Should DNA-based tests for Down syndrome screening replace biochemical tests?

In a previous post I described the clinical performance of DNA-based screening tests for fetal aneuploidies like Down syndrome.  Overall, these tests have excellent detection rates (~99%) with very low false-positive rates (~0.2%).  In other words, these tests are about 99.0% sensitive and 99.8% specific.

With performance like that one might expect these to be considered diagnostic tests.  They are not! Although quite good, test results must not be interpreted as definitive evidence that a fetus does or does not have an aneuploidy.  Recent recommendations from the American College of Obstetricians and Gynecologists (ACOG) are quite clear on that issue.

In those same recommendations, ACOG also states that DNA-based screening tests may be performed only on women who are at increased risk of having a fetus with aneuloidy.  Among the indications listed for women considered to be at increase risk are:

  • Maternal age 35 years or older at delivery
  • Fetal ultrasound findings suggesting aneuploidy
  • A previous aneuploid pregnancy
  • Abnormal biochemical screening test results
The ACOG is right to avoid recommending that DNA-based screening tests are acceptable to use regardless of risk factors.  Unfortunately, many women who are not at increased risk are using these new tests as a primary screening test and that's not a good idea.

To understand why, considered a population of 100,000 pregnant women from the general population and assume that the prevalence of Down syndrome is 1 in 500 pregnancies.  That means that there would be 99,800 unaffected pregnancies and 200 pregnancies with Down syndrome.  The table below compares the results of the most commonly used biochemical screening test (the Quad test) to a DNA-based screening test.

Quad vs DNA performance
Clearly, the DNA-based test has several advantages over the Quad test.  Its positive predictive value is nearly 17 times greater than the Quad's and a positive DNA-based test result substantially increases the odds of having an affected fetus.  So why not use the DNA-based test as a primary screening test?  For the following reasons:
  • No studies have been published that have evaluated the performance of DNA-based tests in women who are not at increased risk of having a fetus with an aneuploidy
  • DNA-based tests are not widely available
  • The time it takes to report results of DNA-based testing is about 3 times greater than it is with biochemical testing
  • DNA-based tests are considerably more expensive than biochemical tests
  • Relative lack of insurance coverage for DNA-based tests
Until these these limitations can be resolved, it makes more sense to use DNA-based testing as a secondary screening test.  In other words, it is only done after one of the risk factors described by ACOG (above) are met.  Doing so greatly improves the performance of both tests (see figure below).  A limitation of this approach is that the detection rate is that of the biochemical test which is not as high as it is with the DNA-based test.  Still, given the current limitations of DNA-based testing, this 2-step testing approach makes the most sense.
DNA as secondary test

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2 thoughts on “Should DNA-based tests for Down syndrome screening replace biochemical tests?

  1. Jessica

    This is a great post and the concluding algorithm makes a lot of sense . . . EXCEPT in a critical arena: timing. One of the real promises of cell-free DNA screening is how early it can be done. Having reliable screening results by 12 weeks (test at 10 weeks + 2 weeks for results) instead of 16-18 weeks for the quad screen is HUGE.

    I think it will be within pretty short order that the bulleted concerns will be addressed and the algorithm will become cell-free DNA screening -> diagnostic testing.


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