Methods of Selection, Reporting and Analysis of Genetic Markers Using Broad-Based Genetic Profiling Applications

Abstract

Disclosed is a method for determining whether an individual has an enhanced, diminished, or average probability of exhibiting one or more phenotypic attributes and related methods of selecting a set of genetic markers; for providing relevant genetic information to an individual; of evaluating the probability that progeny of two individuals of the opposite sex will exhibit one or more phenotypic attributes; and for determining the genomic ethnicity of an individual.

What is claimed is: 
     
         1 . A method for determining a probability of exhibiting one or more phenotypic attributes for an individual, comprising:
 a) evaluating genomic markers from an assay performed on a biological sample of the individual for a genotype at each member of a preselected set of markers, wherein each member of the preselected set of markers has a degree of linkage with one or more of the one or more phenotypic attributes;   b) with a programmed computer, comparing the genotype to a scoring matrix to obtain a marker score, wherein the scoring matrix scores markers at least with respect to two or more criteria selected from the group consisting of penetrance of a given marker in a population of interest, ontological classification, conservation of mutated sequence sites at conserved or less conserved sites, and biological significance;   c) determining whether the marker score is indicative of an enhanced, diminished, or average probability of exhibiting the one or more phenotypic attributes; and   d) providing an output that is indicative of the marker score and/or an indication as to whether the marker score indicates an enhanced, diminished, or average probability of exhibiting the one or more phenotypic attributes.   
     
     
         2 . The method according to  claim 1 , further comprising performing the assay. 
     
     
         3 . The method according to  claim 1 , wherein the assay includes nucleic acid amplification of the biological sample. 
     
     
         4 . The method according to  claim 1 , wherein the assay is targeted to the preselected set of markers. 
     
     
         5 . The method according to  claim 1 , wherein each member of the preselected set of markers is included in the set based upon a determination of measures of phenotypic value and/or prioritization selected from the group consisting of penetrance of the one or more markers in a population or subpopulation of interest, the degree of linkage of the one or more markers to a particular phenotype, the relative contribution of the one or more markers to communicating the phenotype, and the degree of statistical or scientific confidence to be placed in any data associated with any of the measures of phenotypic value and/or priority used. 
     
     
         6 . The method according to  claim 1 , wherein the scoring matrix prioritizes markers with respect to genomic relevance. 
     
     
         7 . The method according to  claim 1 , wherein the preselected set of markers comprises a plurality of exon/intron junction sequences. 
     
     
         8 . The method according to  claim 7 , wherein at least about 20% of the markers in the preselected set are exon/intron junction sequences. 
     
     
         9 . The method according to  claim 1 , wherein the preselected set of markers comprises a plurality of promoter sequences. 
     
     
         10 . The method according to  claim 9 , wherein at least about 20% of the markers in the preselected set are promoter sequences. 
     
     
         11 . The method according to  claim 1 , further comprising determining a genetic profile characteristic of a human population or subpopulation. 
     
     
         12 . The method according to  claim 11 , further comprising using the genetic profile characteristic of the human population or subpopulation in a pharmacogenomic analysis. 
     
     
         13 . The method according to  claim 1 , further comprising assigning a summary marker score for each of the genomic markers based on the comparison to the scoring matrix. 
     
     
         14 . The method according to  claim 1 , wherein the scoring matrix scores markers at least with respect to three or more criteria selected from the group consisting of penetrance of a given marker in a population of interest, ontological classification, conservation of mutated sequence sites at conserved or less conserved sites, and biological significance. 
     
     
         15 . The method according to  claim 14 , wherein the scoring matrix scores markers at least with respect to penetrance of a given marker in a population of interest, ontological classification, and conservation of mutated sequence sites at conserved or less conserved sites. 
     
     
         16 . The method according to  claim 14 , wherein the scoring matrix scores markers at least with respect to penetrance of a given marker in a population of interest, ontological classification, and biological significance. 
     
     
         17 . The method according to  claim 14 , wherein the scoring matrix scores markers at least with respect to penetrance of a given marker in a population of interest, ontological classification, conservation of mutated sequence sites at conserved or less conserved sites, and biological significance. 
     
     
         18 . The method according to  claim 1 , wherein the genomic markers comprise genomic sequence variations. 
     
     
         19 . The method according to  claim 18 , wherein the genomic sequence variations are single nucleotide polymorphisms. 
     
     
         20 . The method according to  claim 1 , wherein the genomic markers are located in functional units of a gene. 
     
     
         21 . The method according to  claim 20 , wherein the functional units of a gene are selected from the group consisting of coding regions, untranslated regions, exon/intron junctions and promoters. 
     
     
         22 . The method according to  claim 21 , wherein the functional units of a gene are exon/intron junctions. 
     
     
         23 . The method according to  claim 1 , wherein the scoring matrix compares at least 1,000 genomic markers from the individual. 
     
     
         24 . The method according to  claim 23 , wherein the scoring matrix compares at least 5,000 genomic markers from the individual. 
     
     
         25 . The method according to  claim 24 , wherein the scoring matrix compares at least 10,000 genomic markers from the individual. 
     
     
         26 . The method according to  claim 1 , wherein ontological classification includes sequence ontology assignment to the genomic variant, gene ontology assignment, disease ontology assignment, human phenotype assignment, and a direct link to a scientific publication describing function of the variant. 
     
     
         27 . The method according to  claim 1 , wherein said output is provided using a graphical user interface. 
     
     
         28 . The method according to  claim 1 , wherein the conservation of mutated sequence sites are selected from the group consisting of exon/intron junction sequences and promoter regions. 
     
     
         29 . The method according to  claim 1 , wherein the conservation of mutated sequence sites provides a splicing strength score. 
     
     
         30 . The method according to  claim 1 , wherein the conservation of mutated sequence sites provide a score utilizing one or more predictive models. 
     
     
         31 . The method according to  claim 1 , wherein the scoring matrix scores markers at least with respect to penetrance of a given marker in a population of interest and ontological classification. 
     
     
         32 . The method according to  claim 1 , wherein the scoring matrix scores markers at least with respect to ontological classification and conservation of mutated sequence sites at conserved or less conserved sites. 
     
     
         33 . The method according to  claim 1 , wherein the scoring matrix scores markers at least with respect to ontological classification and biological significance. 
     
     
         34 . A method for providing genetic information to an individual, comprising:
 a) identifying genotypic characteristics of the individual that correlate with a relative probability of exhibiting one or more phenotypic attributes;   b) determining for each of the one or more phenotypic attributes the probability of exhibiting the one or more phenotypic attributes by: (i) evaluating genomic markers from an assay performed on a biological sample of the individual for a genotype at each member of a preselected set of markers, wherein each member of the preselected set of markers has a degree of linkage with one or more of the one or more phenotypic attributes; (ii) with a programmed computer, comparing the genotype to a scoring matrix to obtain a marker score, wherein the scoring matrix scores markers at least with respect to two or more criteria selected from the group consisting of penetrance of a given marker in a population of interest, ontological classification, conservation of mutated sequence sites at conserved or less conserved sites, and biological significance; and (iii) determining whether the marker score is indicative of an enhanced, diminished, or average probability of exhibiting the one or more phenotypic attributes;   c) applying one or more selection criteria for each of the one or more phenotypic attributes to the resulting determinations of probability;   d) identifying information that is relevant to the probabilities of exhibiting the one or more phenotypic attributes and consistent with the limitations imposed by the one or more selection criteria; and   e) providing an output with the information.   
     
     
         35 . The method according to  claim 34 , further comprising performing the assay. 
     
     
         36 . The method according to  claim 34 , wherein the assay includes nucleic acid amplification of the biological sample. 
     
     
         37 . The method according to  claim 34 , wherein the assay is targeted to the preselected set of markers. 
     
     
         38 . The method according to  claim 34 , wherein each member of the preselected set of markers is included in the set based upon a determination of measures of phenotypic value and/or prioritization selected from the group consisting of penetrance of the one or more markers in a population or subpopulation of interest, the degree of linkage of the one or more markers to a particular phenotype, the relative contribution of the one or more markers to communicating the phenotype, and the degree of statistical or scientific confidence to be placed in any data associated with any of the measures of phenotypic value and/or priority used. 
     
     
         39 . The method according to  claim 34 , wherein the scoring matrix prioritizes markers with respect to genomic relevance. 
     
     
         40 . The method according to  claim 34 , further comprising: applying the same or different selection criteria one or more additional times to the determined probabilities of exhibiting each of the phenotypic attributes; identifying information that is relevant to the individual's probabilities of exhibiting the one or more phenotypic attributes and consistent with the limitations imposed by the selection criteria; and communicating the information to the individual. 
     
     
         41 . The method according to  claim 34 , wherein the scoring matrix comprises a combination of one or more scoring matrix vectors selected from the group consisting of a descriptor of family history, a descriptor of general medical physiological values, a descriptor of mRNA expression levels, a descriptor of methylation profiles, a descriptor of protein expression levels, a descriptor of enzyme activity, and a descriptor of antibody load. 
     
     
         42 . The method according to  claim 34 , wherein at least one of the one or more selection criteria is specified in advance by the individual. 
     
     
         43 . The method according to  claim 42 , wherein at least one of the one or more selection criteria is a function of the availability of treatments effective to modify the phenotypic characteristic. 
     
     
         44 . The method according to  claim 34 , wherein at least one of the one or more selection criteria is a function of the scope and quality of known research relating to the phenotypic characteristic. 
     
     
         45 . The method according to  claim 34 , wherein at least one of the one or more selection criteria is a function of the probability determination(s) for one or more other phenotypic attributes. 
     
     
         46 . The method according to  claim 34 , further comprising, prior to providing the output: formatting the information relating to the relevant phenotypic attributes according to an organizational matrix, wherein the organizational matrix determines the grouping, and presentation of information to the individual. 
     
     
         47 . The method according to  claim 46 , wherein the organizational matrix groups phenotypic characteristics for which the individual has an enhanced probability together. 
     
     
         48 . The method according to  claim 46 , wherein the organizational matrix groups phenotypic attributes related to similar physiological systems together. 
     
     
         49 . The method according to  claim 46 , wherein the organization matrix ranks the phenotypic attributes as a function of the potential impact on the individual's lifestyle or quality of life. 
     
     
         50 . The method according to  claim 46 , wherein the organization matrix ranks the phenotypic characteristics as a function of the genomic ethnicity of the individual. 
     
     
         51 . The method according to  claim 34 , wherein prior to providing the output, the identity of the individual is not associated with data corresponding to the genotypic characteristics, the relative probabilities of exhibiting the phenotypic attributes, or the identified relevant information. 
     
     
         52 . The method according to  claim 34 , wherein said output is provided using a graphical user interface. 
     
     
         53 . The method according to  claim 34 , wherein the scoring matrix scores markers at least with respect to three or more criteria selected from the group consisting of penetrance of a given marker in a population of interest, ontological classification, conservation of mutated sequence sites at conserved or less conserved sites, and biological significance. 
     
     
         54 . The method according to  claim 53 , wherein the scoring matrix scores markers at least with respect to penetrance of a given marker in a population of interest, ontological classification, and conservation of mutated sequence sites at conserved or less conserved sites. 
     
     
         55 . The method according to  claim 53 , wherein the scoring matrix scores markers at least with respect to penetrance of a given marker in a population of interest, ontological classification, and biological significance. 
     
     
         56 . The method according to  claim 53 , wherein the scoring matrix scores markers at least with respect to penetrance of a given marker in a population of interest, ontological classification, conservation of mutated sequence sites at conserved or less conserved sites, and biological significance. 
     
     
         57 . The method according to  claim 34 , wherein the conservation of mutated sequence sites are selected from the group consisting of exon/intron junction sequences and promoter regions. 
     
     
         58 . The method according to  claim 34 , wherein the conservation of mutated sequence sites provides a splicing strength score. 
     
     
         59 . The method according to  claim 34 , wherein the conservation of mutated sequence sites provide a score utilizing one or more predictive models. 
     
     
         60 . The method according to  claim 34 , wherein the scoring matrix scores markers at least with respect to penetrance of a given marker in a population of interest and ontological classification. 
     
     
         61 . The method according to  claim 34 , wherein the scoring matrix scores markers at least with respect to ontological classification and conservation of mutated sequence sites at conserved or less conserved sites. 
     
     
         62 . The method according to  claim 34 , wherein the scoring matrix scores markers at least with respect to ontological classification and biological significance.