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UK Study Proposes Protocol for Cost-Effectively Integrating NIPT into Down Syndrome Screening

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As sequencing-based non-invasive prenatal testing for chromosomal abnormalities is making its way into the clinic, with tens of thousands of tests being administered in the US alone last year, researchers are thinking about ways for integrating NIPT with existing screening programs in a cost-effective way.

Last month, researchers from the Wolfson Institute of Preventive Medicine at Barts and the London School of Medicine and Dentistry in the UK published a screening protocol in PLoS One that combines an existing Down syndrome screening test, called the Integrated test, with reflex DNA-based testing, resulting in "high screening performance with no test failures" at a cost that is "substantially lower" than offering DNA-based testing to all women.

According to Nicholas Wald, director of the Wolfson Institute and an author of the study, the goal is to "seamlessly link" the current screening technology, which is based on ultrasound and immunoassays, with the new DNA tests, "so there would be a rational and understandable transfer from one to the other."

"Many doctors and labs may not want to completely give up the existing methods suddenly, because they are used to them, and this would be a way of bringing in the new technology in a gradual way," he said.

According to the researchers, non-invasive prenatal DNA tests are highly effective, detecting at least 98 percent of Down syndrome cases, with false-positive rates of 0.2 percent or less.

However, the tests are expensive, ranging in list price from about $800 to $2,900; have a failure rate of between 2 percent and 13 percent, according to published studies; and are only available from a small number of commercial providers –Sequenom, Ariosa Diagnostics, Illumina's Verinata Health, and Natera in the US; LifeCodexx in Germany; and BGI and Berry Genomics in China.

For comparison, the Wolfson Institute offers the Integrated test – which combines first-trimester nuchal translucency measurements, serum marker, and maternal age with second-trimester serum markers and has a detection rate between 90 and 94 percent – for about $50 "in a public service context," according to the paper. It also offers a number of other Down syndrome screening tests that are based on similar methods and are similarly priced, such as the Combined test, which Wald said is the most widely used test in the UK.

Wald is a co-founder of a company, Logical Medical Systems, that provides software for the interpretation of existing Down syndrome screening test results, and he is a director for Intema, a company that manages intellectual property covering the Integrated test method. However, he said he strongly supports improved test methods taking over.

In their paper, the researchers suggest a protocol that combines existing screening in all women with DNA testing in some. "The approach that we have proposed avoids this category of failed tests, and it reduces the overall cost because one only has to do DNA sequencing on a proportion of women," who are selected based on the result of the first stage of their Integrated test, Wald said.

Women who don't receive the DNA test, as well as those in whom the DNA test fails, go on to have the second stage of the Integrated test. Invasive testing by amniocentesis is offered to women with positive DNA tests and to women with positive results from the complete Integrated test.

According to the authors, this protocol results in "little loss" in overall screening performance, compared to doing DNA testing in all pregnant women.

To study the performance of their testing scheme, they used screening markers from a large cohort study to simulate 500,000 Down syndrome pregnancies and 500,000 unaffected pregnancies.

Based on those data, they calculated the detection rate and false-positive rate for Down syndrome if reflex DNA testing was offered to various proportions of women after completing the first stage of the Integrated test.

For example, if 10 percent of women received reflex DNA testing, the detection rate would be 92.4 percent, and the false-positive rate would be 0.11 percent. On the other hand, if reflex DNA testing was offered to 90 percent of women, the detection rate would be 98.2 percent and the false-positive rate 0.2 percent.

They also calculated the cost of screening per woman, as the number of DNA tests increases. Because prices for the Integrated test and the non-invasive DNA tests vary widely between providers as well as geographic areas, they used different scenarios, ranging from DNA tests costing 2.5 times to 40 times as much as the Integrated test.

For example, if the price of the DNA test was 10 times that of the Integrated test, the total cost per woman would be twice as much if 10 percent received the DNA test, and 9.8 times as much if 90 percent of women received it.

The premises of the study will likely change over time, though. For example, the failure rate for the DNA tests is expected to go down as scientists gain more experience with them, Wald said. In addition, their cost will likely decrease as DNA sequencing technology improves.

Eventually, NIPT might replace existing tests altogether. "If the DNA test were as cheap as an Integrated test, then there would be a sound reason for doing it on everyone and considering not doing an Integrated test, provided the DNA test failure rate was very low," Wald said.

However, doctors may want to retain current screening methods for other reasons. Ultrasound, for example, allows them to look for other abnormalities, and some of the immunoassays can be used to test for preeclampsia, which DNA testing cannot detect.

Overall, the protocol offers guidelines for how to integrate non-invasive DNA testing into existing Down syndrome screening, in particular cost-sensitive publicly financed programs. "This is a way of mitigating the higher cost of the DNA testing in a program that will achieve nearly the same performance as if all women had the DNA test," Wald said.

According to Thomas Musci, vice president of clinical and medical affairs at Ariosa Diagnostics, many doctors in the US are already using DNA tests, such as Ariosa's, to follow up on positive serum screening tests, so the concept of using them as reflex tests is not novel.

The UK researchers' protocol has merit for programs aiming to "give the most access to the most women for the least amount of money to utilize this technology" and reduce the number of invasive diagnostic procedures as a result, he said. It probably has "a little more appeal" to countries with publicly funded health services, like the UK, where limited resources need to be allocated in the most effective way.

In the US, it could be useful for individual states offering screening programs for certain populations, but it might not be widely applicable. "In the US, we have this issue of people wanting to have the widest variety of choices, and to a certain extent, it's what their insurance [pays for] and what they are willing to pay," he said.

Ariosa offers the least expensive NIPT of the four US providers, and "we know that this will mean much more accessibility to patients from a wider swath of the population," Musci said. "We've been very conscious of that and trying to reduce cost will continue to drive us."

In the UK, some prenatal clinics are starting to offer NIPT as an out-of-pocket test. For example, the Fetal Medicine Center in London adopted Ariosa's test last year (CSN 12/19/2012), but it is currently not covered by the country's National Health Service.

According to Wald, for the NHS to cover non-invasive prenatal fetal DNA testing, demonstration projects would be needed to show its "efficacy in ordinary obstetric practice." It would also need to have an "acceptable cost" and show "a sufficient incremental advantage over the best existing test," in addition to "general professional and public support."

The Wolfson Institute, which screens more than 100,000 pregnancies from the UK and other European countries for Down syndrome and open neural tube defects each year, is currently considering how to incorporate DNA testing into its program. The center is not providing non-invasive DNA testing at the moment but is in discussions with "various groups" about introducing it. "The main obstacle is, who is going to pay for this?" Wald said.

Rather than offering DNA testing only to women who can afford to pay for it out of pocket, he and his colleagues would like to initiate a demonstration project that would integrate the test into a population-based screening program. Such a project would not be funded by the NHS, he said, but require external funding.

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