Chemistry: analytical and immunological testing – Pregnancy or ovulation
Reexamination Certificate
1999-04-29
2003-06-03
Alexander, Lyle A. (Department: 1743)
Chemistry: analytical and immunological testing
Pregnancy or ovulation
C436S086000, C436S814000, C436S818000, C436S510000, C435S004000
Reexamination Certificate
active
06573103
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to a method and apparatus for determining for screening purposes whether a pregnant woman is at an increased risk of fetal Down's syndrome.
The risk of Down's syndrome in a fetus is known to increase with the age of the mother. In addition, abnormally high or low concentrations of certain substances in the maternal serum (biochemical markers), and abnormally large or small measurements of certain ultrasonographic signs (ultrasound markers), are known to be associated with an increased risk of Down's syndrome in the fetus.
Information on one or more of these biochemical or ultrasound markers (collectively called screening markers) can be combined with the age-related risk of Down's syndrome, to form the basis of a screening test.
The aim of a screening test is to identify women who are at a sufficiently high risk of Down's syndrome to justify a further test which is diagnostic of Down's syndrome. Such further diagnostic tests, eg. chorionic villus sampling or amniocentesis, involve sampling procedures that carry a certain risk to the mother and/or fetus, the induction of miscarriage and fetal limb defects being among the recognised hazards. There is, therefore, a need for screening tests that maximise the chance of identifying those pregnancies at highest risk of Down's syndrome, so as to justify further diagnostic tests with their attendant risks.
The effectiveness of a screening test depends on its ability to discriminate between pregnancies with Down's syndrome and unaffected pregnancies. The discriminatory power of a test is usually specified in terms of the detection rate achieved for a given false-positive rate, or in terms of the false-positive rate required to achieve a given detection rate. The detection rate is the proportion of Down's syndrome pregnancies with a positive result. The false-positive rate is the proportion of unaffected pregnancies with a positive result.
Different screening markers generally impart more discriminatory power to a screening test at one stage of the pregnancy than at other stages. Currently employed screening tests rely on certain combinations of biochemical and ultrasound markers that have been identified as being effective when used together at a specific, single stage of pregnancy.
For example, the “combined test” carried out in the first trimester using nuchal translucency and free &bgr;-hCG and PAPP-A as screening markers can achieve an 80% detection rate with a 5% false-positive rate. The “triple test” carried out in the second trimester uses AFT, uE
3
and hCG as screening markers. The “quadruple test” carried out in the second trimester uses the screening markers of the “triple test” plus inhibin-A. The “triple test” and “quadruple test” can achieve an 80% detection rate with a false positive rate of 10% and 6.6% respectively. However, a screening test with greater discriminatory power would be desirable. A high false-positive rate means that a large number of women with screen-positive results in fact have unaffected pregnancies. For these unaffected women the screen-positive result, quite apart from causing considerable anxiety, might lead to a diagnostic procedure such as amniocentesis or chorionic villus sampling which have a risk of miscarriage of about 1 in 100.
An object of the present invention is to derive a screening test which has an improved discriminatory power over the known tests.
Further objects of the invention are to produce an apparatus and a computer program product for implementing the screening test.
BRIEF SUMMARY OF THE INVENTION
The present invention, however, relies on screening markers obtained from two or more different stages of pregnancy. In particular, according to the first aspect of the present invention there is provided a method of determining a pregnant woman's risk of having a fetus with Down's syndrome, the method comprising the steps of:
measuring at least one screening marker level from a first stage of pregnancy by:
(i) assaying a sample obtained from the pregnant woman at said first stage of pregnancy for at least one biochemical screening marker; and/or
(ii) measuring at least one screening marker from an ultrasound scan taken at said first stage of pregnancy;
measuring at least one screening marker level from a second stage of pregnancy by:
(i) assaying a sample obtained from the pregnant woman at said second stage of pregnancy for at least one biochemical screening marker; and/or
(ii) measuring at least one screening marker from an ultrasound scan taken at said second stage of pregnancy; and
determining the risk of Down's syndrome using the measured screening marker levels from both the first and second stages of pregnancy.
The risk of Down's syndrome may be determined from the marker levels by a statistical analysis based on reference data which may be derived from existing or future studies. Preferably the step of determining the risk of Down's syndrome comprises deriving the likelihood ratio of Down's syndrome using a multivariate analysis based on distribution parameters derived from a set of reference data.
Such a method can provide a single integrated screening test that is more effective at identifying affected pregnancies than tests which are based on samples collected at a single stage of pregnancy, that is it yields a higher detection rate at the same false-positive rate or a lower false-positive rate at the same detection rate. For example if the risk of Down's syndrome is determined by a method integrating nuchal translucency measurements and PAPP-A in the first trimester and the “quadruple test” using AFP, uE
3
hCG and inhibin-A as markers in the second trimester, it is estimated that at a detection rate of 80%, the false-positive rate is brought below 1%. This is a considerable improvement over the 5% false positive rate for the “combined test”. This means fewer unaffected pregnancies will be classified as screen-positive. Furthermore, at an 80% detection rate, if the expense of the additional screening measurements amounts to, say, US$100 there would be no overall extra expense because the extra screening costs would be offset by savings from performing substantially fewer invasive diagnostic tests.
The present invention utilises the fact that the ability of different screening markers to discriminate between Down's syndrome pregnancies and unaffected pregnancies varies according to the stage of pregnancy. For example, the screening marker PAPP-A is most useful before 14 weeks, but not afterwards, and vice versa with the screening marker inhibin-A, as summarised in Wald N J, Kennard A, Hackshaw A, McGuire A. (1997); Antenatal screening for Down's syndrome. J Med Screen 4,181-246.
The present invention can also provide the important advantage of permitting the use of the maternal serum AFP for screening for open neural tube defects (which is best done after 15 weeks of pregnancy) as well as using the earlier test results for Down's syndrome screening.
According to a second aspect of the present invention, there is provided a method of determining a pregnant woman's risk of having a fetus with Down's syndrome, the method comprising the steps of:
measuring at least one screening marker level from a first stage of pregnancy by:
(i) assaying a sample obtained from the pregnant woman at said first stage of pregnancy for at least one biochemical screening marker; and/or
(ii) measuring at least one screening marker from an ultrasound scan taken at said first stage of pregnancy;
determining a first risk estimate of Down's syndrome using the measured screening marker levels from the first stage of pregnancy; comparing the first risk estimate with a predetermined cut-off level to initially classify the pregnant woman as screen-positive or screen-negative based on the comparison; and if the pregnant woman is initially classified as screen-negative: measuring at least one screening marker level from a second stage of pregnanc
Alexander Lyle A.
Nixon & Vanderhye P.C.
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