Down's Syndrome Biochemical Screening - Part 3

Question 1

What report was issued in order to define what the best test for Down’s syndrome was? How was this done? What tests did the National Screening Committee end up recommending as a result of this report?

Answer 1

• The department of health commissioned a health technology assessment report called SURUSS.
• Supposed to be the definitive assessment to establish what the best test was which would then be presented to the department of health for people to adopt.
• The SURUSS report standardised the different testing approaches to look at how many women would falsely be detected as positive when the test was carried out to obtain a detection rate is 85%.
• The integrated test has patent restrictions on it but is the best performing test. Only has a false positive rate of 1.2% for an 85% detection rate. However, it is expensive and you have to pay them money to do it because of the patent. You have to do lots of tests - 4 markers. Critically, patients actually have to turn up twice, once for an USS un the first trimester and then again for a blood test later on. Lots of studies have shown that about 30% of women don’t turn up for the second appointment. Therefore the integrated test worked well in the academic study but works less well in real situations.
• The combined test has been chosen as the primary test recommended by the national screening committee. NT, free BHCG and PAPP-A at 10 completed weeks. FPR is 6.1% for an 85% detection rate. Most women prefer get the tests done as early in pregnancy as possible.
• If the women aren’t seen within the first trimester for any reason or if can’t get an NT then will use the Quadruple test instead. AFP, uE3, free BHCG and inhibin-A at 14-20 weeks.

Question 2

What factors contribute to what makes a good screening test for Down’s syndrome in pregnancy?

Answer 2

• Part of it is which test gives the best performance but this is only part of it.
• Also want to look at what’s going to work in practice.
• What is going to work with the limited resources that the NHS has?
• What is going to be acceptable to the women being screened? Ideally not multiple appointments.

Question 3

What tests did the National Screening Committee decide to recommend as the national initial pregnancy screen for Down’s syndrome?

Answer 3

1) . Combined test: at 11 weeks and 1 day to 14 weeks and 1 day. This involves 2 markers in the first trimester (PAPP-A, fbHCG) and a nuchal fold translucency measurement.
2) . Quadruple test: after the period of time where the female would be eligible for the combined test, or if not able to take NT measurement on USS then the quadruple test will be carried out. This can be conducted between 15 weeks and 0 days and 20 weeks and 0 days. Involves 4 biochemical markers including AFP, HCG, uE3 and Inhibin-A.

Question 4

What is quality assurance? What quality assurance systems are in place in laboratories for biochemical Down’s screening?

Answer 4

• Quality assurance may be defined as a broad spectrum of plans, policies and procedures that together provide an administrative structure for a laboratory’s efforts to achieve its quality goals.
• Labs are accredited - Clinical Pathology Accreditation (CPA) based on ISO standards.
• Trained, state-registered staff.
• SOPs to follow.
• Labs perform lots of internal quality control. Perform internal quality control of every batch using quality control samples. Like to know what the statistical behaviours of the tests are, look at random and systematic error and have very fixed and rigid acceptance criteria.
• Systematic error particularly important - as biochemical analysis relies on the use of antibodies from time to time the performance of the assays will change, can get up to 15% swings in performance giving changes in systematic bias over time. Examine performance of individual tests every week and will assess whether the changes in bias are sufficient to adjust the background population values.
• Also do a lot of External Quality Control - compares laboratories.
• Control of software - need to be careful to control software. Will often repeat samples and check we get the same risk calculated. Will look at the screen positive rates coming through - if the background rate is staying the same we should expect the screen positive rates to stay roughly the same. Will plot monthly marker MoM plots to examine bias. Every 6 months have to submit all data to the Downs Quality Assurance and Statistics Service (DQASS).

Question 5

In Down’s syndrome screening much of the focus of the National Screening Programme is now on quality? What does this encompass?

Answer 5

• New national focus on quality.
• Aims:
  1) . Equality of access.
  2) . Standardisation.
  3) . Reduced false-positive rate.
  4) . Improved detection rate.
• Overall Program Objectives (2010) are that labs have to achieve a 90% detection rate (DR%) for a 2% or better screen positive rate (SPR%).

Question 6

What does the future hold for the screening of Down’s syndrome?

Answer 6

• Currently the biochemical screening test looks at surrogate markers for Down’s syndrome that are present in the mother’s blood. We then have to go on and do a diagnostic test.
• The holy grail is that we may somehow be able to find free foetal DNA in the mother’s blood and then be able to use that to be able to tell whether the foetus is affected by trisomy 21. This would be diagnostic, non-invasive.