Systems and methods for determining aneuploidy risk using sample fetal fraction

Abstract

Disclosed herein are system, method, and computer program product embodiments for determining aneuploidy risk in a target sample of maternal blood or plasma based on the amount of fetal DNA. An embodiment operates by receiving known genetic data from known prenatal testing samples and genetic data for the target sample. A fetal fraction distribution is determined for the known genetic data based on gestational age and the maternal weight associated with the target sample. A model is then generated based on a fixed ratio reduction of the determined fetal fraction distribution. A fetal fraction based data likelihood for the target sample is then determined for each of the plurality of ploidy states using the generated model. An aneuploidy risk score is then outputted based on applying a Bayesian probability determination that combines each fetal fraction based data likelihood with a previously determined risk score as a conditional value.

What is claimed is: 
     
         1 . A method for determining aneuploidy risk in a target sample, comprising:
 receiving known genetic data from a plurality of known noninvasive prenatal testing samples;   receiving genetic data for the target sample, the genetic data including a gestational age, a maternal weight, and a fetal fraction associated with the target sample;   determining a fetal fraction distribution for the received known genetic data based on the gestational age and the maternal weight associated with the target sample;   generating a model for a plurality of ploidy states based on a fixed ratio reduction of the determined fetal fraction distribution compared to an expected average fetal fraction for the gestational age and the maternal weight associated with the target sample;   determining a fetal fraction based data likelihood for the target sample for each of the plurality of ploidy states using the generated model and the fetal fraction associated with the target sample;   applying a Bayesian probability determination to combine each fetal fraction based data likelihood with a previously determined risk score as a conditional value; and   outputting an aneuploidy risk score for the target sample based on the applying.   
     
     
         2 . The method of  claim 1 , wherein the previously determined risk score is a SNP based risk score. 
     
     
         3 . The method of  claim 1 , further comprising:
 transforming the determined fetal fraction distribution to logarithm space, wherein a logarithm of the fetal fraction is assumed Gaussian distributed with a mean and standard deviation that are a function of gestational age and maternal weight for the known prenatal testing samples.   
     
     
         4 . The method of  claim 1 , wherein determining a fetal fraction based data likelihood for the target sample comprises computing an integral of a probability density function of the generated model. 
     
     
         5 . The method of  claim 1 , wherein the generated model is associated with trisomy 13. 
     
     
         6 . The method of  claim 1 , wherein the generated model is associated with trisomy 18. 
     
     
         7 . The method of  claim 1 , wherein the generated model is associated with maternal triploidy. 
     
     
         8 . The method of  claim 1 , wherein determining a fetal fraction distribution for the received known genetic data comprises:
 grouping the genetic data for the plurality of known prenatal testing samples into sets according to gestational age and maternal weight; and   generating a grid of distribution parameters corresponding to each set, wherein the distribution parameters include average fetal fraction and standard deviation.   
     
     
         9 . A system for determining aneuploidy risk in a target sample, comprising:
 means for receiving known genetic data from a plurality of known noninvasive prenatal testing samples;   means for receiving genetic data for the target sample, the genetic data including a gestational age, a maternal weight, and a fetal fraction associated with the target sample;   means for determining a fetal fraction distribution for the received known genetic data based on the gestational age and the maternal weight associated with the target sample;   means for generating a model for a plurality of ploidy states based on a fixed ratio reduction of the determined fetal fraction distribution compared to an expected average fetal fraction for the gestational age and the maternal weight associated with the target sample;   means for determining a fetal fraction based data likelihood for the target sample for each of the plurality of ploidy states using the generated model and the fetal fraction associated with the target sample;   means for applying a Bayesian probability determination to combine each fetal fraction based data likelihood with a previously determined risk score as a conditional value; and   means for outputting an aneuploidy risk score for the target sample based on the applying.   
     
     
         10 . The method of  claim 9 , wherein the previously determined risk score is a SNP based risk score. 
     
     
         11 . The method of  claim 9 , further comprising:
 means for transforming the determined fetal fraction distribution to logarithm space, wherein a logarithm of the fetal fraction is assumed Gaussian distributed with a mean and standard deviation that are a function of gestational age and maternal weight for the known prenatal testing samples.   
     
     
         12 . The method of  claim 9 , wherein the means for determining a fetal fraction based data likelihood for the target sample comprises means for computing an integral of a probability density function of the generated model. 
     
     
         13 . The method of  claim 9 , wherein the generated model is associated with trisomy 13. 
     
     
         14 . The method of  claim 9 , wherein the generated model is associated with trisomy 18. 
     
     
         15 . The method of  claim 9 , wherein the generated model is associated with maternal triploidy. 
     
     
         16 . The method of  claim 9 , wherein the means for determining a fetal fraction distribution for the received known genetic data comprises:
 means for grouping the genetic data for the plurality of known prenatal testing samples into sets according to gestational age and maternal weight; and   means for generating a grid of distribution parameters corresponding to each set, wherein the distribution parameters include average fetal fraction and standard deviation.   
     
     
         17 . A system for determining aneuploidy risk in a target sample, comprising:
 a known testing samples database containing known genetic data from a plurality of known noninvasive prenatal testing samples;   a target sample database containing genetic data for at least the target sample, the genetic data including a gestational age, a maternal weight, and a fetal fraction associated with the target sample;   an aneuploidy risk analysis system in communication with the known testing samples database and the target sample database, the aneuploidy risk analysis system comprises:   a logical element configured to determine a fetal fraction distribution for the received known genetic data based on the gestational age and the maternal weight associated with the target sample;   a modeling engine configured to generate a model for a plurality of ploidy states based on a fixed ratio reduction of the determined fetal fraction distribution compared to an expected average fetal fraction for the gestational age and the maternal weight associated with the target sample; and   a probability engine configured to determine a fetal fraction based data likelihood for the target sample for each of the plurality of ploidy states using the generated model and the fetal fraction associated with the target sample, apply a Bayesian probability determination to combine each fetal fraction based data likelihood with a previously determined risk score as a conditional value, and output an aneuploidy risk score for the target sample based on the Bayesian probability determination.   
     
     
         18 . The system of  claim 17 , wherein the previously determined risk score is a SNP based risk score. 
     
     
         19 . The system of  claim 17 , wherein the modeling engine is further configured to transform the determined fetal fraction distribution to logarithm space, wherein a logarithm of the fetal fraction is assumed Gaussian distributed with a mean and standard deviation that are a function of gestational age and maternal weight for the known prenatal testing samples. 
     
     
         20 . The system of  claim 17 , wherein the logic element is configured to determine a fetal fraction based data likelihood for the target sample by computing an integral of a probability density function of the generated model. 
     
     
         21 . The system of  claim 17 , wherein the generated model is associated with trisomy 13. 
     
     
         22 . The system of  claim 17 , wherein the generated model is associated with trisomy 18. 
     
     
         23 . The system of  claim 17 , wherein the generated model is associated with maternal triploidy. The system of  claim 17 , wherein the probability engine is configured to determine a fetal fraction distribution for the received known genetic data by grouping the genetic data for the plurality of known prenatal testing samples into sets according to gestational age and maternal weight, and generating a grid of distribution parameters corresponding to each set, wherein the distribution parameters include average fetal fraction and standard deviation. 
     
     
         24 . The system of  claim 17 , further comprising a DNA sequencer in communication with the target sample database and configured to supply genetic data about the target sample.