Methods for genetic analysis

Abstract

Methods are described for assessing an individual's likelihood of developing or exhibiting a multifactorial trait, and for predicting the effectiveness of a drug treatment regimen in an individual. The methods include determining a plurality of genotypes for the individual at a plurality of biallelic polymorphic loci, using the genotypes to compute a score for the individual, and comparing the score to at least one threshold value. Genetic tests are also described for assessing an individual's likelihood of developing or exhibiting a multifactorial trait.

1 . A method for predicting the effectiveness of a drug treatment regimen in an individual comprising 
 a) determining a genotype for said individual at a plurality of biallelic polymorphic loci, wherein each of said plurality has an associated allele and an unassociated allele, and further wherein the genotype is selected from the group consisting of homozygous for the associated allele, heterozygous, and homozygous for an unassociated allele;    b) computing a score for said individual based on said genotype determined in a); and    c) performing a comparison of the score to at least one threshold value, wherein said comparison is used to predict the effectiveness of said drug treatment regimen in said individual.    
     
     
         2 . The method of  claim 1 , further comprising identifying the associated alleles and the unassociated alleles for said plurality of biallelic polymorphic loci by performing an association study with a case group for whom said drug treatment regimen is not effective and a control group for whom said drug treatment regimen is effective, thereby determining a set of alleles of said polymorphic loci that are significantly more abundant in the case group than the control group, wherein said set of alleles or a subset thereof are the associated alleles.  
     
     
         3 . The method of  claim 2 , wherein at least one of said case and said control group comprises at least 200 individuals.  
     
     
         4 . The method of  claim 2 , wherein said case and said control groups are matched prior to performing the association study.  
     
     
         5 . The method of  claim 2 , wherein said performing an association study further comprises 
 a) genotyping said case group and said control group at a set of polymorphic loci that comprises said plurality of biallelic polymorphic loci;    b) calculating a relative allele frequency for each of said set of polymorphic loci for each of said case group and said control group;    c) for each of said set of polymorphic loci, comparing the relative allele frequency calculated for the case group with the relative allele frequency calculated for the control group, thereby identifying a subset of said set of polymorphic loci, wherein each of said subset has a relative allele frequency that is significantly different for the case group than for the control group; and    d) determining an allele for each of said subset that is more abundant in said case group than said control group, wherein said allele is one of said associated alleles.    
     
     
         6 . The method of  claim 5 , wherein the set of polymorphic loci comprises at least about 500 polymorphic loci.  
     
     
         7 . The method of  claim 5 , wherein the set of polymorphic loci comprises polymorphic loci from every chromosome In the genome of said individual.  
     
     
         8 . (canceled)  
     
     
         9 . (canceled)  
     
     
         10 . The method of  claim 9 , further comprising validating said associated alleles by performing a second association study with said case group and said control group using an individual genotyping methodology, thereby determining which of said associated alleles are significantly more abundant in said case group than said control group based on said second association study, wherein those of said associated alleles that are significantly more abundant in said case group than said control group based on said second association study are the validated associated alleles.  
     
     
         11 . The method of  claim 2 , further comprising validating said associated alleles by performing a second association study with a second case group for whom said drug treatment regimen is not effective and a second control group for whom said drug treatment regimen is effective, thereby determining which of said associated alleles are significantly more abundant in the second case group than the second control group, wherein those of said associated alleles that are significantly more abundant in the second case group than the second control group are the validated associated alleles.  
     
     
         12 . The method of  claim 2 , further comprising determining a one of said at least one threshold value by a method comprising 
 a) calculating a score for each member of said case group and said control group;    b) selecting a series of risk cutoff values;    c) computing a set of values for each of said series of risk cutoff values, wherein said set of values comprises at least one of a sensitivity, a specificity, a PPV, an NPV, an accuracy, a relative risk, an LR+ and an LR−;    d) choosing a one of said series of risk cutoff values as said one of said at least one threshold value based on said set of values, thereby determining said one of said at least one threshold value.    
     
     
         13 . The method of  claim 12 , wherein calculating a score for each member of said case group and said control group comprises 
 a) determining a genotype for said each member at said plurality of biallelic polymorphic loci, wherein the genotype is selected from the group consisting of homozygous for an associated allele, heterozygous, and homozygous for an unassociated allele;    b) assigning a value of zero to each of said polymorphic loci that has a genotype that is homozygous for an allele that is not the associated allele;    c) assigning a value of one to each of said polymorphic loci that has a genotype that is heterozygous;    d) assigning a value of two to each of said polymorphic loci that has a genotype that is homozygous for the associated allele;    e) summing the values determined in steps a) through c) for all said polymorphic loci, thereby calculating a score for said each member of said case group and said control group.    
     
     
         14 . The method of  claim 12 , wherein said selecting a series of risk cutoff values comprises 
 identifying a highest score from the scores calculated for each member of said case group and said control group;    determining a risk cutoff range, wherein the range is from 1 to said highest score;    selecting a series of values from across the risk cutoff range, thereby selecting said series of risk cutoff values.    
     
     
         15 . (canceled)  
     
     
         16 . The method of  claim 12 , wherein said determining said one of said at least one threshold value further comprises using a ROC curve based on said sensitivity and said specificity computed in c), wherein a graphical representation of said ROC curve is referred to as a plot.  
     
     
         17 . The method of  claim 16 , further comprising choosing as said one of said at least one threshold value a risk cutoff value corresponding to a data point on said ROC curve that is nearer an upper left corner of said plot than any other data point on said ROC curve, wherein each data point on said ROC curve corresponds to a different risk cutoff value.  
     
     
         18 . The method of  claim 16 , further comprising 
 a) determining a location on said ROC curve that is nearest an upper left corner of said plot and to determine a sensitivity and a specificity that correspond to said location;    b) analyzing said scores for each member of said case group and said control group to identify a risk cutoff value whose sensitivity and specificity are nearest said sensitivity and specificity that correspond to said location, wherein said risk cutoff value whose sensitivity and specificity are nearest said sensitivity and specificity that correspond to said location is said one of said at least one threshold value.    
     
     
         19 . The method of  claim 12 , wherein for a given risk cutoff value said relative risk is computed by a method comprising 
 a) determining a percentage of sad members of said case group that have a score that is at least as great as said given risk cutoff value;    b) determining a percentage of said members of said control group that have a score that is at least as great as said given risk cutoff value; and    c) dividing said percentage determined in a) by said percentage determined in b) to compute said relative risk.    
     
     
         20 . (canceled)  
     
     
         21 . The method of  claim 1 , wherein if said individual's score is higher than said threshold value, said drug treatment regimen is predicted not to be effective in said individual and alternative treatments are considered for said individual; and if said individual's score is equal to or less than said threshold value, said drug treatment regimen is predicted to be effective and is administered to said individual.  
     
     
         22 . (canceled)  
     
     
         23 . The method of  claim 1 , wherein said computing a score further comprises 
 a) assigning a value of zero to each of said polymorphic loci that has a genotype that is homozygous for an allele that is not the associated allele;    b) assigning a value of one to each of said polymorphic loci that has a genotype that is heterozygous;    c) assigning a value of two to each of said polymorphic loci that has a genotype that is homozygous for the associated allele;    d) summing the values determined in steps a) through c) for all of said polymorphic loci, thereby computing a score for said individual.    
     
     
         24 . A diagnostic or prognostic assay comprising nucleic acid probes designed to detect the associated alleles of  claim 1  in a biological sample.  
     
     
         25 . (canceled)  
     
     
         26 . A genetic test for assessing an individual's likelihood of developing or exhibiting a multifactorial trait comprising 
 a) a means for determining a genotype for said individual at a plurality of biallelic polymorphic loci, wherein each of said plurality has an associated allele and an unassociated allele, and further wherein the genotype is selected from the group consisting of homozygous for the associated allele, heterozygous, and homozygous for the unassociated allele;    b) at least one threshold value; and    c) a comparison between a score computed for said individual based on said genotype determined in a) and said at least one threshold value, wherein said comparison is used to assess said individual's likelihood of developing or exhibiting said multifactorial trait.    
     
     
         27 . The method of  claim 26 , wherein said multifactorial trait is a disease or a response to a drug.  
     
     
         28 . (canceled)  
     
     
         29 . The method of  claim 26 , wherein said multifactorial trait is a lack of an efficacious response to said drug or an adverse event caused by the administration of said drug.  
     
     
         30 . The method of  claim 29  further comprising excluding said individual from treatment with said drug if said score is greater than a one of said at least one threshold value.