in 8.3 Although sensitivity and specificity are unaffected by the condition’s prevalence in the test population, PPV and negative predictive value (NPV) vary considerably with prevalence. At a prevalence of 1 in 8, assuming a constant specificity of 99.7% and a sensitivity of 99.9%, the PPV and NPV are impressively high — 97.94% and 99.99%, respectively. But at a prevalence of 1 in 200 — the approximate prevalence of Down’s syndrome among fetuses of 35-year-old women in the second trimester of pregnancy — the PPV drops to 62.59%.

It is worrisome that some laboratories that performed validation tests may have been aware that the samples included high proportions of specimens with known aneuploidies — but that this isn’t always made clear in the studies’ descriptions. Prior knowledge about the prevalence of aneuploidies in the samples may well have affected an analyst’s decisions about how to classify ambiguous test results: someone who believes 1 in 8 samples is abnormal may be more likely to classify a questionable result as abnormal than someone who believes that 1 in 200 is abnormal. Not all published studies of cfDNA testing have this problem, and one study of a sample without a high prevalence of aneuploidies suggests that the false positive rate for the Harmony test (Natera) is low.1 Without additional evidence, however, the clinical utility of cfDNA remains uncertain.

Given this unproven utility in the general population, the leading professional organizations, including the American Congress of Obstetricians and Gynecologists, the Society for Maternal–Fetal Medicine, and the National Society of Genetic Counselors, recommend cfDNA testing only for “high-risk pregnancies,” without specifically defining “high risk.” Furthermore, they recommend that positive results be confirmed through invasive testing. That recommendation is important for patients to understand, because if patients with positive results on cfDNA testing are counseled to wait until their diagnosis is confirmed before taking action, an important potential benefit of cfDNA testing is lost.

Patients must also weigh the benefits of earlier detection against other informational costs. Tests of cfDNA do not provide information about some disorders that are identified through standard screening, including chromosomal abnormalities other than trisomies. It is thus crucial that providers carefully counsel patients about the test’s advantages and disadvantages. Decision making is further complicated by the fact that cfDNA testing is costly and not widely covered by insurance. Four versions of the test are available in the United States, priced from $795 to more than $2,000 (see table). A few major insurers cover cfDNA testing if it’s accompanied by confirmatory testing for positive results, but many have yet to decide whether to cover it.

Meanwhile, testing companies have pursued various strategies to build consumer demand, including reaching out to expectant mothers through YouTube, Facebook, and Twitter. Some companies have capped out-of-pocket costs and offered “introductory pricing” specials with costs ranging from $200 to $235. This strategy has had apparent success, with one company boasting a “spectacular” adoption rate of 60,000 tests performed in 2012.4

The companies’ marketing strategy risks building demand for tests that may not offer a substantial benefit, particularly for women with low-risk pregnancies. Expectant parents’ excitement about the opportunity to learn their child’s sex and rule out trisomies earlier may lead to discounting the tradeoffs involved, push the standard of care away from professional recommendations for confining use to high-risk populations, and contribute to higher costs. The evidentiary gaps concerning cfDNA testing, aggressive marketing, and rapid diffusion into routine practice can be traced, at least partially, to our country’s regulatory scheme for laboratory-developed tests. Under FDA regulations, commercial test kits — which are distributed to multiple laboratories and health care facilities — are subject to both premarketing assessments of analytic and clinical validity and postmarketing reporting of adverse events. No similar requirements exist for tests, like the cfDNA tests, developed for in-house use by a single laboratory.

Laboratory-developed tests are governed, instead, by the Clinical Laboratory Improvement Amendments of 1988. Laboratories must demonstrate such a test’s accuracy, precision, specificity, and sensitivity — but not its clinical validity or utility. Although companies offering noninvasive prenatal tests have chosen to perform studies in the targeted population, they aren’t obliged to do so,2 nor must they design studies so as to provide robust evidence about clinical utility.

Congress’s choice to require a less onerous regulatory approach for laboratory-developed tests arguably promotes the availability of new tests, but it leaves the real-world benefits and risks of these tests more uncertain than those of commercial tests. The rapid proliferation of direct-to-consumer genetic tests and other laboratory-developed tests has led to controversy, culminating in two unsuccessful congressional attempts to strengthen oversight.5 For now, as with many medical innovations, it will fall to physicians to hold the line against pressures promoting diffusion of cfDNA testing beyond the boundaries of available evidence.

 

REFERENCES

  1. 1

Nicolaides KH, Syngelaki A, Ashoor G, Birdir C, Touzet G. Noninvasive prenatal testing for fetal trisomies in a routinely screened first-trimester population. Am J Obstet Gynecol 2012;207(5):374.e1-374.e6.

  1. 2

Norton ME, Rose NC, Benn P. Noninvasive prenatal testing for fetal aneuploidy: clinical assessment and a plea for restraint. Obstet Gynecol 2013;121:847-850
CrossRef | Web of Science | Medline

  1. 3

Palomaki GE, Kloza EM, Lambert-Messerlian GM, et al. DNA sequencing of maternal plasma to detect Down syndrome: an international clinical validation study. Genet Med 2011;13:913-920
CrossRef | Web of Science | Medline

  1. 4

Lindsay R, Maier P. Sequenom Management Presents at Barclays Capital 2013 Global Healthcare Conference (Transcript). March 13, 2013 (http://seekingalpha.com/article/1272301-sequenom-management-presents-at-barclays-capital-2013-global-healthcare-conference-transcript?part=single).

  1. 5

Weiss RL. The long and winding regulatory road for laboratory-developed tests. Am J Clin Pathol 2012;138:20-26
CrossRef | Web of Science | Medline

Source: NEJM

 

Delayed Cord-Cutting Seems Warranted, Meta-Analysis Concludes.

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Delaying clamping of the umbilical cord for more than 1 minute after birth increases the infant’s iron stores and hemoglobin concentration, aCochrane Library meta-analysis finds.

The analysis included 15 randomized trials comprising almost 4000 mother-infant pairs. Severe maternal postpartum hemorrhage was no more frequent with delayed clamping. Neonatal mortality rates did not differ between the early- and late-clamping groups; phototherapy for jaundice was less common with early clamping (relative risk, 0.62).

Late clamping was associated with higher neonatal hemoglobin levels in the early postpartum period, as well as a lower risk for iron deficiency at 3 to 6 months postpartum.

The authors conclude that delayed clamping “is likely to be beneficial as long as access to treatment for jaundice requiring phototherapy is available.”

Source:Cochrane Library

span� sy�8 ��m size:9.0pt;font-family:”Helvetica“,”sans-serif”;color:#454545′>In a prospective study, endoscopists were given training to ensure familiarity with the classification of polypoid versus nonpolypoid colorectal neoplasms. Among 59 patients with Lynch syndrome undergoing colonoscopy, and 590 matched control patients, conventional adenomas were more likely to be nonpolypoid in patients with Lynch syndrome than in control patients — both overall (43.4% vs. 16.9%) and in the proximal colon (58.1% vs. 16.3%). Serrated polyps were also more likely to be nonpolypoid in patients with Lynch syndromes than in control patients (49.2% vs. 20.4%).

 

COMMENT

Current guidelines recommend that patients with Lynch syndrome undergo colonoscopy at 2-year intervals beginning at age 20 to 25 years, and annually after age 40. Many experts perform colonoscopy at 1-year intervals even in younger patients who are proven gene carriers. The basis for these short intervals is the repeated observation that patients appear to develop colorectal cancers within a few years of a normal colonoscopy. The current study suggests that this phenomenon could be based not only on the rapid accumulation of mutations in small lesions, but also on an increased tendency toward nonpolypoid shape that could contribute to missing neoplasms during colonoscopy. The data certainly support performance of colonoscopy in patients with Lynch syndrome by endoscopists who are thoroughly trained in the full endoscopic spectrum of both conventional adenoma and serrated lesion appearances.

Source: NEJM

First-Trimester Noninvasive DNA Test Identifies Fetal Aneuploidies.

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Invasive testing for fetal aneuploidies with chorionic villus sampling can be minimized by analyzing fetal DNA from the mother’s blood during the first trimester, according to two U.K. studies in Ultrasound in Obstetrics and Gynecology.

The first study, involving some 90,000 singleton pregnancies, examined which women should undergo maternal blood cell-free DNA (cfDNA) testing to detect trisomy 21, in addition to ultrasound and biochemical screening. Researchers found that by offering cfDNA testing to women with high-risk biochemical test results, a 98% detection rate could be achieved, with an invasive testing rate below 1%.

The other study used cfDNA testing routinely in 1000 singleton pregnancies, in addition to ultrasound and biochemical studies, to screen for trisomies 21, 18, and 13. All trisomies were detected; the false-positive rate for cfDNA was 0.1%, while ultrasound and biochemical screens had a 3.4% false-positivity.

The authors emphasize that the potential for false-positives dictates the need for invasive testing following abnormal results.

Source: Ultrasound in Obstetrics and Gynecology

 

Brain cells give insight into Down’s syndrome.

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downs

Brain cells have been grown from skin cells of adults with Down’s syndrome in research that could shed new light on the condition.

US scientists found a reduction in connections among the brain cells and possible faults in genes that protect the body from ageing.

The research in the Proceedings of the National Academy of Sciences gives an insight into early brain development.

Down’s syndrome results from an extra copy of one chromosome.

This generally causes some level of learning disability and a range of distinctive physical features.

A team led by Anita Bhattacharyya, a neuroscientist at the Waisman Center at the University of Wisconsin-Madison, grew brain cells from skin cells of two individuals with Down’s syndrome.

This involved reprogramming skin cells to transform them into a type of stem cell that could be turned into any cell in the body.

Brain cells were then grown in the lab, providing a way to look at early brain development in Down’s syndrome.

One significant finding was a reduction in connections among the neurons, said Dr Bhattacharyya.

“They communicate less, are quieter. This is new, but it fits with what little we know about the Down syndrome brain.”

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It seems to be another step forward, giving us insight into the effects of having three copies of chromosome 21”

Carol BoysChief executive, Down’s Syndrome Association

Brain cells communicate through connections known as synapses. The brain cells in Down’s syndrome individuals had only about 60% of the usual number of synapses and synaptic activity.

“This is enough to make a difference,” added Dr Bhattacharyya. “Even if they recovered these synapses later on, you have missed this critical window of time during early development.”

The researchers looked at genes that were affected in the stem cells and neurons from two individuals with Down’s syndrome.

They found that genes on the extra chromosome, chromosome 21, were increased greatly, particularly genes that responded to damage from free radicals, which may play a role in ageing.

This could explain why people with Down’s syndrome appear to age quickly, although this remains to be tested, said the University of Wisconsin-Madison team.

Commenting on the study, Carol Boys, chief executive of the UK Down’s Syndrome Association, said it was interesting work from an established, well-known team.

“It seems to be another step forward, giving us insight into the effects of having three copies of chromosome 21,” she said.

“We are learning more all the time about the mechanisms that cause certain aspects of the condition Down’s syndrome and this may ultimately result in the development of therapies for treatment.”

Source: BBC