Antenatal screening for Down's syndrome

Abstract

A method of screening for fetal Down's syndrome is described. Screening marker levels are measured. These may be measurements of a biochemical marker in a maternal sample or measurements of a marker from an ultrasound scan. The marker levels are used to calculate a risk of Down's syndrome. Instead of using markers from a single stage of pregnancy, the method uses markers from two or more different stages of pregnancy, typically one being in the first and another being in second trimester. The method may be automated.

1 . A method of determining whether a pregnant woman is at an increased 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.    
     
     
         2 . A method according to  claim 1 , wherein 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.  
     
     
         3 . A method according to  claim 2 , wherein said multivariate analysis is a multivariate Gaussian analysis.  
     
     
         4 . A method according to  claim 2 , wherein the step of determining the risk of Down's syndrome further comprises multiplying the likelihood ratio by an age-specific risk.  
     
     
         5 . A method according to  claim 1 , further comprising the step of re-expressing each measured screening marker level as a multiple of the median level of the respective screening marker in unaffected pregnancies of the same gestational age as the fetus of the pregnant woman.  
     
     
         6 . A method according to  claim 1 , further comprising comparing the determined risk with a predetermined cut-off level to classify the pregnant women as screen-positive or screen negative based on the comparison.  
     
     
         7 . A method according to  claim 1 , wherein said step of measuring at least one screening marker level from a first stage of pregnancy includes assaying a serum sample obtained from the pregnant woman at said first stage of pregnancy for one selected from the group of PAPP-A, free β-hCG and both.  
     
     
         8 . A method according to  claim 7 , wherein said step of measuring at least one screening marker level from a second stage of pregnancy includes assaying a serum sample obtained from the pregnant woman at said second stage of pregnancy for one selected from the group of AFP, uE 3 , inhibin-A, free β-hCG, free α-hCG, total hCG and combinations thereof.  
     
     
         9 . A method according to  claim 7 , wherein said step of measuring at least one screening marker level from a second stage of pregnancy includes assaying a urine sample obtained from the pregnant woman at said second stage of pregnancy for one selected from the group of β-core hCG, total oestriol and both.  
     
     
         10 . A method according to  claim 1 , wherein said step of measuring at least one screening marker level from a first or a second stage of pregnancy includes assaying a sample of cells obtained from the pregnant woman at said first or second stage of pregnancy.  
     
     
         11 . A method according to  claim 1 , further comprising adjusting any or all of the screening marker levels to allow for one or more factors selected from the group of maternal race, maternal weight, multiple birth and diabetic status.  
     
     
         12 . A method according to  claim 1 , further comprising the steps of: 
 obtaining said sample from the pregnant woman at said first stage of pregnancy and/or taking said ultrasound scan at said first stage of pregnancy; and    obtaining said sample from the pregnant woman at said second stage of pregnancy and/or taking said ultrasound scan at said second stage of pregnancy.    
     
     
         13 . A method according to  claim 1 , further comprising the steps of: 
 obtaining a first sample from the pregnant woman at said first stage of pregnancy;    storing the first sample under refrigeration; and    obtaining a second sample from the pregnant woman at said second stage of pregnancy,    wherein the first and second samples are assayed at the same time.    
     
     
         14 . A method according to  claim 1 , further comprising measuring at least one further screening marker level from at least one further stage of pregnancy and additionally using said at least one further screening marker in said step of determining the risk of Down's syndrome.  
     
     
         15 . A method according to  claim 1 , further comprising: 
 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    performing said steps of measuring at least one screening marker level from a 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 if the pregnant woman is initially classified as screen-negative.    
     
     
         16 . A method according to  claim 15 , wherein said step of determining the risk of Down's syndrome comprises calculating a likelihood ratio and multiplying by an age-specific risk which is adjusted, relative to the original age-specific risk of the original population presenting for the test at the first stage of pregnancy, to allow for fact that the proportion of affected pregnancies initially classified as screen-positive have been removed from the sample presenting for the test at the second stage of pregnancy.  
     
     
         17 . A method according to  claim 15 , wherein said step of determining the risk of Down's syndrome comprises calculating a likelihood ratio and multiplying by an age-specific risk which is adjusted, relative to the original age-specific risk of the original population presenting for the test at the first stage of pregnancy, to allow for the fact that the age-specific proportions of affected and unaffected pregnancies initially classified as screen-positive have been removed from the sample presenting for the test at the second stage of the pregnancy.  
     
     
         18 . A method according to  claim 15 , wherein said step of determining the risk of Down's syndrome comprises calculating a likelihood ratio based on distributions of markers which are modified, relative to the original distributions of markers of the original population presenting for the test at the first stage of pregnancy, to allow for the fact that women initially classified as screen-positive have been removed from the sample presenting for the test at the second stage of pregnancy.  
     
     
         19 . A method according to  claim 15 , further comprising comparing the determined risk with a second predetermined cut-off level to classify the pregnant woman as screen-positive or screen negative based on the comparison, wherein said second cut-off level is determined based on the residual age distribution of pregnant women initially classified as screen-negative.  
     
     
         20 . A method of determining whether a pregnant woman is at an increased 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 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 second stage of pregnancy.    
     
     
         21 . A method according to  claim 20 , wherein said step of determining the risk of Down's syndrome comprises calculating a likelihood ratio and multiplying by an age-specific risk which is adjusted, relative to the original age-specific risk of the original population presenting for the test at the first stage of pregnancy, to allow for fact that the proportion of affected pregnancies initially classified as screen-positive have been removed from the sample presenting for the test at the second stage of pregnancy.  
     
     
         22 . A method according to  claim 20 , wherein said step of determining the risk of Down's syndrome comprises calculating a likelihood ratio and multiplying by an age-specific risk which is adjusted, relative to the original age-specific risk of the original population presenting for the test at the first stage of pregnancy, to allow for the fact that the age-specific proportions of affected and unaffected pregnancies initially classified as screen-positive have been removed from the sample presenting for the test at the second stage of the pregnancy.  
     
     
         23 . A method according to  claim 20 , wherein said step of determining the risk of Down's syndrome comprises calculating a likelihood ratio based on distributions of markers which are modified, relative to the original distributions of markers of the original population presenting for the test at the first stage of pregnancy, to-allow for the fact that women initially classified as screen-positive have been removed from the sample presenting for the test at the second stage of pregnancy.  
     
     
         24 . A method according to  claim 20 , further comprising comparing the determined risk with a second predetermined cut-off level to classify the pregnant woman as screen-positive or screen negative based on the comparison wherein said second-mentioned cut-off level is determined based on the residual age distribution of pregnant women initially classified as screen-negative.  
     
     
         25 . A method according to any one of the preceding claims, wherein said first stage of pregnancy is in the first trimester of pregnancy and said second stage of pregnancy is in the second trimester of pregnancy.  
     
     
         26  A method according to any one of the preceding claims, wherein said first stage of pregnancy is between 8 and 13 weeks of pregnancy and said second stage of pregnancy is between 14 and 22 weeks of pregnancy.  
     
     
         27 . A computer program storage medium readable by a computing system and encoding a computer program of instructions for executing a computer process for determining a pregnant woman's risk of having a fetus with Down's syndrome, said computer process comprising the steps of: 
 inputting a measurement of at least one screening marker level from a first stage of pregnancy obtained 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;  
   inputting a measurement of at least one screening marker level from a second stage of pregnancy obtained 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 input screening marker levels from both the first and second stages of pregnancy.    
     
     
         28 . A computer program storage medium according to  claim 27 , wherein said step of determining the risk of Down's syndrome is performed by deriving the likelihood ratio of Down's syndrome using a multivariate analysis based on distribution parameters derived from a set of reference data.  
     
     
         29 . A computer program storage medium according to  claim 28 , wherein said multivariate analysis is a multivariate Gaussian analysis.  
     
     
         30 . A computer program storage medium according to  claim 28 , wherein said computer process further comprises the step of re-expressing each input screening marker level as a multiple of the median level of the respective screening marker in unaffected pregnancies of the same gestational age as the fetus of the pregnant woman, the re-expressed screening marker levels being used in said step of determining the risk of Down's syndrome.  
     
     
         31 . A computer program storage medium according to  claim 27 , wherein said computer process further comprises the step of inputting a measurement of at least one further screening marker level from at least one further stage of pregnancy, the further screening marker level being additionally used in said step of determining the risk of Down's syndrome.  
     
     
         32 . A computer program storage medium according to  claim 27 , wherein said computer process further comprises the step of comparing the determined risk with a predetermined cut-off level to classify the pregnant woman as screen-positive or screen-negative based on the comparison.  
     
     
         33 . An apparatus for determining a pregnant woman's risk of having a fetus with Down's syndrome, the apparatus comprising: 
 a data input module for inputting a measurement of at least one screening marker level from a first stage of pregnancy obtained 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;  
   a data input module for inputting a measurement of at least one screening marker level from a second stage of pregnancy obtained 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  
   calculation module for determining the risk of Down's syndrome using the input screening marker levels from both the first and second stages of pregnancy.    
     
     
         34 . An apparatus according to  claim 33 , wherein said calculation module is arranged to determine the risk of Down's syndrome by deriving the likelihood ratio of Down's syndrome using a multivariate analysis based on distribution parameters derived from a set of reference data.  
     
     
         35 . An apparatus according to  claim 34 , wherein said multivariate analysis is a multivariate Gaussian analysis.  
     
     
         36 . An apparatus according to  claim 33 , further comprising a module for re-expressing each input screening marker level as a multiple of the median level of the respective screening marker in unaffected pregnancies of the same gestational age as the fetus of the pregnant woman, and supplying the re-expressed screening marker level to said calculation module.  
     
     
         37 . An apparatus according to  claim 33  further comprising a data input module for inputting a measurement of at least one further screening marker level from at least one further state of pregnancy and wherein said calculation module is arranged to determine the risk of Down's syndrome additionally using said at least one further screening marker level.  
     
     
         38 . An apparatus according to  claim 33 , further comprising a comparison module for comparing the determined risk with a predetermined cut-off level to classify the pregnant woman as screen-positive or screen-negative based on the comparison.