| Methods and apparatus for screening for chromosomal abmormalities -> Monitor Keywords |
|
|
 
Methods and apparatus for screening for chromosomal abmormalitiesRelated Patent Categories: Chemistry: Molecular Biology And Microbiology, Measuring Or Testing Process Involving Enzymes Or Micro-organisms; Composition Or Test Strip Therefore; Processes Of Forming Such Composition Or Test StripMethods and apparatus for screening for chromosomal abmormalities description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070148631, Methods and apparatus for screening for chromosomal abmormalities. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] This invention generally relates to methods, apparatus, and computer program code for antenatal screening for chromosomal abnormalities, in particular Down's Syndrome. [0002] A recent large-scale study by Wald et al. commissioned by the UK National Health Service Health Technology Assessment Program aimed to identify the most effective, safe and cost-effective method of antenatal screening for Down's Syndrome using nuchal translucency (NT), maternal serum and urine markers in the first and second trimesters of pregnancy, and maternal age in various combinations (Wald N J, Rodeck C, Hackshaw A K, Walters J, Chitty L, Mackinson A M, "First and second trimester antenatal screening for Down's syndrome: the results of the Serum, Urine and Ultrasound Screening Study (SURRUS)", Health Technology Assessments 2003:7(11); http://www.hta.nhsweb.nhs.uk; see also Wald N J, Watt H C, Hackshaw A K, "Integrated screening for Down's syndrome based on tests performed during the first and second trimesters", N Engl J Med 1999:341:461-7). [0003] The study concluded that an integrated test using measurements of four biochemical markers all at 14-20 weeks gestation with the ultrasound marker NT and a fifth biochemical marker measured at 10 completed weeks provided the most effective and safe method of screening (see, for example, the executive summary of Wald et al at page (iv)). Patent protection for the technique was sought (WO99/56132; U.S. Pat. No. 6,573,103). [0004] A number of tests for antenatal screening for Down's Syndrome are known. The so-called combined test is a first trimester test based upon combining nuchal translucency measurement with free .beta.-human chorionic gonadotrophin (.beta.-hCG), pregnancy-associated plasma protein A (PAPP-A) and maternal age. The quadruple test is a second trimester test based on measurement of AFP (.alpha.-fetoprotein), uncongugated oestriol (uE.sub.3), free .beta.-hCG (or total hCG), and inhibin-A together with maternal age. [0005] The integrated test integrates measurements performed during the first and second trimester of pregnancy into a single test result and performs better than either than the combined or quadruple test alone. Generally "integrated test" refers to the integration of nuchal translucency and PAPP-A measurements in the first trimester with the quadruple test markers in the second. The nuchal translucency (NT) measurement is a measurement of the width of an area of translucency at the back of the foetal neck, usually measured at about 10-13 weeks of pregnancy using ultrasound. Various other forms of tests are also known such as the so-called triple test, the double test, and the serum integrated test (a variant of the integrated test using serum markers only--PAPP-A in the first trimester and the quadruple test markers in the second trimester). [0006] A good antenatal screening test has a good true-positive rate (a true-positive is an affected pregnancy with a positive test result) and a low-false positive rate (a false-positive is an unaffected pregnancy with a positive test result). A cut-off level is chosen to define a positive result and distinguish it from a negative result. With a single marker this comprises a specified level of the marker; with tests based on a combination of markers this generally comprises a form of risk estimate. An affected pregnancy in this context is a pregnancy with a fetus with a chromosomal abnormality and the techniques described herein are particularly applicable to Down's Syndrome, that is trisomy of chromosome 21. [0007] A detection rate, that is a rate of detection of affected pregnancies, may also be defined so that, for example, a detection rate of 85 percent implies that fifteen percent of affected pregnancies will not be detected by a test. There is a relationship between detection rate and false-positive rate which is given by a so-called ROC (Receiver Operating Characteristic) curve for the test. There is a human and financial cost associated with both false-positive and missed detections. The human cost of a missed detection rate of, say, fifteen percent is easy to appreciate. The financial cost of a false-positive relates to follow-up procedures since a positive test result is generally further investigated by amniocentesis or CVS (Choronic Villus Sampling), which have a financial cost and also an associated risk of miscarriage (approximately one percent). [0008] The present inventor has re-analysed the data from the Wald study and has identified a new approach to the determination of chromosomal abnormalities which can provide significantly better results than the procedures of Wald, based upon a counter-intuitive recognition of the way in which the data can be utilised. [0009] As mentioned above there are a number of more or less standard biochemical and ultrasound markers for Down's Syndrome. Generally these markers are effective as markers at only one stage or trimester of pregnancy although one, free P-hCO is effective in both the first and second trimesters. [0010] Broadly speaking the approach of Wald et al is to pick the best individual markers at each stage of pregnancy and to combine these into a single, integrated screening test. Wald does not use markers which are ineffective at any particular stage and furthermore teaches against the use of highly correlated markers (see, for example, WO'132 at page 8 lines 20-23), broadly because one would expect markers which are correlated with one another to provide little new information. [0011] The present inventor has recognised, however, that this approach conceals two statistical fallacies and that using data relating to a level of a marker (perhaps here better termed a feature) from a stage of pregnancy at which the marker is substantially ineffective can lead significant benefits in screening performance. It has further been recognised that it is helpful if parameters ("markers" or "features") measured at two different gestational ages are highly correlated with one another because (as will be explained further below) this enables some degree of compensation for natural variations in a parameter between subjects. [0012] Thus we will describe methods (and computer programmes and corresponding apparatus) in which repeated measurements of one or more biological parameters of a fetus are made at different stages of a pregnancy, in one of the stages the parameter or parameters acting as a marker for a chromosomal abnormality, in particular Downs Syndrome, in the other of the stages the parameter not having any significant value as such as a marker. The parameters are preferably levels of biological chemicals associated with pregnancy. Preferably these are highly correlated since, broadly speaking, the stronger the correlation the more discrimatory power. The parameters are preferably normalised for gestational age of the fetus and, optionally, for other factors such as maternal weight and smoking status. [0013] To aid understanding of embodiments of the invention described later it is helpful to explain the origin of the two above mentioned statistical fallacies. [0014] The fallacy of high correlations is that "a second marker adds little to the first if the correlation between the markers in Down's syndrome and unaffected pregnancies is high". (`If two variables are perfectly correlated one adds nothing to the other in determining risk . . . `--Wald et al. (1988)). [0015] The statement of Wald et al. (1988) is correct--it is the case that if there is a perfect relationship between two features then knowledge of one determines the other so one of the features is redundant. Similarly, if there is a near perfect relationship, one feature adds very little to the other. However, in screening the strength of association is usually measured in terms of separate correlations for Down syndrome outcomes and unaffected outcomes. In cases where these correlations are high and the underlying relationships are different in Down's syndrome and unaffected pregnancies, the joint values are generally highly discriminatory. This is illustrated for the case of first and second trimester PAPP-A measurements in FIG. 1. [0016] Levels of biological markers are generally given as a logarithm (base 10 or natural) of an MoM (Multiple of Median) value. FIG. 1a shows samples of log(MoM PAPP-A) in the first (horizontal axis) and the second (vertical axis) trimesters for 1000 Down's syndrome pregnancies 10 and 1000 unaffected pregnancies 20. These samples were drawn from bivariate Gaussian distributions using parameter estimates taken from Wald et al. (2003). The ellipse represents the 90% contour containing 90% of the distribution of values. FIG. 1b demonstrates what happens when the correlations in Down's syndrome and unaffected pregnancies are increased to 0.95. If this were the case discrimination would be almost perfect. FIG. 1c illustrates what happens when the correlations in Down's syndrome and unaffected pregnancies are zero. In this case the discriminatory power is worse than in FIG. 1a. [0017] The second fallacy is that "if a feature has no discriminatory power when viewed in alone, it has no discriminatory power when used jointly with other features"; this is addressed using the same example of PAPP-A. In the second trimester PAPP-A has little or no discriminatory power but when used in conjunction with the first trimester PAPP-A values it greatly enhances discriminatory power. In fact for an 85% detection rate the FPR for PAPP-A in the first trimester, using the parameters of Wald et al (2003), when applied to the maternal age distribution of England and Wales (1996 to 1998) is 17%. Using PAPP-A in the first and second trimester reduces the false positive rate for an 85% detection rate to 1.9%. The way the second trimester measure increases discrimination is illustrated in FIG. 2. FIG. 2a shows samples of log(MoM PAPP-A) in first (horizontal axis) and second trimester (vertical axis) for 1000 Down's syndrome pregnancies 10 and 1000 unaffected pregnancies 20. These values were drawn from the distributions fitted by Wald et al. (2003). Projecting the points onto the horizontal axis there is clearly a good discrimination PAPP-A in the first trimester. Projecting points onto the vertical axis there is very little discriminatory power with second trimester PAPP-A. However, the joint distribution separates Down's from unaffected pregnancies much more effectively than PAPP-A in trimester 1. FIG. 2b shows a hypothetical situation in which PAPP-A is assumed to have the same median MoM in the second trimester as it does in the first. In this case there is more overlap in the joint distribution than there is in FIG. 2a. FIG. 2c shows a hypothetical situation in which the median MoM for PAPP-A in the second trimester is in the opposite direction to that in the first. This situation would give near perfect discrimination. [0018] Broadly speaking referring to the above scattergraphs although two distributions may overlap when projected on to one or other axis the points representing unaffected and affected pregnancies may nonetheless lie on separable lines and the higher the correlation coefficient the better the lines can be separated. The value of measuring the level of a biological parameter ("marker" or "feature") at a stage of pregnancy where the parameter is ineffective as a marker can be understood by considering a (much simplified) example. Consider a syndrome which has the effect of making a child unnaturally shorter at the age of five, but which has no effect on a child of age ten. The height of a child is a feature that varies considerably between children but and it is difficult on the basis of a short height at 5 years to distinguish between those children that are naturally short and those that have the syndrome. However by making measurements on the same child at age five and at age ten the age ten height can effectively be used as a yardstick to normalise the height measurement at age five and hence better determine whether or not the child at age five is abnormally small. [0019] A number of features have similar characteristics to PAPP-A in that (a) first and second trimester log (MoM) values are highly correlated in both Down's syndrome and unaffected pregnancies and (b) they discriminate in one trimester but not the other. [0020] According to a first aspect of the present invention there is therefore provided a method of determining a likelihood of a fetus carried by a pregnant mother having a chromosomal abnormality, a first biological, parameter being suitable for screening said fetus for said chromosomal abnormality, the method comprising: receiving first data from a first stage of pregnancy of said mother, said first data comprising data representing a first value of said first biological parameter; receiving second data from a second, later stage of said pregnancy, said second data comprising data representing a second value of said first biological parameter; and determining likelihood data from said first and second data, said likelihood data representing the likelihood of said fetus having a chromosomal abnormality. [0021] In embodiments of the method by making repeated measurements of the same biological parameter at different stages, enhance discriminatory power is achieved and for a given detection rate the false positive rate may be reduced as compared with the above mentioned integrated test. The biological parameter is preferably a marker for the chromosomal abnormality at one of the first and second stages of pregnancy but preferably has substantially no value as a marker at a time during the other of the first and second stages of pregnancy. The first and second stages of pregnancy preferably comprise first and second trimesters of the pregnancy, generally taken for a human being as being from 8-13 weeks and from 14 to 22 weeks of the pregnancy respectively. Whether or not the biological parameter has a value as a marker may be judged at a reference point during one or both of the stages of pregnancy, for example at the ten week point during the first trimester and, for example, at the 14, 18 or 22 week point during the second trimester (or an average of the value of the parameter as a marker during a stage of pregnancy may be employed). [0022] The value of a biological parameter as a marker is generally expressed as a logarithm of a multiple of median value, that is a median value for the biological parameter is determined adjusted for gestational age of the fetus and, optionally, for maternal-related factors such as weight, smoking status and the like. A measured value of the parameter may then be expressed as a multiple of the expected median (or other average) value (MoM) so that if the measured value is equal to the expected value the MoM value is equal to 1.0 and the log MoM value is equal to zero. Thus a smaller than expected measured value results in a negative log MoM median marker level and a greater than expected value a positive log MoM median marker level. [0023] Whether a parameter measured at a particular stage of pregnancy has substantial value as a marker when used individually is determined largely from the mean log MoM in affected pregnancies. If this is small in absolute magnitude relative to the standard deviation of the log MoM values, then the parameter will individually have little value. Preferred embodiments of the method described here rely on the use of repeated measures that have mean log MoM values at one stage of pregnancy that differ from zero by less than, in order of increasing preference, 100%, 90%, 50%, and 25% of a standard deviation. For example, a parameter may be considered a useful marker for Down's syndrome pregnancies if during a stage of pregnancy it differs from zero by more than 90% of the standard deviation in Down's syndrome pregnancies. Thus a marker may be considered as having substantially no value if at a point during a stage of pregnancy the logarithm MoM value is not substantially different from zero, that is if the logarithm MoM value is less than one standard deviation, preferably 0.9 standard deviation, more preferably 0.5 standard deviation, still more preferably 0.25 of a standard deviation (SD) from zero in affected pregnancies. [0024] Median marker level data and standard deviation data for a range of biochemical markers may be found in Wald et al (HTA 2003, 7(11), ibid) tables 33 and 34 specifically hereby incorporated by reference. Gestational age may be based upon either the first day of the last menstrual period (LMP) or on an ultrasound scan measure of the fetus, generally a BPD (biparietal diameter) or a CRL (crown-rump length) measurement. Continue reading about Methods and apparatus for screening for chromosomal abmormalities... Full patent description for Methods and apparatus for screening for chromosomal abmormalities Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Methods and apparatus for screening for chromosomal abmormalities patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. Start now! - Receive info on patent apps like Methods and apparatus for screening for chromosomal abmormalities or other areas of interest. ### Previous Patent Application: Levenberg-marquardt outlier spike removal method Next Patent Application: Immobilized carbohydrate biosensor Industry Class: Chemistry: molecular biology and microbiology ### FreshPatents.com Support Thank you for viewing the Methods and apparatus for screening for chromosomal abmormalities patent info. IP-related news and info Results in 0.12435 seconds Other interesting Feshpatents.com categories: Software: Finance , AI , Databases , Development , Document , Navigation , Error 174 |
 * Protect your Inventions * US Patent Office filing 
PATENT INFO |
|
