Patent Publication Number: US-2022228207-A1

Title: Polymorphic markers for pharmacogenetic hla risk alleles

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
     This application claims the benefit of U.S. Provisional Application No. 62/858,326, filed Jun. 7, 2019; U.S. Provisional Application No. 62/884,661 filed Aug. 8, 2019; and U.S. Provisional Application No. 62/915,171 filed Oct. 15, 2019 which are each incorporated by reference herein in their entireties. 
    
    
     INTRODUCTION 
     Pharmacogenetics offers the potential to improve health outcomes by identifying individuals who are at greater risk of developing side effects and/or predicting the efficacy of medicines. The growing scientific literature supporting the validity of pharmacogenetics for selected medications has prompted recent clinical practice guidelines for genotype-directed prescribing. In addition, a growing number of approved medications have pharmacogenetic information included on the FDA label. Many of the medications with very high evidence supporting a pharmacogenetic effect are associated with specific HLA risk alleles, which are major risk factors for several life-threatening drug-specific immune-mediated adverse events (e.g., acute hepatitis, hypersensitivity syndrome, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN)). 
     Clinical guidelines and FDA/EMA testing recommendations are available for several adverse events such as abacavir-induced hypersensitivity syndrome (associated with HLA-B*57:01), carbamazepine or phenytoin induced SJS/TEN (associated with HLA-B*15:02), carbamazepine-induced SJS/TEN (associated with HLA-A*31:01), and allopurinol-induced SJS/TEN (associated with HLA-B*58:01). 
     Routine HLA typing for pharmacogenomic risk prediction is not cost-effective due to the technical challenges associated with interrogating the polymorphic HLA gene region. The technical challenges are due to the highly polymorphic nature of the HLA gene family region on chromosome 6p. To facilitate pharmacogenomic HLA allele screening, some single nucleotide polymorphisms (SNPs) have been associated with the most relevant HLA risk alleles. However, those proxy-SNPs have inadequate specificity and sensitivity within and across multi-ethnic populations, which has limited their use in clinical practice. 
     SUMMARY 
     Drug-induced hypersensitivity reactions can be life-threating adverse events that have been strongly associated with specific human leucocyte antigen (HLA) alleles such as HLA-B*57:01 (abacavir), HLA-B*15:02 (carbamazepine, phenytoin) and HLA-A*31:01 (carbamazepine), and HLA-B*58:01 (allopurinol). We have identified panels of proxy single nucleotide polymorphisms (SNPs) that are highly predictive of particular HLA risk alleles, and concordant across multi-ethnic populations. 
     Accordingly, the present disclosure describes methods involving clinical DNA testing for the HLA panel markers to assess or predict risk for life-threatening adverse drug reactions associated with the human leucocyte antigen (HLA) alleles HLA-B*57:01, HLA-B*15:02, HLA-A*31:01 and HLA-B*58:01. Methods of treating a subject with a drug associated with an adverse drug reaction (ADR) are provided. Based on the assessed risk to a subject for developing an adverse drug reaction in response to a drug, a suitable dosage regimen for administration of the drug can be selected. In some embodiments of the method, the drug is administered when there is a low assessed risk of ADR in the subject. Alternatively, when there is a high assessed risk of ADR in the subject, a reduced dosage of the drug, or no drug, or an alternative therapy can be administered. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       These and other features, aspects, and advantages of the present disclosure will become better understood with regard to the following description, and accompanying drawings. 
         FIG. 1  shows a schematic of the datasets utilized in the analysis leading to identification of panels of proxy single nucleotide polymorphisms (SNPs) for HLA risk alleles. (1) Gourraud, et al., 2014, “HLA diversity in the 1000 genomes dataset”, PLoS One 9(7): e97282. (2) Abi-Rached, et al., 2018, “Immune diversity sheds light on missing variation in worldwide genetic diversity panels”, PLoS One 13(10):e0206512. (3) Bettinotti, et al., 2018, “Characterization of 108 Genomic DNA Reference Materials for 11 Human Leukocyte Antigen Loci: A GeT-RM Collaborative Project”, J. Mol. Diagn. 20(5):703-715. 
     
    
    
     DETAILED DESCRIPTION 
     Drug-induced hypersensitivity reactions can be life-threating adverse events that have been strongly associated with specific human leucocyte antigen (HLA) alleles such as HLA-B*57:01, HLA-B*15:02 and HLA-A*31:01, and HLA-B*58:01. 
     We analyzed the 1000 Genome project dataset including samples across super populations with whole genome sequencing and HLA typing data (see e.g.,  FIG. 1 , discovery cohort). The HLA allele tagging performance of each variant within MHC region (n=608,256) was assessed, and their carriage sensitivity and specificity estimated. False positive and false negative samples were typed to confirm the predicted estimations for the best proxy-SNPs. We then genotyped those identified proxy-SNPs on 79 multiethnic samples, 60 of which carry at least one of the four HLA alleles ( FIG. 1 , replication cohort) to confirm sensibility and sensitivity in an independent cohort. 
     Based on this analysis, we have identified panels of proxy single nucleotide polymorphisms (SNPs) that are highly predictive of particular HLA risk alleles, and concordant across multi-ethnic populations. As summarized above, this disclosure provides methods that include assessing the subject for pharmacogenetic HLA risk alleles associated with an adverse drug reaction (ADR). 
     Pharmacogenomic Human Leucocyte Antigen (HLA) Alleles 
     The HLA system is a gene complex encoding the major histocompatibility complex (MHC) proteins in humans, cell-surface proteins responsible for the regulation of the immune system. The HLA gene complex is located on a 3 Mbp section within chromosome 6p21. HLA genes are highly polymorphic allowing them to fine-tune the adaptive immune system. The HLA-A gene is located on the short arm of chromosome 6 and encodes the larger, a-chain, constituent of HLA-A. Over 2000 variants (alleles) of HLA-A are known, and all alleles receive at least a four-digit classification. More than 1000 alleles of HLA-B gene are known, each of which is given a particular number (such as HLA-B27). Closely related alleles are categorized together; for example, at least 28 very similar alleles are subtypes of HLA-B27. These subtypes are designated as HLA-B*27:01 to HLA-B*27:28. HLA-A*31:01 
     The HLA-A*31:01 allele predisposes a subject to multiple phenotypes of carbamazepine hypersensitivity including maculopapular exanthema, hypersensitivity syndrome, and SJS/TEN in a range of populations including Europeans, Japanese, South Koreans and Han Chinese, although the effect size varies between the different phenotypes and populations. The HLA-A*31:01 allele has been shown to be a strong predictor of both mild and severe adverse reactions to carbamazepine, such as the DRESS syndrome form of severe cutaneous reactions. For patients who test positive for HLA-A*31:01, alternative treatments to CBZ are available. HLA-B*15:02 
     The presence of HLA-B*15:02 allele is considered a risk factor for development of Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) in patients taking aromatic anticonvulsant drugs like carbamazepine and phenytoin. 
     Carbamazepine (CBZ) is a sodium channel inhibitor, and is an anticonvulsant medication used primarily in the treatment of epilepsy and neuropathic pain. Serious skin reactions such as Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) due to CBZ therapy are more common in people with a particular human leukocyte antigen alleles, such as HLA-B*1502. HLA-B*1502 occurs almost exclusively in people with ancestry across broad areas of Asia, but has a very low or absent frequency in European, Japanese, Korean and African populations. Screening for HLA-B*15:02 is mandated in patients from South East Asia because of a strong association of CBZ hypersensitivity with SJS and TEN. 
     HLA-B*57:01 
     The HLA-B*57:01 variant occurs in about 6% of individuals of European or Asian descent. 
     Abacavir is a nucleoside reverse transcriptase inhibitor (NRTI) that is widely used in combination with other antiretroviral agents to achieve viral suppression and immunologic improvement in HIV therapy. Abacavir has been linked to potentially fatal hypersensitivity reactions (HSR), and is thought to induce HSR by altering self-peptides presented to T-cells, resulting in an immune response. This effect is heightened in patients carrying HLA-B*57:01 due to a direct, metabolism-independent and non-covalent interaction of abacavir with HLA-B*57:01. 
     HLA-B*58:01 
     The frequency of the HLA-B*58:01 allele varies between ethnicities. Han Chinese and Thai populations have HLA-B*58:01 allele frequencies of around 8%, as compared to European and Japanese populations, who have allele frequencies of around 1.0% and 0.5%, respectively. 
     Subjects with one or two copies of the HLA-B*58:01 allele have an increased risk of hypersensitivity reactions, such as Stevens-Johnson Syndrome, toxic epidermal necrolysis or maculopapular eruption, when treated with lamotrigine. 
     Allopurinol is a purine analog inhibitor of xanthine oxidase that is used to decrease high blood uric acid levels, e.g., in the treatment and/or prevention of gout, specific types of kidney stones, and side effects of chemotherapy. 
     Allopurinol associated SCAR (severe cutaneous adverse drug reaction) including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) has been shown to be associated with the HLA-B*58:01 allele. 
     Polymorphic Markers for HLA Alleles 
     Described in the experimental section below are details of the analysis that lead to the identification of polymorphic markers in linkage disequilibrium (LD) with particular pharmacogenomic HLA risk alleles associated with ADRs. Linkage Disequilibrium refers to a non-random association of genetic variations or alleles at different loci in a given population. Such genetic variations and alleles are said to be in linkage disequilibrium when their frequency of association is higher or lower than what would be expected if they were independent and associated randomly. 
     Table 6 shows specificity and sensitivity for selected proxy-SNPs for HLA-B*57:01, HLA-B*15:02, HLA-A*31:01 and HLA-B*58:01. Table 7 shows sensibility and sensitivity data by ethnicity for the selected proxy-SNPs. In general, the data shows consistency across multi-ethnic populations. 
     Aspects of this disclosure include assaying for genetic markers in a sample from a subject in order to assess whether the subject has a pharmacogenomic HLA risk allele associated with an ADR. 
     In some embodiments, the HLA allele is HLA-A*31:01, and the one or more markers in LD are selected from rs114776910_G, rs138415245_G, rs12665140_A, rs147023494_T, rs148590958_C and rs114716190_G. In some embodiments, the one or more markers in LD with HLA-A*31:01 are 2 or more markers, 3 or more markers, 4 or more markers, 5 or more markers, or 6 or more markers. 
     In some embodiments, the HLA allele is HLA-B*15:02, and the one or more markers in LD are selected from rs144012689_A, rs151107659_A, rs188729361_A and rs181377228_A. In some embodiments, the one or more markers in LD with HLA-B*15:02 are 2 or more markers, 3 or more markers, or 4 or more markers. 
     In some embodiments, the HLA allele is HLA-B*58:01, and the one or more markers in LD are selected from rs78090769_T, rs79815527_A, rs75412754_C, and rs6936478_A. In some embodiments, the one or more markers in LD with HLA-B*58:01 are 2 or more markers, 3 or more markers, or 4 or more markers. 
     In some embodiments, the HLA allele is HLA-B*57:01, and the one or more markers in LD are selected from rs115986568_A, rs149663102_T, rs114170382_A, rs114607072_T, rs138099588_G, rs41558312_G, rs58102217_A, and rs41543314_G. In some embodiments, the one or more markers in LD with HLA-B*57:01 are 2 or more markers, 3 or more markers, 4 or more markers, 5 or more markers, 6 or more markers, 7 or more markers, or 8 or more markers. 
     Tables 1-4 show expanded groups of polymorphic markers that are in linkage disequilibrium (LD) with HLA-A*31:01, HLA-B*15:02, HLA-B*57:01, or HLA-B*58:01, respectively, listed according to the specificity and sensitivity values determined in the analysis. 
     In some embodiments, the HLA allele is HLA-A*31:01, and the one or more markers in LD are selected from Table 1. In some embodiments, the one or more markers in LD with HLA-A*31:01 are selected from markers numbered 1 to 100 of Table 1, such as markers numbered 1 to 50, 1 to 40, 1 to 30, 1 to 20, 1 to 15, 1 to 10, 1 to 8, or 1 to 6 of Table 1. In some embodiments, the one or more markers of Table 1 in LD with HLA-A*31:01 are 2 or more markers, such as 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 10 or more, 12 or more, 15 or more, 20 or more, 30 or more, 40 or more, 50 or more, 100 or more markers. 
     In some embodiments, the HLA allele is HLA-B*15:02, and the one or more markers in LD are selected from Table 2. In some embodiments, the one or more markers in LD with HLA-B*15:02 are selected from markers numbered 1 to 100 of Table 2, such as markers numbered 1 to 50, 1 to 40, 1 to 30, 1 to 20, 1 to 15, 1 to 10, 1 to 8, 1 to 6, or 1 to 4 of Table 2. In some embodiments, the one or more markers of Table 2 in LD with HLA-B*15:02 are 2 or more markers, such as 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 10 or more, 12 or more, 15 or more, 20 or more, 30 or more, 40 or more, 50 or more, 100 or more, 150 or more, or 200 or more markers. 
     In some embodiments, the HLA allele is HLA-B*57:01, and the one or more markers in LD are selected from Table 3. In some embodiments, the one or more markers in LD with HLA-B*57:01 are selected from markers numbered 1 to 100 of Table 3, such as markers numbered 1 to 50, 1 to 40, 1 to 30, 1 to 20, 1 to 15, 1 to 10, or 1 to 8 of Table 3. In some embodiments, the one or more markers of Table 3 in LD with HLA-B*57:01 are 2 or more markers, such as 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 10 or more, 12 or more, 15 or more, 20 or more, 30 or more, 40 or more, 50 or more, 100 or more, 150 or more, or 200 or more markers. 
     In some embodiments, the HLA allele is HLA-B*58:01, and the one or more markers in LD are selected from Table 4. In some embodiments, the one or more markers in LD with HLA-B*58:01 are selected from markers numbered 1 to 15 of Table 4, such as markers numbered 1 to 12, 1 to 10, 1 to 8, 1 to 6, or 1 to 4 of Table 4. In some embodiments, the one or more markers of Table 4 in LD with HLA-B*58:01 are 2 or more markers, such as 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 10 or more, or 12 or more markers. 
     Table 5 shows a group of polymorphic markers that are in linkage disequilibrium (LD) with HLA-A*58:02, listed according to the specificity and sensitivity values determined in the analysis. In some embodiments, the polymorphic markers of Table 5 can be utilized to distinguish a subject predicted to carry a different allele, e.g., HLA-A*58:01. In some embodiments, the method includes assessing whether one or more markers in LD with HLA-B*58:02 and selected from Table 4 are absent. In some embodiments, an assessment of the presence or absence of one or more markers in LD with HLA-B*58:02 provides an indication of whether or not the subject carries the allele HLA-B*58:01 that is associated with an ADR. 
     When assessing a subject for the presence of absence of a particular HLA allele, the number and selection of markers that can be utilized as proxy for that HLA allele can depend in part on the specificity and/or sensitivity values of the markers. In some embodiments, markers having specificity and/or sensitivity values of 95% or more, such as 96% or more, 97% or more, 98% or more, 98.5% or more, 99% or more, or 99.5% or more, are assessed and provide a high probability of the presence of the HLA allele with which the markers are in LD. In some embodiments, markers having PPV and/or NPV values of 95% or more, such as 96% or more, 97% or more, 98% or more, 98.5% or more, 99% or more, or 99.5% or more, are assessed and provide a high probability of the presence or absence of the HLA allele with which the markers are in LD. 
     Aspects of this disclosure include panels of genetic markers that are capable of providing cost effective and rapid genotype-based screening for multiple pharmacogenomic HLA risk alleles associated with ADRs. 
     In some embodiments, the HLA allele status of the subject for two or more of the HLA risk alleles HLA-A*31:01, HLA-B*15:02, HLA-B*57:01, and HLA-B*58:01 is identified using the methods and panels of this disclosure, such as 2, 3 or all of the HLA risk alleles HLA-A*31:01, HLA-B*15:02, HLA-B*57:01, and HLA-B*58:01. In some embodiments, the panel includes one or more genetic markers of two of Tables 1-4. In some embodiments, the panel includes one or more genetic markers of three of Tables 1-4. In some embodiments, the panel includes one or more genetic markers of each of Tables 1-4. 
     In some embodiments, the panel includes 4 or more genetic markers of Table 6, such as 5 or more, 10 or more, or 15 or more. In some embodiments, the panel of Table 6 includes at least one genetic marker for each of the HLA risk alleles HLA-A*31:01, HLA-B*15:02, HLA-B*57:01, and HLA-B*58:01. In some embodiments, the panel of Table 6 includes two or more genetic markers for each of the HLA risk alleles HLA-A*31:01, HLA-B*15:02, HLA-B*57:01, and HLA-B*58:01, such as 3 or more, or 4 or more genetic markers for each of the HLA risk alleles. 
     Aspects of the disclosure include panels of oligonucleotide probes that are complementary to the panels of genetic markers of Table 6 (e.g., described herein). 
     Risk Assessment 
     Aspects of this disclosure include assaying for the presence or absence of particular genetic markers in a subject, and thus predicting or assessing the presence or absence of pharmacogenomic HLA risk alleles in the subject. A high probability of the presence of a pharmacogenomic HLA risk allele in the subject can indicate a high risk of ADR associated with allele. A low risk of ADR for the subject can be assessed when the subject lacks a panel of genetic markers in LD with the pharmacogenomic HLA risk allele. 
     Tables 1-7 provide lists of genetic markers of interest in LD with the pharmacogenomic HLA risk alleles and ranked according to specificity, sensitivity, PPV and NPV scores, as shown. A positive predictive value (PPV) is the probability that a subject with a positive screening test for the genetic marker truly have the pharmacogenomic HLA risk allele. A negative predictive value (NPV) is the probability that a subject with a negative screening test for the genetic marker truly have the pharmacogenomic HLA risk allele. 
     The level of risk of the ADR in a subject can be assessed qualitatively or quantitively based on the results of assaying for the genetic markers described herein. In some embodiments, one or more of the genetic markers of Tables 1-7 in LD with a particular HLA risk allele are assayed, and a high risk of the ADR is assessed when all of the genetic markers that are assayed are determined to be present. In some embodiments, one or more of the genetic markers of Table 6 in LD with a particular HLA risk allele are assayed, and a low risk of the ADR is assessed when all of the genetic markers that are assayed are determined to be absent. In some embodiments, the one or more genetic markers are 2 or more, such as 3, 4, 5, 6, 7, 8, 9, 10 or more markers. 
     In some embodiments, the HLA allele is HLA-A*31:01, and the one or more markers in LD that are assayed and determined to be present (or absent) are selected from rs114776910_G, rs138415245_G, rs12665140_A, rs147023494_T, rs148590958_C and rs114716190_G. In some embodiments, the one or more markers in LD with HLA-A*31:01 that are assayed and determined to be present (or absent) are 2 or more markers, such as 3, 4, 5, or 6 markers. 
     In some embodiments, the HLA allele is HLA-B*15:02, and the one or more markers in LD that are assayed and determined to be present (or absent) are selected from rs144012689_A, rs151107659_A, rs188729361_A and rs181377228_A. In some embodiments, the one or more markers in LD with HLA-B*15:02 that are assayed and determined to be present (or absent) are 2 or more markers, such as 3, or 4 markers. 
     In some embodiments, the HLA allele is HLA-B*58:01, and the one or more markers in LD that are assayed and determined to be present (or absent) are selected from rs78090769_T, rs79815527_A, rs75412754_C, and rs6936478_A. In some embodiments, the one or more markers in LD with HLA-B*58:01 that are assayed and determined to be present (or absent) are 2 or more markers, such as 3, or 4 markers. 
     In some embodiments, the HLA allele is HLA-B*57:01, and the one or more markers in LD that are assayed and determined to be present (or absent) are selected from rs115986568_A, rs149663102_T, rs114170382_A, rs114607072_T, rs138099588_G, rs41558312_G, rs58102217_A, and rs41543314_G. In some embodiments, the one or more markers in LD with HLA-B*57:01 that are assayed and determined to be present (or absent) are 2 or more markers, such as 3, 4, 5, 6, 7, or 8 markers. 
     It is understood that a HLA risk score for a subject can be assessed or calculated, based at least in part on the number of individual markers or SNPs (e.g., as described herein) that are assessed, weighted according to the relative predictive strengths of the markers or SNPs (e.g., their PPV and NPV values). The risk score can represent a probability that a particular HLA risk allele is present or absent in the subject. A variety of methods for calculating such risk scores are available to the skilled artisan. In some embodiments, the risk is assessed across a multi-ethnic population. In some embodiments, the risk is assessed across a particular ethnicity. The genetic markers described herein can be highly predictive of particular HLA risk alleles, and concordant across multi-ethnic populations, avoiding the possibility of false positive or negative results within ethnicities that are not concordant. 
     In some embodiments, the subject has a low risk of an ADR when the risk that the associated HLA allele is absent is assessed with a risk score probability of 0.5 or more, such as 0.6 or more, 0.7 or more, 0.8 or more, 0.9 or more, 0.95 or more, 0.96 or more, 0.98 or more, 0.99 or more, or 1.0. 
     In some embodiments, the subject has a high risk of an ADR when the risk that the associated HLA allele is present is assessed with a risk score probability of 0.5 or more, such as 0.6 or more, 0.7 or more, 0.8 or more, 0.9 or more, 0.95 or more, 0.96 or more, 0.98 or more, 0.99 or more, or 1.0. 
     In some embodiments, all of the genetic markers of Table 6 in LD with HLA-A*31:01 are assayed, and a high risk of the ADR is assessed when all of the genetic markers are determined to be present. In some embodiments, all of the genetic markers of Table 6 in LD with HLA-A*31:01 are assayed, and a low risk of the ADR is assessed when none of the genetic markers are determined to be present. 
     In some embodiments, all of the genetic markers of Table 6 in LD with HLA-B*15:02 are assayed, and a high risk of the ADR is assessed when all of the genetic markers are determined to be present. In some embodiments, all of the genetic markers of Table 6 in LD with HLA-B*15:02 are assayed, and a low risk of the ADR is assessed when none of the genetic markers are determined to be present. 
     In some embodiments, all of the genetic markers of Table 6 in LD with HLA-B*57:01 are assayed, and a high risk of the ADR is assessed when all of the genetic markers are determined to be present. In some embodiments, all of the genetic markers of Table 6 in LD with HLA-B*57:01 are assayed, and a low risk of the ADR is assessed when none of the genetic markers are determined to be present. 
     In some embodiments, all of the genetic markers of Table 6 in LD with HLA-B*58:01 are assayed, and a high risk of the ADR is assessed when all of the genetic markers are determined to be present. In some embodiments, all of the genetic markers of Table 6 in LD with HLA-B*58:01 are assayed, and a low risk of the ADR is assessed when none of the genetic markers are determined to be present. 
     SNP Assays 
     Polymorphic sites (PS) and SNPs described herein can be identified according to the SNP NCBI database. As recognized by the skilled artisan, nucleic acid samples containing a particular PS may be complementary double stranded molecules and thus reference to a particular site on the sense strand refers as well to the corresponding site on the complementary antisense strand. Similarly, reference to a particular genotype obtained for a PS on both copies of one strand of a chromosome is equivalent to the complementary genotype obtained for the same PS on both copies of the other strand. 
     The sequences of the genetic markers (e.g., SNPs) recited herein, as well as their complementary sequence, may be used to design probes and primers for genotyping the markers in a nucleic acid sample obtained from a human subject of interest using any of a variety of methods well known in the art that permits the determination of whether the individual has at least one copy of the genetic marker. Nucleic acid molecules utilized in such methods generally include RNA, genomic DNA, or cDNA derived from RNA. 
     Typically, genotyping methods involve assaying a nucleic acid sample prepared from a biological sample obtained from the individual to determine the identity of a nucleotide or nucleotide pair present at one or more polymorphic sites of interest. Nucleic acid samples may be prepared from virtually any biological sample. The genetic sample can be obtained from a biological sample selected from blood, hair, skin, saliva, semen, urine, fecal material, sweat, and buccal sample. In some embodiments, the sample is an oral tissue sample, scraping, or wash or a biological fluid sample, preferably saliva, urine or blood. 
     Nucleic acid samples may be prepared for analysis using any technique known to those skilled in the art. Preferably, such techniques result in the isolation of genomic DNA sufficiently pure for determining the genotype for the desired polymorphic site(s) in the nucleic acid molecule. To enhance the sensitivity and specificity of that determination, it is frequently desirable to amplify from the nucleic acid sample a target region containing the PS to be genotyped. 
     Any amplification technique known to those of skill in the art may be used in practicing the present invention including, but not limited to, polymerase chain reaction (PCR) techniques. Other suitable amplification methods include the ligase chain reaction (LCR), transcription amplification, self-sustained sequence replication, isothermal methods, and nucleic acid-based sequence amplification (NASBA). 
     In some embodiments, the presence or absence of a polynucleotide is identified by amplifying or failing to amplify an amplification product from the sample, where the amplification product is preferably digested with a restriction enzyme before analysis and/or where the SNP is identified by hybridizing the nucleic acid sample with a primer label which is a detectable moiety. In some embodiments, the presence or absence of the polynucleotide is identified by hybridization to specific Hairloop™ probes spotted on a microarray, by allele-specific PCR, by KASP genotyping chemistry or TaqMan Assays. 
     Administration Methods 
     This disclosure provides methods including administration of a drug associated with an ADR (e.g., as described herein) to a subject, e.g., to treat the subject for a disease or condition without significant adverse side effects. Drugs that may be administered to the subject according to the methods of this disclosure include, but are not limited to, aromatic anticonvulsant drugs such as carbamazepine and phenytoin, allopurinol, abacavir, and pharmaceutically acceptable salts thereof. 
     In some embodiments, the drug is an aromatic anticonvulsant drug. In some embodiments, the drug is carbamazepine. Carbamazepine can be used to treat subjects for epilepsy, bipolar disorder, or conditions associated with nerve pain such as trigeminal neuralgia. 
     In some embodiments, the drug is phenytoin. Phenytoin can be used to treat subjects for epilepsy, or conditions associated with anxiety control and mood stabilization. 
     In some embodiments, the drug is a nucleoside reverse transcriptase inhibitor (NRTI). In some embodiments, the drug is abacavir. Abacavir can be used to treat subjects for HIV and AIDS. 
     In some embodiments, the drug is an inhibitor of xanthine oxidase. In some embodiments, the drug is allopurinol. Allopurinol can be used to treat subjects for primary or secondary gout (acute attacks, tophi, joint destruction, uric acid lithiasis, and/or nephropathy). 
     Based on the assessed risk to a subject for developing an adverse drug reaction in response to a drug, a suitable dosage regimen for administration of the drug can be selected. In some embodiments of the method, the drug is administered with a normal dosage when there is a low assessed risk of ADR in the subject. By normal dosage is meant a dosage of a particular drug that is medically appropriate to administer to a subject having an average level of risk for ADR as compared to a reference population, e.g., without regard to an elevated level of risk of ADR as described herein. 
     In some embodiments of the method, when there is a high assessed risk of ADR in the subject, a reduced dosage of the drug. In some embodiments of the method, when there is a high assessed risk of ADR in the subject, the drug associated with the ADR is not administered to the subject. In some embodiments of the method, when there is a high assessed risk of ADR in the subject, an alternative therapy or drug can be administered. 
     Definitions 
     Hypersensitivity is an extreme form of adaptive immune response occurring when the immune system reacts inappropriately to certain antigens, and may lead to inflammatory reactions and tissue damage. 
     The term “biological sample” refers to any biological sample that can be isolated from an individual, including samples from which genetic material may be isolated. A “genetic sample” refers to DNA and/or RNA obtained or derived from an individual. 
     The terms “treat” and “treating” mean to administer a therapeutic agent, such as a drug described herein, internally or externally to an individual in need of the therapeutic agent. Typically, the therapeutic agent is administered in a therapeutically effective amount, which means an amount effective to produce one or more beneficial results. The therapeutically effective amount of a particular agent may vary according to factors such as the disease state, age, and weight of the patient being treated, and the sensitivity of the patient, e.g., ability to respond, to the therapeutic agent. Whether a beneficial or clinical result has been achieved can be assessed by any clinical measurement typically used by physicians, physician&#39;s assistants or other skilled healthcare providers to assess the presence, severity or progression status of the targeted disease, symptom or adverse effect. Typically, a therapeutically effective amount of an agent will result in an improvement in the relevant clinical measurement(s) over the baseline status, or over the expected status if not treated, of at least 5%, usually by at least 10%, more usually at least 20%, most usually at least 30%, preferably at least 40%), more preferably at least 50%, most preferably at least 60%, ideally at least 70%, more ideally at least 80%, and most ideally at least 90%. While an embodiment of the present disclosure (e.g., a treatment method or article of manufacture) may not achieve the desired clinical benefit or result in every patient, it should do so in a statistically significant number of patients as determined by any statistical test known in the art such as the likelihood ratio test based logistic regression with 2 degree freedom, etc. 
     It is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims. 
     Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention. 
     Certain ranges are presented herein with numerical values being preceded by the term “about.” The term “about” is used herein to provide literal support for the exact number that it precedes, as well as a number that is near to or approximately the number that the term precedes. In determining whether a number is near to or approximately a specifically recited number, the near or approximating unrecited number may be a number which, in the context in which it is presented, provides the substantial equivalent of the specifically recited number. 
     Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, representative illustrative methods and materials are now described. 
     It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely,” “only” and the like in connection with the recitation of claim elements, or use of a “negative” limitation. 
     All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference and are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed. 
     As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present invention. Any recited method can be carried out in the order of events recited or in any other order which is logically possible. 
     EXAMPLES 
     The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present invention, and are not intended to limit the scope of what the inventors regard as their invention nor are they intended to represent that the experiments below are all or the only experiments performed. 
     Example 1: Multi-Ethnic Single Nucleotide Polymorphism (SNP)-Based Screening of Pharmacogenomic HLA Alleles Implicated in Drug-Induced Hypersensitivity Reactions 
     Abstract: 
     Drug-induced hypersensitivity reactions are life-threating adverse events that have been strongly associated with specific human leucocyte antigen (HLA) alleles. Among the reported pharmacogenomic HLA risk alleles, clinical practice guidelines and/or FDA/EMA testing recommendations are currently available for HLA-B*57:01 (abacavir), HLA-B*15:02 (carbamazepine, phenytoin) and HLA-A*31:01 (carbamazepine), and HLA-B*58:01 (allopurinol). However, routine HLA typing for pharmacogenomic risk prediction is not cost-effective due to the technical challenges with interrogating the polymorphic HLA gene region. To facilitate pharmacogenomic HLA allele screening, previous studies identified single nucleotide polymorphisms (SNPs) in linkage disequilibrium with the most relevant HLA risk alleles; however, these proxy-SNPs have inadequate sensitivity across multi-ethnic populations and poor specificity, which has limited their use in clinical practice. To identify a multi-ethnic panel of proxy-SNPs for HLA-B*57:01, HLA-B*15:02, HLA-A*31:01 and HLA-B*58:01, publicly available whole genome sequencing and HLA typing data from the 1000 Genomes (1KG) Project were interrogated (Abi-Rached et al., 2018, “Immune diversity sheds light on missing variation in worldwide genetic diversity panels”, PLoS One 13(10):e0206512; Bettinotti et al., 2018, “Characterization of 108 Genomic DNA Reference Materials for 11 Human Leukocyte Antigen Loci: A GeT-RM Collaborative Project”, J. Mol. Diagn. 20(5):703-715; Bykova et al., 2018, “In Silico Analysis of the Minor Histocompatibility Antigen Landscape Based on the 1000 Genomes Project”, Front Immunol. 9:1819; Genomes Project et al., 2015, “A global reference for human genetic variation”, Nature 526(7571):68-74; Gourraud et al., 2014, “HLA diversity in the 1000 genomes dataset”, PLoS One 9(7):e97282). 
     The sensitivity and specificity of all SNPs in the MHC region (n=608,256) were initially assessed across a multi-ethnic subset of 1KG subjects (n=1079), which identified a panel of 18 proxy-SNPs that detected the four pharmacogenomic HLA risk alleles with a mean sensitivity and specificity of 99%. 
     Selected false positive and negative 1KG samples were clarified by confirmatory genotyping (Agena Bioscience), which resulted in the proxy-SNP panel having sensitivity and specificity &gt;99% for HLA-B*57:01 (N carriers =69; N SNPs =8), HLA-B*15:02 (N carriers =65; N SNPs =3) and HLA-A*31:01 (N carriers =88; N SNPs =4); and &gt;95% for HLA-B*58:01 (N carriers =77; N SNPs =3). The validity of the proxy-SNP panel was confirmed in an independent 1KG subset (n=1425), and in the combined cohort (n=2504) the majority of proxy-SNPs had 100% sensitivity and 99% specificity for the four pharmacogenomic HLA alleles in the Asian, European and Hispanic populations. Importantly, the panel also included proxy-SNPs with 98% sensitivity and specificity for HLA-A*31:01 and HLA-B*58:01 in the African population. Taken together, these data indicate that the identified novel proxy-SNP panel could provide cost-effective and rapid genotype-based screening to predict pharmacogenomic HLA allele risk in diverse patient populations. 
     Summary: The Sema4 pharmacogenetic HLA panel described herein predicts specific HLA alleles by a haplotype of markers, which improves the positive and negative predictive values. The Sema4 pharmacogenetic HLA panel markers are very concordant across multi-ethnic populations. A series of polymorphic markers were identified in LD with four pharmacogenetic HLA alleles (see e.g., Tables 1-4) implicated in life-threatening adverse drug reactions. Sensitive and specific haplotype analysis using this novel pharmacogenetic HLA panel could be a cost-effective and rapid genotype-based screening test to predict pharmacogenetic HLA allele carrier status across multi-ethnic populations. The pharmacogenetic HLA panel could also be extended to other indications (as appropriate), as these HLA risk alleles are involved in additional severe adverse drug reactions as well as susceptibility/prognosis for some complex diseases. 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 Polymorphic markers in LD with HLA-A*31:01. PPV and 
               
               
                 NPV refer to positive and negative predictive values, 
               
               
                 respectively. Markers 1-6 of table 1 provide a panel 
               
               
                 of preferred markers for HLA-A*31:01. 
               
            
           
           
               
               
               
               
               
               
            
               
                 Marker 
                 SNP 
                 specificity 
                 sensitivity 
                 ppv 
                 npv 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 1 
                 rs114776910_G 
                 0.998 
                 0.968 
                 0.968 
                 0.998 
               
               
                 2 
                 rs138415245_G 
                 0.998 
                 0.960 
                 0.968 
                 0.997 
               
               
                 3 
                 rs148590958_C 
                 0.998 
                 0.952 
                 0.967 
                 0.997 
               
               
                 4 
                 rs114716190_G 
                 0.998 
                 0.952 
                 0.967 
                 0.997 
               
               
                 5 
                 rs12665140_A 
                 0.997 
                 0.960 
                 0.960 
                 0.997 
               
               
                 6 
                 rs147023494_T 
                 0.996 
                 0.992 
                 0.939 
                 0.999 
               
               
                 7 
                 rs117117960_A 
                 0.998 
                 0.912 
                 0.974 
                 0.995 
               
               
                 8 
                 rs185367427_C 
                 0.985 
                 0.992 
                 0.781 
                 0.999 
               
               
                 9 
                 rs17179220_A 
                 0.980 
                 0.968 
                 0.726 
                 0.998 
               
               
                 10 
                 rs74345156_G 
                 0.907 
                 1 
                 0.365 
                 1 
               
               
                 11 
                 rs28733991_A 
                 0.906 
                 1 
                 0.362 
                 1 
               
               
                 12 
                 rs72495971_G 
                 0.905 
                 1 
                 0.36 
                 1 
               
               
                 13 
                 rs140821968_T 
                 0.905 
                 1 
                 0.358 
                 1 
               
               
                 14 
                 rs144608908_CATGT 
                 0.904 
                 1 
                 0.357 
                 1 
               
               
                 15 
                 rs17179816_T 
                 0.893 
                 0.984 
                 0.328 
                 0.999 
               
               
                 16 
                 rs12665039_C 
                 0.890 
                 0.984 
                 0.322 
                 0.999 
               
               
                 17 
                 rs6916499_C 
                 0.869 
                 0.983 
                 0.316 
                 0.998 
               
               
                 18 
                 rs1059449_A 
                 0.889 
                 1 
                 0.323 
                 1 
               
               
                 19 
                 rs41541222_T 
                 0.889 
                 1 
                 0.323 
                 1 
               
               
                 20 
                 rs7760172_C 
                 0.887 
                 1 
                 0.320 
                 1 
               
               
                 21 
                 rs142270424_A 
                 0.887 
                 1 
                 0.320 
                 1 
               
               
                 22 
                 rs116432652_T 
                 0.887 
                 0.992 
                 0.318 
                 0.999 
               
               
                 23 
                 rs77899164_C 
                 0.887 
                 1 
                 0.319 
                 1 
               
               
                 24 
                 rs10677323_CAG 
                 0.887 
                 1 
                 0.319 
                 1 
               
               
                 25 
                 rs17185784_G 
                 0.887 
                 1 
                 0.319 
                 1 
               
               
                 26 
                 rs28544296_C 
                 0.887 
                 1 
                 0.319 
                 1 
               
               
                 27 
                 rs72492287_A 
                 0.887 
                 1 
                 0.319 
                 1 
               
               
                 28 
                 rs115691105_T 
                 0.887 
                 1 
                 0.319 
                 1 
               
               
                 29 
                 rs28555376_C 
                 0.887 
                 1 
                 0.319 
                 1 
               
               
                 30 
                 rs2571375_G 
                 0.886 
                 0.873 
                 0.290 
                 0.992 
               
               
                 31 
                 rs72495912_A 
                 0.886 
                 1 
                 0.318 
                 1 
               
               
                 32 
                 rs75134279_C 
                 0.886 
                 1 
                 0.317 
                 1 
               
               
                 33 
                 rs72492295_T 
                 0.886 
                 1 
                 0.317 
                 1 
               
               
                 34 
                 rs151233761_C 
                 0.886 
                 1 
                 0.317 
                 1 
               
               
                 35 
                 rs74185225_C 
                 0.886 
                 1 
                 0.317 
                 1 
               
               
                 36 
                 rs72492302_C 
                 0.886 
                 1 
                 0.317 
                 1 
               
               
                 37 
                 rs72495906_G 
                 0.886 
                 0.992 
                 0.315 
                 0.999 
               
               
                 38 
                 rs147862323_C 
                 0.885 
                 1 
                 0.316 
                 1 
               
               
                 39 
                 rs115980375_C 
                 0.885 
                 1 
                 0.316 
                 1 
               
               
                 40 
                 rs116363141_A 
                 0.885 
                 1 
                 0.316 
                 1 
               
               
                 41 
                 rs72495910_C 
                 0.885 
                 1 
                 0.316 
                 1 
               
               
                 42 
                 rs76665055_T 
                 0.885 
                 1 
                 0.315 
                 1 
               
               
                 43 
                 rs11758504_T 
                 0.885 
                 1 
                 0.315 
                 1 
               
               
                 44 
                 rs138348864_A 
                 0.885 
                 1 
                 0.315 
                 1 
               
               
                 45 
                 rs192326368_T 
                 0.884 
                 1 
                 0.315 
                 1 
               
               
                 46 
                 rs72495975_T 
                 0.884 
                 1 
                 0.315 
                 1 
               
               
                 47 
                 rs184553151_T 
                 0.884 
                 1 
                 0.314 
                 1 
               
               
                 48 
                 rs11759097_A 
                 0.884 
                 1 
                 0.314 
                 1 
               
               
                 49 
                 rs115456943_A 
                 0.884 
                 1 
                 0.314 
                 1 
               
               
                 50 
                 rs75298535_C 
                 0.884 
                 1 
                 0.314 
                 1 
               
               
                 51 
                 rs551457015_G 
                 0.884 
                 0.992 
                 0.312 
                 0.999 
               
               
                 52 
                 rs28896571_T 
                 0.883 
                 1 
                 0.313 
                 1 
               
               
                 53 
                 rs28533954_A 
                 0.883 
                 1 
                 0.313 
                 1 
               
               
                 54 
                 rs11760172_T 
                 0.883 
                 1 
                 0.313 
                 1 
               
               
                 55 
                 rs28688639_G 
                 0.883 
                 1 
                 0.313 
                 1 
               
               
                 56 
                 rs11752319_A 
                 0.883 
                 1 
                 0.313 
                 1 
               
               
                 57 
                 rs72495983_A 
                 0.883 
                 1 
                 0.313 
                 1 
               
               
                 58 
                 rs13194536_T 
                 0.883 
                 1 
                 0.312 
                 1 
               
               
                 59 
                 rs74196807_G 
                 0.883 
                 0.992 
                 0.310 
                 0.999 
               
               
                 60 
                 rs143182422_T 
                 0.882 
                 1 
                 0.311 
                 1 
               
               
                 61 
                 rs77997154_T 
                 0.875 
                 0.992 
                 0.301 
                 0.999 
               
               
                 62 
                 rs114839838_A 
                 0.877 
                 0.984 
                 0.298 
                 0.999 
               
               
                 63 
                 rs116001094_C 
                 0.877 
                 0.984 
                 0.298 
                 0.999 
               
               
                 64 
                 rs9259811. 
                 0.870 
                 1 
                 0.295 
                 1 
               
               
                   
                 rs141296323_A 
               
               
                 65 
                 rs12663276_G 
                 0.875 
                 1 
                 0.299 
                 1 
               
               
                 66 
                 rs74211750_G 
                 0.875 
                 1 
                 0.299 
                 1 
               
               
                 67 
                 rs201477120_G 
                 0.875 
                 1 
                 0.299 
                 1 
               
               
                 68 
                 rs427995_C 
                 0.868 
                 1 
                 0.290 
                 1 
               
               
                 69 
                 rs79437615_G 
                 0.875 
                 1 
                 0.298 
                 1 
               
               
                 70 
                 rs74218766_T 
                 0.875 
                 1 
                 0.298 
                 1 
               
               
                 71 
                 rs79231337_C 
                 0.875 
                 1 
                 0.298 
                 1 
               
               
                 72 
                 rs41272547_A 
                 0.875 
                 1 
                 0.298 
                 1 
               
               
                 73 
                 rs41562315_A 
                 0.875 
                 1 
                 0.298 
                 1 
               
               
                 74 
                 rs41543916_A 
                 0.875 
                 1 
                 0.298 
                 1 
               
               
                 75 
                 rs41543412_G 
                 0.875 
                 1 
                 0.298 
                 1 
               
               
                 76 
                 rs1061235_T 
                 0.875 
                 1 
                 0.298 
                 1 
               
               
                 77 
                 rs77309262_T 
                 0.875 
                 1 
                 0.298 
                 1 
               
               
                 78 
                 rs10947038_A 
                 0.875 
                 0.984 
                 0.295 
                 0.999 
               
               
                 79 
                 rs11757135_T 
                 0.875 
                 0.984 
                 0.295 
                 0.999 
               
               
                 80 
                 rs17179957_A 
                 0.875 
                 0.984 
                 0.295 
                 0.999 
               
               
                 81 
                 rs189990623_T 
                 0.875 
                 1 
                 0.297 
                 1 
               
               
                 82 
                 rs114058671_A 
                 0.875 
                 1 
                 0.297 
                 1 
               
               
                 83 
                 rs79857957_T 
                 0.875 
                 1 
                 0.297 
                 1 
               
               
                 84 
                 rs78993465_A 
                 0.875 
                 1 
                 0.297 
                 1 
               
               
                 85 
                 rs115694430_G 
                 0.875 
                 1 
                 0.297 
                 1 
               
               
                 86 
                 rs72500497_T 
                 0.875 
                 0.984 
                 0.294 
                 0.999 
               
               
                 87 
                 rs199947646_T 
                 0.875 
                 0.984 
                 0.294 
                 0.999 
               
               
                 88 
                 rs183401702_A 
                 0.875 
                 0.984 
                 0.294 
                 0.999 
               
               
                 89 
                 rs11756376_G 
                 0.875 
                 0.984 
                 0.294 
                 0.999 
               
               
                 90 
                 rs116451203_C 
                 0.875 
                 0.984 
                 0.294 
                 0.999 
               
               
                 91 
                 rs143328784_T 
                 0.875 
                 0.984 
                 0.294 
                 0.999 
               
               
                 92 
                 rs149964608_A 
                 0.875 
                 0.984 
                 0.294 
                 0.999 
               
               
                 93 
                 rs200286021_G 
                 0.874 
                 1 
                 0.297 
                 1 
               
               
                 94 
                 rs72498354_T 
                 0.874 
                 1 
                 0.297 
                 1 
               
               
                 95 
                 rs149645832_T 
                 0.874 
                 1 
                 0.297 
                 1 
               
               
                 96 
                 rs74295242_A 
                 0.874 
                 1 
                 0.297 
                 1 
               
               
                 97 
                 rs115334476_C 
                 0.874 
                 1 
                 0.297 
                 1 
               
               
                 98 
                 rs145720557_A 
                 0.874 
                 1 
                 0.297 
                 1 
               
               
                 99 
                 rs76895251_C 
                 0.874 
                 1 
                 0.297 
                 1 
               
               
                 100 
                 rs72498357_G 
                 0.874 
                 1 
                 0.297 
                 1 
               
               
                 101 
                 rs114766850_A 
                 0.874 
                 1 
                 0.297 
                 1 
               
               
                 102 
                 rs75367802_A 
                 0.874 
                 0.984 
                 0.293 
                 0.999 
               
               
                 103 
                 rs11754264_C 
                 0.874 
                 0.984 
                 0.293 
                 0.999 
               
               
                 104 
                 rs72498353_T 
                 0.874 
                 1 
                 0.296 
                 1 
               
               
                 105 
                 rs150671547_A 
                 0.873 
                 1 
                 0.295 
                 1 
               
               
                 106 
                 rs538730912_A 
                 0.873 
                 0.992 
                 0.294 
                 0.999 
               
               
                 107 
                 rs7772638_G 
                 0.873 
                 1 
                 0.295 
                 1 
               
               
                 108 
                 rs35114469_T 
                 0.872 
                 1 
                 0.293 
                 1 
               
               
                 109 
                 rs140923546_A 
                 0.872 
                 1 
                 0.293 
                 1 
               
               
                 110 
                 rs114304833_C 
                 0.872 
                 1 
                 0.293 
                 1 
               
               
                 111 
                 rs115106715_T 
                 0.872 
                 1 
                 0.293 
                 1 
               
               
                 112 
                 rs115521177_A 
                 0.872 
                 1 
                 0.293 
                 1 
               
               
                 113 
                 rs34354617_C 
                 0.871 
                 1 
                 0.292 
                 1 
               
               
                 114 
                 rs35575266_C 
                 0.871 
                 1 
                 0.292 
                 1 
               
               
                 115 
                 rs114777139_A 
                 0.871 
                 1 
                 0.292 
                 1 
               
               
                 116 
                 rs72498352_C 
                 0.871 
                 1 
                 0.292 
                 1 
               
               
                 117 
                 rs12665310_C 
                 0.871 
                 1 
                 0.292 
                 1 
               
               
                 118 
                 rs376173738_GAT 
                 0.871 
                 0.992 
                 0.290 
                 0.999 
               
               
                 119 
                 rs12664958_C 
                 0.871 
                 1 
                 0.291 
                 1 
               
               
                 120 
                 rs74202021_A 
                 0.871 
                 1 
                 0.291 
                 1 
               
               
                 121 
                 rs11754005_T 
                 0.870 
                 1 
                 0.290 
                 1 
               
               
                 122 
                 rs17185650_A 
                 0.870 
                 1 
                 0.289 
                 1 
               
               
                 123 
                 rs17179270_G 
                 0.870 
                 1 
                 0.289 
                 1 
               
               
                 124 
                 rs12528253_A 
                 0.870 
                 0.984 
                 0.286 
                 0.999 
               
               
                 125 
                 rs78455625_A 
                 0.869 
                 1 
                 0.288 
                 1 
               
               
                 126 
                 rs78380318_A 
                 0.868 
                 1 
                 0.287 
                 1 
               
               
                 127 
                 rs114157794_G 
                 0.868 
                 1 
                 0.287 
                 1 
               
               
                 128 
                 rs116252145_C 
                 0.865 
                 0.984 
                 0.279 
                 0.999 
               
               
                 129 
                 rs78810446_G 
                 0.865 
                 0.952 
                 0.272 
                 0.997 
               
               
                 130 
                 rs12660668_G 
                 0.864 
                 1 
                 0.281 
                 1 
               
               
                 131 
                 rs116031481_C 
                 0.864 
                 1 
                 0.280 
                 1 
               
               
                 132 
                 rs116076476_A 
                 0.863 
                 0.992 
                 0.277 
                 0.999 
               
               
                 133 
                 rs74184772_G 
                 0.863 
                 0.976 
                 0.274 
                 0.998 
               
               
                 134 
                 rs115760798_T 
                 0.862 
                 1 
                 0.278 
                 1 
               
               
                 135 
                 rs199710390_C 
                 0.862 
                 0.976 
                 0.273 
                 0.998 
               
               
                 136 
                 rs72495985_G 
                 0.862 
                 1 
                 0.278 
                 1 
               
               
                 137 
                 rs74223603_T 
                 0.862 
                 1 
                 0.278 
                 1 
               
               
                 138 
                 rs12662520_T 
                 0.862 
                 1 
                 0.278 
                 1 
               
               
                 139 
                 rs72495986_T 
                 0.862 
                 1 
                 0.278 
                 1 
               
               
                 140 
                 rs147496146_T 
                 0.862 
                 1 
                 0.278 
                 1 
               
               
                 141 
                 rs139102237_T 
                 0.862 
                 1 
                 0.278 
                 1 
               
               
                 142 
                 rs6921957_C 
                 0.862 
                 1 
                 0.278 
                 1 
               
               
                 143 
                 rs6927115_C 
                 0.862 
                 1 
                 0.278 
                 1 
               
               
                 144 
                 rs117143236_C 
                 0.862 
                 1 
                 0.278 
                 1 
               
               
                 145 
                 rs115731392_A 
                 0.862 
                 1 
                 0.278 
                 1 
               
               
                 146 
                 rs77849405_A 
                 0.862 
                 1 
                 0.278 
                 1 
               
               
                 147 
                 rs150655579_A 
                 0.862 
                 1 
                 0.278 
                 1 
               
               
                 148 
                 rs151034657_G 
                 0.862 
                 1 
                 0.278 
                 1 
               
               
                 149 
                 rs72498350_C 
                 0.862 
                 0.992 
                 0.276 
                 0.999 
               
               
                 150 
                 rs3901687_T 
                 0.862 
                 1 
                 0.277 
                 1 
               
               
                 151 
                 rs1962778_T 
                 0.862 
                 1 
                 0.277 
                 1 
               
               
                 152 
                 rs11758670_C 
                 0.862 
                 1 
                 0.277 
                 1 
               
               
                 153 
                 rs35541854_T 
                 0.862 
                 1 
                 0.277 
                 1 
               
               
                 154 
                 rs74187129_G 
                 0.862 
                 1 
                 0.277 
                 1 
               
               
                 155 
                 rs75525135_G 
                 0.862 
                 1 
                 0.277 
                 1 
               
               
                 156 
                 rs74590183_G 
                 0.862 
                 1 
                 0.277 
                 1 
               
               
                 157 
                 rs546947741_C 
                 0.862 
                 1 
                 0.277 
                 1 
               
               
                 158 
                 rs34146016_C 
                 0.862 
                 1 
                 0.277 
                 1 
               
               
                 159 
                 rs6922132_C 
                 0.861 
                 1 
                 0.276 
                 1 
               
               
                 160 
                 rs72498347_T 
                 0.861 
                 1 
                 0.276 
                 1 
               
               
                 161 
                 rs147394713_A 
                 0.858 
                 1 
                 0.272 
                 1 
               
               
                 162 
                 rs28397212_A 
                 0.857 
                 1 
                 0.271 
                 1 
               
               
                 163 
                 rs1611593_A 
                 0.851 
                 1 
                 0.268 
                 1 
               
               
                 164 
                 rs115367733_T 
                 0.857 
                 1 
                 0.270 
                 1 
               
               
                 165 
                 rs72492286_A 
                 0.856 
                 1 
                 0.269 
                 1 
               
               
                 166 
                 rs74206461_T 
                 0.856 
                 1 
                 0.269 
                 1 
               
               
                 167 
                 rs17185791_C 
                 0.855 
                 1 
                 0.268 
                 1 
               
               
                 168 
                 rs72492285_T 
                 0.855 
                 1 
                 0.268 
                 1 
               
               
                 169 
                 rs28678129_A 
                 0.855 
                 1 
                 0.268 
                 1 
               
               
                 170 
                 rs72492288_C 
                 0.855 
                 1 
                 0.268 
                 1 
               
               
                 171 
                 rs149028986_G 
                 0.855 
                 1 
                 0.268 
                 1 
               
               
                 172 
                 rs139978410_T 
                 0.855 
                 1 
                 0.268 
                 1 
               
               
                 173 
                 rs28533123_G 
                 0.854 
                 1 
                 0.267 
                 1 
               
               
                 174 
                 rs116123788_C 
                 0.854 
                 1 
                 0.266 
                 1 
               
               
                 175 
                 rs150513929_C 
                 0.853 
                 1 
                 0.265 
                 1 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Polymorphic markers in LD with HLA-B*15:02. PPV and 
               
               
                 NPV refer to positive and negative predictive values, 
               
               
                 respectively. In some cases, markers 1-6 of table 
               
               
                 2 provide a panel of markers for HLA-B*15:02. 
               
            
           
           
               
               
               
               
               
               
            
               
                 Marker 
                 SNP 
                 spec 
                 sens 
                 ppv 
                 npv 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 1 
                 rs144012689_A 
                 0.999 
                 1 
                 0.977 
                 1 
               
               
                 2 
                 rs151107659_A 
                 0.999 
                 1 
                 0.977 
                 1 
               
               
                 3 
                 rs188729361_A 
                 0.999 
                 0.988 
                 0.977 
                 0.999 
               
               
                 4 
                 rs181377228_A 
                 0.999 
                 0.988 
                 0.977 
                 0.999 
               
               
                 5 
                 rs190938408_C 
                 0.994 
                 1 
                 0.862 
                 1 
               
               
                 6 
                 rs138238859_C 
                 0.993 
                 0.988 
                 0.852 
                 0.999 
               
               
                 7 
                 rs371096447_C 
                 0.998 
                 0.943 
                 0.965 
                 0.997 
               
               
                 8 
                 rs140855588_G 
                 0.998 
                 0.954 
                 0.965 
                 0.998 
               
               
                 9 
                 rs185615899_G 
                 0.998 
                 0.954 
                 0.965 
                 0.998 
               
               
                 10 
                 rs186302377_A 
                 0.998 
                 0.954 
                 0.965 
                 0.998 
               
               
                 11 
                 rs190335533_A 
                 0.998 
                 0.909 
                 0.952 
                 0.996 
               
               
                 12 
                 rs149481627_A 
                 0.998 
                 0.909 
                 0.952 
                 0.996 
               
               
                 13 
                 rs191392216_G 
                 0.998 
                 0.943 
                 0.954 
                 0.997 
               
               
                 14 
                 rs183151869_G 
                 0.997 
                 0.954 
                 0.943 
                 0.998 
               
               
                 15 
                 rs112214065_A 
                 0.997 
                 0.954 
                 0.943 
                 0.998 
               
               
                 16 
                 rs185092079_T 
                 0.997 
                 0.943 
                 0.932 
                 0.997 
               
               
                 17 
                 rs572250590_TA 
                 0.997 
                 0.943 
                 0.922 
                 0.997 
               
               
                 18 
                 rs149203328_T 
                 0.996 
                 0.954 
                 0.903 
                 0.998 
               
               
                 19 
                 rs143114181_G 
                 0.996 
                 0.943 
                 0.902 
                 0.997 
               
               
                 20 
                 rs191184615_C 
                 0.996 
                 0.886 
                 0.896 
                 0.995 
               
               
                 21 
                 rs191579971_G 
                 0.996 
                 0.886 
                 0.896 
                 0.995 
               
               
                 22 
                 rs148931659_G 
                 0.996 
                 0.886 
                 0.896 
                 0.995 
               
               
                 23 
                 rs189418663_T 
                 0.995 
                 0.897 
                 0.868 
                 0.996 
               
               
                 24 
                 rs146122378_A 
                 0.995 
                 0.897 
                 0.868 
                 0.996 
               
               
                 25 
                 rs140202631_A 
                 0.995 
                 0.897 
                 0.868 
                 0.996 
               
               
                 26 
                 rs192693532_A 
                 0.995 
                 0.897 
                 0.868 
                 0.996 
               
               
                 27 
                 rs193043557_C 
                 0.995 
                 0.897 
                 0.868 
                 0.996 
               
               
                 28 
                 rs185642961_T 
                 0.993 
                 0.909 
                 0.842 
                 0.996 
               
               
                 29 
                 rs150361898_T 
                 0.993 
                 0.988 
                 0.844 
                 0.999 
               
               
                 30 
                 rs184043553_C 
                 0.990 
                 0.954 
                 0.785 
                 0.998 
               
               
                 31 
                 rs189011516_C 
                 0.990 
                 0.954 
                 0.785 
                 0.998 
               
               
                 32 
                 rs149084446_A 
                 0.990 
                 0.954 
                 0.785 
                 0.998 
               
               
                 33 
                 rs143205755_G 
                 0.990 
                 0.954 
                 0.785 
                 0.998 
               
               
                 34 
                 rs186137290_A 
                 0.990 
                 0.954 
                 0.785 
                 0.998 
               
               
                 35 
                 rs144528645_A 
                 0.990 
                 0.954 
                 0.785 
                 0.998 
               
               
                 36 
                 rs149186815_A 
                 0.990 
                 0.943 
                 0.783 
                 0.997 
               
               
                 37 
                 rs377473202_A 
                 0.990 
                 0.954 
                 0.785 
                 0.998 
               
               
                 38 
                 rs185803278_T 
                 0.990 
                 0.954 
                 0.785 
                 0.998 
               
               
                 39 
                 rs188083561_C 
                 0.990 
                 0.943 
                 0.783 
                 0.997 
               
               
                 40 
                 rs563052401_T 
                 0.990 
                 0.931 
                 0.780 
                 0.997 
               
               
                 41 
                 rs183111482_A 
                 0.990 
                 0.954 
                 0.777 
                 0.998 
               
               
                 42 
                 rs146215260_G 
                 0.990 
                 0.954 
                 0.777 
                 0.998 
               
               
                 43 
                 rs181964803_G 
                 0.990 
                 0.954 
                 0.777 
                 0.998 
               
               
                 44 
                 rs373371958_T 
                 0.990 
                 0.977 
                 0.781 
                 0.999 
               
               
                 45 
                 rs139479797_A 
                 0.989 
                 1 
                 0.771 
                 1 
               
               
                 46 
                 rs148144626_G 
                 0.987 
                 1 
                 0.739 
                 1 
               
               
                 47 
                 rs183454889_A 
                 0.987 
                 1 
                 0.739 
                 1 
               
               
                 48 
                 rs117246140_A 
                 0.986 
                 1 
                 0.727 
                 1 
               
               
                 49 
                 rs139655885_A 
                 0.985 
                 0.988 
                 0.719 
                 0.999 
               
               
                 50 
                 rs574446645_T 
                 0.985 
                 0.965 
                 0.708 
                 0.998 
               
               
                 51 
                 rs188898809_A 
                 0.985 
                 0.988 
                 0.713 
                 0.999 
               
               
                 52 
                 rs146671208_C 
                 0.985 
                 0.977 
                 0.710 
                 0.999 
               
               
                 53 
                 rs147099772_A 
                 0.982 
                 0.988 
                 0.674 
                 0.999 
               
               
                 54 
                 rs141102944_C 
                 0.982 
                 0.988 
                 0.674 
                 0.999 
               
               
                 55 
                 rs535710313_C 
                 0.982 
                 0.977 
                 0.671 
                 0.999 
               
               
                 56 
                 rs368752130_T 
                 0.981 
                 0.954 
                 0.656 
                 0.998 
               
               
                 57 
                 rs141884536_A 
                 0.980 
                 1 
                 0.656 
                 1 
               
               
                 58 
                 rs150140732_C 
                 0.980 
                 0.977 
                 0.641 
                 0.999 
               
               
                 59 
                 rs183506958_A 
                 0.980 
                 0.977 
                 0.641 
                 0.999 
               
               
                 60 
                 rs188043002_C 
                 0.980 
                 0.977 
                 0.641 
                 0.999 
               
               
                 61 
                 rs138563211_T 
                 0.979 
                 0.988 
                 0.639 
                 0.999 
               
               
                 62 
                 rs142858529_G 
                 0.975 
                 0.897 
                 0.576 
                 0.996 
               
               
                 63 
                 rs117406933_A 
                 0.970 
                 0.920 
                 0.529 
                 0.997 
               
               
                 64 
                 rs200098765_CT 
                 0.970 
                 0.954 
                 0.538 
                 0.998 
               
               
                 65 
                 rs111959410_A 
                 0.970 
                 0.954 
                 0.538 
                 0.998 
               
               
                 66 
                 rs117941869_A 
                 0.969 
                 0.920 
                 0.525 
                 0.997 
               
               
                 67 
                 rs146482738_C 
                 0.969 
                 0.920 
                 0.525 
                 0.997 
               
               
                 68 
                 rs117321340_C 
                 0.969 
                 0.920 
                 0.525 
                 0.997 
               
               
                 69 
                 rs117322540_A 
                 0.969 
                 0.920 
                 0.525 
                 0.997 
               
               
                 70 
                 rs117618911_G 
                 0.969 
                 0.920 
                 0.525 
                 0.997 
               
               
                 71 
                 rs185998437_T 
                 0.969 
                 0.920 
                 0.525 
                 0.997 
               
               
                 72 
                 rs182965382_T 
                 0.969 
                 0.920 
                 0.525 
                 0.997 
               
               
                 73 
                 rs73396821_T 
                 0.969 
                 0.954 
                 0.535 
                 0.998 
               
               
                 74 
                 rs10484555_C 
                 0.969 
                 0.954 
                 0.535 
                 0.998 
               
               
                 75 
                 rs112489947_A 
                 0.969 
                 0.954 
                 0.535 
                 0.998 
               
               
                 76 
                 rs113085541_G 
                 0.969 
                 0.954 
                 0.535 
                 0.998 
               
               
                 77 
                 rs112351161_C 
                 0.969 
                 0.954 
                 0.535 
                 0.998 
               
               
                 78 
                 rs111300804_C 
                 0.969 
                 0.954 
                 0.535 
                 0.998 
               
               
                 79 
                 rs113856689_G 
                 0.969 
                 0.954 
                 0.535 
                 0.998 
               
               
                 80 
                 rs111990896_C 
                 0.969 
                 0.954 
                 0.535 
                 0.998 
               
               
                 81 
                 rs113036952_A 
                 0.969 
                 0.943 
                 0.532 
                 0.997 
               
               
                 82 
                 rs73400622_T 
                 0.969 
                 0.943 
                 0.532 
                 0.997 
               
               
                 83 
                 rs112254995_G 
                 0.969 
                 0.954 
                 0.535 
                 0.998 
               
               
                 84 
                 rs117733669_A 
                 0.969 
                 0.954 
                 0.535 
                 0.998 
               
               
                 85 
                 rs142470226_C 
                 0.969 
                 0.909 
                 0.519 
                 0.996 
               
               
                 86 
                 rs139287227_C 
                 0.969 
                 0.954 
                 0.531 
                 0.998 
               
               
                 87 
                 rs530539237_A 
                 0.969 
                 0.954 
                 0.531 
                 0.998 
               
               
                 88 
                 rs142340836_C 
                 0.968 
                 0.909 
                 0.516 
                 0.996 
               
               
                 89 
                 rs145372685_T 
                 0.968 
                 0.909 
                 0.516 
                 0.996 
               
               
                 90 
                 rs3893132_A 
                 0.968 
                 0.943 
                 0.525 
                 0.997 
               
               
                 91 
                 rs185207145_T 
                 0.968 
                 0.931 
                 0.522 
                 0.997 
               
               
                 92 
                 rs139021429_C 
                 0.968 
                 0.943 
                 0.525 
                 0.997 
               
               
                 93 
                 rs41552817_T 
                 0.968 
                 0.943 
                 0.525 
                 0.997 
               
               
                 94 
                 rs11547346_G 
                 0.968 
                 0.943 
                 0.525 
                 0.997 
               
               
                 95 
                 rs111715297_C 
                 0.968 
                 0.954 
                 0.528 
                 0.998 
               
               
                 96 
                 rs116646009_A 
                 0.968 
                 0.954 
                 0.528 
                 0.998 
               
               
                 97 
                 rs113424831_A 
                 0.968 
                 0.954 
                 0.525 
                 0.998 
               
               
                 98 
                 rs182442744_T 
                 0.966 
                 0.931 
                 0.506 
                 0.997 
               
               
                 99 
                 rs147853218_A 
                 0.966 
                 0.954 
                 0.512 
                 0.998 
               
               
                 100 
                 rs112392510_T 
                 0.966 
                 0.954 
                 0.512 
                 0.998 
               
               
                 101 
                 rs138594816_A 
                 0.966 
                 0.943 
                 0.506 
                 0.997 
               
               
                 102 
                 rs118067913_A 
                 0.966 
                 0.943 
                 0.503 
                 0.997 
               
               
                 103 
                 rs117345749_G 
                 0.966 
                 0.931 
                 0.5 
                 0.997 
               
               
                 104 
                 rs190925576_A 
                 0.966 
                 0.943 
                 0.503 
                 0.997 
               
               
                 105 
                 rs150400725_T 
                 0.966 
                 0.943 
                 0.503 
                 0.997 
               
               
                 106 
                 rs138932482_T 
                 0.966 
                 0.943 
                 0.503 
                 0.997 
               
               
                 107 
                 rs117573397_A 
                 0.966 
                 0.943 
                 0.503 
                 0.997 
               
               
                 108 
                 rs182159831_T 
                 0.965 
                 0.943 
                 0.5 
                 0.997 
               
               
                 109 
                 rs180756175_C 
                 0.965 
                 0.943 
                 0.5 
                 0.997 
               
               
                 110 
                 rs143350908_T 
                 0.965 
                 0.943 
                 0.5 
                 0.997 
               
               
                 111 
                 rs117761656_T 
                 0.965 
                 0.954 
                 0.5 
                 0.998 
               
               
                 112 
                 rs117508387_G 
                 0.965 
                 0.954 
                 0.5 
                 0.998 
               
               
                 113 
                 rs117514434_C 
                 0.965 
                 0.954 
                 0.5 
                 0.998 
               
               
                 114 
                 rs116931476_A 
                 0.964 
                 0.931 
                 0.491 
                 0.997 
               
               
                 115 
                 rs117927250_T 
                 0.964 
                 0.931 
                 0.491 
                 0.997 
               
               
                 116 
                 rs146502008_A 
                 0.964 
                 0.931 
                 0.491 
                 0.997 
               
               
                 117 
                 rs138351562_A 
                 0.964 
                 0.931 
                 0.491 
                 0.997 
               
               
                 118 
                 rs117277006_G 
                 0.964 
                 0.931 
                 0.491 
                 0.997 
               
               
                 119 
                 rs118004259_A 
                 0.964 
                 0.931 
                 0.491 
                 0.997 
               
               
                 120 
                 rs149945194_A 
                 0.964 
                 0.931 
                 0.491 
                 0.997 
               
               
                 121 
                 rs117104932_T 
                 0.964 
                 0.931 
                 0.491 
                 0.997 
               
               
                 122 
                 rs117952735_T 
                 0.964 
                 0.931 
                 0.491 
                 0.997 
               
               
                 123 
                 rs146651644_A 
                 0.964 
                 0.931 
                 0.491 
                 0.997 
               
               
                 124 
                 rs137976064_A 
                 0.964 
                 0.931 
                 0.491 
                 0.997 
               
               
                 125 
                 rs147827468_G 
                 0.964 
                 0.943 
                 0.494 
                 0.997 
               
               
                 126 
                 rs117105459_G 
                 0.964 
                 0.943 
                 0.494 
                 0.997 
               
               
                 127 
                 rs141225527_A 
                 0.964 
                 0.943 
                 0.494 
                 0.997 
               
               
                 128 
                 rs117304527_T 
                 0.964 
                 0.943 
                 0.494 
                 0.997 
               
               
                 129 
                 rs117138694_C 
                 0.964 
                 0.943 
                 0.494 
                 0.997 
               
               
                 130 
                 rs116967475_C 
                 0.964 
                 0.943 
                 0.494 
                 0.997 
               
               
                 131 
                 rs117876434_T 
                 0.964 
                 0.943 
                 0.494 
                 0.997 
               
               
                 132 
                 rs116849356_C 
                 0.964 
                 0.943 
                 0.494 
                 0.997 
               
               
                 133 
                 rs188050700_G 
                 0.964 
                 0.943 
                 0.494 
                 0.997 
               
               
                 134 
                 rs117311356_A 
                 0.964 
                 0.943 
                 0.494 
                 0.997 
               
               
                 135 
                 rs117646937_G 
                 0.964 
                 0.943 
                 0.494 
                 0.997 
               
               
                 136 
                 rs116977957_C 
                 0.964 
                 0.943 
                 0.494 
                 0.997 
               
               
                 137 
                 rs117062631_T 
                 0.964 
                 0.943 
                 0.494 
                 0.997 
               
               
                 138 
                 rs118182436_G 
                 0.964 
                 0.943 
                 0.494 
                 0.997 
               
               
                 139 
                 rs116974494_C 
                 0.964 
                 0.943 
                 0.494 
                 0.997 
               
               
                 140 
                 rs117131177_C 
                 0.964 
                 0.943 
                 0.494 
                 0.997 
               
               
                 141 
                 rs376322896_CT 
                 0.964 
                 0.931 
                 0.488 
                 0.997 
               
               
                 142 
                 rs117563601_T 
                 0.964 
                 0.931 
                 0.488 
                 0.997 
               
               
                 143 
                 rs117943000_G 
                 0.964 
                 0.943 
                 0.491 
                 0.997 
               
               
                 144 
                 rs17192218_T 
                 0.964 
                 0.943 
                 0.503 
                 0.997 
               
               
                 145 
                 rs117308456_A 
                 0.963 
                 0.943 
                 0.488 
                 0.997 
               
               
                 146 
                 rs73394901_A 
                 0.961 
                 0.954 
                 0.474 
                 0.998 
               
               
                 147 
                 rs116969494_A 
                 0.961 
                 0.909 
                 0.459 
                 0.996 
               
               
                 148 
                 rs117552809_T 
                 0.961 
                 0.909 
                 0.459 
                 0.996 
               
               
                 149 
                 rs3757349_G 
                 0.961 
                 0.909 
                 0.459 
                 0.996 
               
               
                 150 
                 rs117585298_T 
                 0.961 
                 0.909 
                 0.459 
                 0.996 
               
               
                 151 
                 rs117932423_C 
                 0.960 
                 0.909 
                 0.457 
                 0.996 
               
               
                 152 
                 rs73396806_C 
                 0.959 
                 0.954 
                 0.464 
                 0.998 
               
               
                 153 
                 rs144724632_G 
                 0.959 
                 0.954 
                 0.461 
                 0.998 
               
               
                 154 
                 rs16899202_C 
                 0.959 
                 0.954 
                 0.459 
                 0.998 
               
               
                 155 
                 rs75881311_A 
                 0.955 
                 0.909 
                 0.430 
                 0.996 
               
               
                 156 
                 rs111343098_G 
                 0.948 
                 0.954 
                 0.403 
                 0.998 
               
               
                 157 
                 rs112587708_T 
                 0.948 
                 0.954 
                 0.401 
                 0.998 
               
               
                 158 
                 rs111892155_T 
                 0.948 
                 0.954 
                 0.401 
                 0.998 
               
               
                 159 
                 rs113727715_T 
                 0.948 
                 0.954 
                 0.401 
                 0.998 
               
               
                 160 
                 rs112999185_A 
                 0.948 
                 0.954 
                 0.401 
                 0.998 
               
               
                 161 
                 rs113679636_A 
                 0.948 
                 0.954 
                 0.401 
                 0.998 
               
               
                 162 
                 rs111603143_A 
                 0.948 
                 0.954 
                 0.401 
                 0.998 
               
               
                 163 
                 rs113109076_T 
                 0.948 
                 0.954 
                 0.401 
                 0.998 
               
               
                 164 
                 rs111789237_A 
                 0.948 
                 0.954 
                 0.401 
                 0.998 
               
               
                 165 
                 rs112491786_G 
                 0.948 
                 0.954 
                 0.401 
                 0.998 
               
               
                 166 
                 rs114516477_G 
                 0.947 
                 0.954 
                 0.4 
                 0.998 
               
               
                 167 
                 rs112906071_G 
                 0.947 
                 0.954 
                 0.4 
                 0.998 
               
               
                 168 
                 rs114617616_G 
                 0.947 
                 0.954 
                 0.4 
                 0.998 
               
               
                 169 
                 rs80209589_A 
                 0.947 
                 0.954 
                 0.4 
                 0.998 
               
               
                 170 
                 rs58432298_C 
                 0.947 
                 0.954 
                 0.4 
                 0.998 
               
               
                 171 
                 rs59994501_G 
                 0.947 
                 0.954 
                 0.4 
                 0.998 
               
               
                 172 
                 rs116541664_T 
                 0.947 
                 0.954 
                 0.4 
                 0.998 
               
               
                 173 
                 rs59636752_A 
                 0.947 
                 0.954 
                 0.4 
                 0.998 
               
               
                 174 
                 rs112544348_G 
                 0.947 
                 0.954 
                 0.4 
                 0.998 
               
               
                 175 
                 rs112401274_A 
                 0.947 
                 0.954 
                 0.4 
                 0.998 
               
               
                 176 
                 rs113021938_G 
                 0.947 
                 0.954 
                 0.4 
                 0.998 
               
               
                 177 
                 rs191524270_C 
                 0.947 
                 0.954 
                 0.4 
                 0.998 
               
               
                 178 
                 rs181158919_G 
                 0.947 
                 0.954 
                 0.4 
                 0.998 
               
               
                 179 
                 rs143579819_T 
                 0.947 
                 0.954 
                 0.4 
                 0.998 
               
               
                 180 
                 rs113370283_A 
                 0.947 
                 0.954 
                 0.4 
                 0.998 
               
               
                 181 
                 rs113367014_A 
                 0.947 
                 0.954 
                 0.4 
                 0.998 
               
               
                 182 
                 rs527948201_T 
                 0.947 
                 0.954 
                 0.4 
                 0.998 
               
               
                 183 
                 rs114199487_A 
                 0.947 
                 0.954 
                 0.4 
                 0.998 
               
               
                 184 
                 rs115607159_G 
                 0.947 
                 0.954 
                 0.398 
                 0.998 
               
               
                 185 
                 rs112560101_T 
                 0.947 
                 0.954 
                 0.398 
                 0.998 
               
               
                 186 
                 rs58792975_A 
                 0.947 
                 0.954 
                 0.398 
                 0.998 
               
               
                 187 
                 rs2854021_A 
                 0.947 
                 0.954 
                 0.396 
                 0.998 
               
               
                 188 
                 rs60004964_C 
                 0.942 
                 0.909 
                 0.366 
                 0.996 
               
               
                 189 
                 rs73397100_A 
                 0.942 
                 0.909 
                 0.365 
                 0.996 
               
               
                 190 
                 rs112971796_C 
                 0.942 
                 0.909 
                 0.365 
                 0.996 
               
               
                 191 
                 rs57243444_T 
                 0.942 
                 0.909 
                 0.365 
                 0.996 
               
               
                 192 
                 rs17200670_T 
                 0.940 
                 0.909 
                 0.358 
                 0.996 
               
               
                 193 
                 rs151064822_T 
                 0.940 
                 0.909 
                 0.357 
                 0.996 
               
               
                 194 
                 rs149637252_A 
                 0.923 
                 0.909 
                 0.301 
                 0.996 
               
               
                 195 
                 rs17198238_G 
                 0.917 
                 0.931 
                 0.290 
                 0.997 
               
               
                 196 
                 rs28507710_C 
                 0.916 
                 0.931 
                 0.289 
                 0.997 
               
               
                 197 
                 rs60056504_C 
                 0.915 
                 0.988 
                 0.297 
                 0.999 
               
               
                 198 
                 rs377634126_G 
                 0.911 
                 0.977 
                 0.286 
                 0.999 
               
               
                 199 
                 rs74290509_A 
                 0.911 
                 0.977 
                 0.286 
                 0.999 
               
               
                 200 
                 rs146848089_G 
                 0.911 
                 0.977 
                 0.285 
                 0.999 
               
               
                 201 
                 rs79022003_C 
                 0.909 
                 0.977 
                 0.282 
                 0.999 
               
               
                 202 
                 rs569068189_A 
                 0.908 
                 0.965 
                 0.278 
                 0.998 
               
               
                 203 
                 rs371740078_CA 
                 0.907 
                 0.943 
                 0.270 
                 0.997 
               
               
                 204 
                 rs183893204_A 
                 0.898 
                 0.863 
                 0.236 
                 0.994 
               
               
                 205 
                 rs200226984_C 
                 0.898 
                 0.863 
                 0.236 
                 0.994 
               
               
                 206 
                 rs140835803_C 
                 0.892 
                 0.943 
                 0.242 
                 0.997 
               
               
                 207 
                 rs28380929_T 
                 0.872 
                 0.943 
                 0.212 
                 0.997 
               
               
                 208 
                 rs141986043_GAAA 
                 0.869 
                 0.938 
                 0.212 
                 0.997 
               
               
                 209 
                 rs140558131_T 
                 0.867 
                 0.965 
                 0.209 
                 0.998 
               
               
                 210 
                 rs184149624_G 
                 0.866 
                 0.965 
                 0.208 
                 0.998 
               
               
                 211 
                 rs541741946_T 
                 0.865 
                 0.954 
                 0.205 
                 0.998 
               
               
                 212 
                 rs568023593_G 
                 0.865 
                 0.954 
                 0.205 
                 0.998 
               
               
                 213 
                 rs3130691_T 
                 0.865 
                 0.954 
                 0.205 
                 0.998 
               
               
                 214 
                 rs3130690_T 
                 0.865 
                 0.954 
                 0.205 
                 0.998 
               
               
                 215 
                 rs9265141_C 
                 0.865 
                 0.954 
                 0.205 
                 0.998 
               
               
                 216 
                 rs545227273_TTG 
                 0.865 
                 0.954 
                 0.205 
                 0.998 
               
               
                 217 
                 rs9265147_A 
                 0.865 
                 0.954 
                 0.205 
                 0.998 
               
               
                 218 
                 rs2844591_C 
                 0.865 
                 0.954 
                 0.205 
                 0.998 
               
               
                 219 
                 rs3998364_T 
                 0.865 
                 0.954 
                 0.205 
                 0.998 
               
               
                 220 
                 rs9265190_T 
                 0.865 
                 0.954 
                 0.205 
                 0.998 
               
               
                 221 
                 rs9265257_C 
                 0.865 
                 0.954 
                 0.205 
                 0.998 
               
               
                 222 
                 rs3094683_G 
                 0.865 
                 0.954 
                 0.205 
                 0.998 
               
               
                 223 
                 rs3130704_A 
                 0.865 
                 0.954 
                 0.205 
                 0.998 
               
               
                 224 
                 rs9265515_C 
                 0.865 
                 0.954 
                 0.205 
                 0.998 
               
               
                 225 
                 rs9265584_C 
                 0.865 
                 0.954 
                 0.205 
                 0.998 
               
               
                 226 
                 rs2079174_G 
                 0.865 
                 0.954 
                 0.205 
                 0.998 
               
               
                 227 
                 rs2079173_C 
                 0.865 
                 0.954 
                 0.205 
                 0.998 
               
               
                 228 
                 rs9265144_C 
                 0.865 
                 0.954 
                 0.205 
                 0.998 
               
               
                 229 
                 rs9265348_A 
                 0.865 
                 0.954 
                 0.205 
                 0.998 
               
               
                 230 
                 rs9265416_C 
                 0.865 
                 0.954 
                 0.205 
                 0.998 
               
               
                 231 
                 rs561443073_T 
                 0.865 
                 0.954 
                 0.205 
                 0.998 
               
               
                 232 
                 rs532088383_G 
                 0.865 
                 0.954 
                 0.205 
                 0.998 
               
               
                 233 
                 rs9265589_A 
                 0.864 
                 0.954 
                 0.204 
                 0.998 
               
               
                 234 
                 rs72847209_C 
                 0.864 
                 0.897 
                 0.194 
                 0.995 
               
               
                 235 
                 rs77192564_T 
                 0.864 
                 0.897 
                 0.194 
                 0.995 
               
               
                 236 
                 rs9264793_A 
                 0.860 
                 0.897 
                 0.189 
                 0.995 
               
               
                 237 
                 rs9264792_A 
                 0.858 
                 0.897 
                 0.188 
                 0.995 
               
               
                 238 
                 rs9264871_A 
                 0.856 
                 0.920 
                 0.189 
                 0.996 
               
               
                 239 
                 rs9264872_T 
                 0.856 
                 0.920 
                 0.189 
                 0.996 
               
               
                 240 
                 rs548484308_T 
                 0.856 
                 0.920 
                 0.189 
                 0.996 
               
               
                 241 
                 rs551344396_GAA 
                 0.856 
                 0.943 
                 0.193 
                 0.997 
               
               
                 242 
                 rs2524050_C 
                 0.855 
                 0.954 
                 0.193 
                 0.998 
               
               
                 243 
                 rs2524043_G 
                 0.855 
                 0.954 
                 0.193 
                 0.998 
               
               
                 244 
                 rs1049853_A 
                 0.855 
                 0.943 
                 0.191 
                 0.997 
               
               
                 245 
                 rs9264621_C 
                 0.855 
                 0.943 
                 0.191 
                 0.997 
               
               
                 246 
                 rs9264639_T 
                 0.855 
                 0.943 
                 0.191 
                 0.997 
               
               
                 247 
                 rs1050428_T 
                 0.855 
                 0.943 
                 0.191 
                 0.997 
               
               
                 248 
                 rs2253842_A 
                 0.855 
                 0.954 
                 0.193 
                 0.998 
               
               
                 249 
                 rs2844602_T 
                 0.855 
                 0.954 
                 0.193 
                 0.998 
               
               
                 250 
                 rs2524056_C 
                 0.855 
                 0.954 
                 0.193 
                 0.998 
               
               
                 251 
                 rs2524055_C 
                 0.855 
                 0.954 
                 0.193 
                 0.998 
               
               
                 252 
                 rs534659501_C 
                 0.855 
                 0.954 
                 0.193 
                 0.998 
               
               
                 253 
                 rs2844600_T 
                 0.855 
                 0.954 
                 0.193 
                 0.998 
               
               
                 254 
                 rs2853934_T 
                 0.855 
                 0.954 
                 0.193 
                 0.998 
               
               
                 255 
                 rs2853932_A 
                 0.855 
                 0.954 
                 0.193 
                 0.998 
               
               
                 256 
                 rs146805812_C 
                 0.855 
                 0.954 
                 0.193 
                 0.998 
               
               
                 257 
                 rs2844599_C 
                 0.855 
                 0.954 
                 0.193 
                 0.998 
               
               
                 258 
                 rs2524048_C 
                 0.855 
                 0.954 
                 0.193 
                 0.998 
               
               
                 259 
                 rs2524047_G 
                 0.855 
                 0.954 
                 0.193 
                 0.998 
               
               
                 260 
                 rs2844597_T 
                 0.855 
                 0.954 
                 0.193 
                 0.998 
               
               
                 261 
                 rs2844596_A 
                 0.855 
                 0.954 
                 0.193 
                 0.998 
               
               
                 262 
                 rs2853927_T 
                 0.855 
                 0.954 
                 0.193 
                 0.998 
               
               
                 263 
                 rs137962016_C 
                 0.855 
                 0.954 
                 0.193 
                 0.998 
               
               
                 264 
                 rs369795453_CT 
                 0.855 
                 0.954 
                 0.193 
                 0.998 
               
               
                 265 
                 rs1819788_C 
                 0.855 
                 0.954 
                 0.193 
                 0.998 
               
               
                 266 
                 rs2524164_A 
                 0.855 
                 0.954 
                 0.193 
                 0.998 
               
               
                 267 
                 rs2524160_A 
                 0.855 
                 0.954 
                 0.193 
                 0.998 
               
               
                 268 
                 rs2524155_G 
                 0.855 
                 0.954 
                 0.193 
                 0.998 
               
               
                 269 
                 rs2524154_T 
                 0.855 
                 0.954 
                 0.193 
                 0.998 
               
               
                 270 
                 rs2524151_A 
                 0.855 
                 0.954 
                 0.193 
                 0.998 
               
               
                 271 
                 rs2524148_G 
                 0.855 
                 0.954 
                 0.193 
                 0.998 
               
               
                 272 
                 rs9264672_T 
                 0.854 
                 0.943 
                 0.191 
                 0.997 
               
               
                 273 
                 rs2853937_C 
                 0.854 
                 0.954 
                 0.193 
                 0.998 
               
               
                 274 
                 rs2853930_C 
                 0.854 
                 0.954 
                 0.193 
                 0.998 
               
               
                 275 
                 rs2853929_T 
                 0.854 
                 0.954 
                 0.193 
                 0.998 
               
               
                 276 
                 rs2524051_G 
                 0.854 
                 0.954 
                 0.193 
                 0.998 
               
               
                 277 
                 rs537625500_A 
                 0.854 
                 0.954 
                 0.193 
                 0.998 
               
               
                 278 
                 rs140598632_A 
                 0.854 
                 0.954 
                 0.192 
                 0.998 
               
               
                 279 
                 rs9264875_C 
                 0.853 
                 0.931 
                 0.188 
                 0.997 
               
               
                 280 
                 rs9264876_C 
                 0.853 
                 0.931 
                 0.188 
                 0.997 
               
               
                 281 
                 rs9264767_A 
                 0.852 
                 0.954 
                 0.190 
                 0.998 
               
               
                 282 
                 rs9264878_T 
                 0.852 
                 0.931 
                 0.186 
                 0.997 
               
               
                 283 
                 rs28361006_C 
                 0.851 
                 0.931 
                 0.186 
                 0.997 
               
               
                 284 
                 rs28361007_G 
                 0.851 
                 0.931 
                 0.186 
                 0.997 
               
               
                 285 
                 rs28361009_A 
                 0.851 
                 0.931 
                 0.186 
                 0.997 
               
               
                 286 
                 rs9264879_C 
                 0.851 
                 0.931 
                 0.186 
                 0.997 
               
               
                 287 
                 rs9264881_A 
                 0.851 
                 0.931 
                 0.185 
                 0.997 
               
               
                 288 
                 rs9264882_T 
                 0.851 
                 0.931 
                 0.185 
                 0.997 
               
               
                 289 
                 rs9264883_G 
                 0.851 
                 0.931 
                 0.185 
                 0.997 
               
               
                 290 
                 rs9279098_A 
                 0.850 
                 0.909 
                 0.181 
                 0.996 
               
               
                 291 
                 rs9264886_G 
                 0.850 
                 0.909 
                 0.181 
                 0.996 
               
               
                 292 
                 rs9264892_G 
                 0.850 
                 0.943 
                 0.187 
                 0.997 
               
               
                 293 
                 rs9264893_T 
                 0.850 
                 0.943 
                 0.187 
                 0.997 
               
               
                 294 
                 rs9264924_A 
                 0.850 
                 0.954 
                 0.189 
                 0.998 
               
               
                 295 
                 rs9264925_A 
                 0.850 
                 0.954 
                 0.189 
                 0.998 
               
               
                 296 
                 rs9264926_T 
                 0.850 
                 0.954 
                 0.189 
                 0.998 
               
               
                 297 
                 rs2508006_C 
                 0.850 
                 0.954 
                 0.189 
                 0.998 
               
               
                 298 
                 rs77530144_C 
                 0.850 
                 0.965 
                 0.191 
                 0.998 
               
               
                 299 
                 rs376020605_T 
                 0.850 
                 0.920 
                 0.183 
                 0.996 
               
               
                 300 
                 rs9264856_G 
                 0.850 
                 0.943 
                 0.186 
                 0.997 
               
               
                 301 
                 rs9264857_A 
                 0.850 
                 0.943 
                 0.186 
                 0.997 
               
               
                 302 
                 rs9264887_G 
                 0.850 
                 0.909 
                 0.181 
                 0.996 
               
               
                 303 
                 rs9264889_C 
                 0.850 
                 0.954 
                 0.188 
                 0.998 
               
               
                 304 
                 rs9264891_T 
                 0.850 
                 0.954 
                 0.188 
                 0.998 
               
               
                 305 
                 rs9264852_G 
                 0.850 
                 0.920 
                 0.182 
                 0.996 
               
               
                 306 
                 rs9264853_G 
                 0.850 
                 0.920 
                 0.182 
                 0.996 
               
               
                 307 
                 rs9264854_A 
                 0.850 
                 0.920 
                 0.182 
                 0.996 
               
               
                 308 
                 rs532186099_C 
                 0.850 
                 0.931 
                 0.184 
                 0.997 
               
               
                 309 
                 rs9264890_A 
                 0.850 
                 0.954 
                 0.188 
                 0.998 
               
               
                 310 
                 rs9264931_C 
                 0.850 
                 0.954 
                 0.188 
                 0.998 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 Polymorphic markers in LD with HLA-B*57:01. PPV and 
               
               
                 NPV refer to positive and negative predictive values, 
               
               
                 respectively. In some cases, markers 1-19 of table 
               
               
                 3 provide a panel of markers for HLA-B*57:01. 
               
            
           
           
               
               
               
               
               
               
            
               
                 Marker 
                 SNP 
                 specificity 
                 sensitivity 
                 ppv 
                 npv 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 1 
                 rs114170382_A 
                 0.997 
                 1 
                 0.967 
                 1 
               
               
                 2 
                 rs114607072_T 
                 0.997 
                 0.993 
                 0.967 
                 0.999 
               
               
                 3 
                 rs149663102_T 
                 0.997 
                 0.986 
                 0.961 
                 0.999 
               
               
                 4 
                 rs41558312_G 
                 0.997 
                 0.993 
                 0.961 
                 0.999 
               
               
                 5 
                 rs140810304_A 
                 0.997 
                 0.993 
                 0.961 
                 0.999 
               
               
                 6 
                 rs115841246_G 
                 0.997 
                 0.993 
                 0.961 
                 0.999 
               
               
                 7 
                 rs116081995_A 
                 0.997 
                 0.993 
                 0.961 
                 0.999 
               
               
                 8 
                 rs116339333_A 
                 0.997 
                 0.993 
                 0.961 
                 0.999 
               
               
                 9 
                 rs138130755_G 
                 0.997 
                 0.993 
                 0.961 
                 0.999 
               
               
                 10 
                 rs138117378_A 
                 0.997 
                 0.993 
                 0.961 
                 0.999 
               
               
                 11 
                 rs148792134_G 
                 0.997 
                 0.993 
                 0.961 
                 0.999 
               
               
                 12 
                 rs115986568_A 
                 0.997 
                 0.993 
                 0.955 
                 0.999 
               
               
                 13 
                 rs138099588_G 
                 0.997 
                 0.993 
                 0.955 
                 0.999 
               
               
                 14 
                 rs116419909_A 
                 0.997 
                 0.993 
                 0.955 
                 0.999 
               
               
                 15 
                 rs140991764_C 
                 0.997 
                 0.986 
                 0.955 
                 0.999 
               
               
                 16 
                 rs144027808_G 
                 0.996 
                 0.993 
                 0.949 
                 0.999 
               
               
                 17 
                 rs57989216_A 
                 0.985 
                 1 
                 0.816 
                 1 
               
               
                 18 
                 rs58102217_A 
                 0.985 
                 1 
                 0.816 
                 1 
               
               
                 19 
                 rs41543314_G 
                 0.985 
                 1 
                 0.811 
                 1 
               
               
                 20 
                 rs115846244_T 
                 0.994 
                 0.986 
                 0.914 
                 0.999 
               
               
                 21 
                 rs2395029_G 
                 0.993 
                 0.986 
                 0.908 
                 0.999 
               
               
                 22 
                 rs2905741_A 
                 0.992 
                 0.927 
                 0.891 
                 0.995 
               
               
                 23 
                 rs28732145_G 
                 0.991 
                 0.887 
                 0.875 
                 0.992 
               
               
                 24 
                 rs202036493_A 
                 0.990 
                 0.993 
                 0.872 
                 0.999 
               
               
                 25 
                 rs2923003_C 
                 0.990 
                 0.993 
                 0.867 
                 0.999 
               
               
                 26 
                 rs2516484_T 
                 0.989 
                 0.907 
                 0.845 
                 0.994 
               
               
                 27 
                 rs114118665_G 
                 0.986 
                 0.966 
                 0.824 
                 0.997 
               
               
                 28 
                 rs112168410_A 
                 0.985 
                 1 
                 0.816 
                 1 
               
               
                 29 
                 rs113223977_T 
                 0.985 
                 0.993 
                 0.815 
                 0.999 
               
               
                 30 
                 rs201415628_C 
                 0.985 
                 0.986 
                 0.814 
                 0.999 
               
               
                 31 
                 rs59440261_A 
                 0.983 
                 0.993 
                 0.789 
                 0.999 
               
               
                 32 
                 rs3021366_A 
                 0.980 
                 0.927 
                 0.752 
                 0.995 
               
               
                 33 
                 rs2905736_A 
                 0.980 
                 0.927 
                 0.752 
                 0.995 
               
               
                 34 
                 rs2905734_C 
                 0.980 
                 0.927 
                 0.752 
                 0.995 
               
               
                 35 
                 rs201725498_C 
                 0.980 
                 0.854 
                 0.737 
                 0.990 
               
               
                 36 
                 rs199923645_C 
                 0.980 
                 0.854 
                 0.737 
                 0.990 
               
               
                 37 
                 rs7757162_A 
                 0.980 
                 0.907 
                 0.748 
                 0.993 
               
               
                 38 
                 rs7757383_T 
                 0.980 
                 0.913 
                 0.75 
                 0.994 
               
               
                 39 
                 rs113688927_G 
                 0.979 
                 1 
                 0.758 
                 1 
               
               
                 40 
                 rs535476796. 
                 0.979 
                 1 
                 0.767 
                 1 
               
               
                   
                 rs535476796. 
               
               
                   
                 rs145010040_GTT 
               
               
                 41 
                 rs28732144_A 
                 0.978 
                 0.900 
                 0.727 
                 0.993 
               
               
                 42 
                 rs28895004_C 
                 0.977 
                 0.880 
                 0.718 
                 0.992 
               
               
                 43 
                 rs41293911_T 
                 0.977 
                 0.907 
                 0.724 
                 0.993 
               
               
                 44 
                 rs41293915_C 
                 0.977 
                 0.907 
                 0.724 
                 0.993 
               
               
                 45 
                 rs2516474_G 
                 0.977 
                 0.907 
                 0.724 
                 0.993 
               
               
                 46 
                 rs41293919_T 
                 0.977 
                 0.907 
                 0.724 
                 0.993 
               
               
                 47 
                 rs41293923_T 
                 0.977 
                 0.907 
                 0.724 
                 0.993 
               
               
                 48 
                 rs28732141_T 
                 0.977 
                 0.907 
                 0.724 
                 0.993 
               
               
                 49 
                 rs28732142_T 
                 0.977 
                 0.907 
                 0.724 
                 0.993 
               
               
                 50 
                 rs28732143_A 
                 0.977 
                 0.907 
                 0.724 
                 0.993 
               
               
                 51 
                 rs202125618_T 
                 0.977 
                 0.907 
                 0.724 
                 0.993 
               
               
                 52 
                 rs3093726_C 
                 0.977 
                 0.907 
                 0.724 
                 0.993 
               
               
                 53 
                 rs3093727_A 
                 0.977 
                 0.907 
                 0.724 
                 0.993 
               
               
                 54 
                 rs28895015_T 
                 0.977 
                 0.887 
                 0.720 
                 0.992 
               
               
                 55 
                 rs199682092_CATAT 
                 0.977 
                 0.887 
                 0.712 
                 0.992 
               
               
                 56 
                 rs17207190_A 
                 0.977 
                 0.887 
                 0.712 
                 0.992 
               
               
                 57 
                 rs13203101_A 
                 0.976 
                 0.913 
                 0.711 
                 0.994 
               
               
                 58 
                 rs28894981_T 
                 0.976 
                 0.933 
                 0.715 
                 0.995 
               
               
                 59 
                 rs28894982_T 
                 0.976 
                 0.933 
                 0.715 
                 0.995 
               
               
                 60 
                 rs141759545_A 
                 0.975 
                 0.920 
                 0.705 
                 0.994 
               
               
                 61 
                 rs13196399_G 
                 0.975 
                 0.920 
                 0.705 
                 0.994 
               
               
                 62 
                 rs28732096_A 
                 0.975 
                 0.920 
                 0.705 
                 0.994 
               
               
                 63 
                 rs28732101_T 
                 0.975 
                 0.900 
                 0.701 
                 0.993 
               
               
                 64 
                 rs28732081_A 
                 0.974 
                 0.907 
                 0.698 
                 0.993 
               
               
                 65 
                 rs28732099_A 
                 0.974 
                 0.920 
                 0.702 
                 0.994 
               
               
                 66 
                 rs537579418_T 
                 0.974 
                 0.913 
                 0.700 
                 0.994 
               
               
                 67 
                 rs28732100_T 
                 0.974 
                 0.913 
                 0.700 
                 0.994 
               
               
                 68 
                 rs531383859_T 
                 0.974 
                 0.913 
                 0.696 
                 0.994 
               
               
                 69 
                 rs112515516_G 
                 0.974 
                 1 
                 0.715 
                 1 
               
               
                 70 
                 rs563209172_G 
                 0.974 
                 1 
                 0.712 
                 1 
               
               
                 71 
                 rs1057151_C 
                 0.974 
                 1 
                 0.712 
                 1 
               
               
                 72 
                 rs111301312_G 
                 0.974 
                 1 
                 0.712 
                 1 
               
               
                 73 
                 rs151341415_G 
                 0.974 
                 1 
                 0.712 
                 1 
               
               
                 74 
                 rs41561016_T 
                 0.974 
                 1 
                 0.712 
                 1 
               
               
                 75 
                 rs1140487_T 
                 0.974 
                 1 
                 0.712 
                 1 
               
               
                 76 
                 rs41557415_G 
                 0.974 
                 1 
                 0.712 
                 1 
               
               
                 77 
                 rs41556417_C 
                 0.974 
                 0.980 
                 0.708 
                 0.998 
               
               
                 78 
                 rs147887806_T 
                 0.974 
                 0.986 
                 0.709 
                 0.999 
               
               
                 79 
                 rs28732097_G 
                 0.972 
                 0.920 
                 0.684 
                 0.994 
               
               
                 80 
                 rs111518019_A 
                 0.971 
                 1 
                 0.692 
                 1 
               
               
                 81 
                 rs28732093_T 
                 0.968 
                 0.920 
                 0.652 
                 0.994 
               
               
                 82 
                 rs144888775_A 
                 0.967 
                 0.993 
                 0.660 
                 0.999 
               
               
                 83 
                 rs199503730_T 
                 0.967 
                 0.993 
                 0.660 
                 0.999 
               
               
                 84 
                 rs113265260_TAC 
                 0.967 
                 0.874 
                 0.631 
                 0.991 
               
               
                 85 
                 rs112689184_A 
                 0.967 
                 0.993 
                 0.660 
                 0.999 
               
               
                 86 
                 rs79479695_T 
                 0.966 
                 0.993 
                 0.657 
                 0.999 
               
               
                 87 
                 rs75119533_A 
                 0.966 
                 0.993 
                 0.657 
                 0.999 
               
               
                 88 
                 rs79411911_T 
                 0.966 
                 0.986 
                 0.656 
                 0.999 
               
               
                 89 
                 rs201023435_C 
                 0.966 
                 0.993 
                 0.657 
                 0.999 
               
               
                 90 
                 rs74655380_G 
                 0.966 
                 0.993 
                 0.657 
                 0.999 
               
               
                 91 
                 rs77311173_T 
                 0.966 
                 0.993 
                 0.657 
                 0.999 
               
               
                 92 
                 rs13211972_A 
                 0.965 
                 0.874 
                 0.619 
                 0.991 
               
               
                 93 
                 rs13191258_T 
                 0.965 
                 0.867 
                 0.617 
                 0.991 
               
               
                 94 
                 rs28732088_A 
                 0.965 
                 0.913 
                 0.627 
                 0.994 
               
               
                 95 
                 rs17200095_G 
                 0.965 
                 0.993 
                 0.646 
                 0.999 
               
               
                 96 
                 rs13214865_T 
                 0.961 
                 0.907 
                 0.600 
                 0.993 
               
               
                 97 
                 rs73400361_G 
                 0.960 
                 0.993 
                 0.614 
                 0.999 
               
               
                 98 
                 rs41293856_T 
                 0.960 
                 0.913 
                 0.594 
                 0.994 
               
               
                 99 
                 rs13210132_G 
                 0.958 
                 0.907 
                 0.585 
                 0.993 
               
               
                 100 
                 rs28732080_C 
                 0.958 
                 0.907 
                 0.585 
                 0.993 
               
               
                 101 
                 rs577634159_C 
                 0.958 
                 0.913 
                 0.584 
                 0.994 
               
               
                 102 
                 rs41293899_T 
                 0.958 
                 0.913 
                 0.584 
                 0.994 
               
               
                 103 
                 rs41293883_T 
                 0.957 
                 0.913 
                 0.582 
                 0.994 
               
               
                 104 
                 rs41293887_A 
                 0.957 
                 0.913 
                 0.582 
                 0.994 
               
               
                 105 
                 rs41293895_C 
                 0.957 
                 0.913 
                 0.582 
                 0.994 
               
               
                 106 
                 rs41293860_A 
                 0.957 
                 0.913 
                 0.579 
                 0.994 
               
               
                 107 
                 rs3828917_T 
                 0.957 
                 0.913 
                 0.579 
                 0.994 
               
               
                 108 
                 rs41293879_A 
                 0.957 
                 0.913 
                 0.579 
                 0.994 
               
               
                 109 
                 rs4959077_A 
                 0.957 
                 0.913 
                 0.579 
                 0.994 
               
               
                 110 
                 rs41293891_A 
                 0.957 
                 0.913 
                 0.577 
                 0.994 
               
               
                 111 
                 rs4959078_A 
                 0.957 
                 0.913 
                 0.577 
                 0.994 
               
               
                 112 
                 rs41293907_T 
                 0.957 
                 0.913 
                 0.577 
                 0.994 
               
               
                 113 
                 rs111281598_C 
                 0.954 
                 0.993 
                 0.585 
                 0.999 
               
               
                 114 
                 rs3093668_C 
                 0.953 
                 0.907 
                 0.556 
                 0.993 
               
               
                 115 
                 rs3093661_A 
                 0.951 
                 0.907 
                 0.545 
                 0.993 
               
               
                 116 
                 rs12212594_C 
                 0.951 
                 0.913 
                 0.545 
                 0.994 
               
               
                 117 
                 rs2905725_T 
                 0.950 
                 0.927 
                 0.546 
                 0.995 
               
               
                 118 
                 rs146647111_AC 
                 0.949 
                 1 
                 0.557 
                 1 
               
               
                 119 
                 rs13210419_A 
                 0.947 
                 0.940 
                 0.533 
                 0.995 
               
               
                 120 
                 rs4947326_G 
                 0.935 
                 0.907 
                 0.475 
                 0.993 
               
               
                 121 
                 rs4947327_A 
                 0.935 
                 0.907 
                 0.475 
                 0.993 
               
               
                 122 
                 rs9267497_G 
                 0.935 
                 0.907 
                 0.475 
                 0.993 
               
               
                 123 
                 rs361525_A 
                 0.933 
                 0.907 
                 0.467 
                 0.993 
               
               
                 124 
                 rs112630608_C 
                 0.927 
                 0.993 
                 0.467 
                 0.999 
               
               
                 125 
                 rs112968142_G 
                 0.927 
                 0.993 
                 0.467 
                 0.999 
               
               
                 126 
                 rs9267454_T 
                 0.926 
                 0.907 
                 0.443 
                 0.993 
               
               
                 127 
                 rs9267466_T 
                 0.926 
                 0.907 
                 0.441 
                 0.993 
               
               
                 128 
                 rs2734576_C 
                 0.926 
                 0.907 
                 0.441 
                 0.993 
               
               
                 129 
                 rs9267492_T 
                 0.926 
                 0.907 
                 0.441 
                 0.993 
               
               
                 130 
                 rs9267456_A 
                 0.926 
                 0.907 
                 0.440 
                 0.993 
               
               
                 131 
                 rs9267457_T 
                 0.926 
                 0.907 
                 0.440 
                 0.993 
               
               
                 132 
                 rs4959079_T 
                 0.926 
                 0.907 
                 0.440 
                 0.993 
               
               
                 133 
                 rs9267461_G 
                 0.926 
                 0.907 
                 0.440 
                 0.993 
               
               
                 134 
                 rs9267462_C 
                 0.926 
                 0.907 
                 0.440 
                 0.993 
               
               
                 135 
                 rs9267463_A 
                 0.926 
                 0.907 
                 0.440 
                 0.993 
               
               
                 136 
                 rs9267464_T 
                 0.926 
                 0.907 
                 0.440 
                 0.993 
               
               
                 137 
                 rs9267465_A 
                 0.925 
                 0.907 
                 0.439 
                 0.993 
               
               
                 138 
                 rs9267487_C 
                 0.925 
                 0.907 
                 0.439 
                 0.993 
               
               
                 139 
                 rs28732092_T 
                 0.922 
                 0.920 
                 0.433 
                 0.994 
               
               
                 140 
                 rs113708600_C 
                 0.921 
                 0.993 
                 0.449 
                 0.999 
               
               
                 141 
                 rs1055821_T 
                 0.919 
                 1 
                 0.444 
                 1 
               
               
                 142 
                 rs76518703_G 
                 0.919 
                 1 
                 0.442 
                 1 
               
               
                 143 
                 rs566305135_T 
                 0.912 
                 0.920 
                 0.401 
                 0.994 
               
               
                 144 
                 rs2233956_C 
                 0.910 
                 0.960 
                 0.407 
                 0.997 
               
               
                 145 
                 rs28732089_G 
                 0.908 
                 0.913 
                 0.389 
                 0.993 
               
               
                 146 
                 rs368001137_T 
                 0.908 
                 0.993 
                 0.409 
                 0.999 
               
               
                 147 
                 rs28732087_T 
                 0.907 
                 0.913 
                 0.388 
                 0.993 
               
               
                 148 
                 rs4418214_C 
                 0.907 
                 0.993 
                 0.408 
                 0.999 
               
               
                 149 
                 rs28732082_A 
                 0.906 
                 0.913 
                 0.385 
                 0.993 
               
               
                 150 
                 rs3093553_G 
                 0.906 
                 0.900 
                 0.382 
                 0.993 
               
               
                 151 
                 rs12055599_C 
                 0.903 
                 0.852 
                 0.371 
                 0.989 
               
               
                 152 
                 rs141484466_C 
                 0.901 
                 0.887 
                 0.366 
                 0.992 
               
               
                 153 
                 rs28732138_A 
                 0.899 
                 0.940 
                 0.374 
                 0.995 
               
               
                 154 
                 rs3093664_G 
                 0.898 
                 0.907 
                 0.364 
                 0.993 
               
               
                 155 
                 rs12199223_A 
                 0.898 
                 0.940 
                 0.371 
                 0.995 
               
               
                 156 
                 rs12189871_T 
                 0.898 
                 0.940 
                 0.371 
                 0.995 
               
               
                 157 
                 rs12211087_A 
                 0.897 
                 0.940 
                 0.370 
                 0.995 
               
               
                 158 
                 rs28894993_T 
                 0.897 
                 0.940 
                 0.369 
                 0.995 
               
               
                 159 
                 rs564450374_C 
                 0.896 
                 0.993 
                 0.381 
                 0.999 
               
               
                 160 
                 rs4406273_A 
                 0.896 
                 0.940 
                 0.367 
                 0.995 
               
               
                 161 
                 rs3093662_G 
                 0.896 
                 0.907 
                 0.359 
                 0.993 
               
               
                 162 
                 rs28732084_C 
                 0.895 
                 0.913 
                 0.359 
                 0.993 
               
               
                 163 
                 rs28732086_A 
                 0.895 
                 0.913 
                 0.359 
                 0.993 
               
               
                 164 
                 rs28732083_C 
                 0.892 
                 0.913 
                 0.353 
                 0.993 
               
               
                 165 
                 rs559867198_G 
                 0.892 
                 0.947 
                 0.361 
                 0.996 
               
               
                 166 
                 rs375233420_T 
                 0.892 
                 0.993 
                 0.372 
                 0.999 
               
               
                 167 
                 rs9267502_A 
                 0.890 
                 0.900 
                 0.345 
                 0.992 
               
               
                 168 
                 rs114122095_G 
                 0.888 
                 0.986 
                 0.362 
                 0.999 
               
               
                 169 
                 rs3132514_C 
                 0.886 
                 0.953 
                 0.349 
                 0.996 
               
               
                 170 
                 rs28894977_C 
                 0.883 
                 0.913 
                 0.335 
                 0.993 
               
               
                 171 
                 rs59438896_T 
                 0.883 
                 0.993 
                 0.354 
                 0.999 
               
               
                 172 
                 rs76332236_C 
                 0.883 
                 0.993 
                 0.353 
                 0.999 
               
               
                 173 
                 rs112243036_A 
                 0.880 
                 0.993 
                 0.347 
                 0.999 
               
               
                 174 
                 rs1131201_C 
                 0.878 
                 0.887 
                 0.318 
                 0.991 
               
               
                 175 
                 rs1793893_C 
                 0.874 
                 0.965 
                 0.327 
                 0.997 
               
               
                 176 
                 rs527987255_G 
                 0.873 
                 0.993 
                 0.335 
                 0.999 
               
               
                 177 
                 rs34105339_C 
                 0.862 
                 0.947 
                 0.306 
                 0.996 
               
               
                 178 
                 rs1265178_A 
                 0.860 
                 0.953 
                 0.305 
                 0.996 
               
               
                 179 
                 rs1265177_G 
                 0.860 
                 0.953 
                 0.305 
                 0.996 
               
               
                 180 
                 rs561768797_A 
                 0.860 
                 0.953 
                 0.305 
                 0.996 
               
               
                 181 
                 rs78405443_C 
                 0.860 
                 0.993 
                 0.313 
                 0.999 
               
               
                 182 
                 rs1265181_C 
                 0.859 
                 0.953 
                 0.303 
                 0.996 
               
               
                 183 
                 rs1131446_T 
                 0.859 
                 1 
                 0.313 
                 1 
               
               
                 184 
                 rs73390248_T 
                 0.858 
                 1 
                 0.312 
                 1 
               
               
                 185 
                 rs28732090_G 
                 0.858 
                 0.920 
                 0.294 
                 0.994 
               
               
                 186 
                 rs35166487_AC 
                 0.856 
                 0.920 
                 0.292 
                 0.994 
               
               
                 187 
                 rs12195316_A 
                 0.856 
                 0.920 
                 0.292 
                 0.994 
               
               
                 188 
                 rs13198298_T 
                 0.856 
                 0.920 
                 0.291 
                 0.994 
               
               
                 189 
                 rs74594159_AG 
                 0.855 
                 1 
                 0.307 
                 1 
               
               
                 190 
                 rs28732157_T 
                 0.855 
                 0.860 
                 0.276 
                 0.989 
               
               
                 191 
                 rs9391731_A 
                 0.854 
                 0.860 
                 0.275 
                 0.989 
               
               
                 192 
                 rs9404941_C 
                 0.854 
                 0.860 
                 0.275 
                 0.989 
               
               
                 193 
                 rs2280801_T 
                 0.854 
                 0.860 
                 0.274 
                 0.989 
               
               
                 194 
                 rs2295663_G 
                 0.854 
                 0.860 
                 0.274 
                 0.989 
               
               
                 195 
                 rs1639110_A 
                 0.853 
                 0.966 
                 0.297 
                 0.997 
               
               
                 196 
                 rs1793895_T 
                 0.853 
                 0.966 
                 0.297 
                 0.997 
               
               
                 197 
                 rs3087617_T 
                 0.853 
                 0.913 
                 0.285 
                 0.993 
               
               
                 198 
                 rs28732154_T 
                 0.853 
                 0.854 
                 0.272 
                 0.989 
               
               
                 199 
                 rs28732150_A 
                 0.852 
                 0.860 
                 0.273 
                 0.989 
               
               
                 200 
                 rs527864796_A 
                 0.852 
                 0.966 
                 0.295 
                 0.997 
               
               
                 201 
                 rs9380266_C 
                 0.851 
                 0.860 
                 0.271 
                 0.989 
               
               
                 202 
                 rs9378164_A 
                 0.851 
                 0.860 
                 0.271 
                 0.989 
               
               
                 203 
                 rs28732158_G 
                 0.851 
                 0.860 
                 0.276 
                 0.989 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 Polymorphic markers in LD with HLA-B*58:01. PPV and 
               
               
                 NPV refer to positive and negative predictive values, 
               
               
                 respectively. In some cases, markers 1-4 of table 
               
               
                 4 provide a panel of markers for HLA-B*58:01. 
               
            
           
           
               
               
               
               
               
               
            
               
                 Marker 
                 SNP 
                 specificity 
                 sensitivity 
                 ppv 
                 npv 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 1 
                 rs78090769_T 
                 0.979 
                 0.994 
                 0.772 
                 0.999 
               
               
                 2 
                 rs79815527_A 
                 0.977 
                 0.970 
                 0.757 
                 0.997 
               
               
                 3 
                 rs75412754_C 
                 0.977 
                 0.958 
                 0.754 
                 0.996 
               
               
                 4 
                 rs143527370_TTA 
                 0.975 
                 0.934 
                 0.732 
                 0.995 
               
               
                 5 
                 rs7769586_T 
                 0.855 
                 0.970 
                 0.324 
                 0.997 
               
               
                 6 
                 rs9264041_G 
                 0.855 
                 0.970 
                 0.324 
                 0.997 
               
               
                 7 
                 rs7739334_C 
                 0.853 
                 0.970 
                 0.321 
                 0.997 
               
               
                 8 
                 rs9264132_C 
                 0.854 
                 0.970 
                 0.322 
                 0.997 
               
               
                 9 
                 rs542772601_TA 
                 0.854 
                 0.970 
                 0.322 
                 0.997 
               
               
                 10 
                 rs4084090_G 
                 0.853 
                 0.970 
                 0.321 
                 0.997 
               
               
                 11 
                 rs4416711_T 
                 0.851 
                 0.970 
                 0.318 
                 0.997 
               
               
                 12 
                 rs141484466_C 
                 0.907 
                 0.898 
                 0.409 
                 0.992 
               
               
                 13 
                 rs1131201_C 
                 0.883 
                 0.886 
                 0.351 
                 0.990 
               
               
                 14 
                 rs1131214_C 
                 0.899 
                 0.868 
                 0.380 
                 0.989 
               
               
                 15 
                 rs1140404_G 
                 0.899 
                 0.868 
                 0.380 
                 0.989 
               
               
                 16 
                 rs41541616_C 
                 0.897 
                 0.856 
                 0.374 
                 0.988 
               
               
                 17 
                 rs41543121_T 
                 0.899 
                 0.856 
                 0.378 
                 0.988 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                 Polymorphic markers in LD with HLA-B*58:02, an allele related 
               
               
                 to HLA- B*58:01. PPV and NPV refer to positive and negative 
               
               
                 predictive values, respectively. In some cases, the marker(s) 
               
               
                 of Table 5 (e.g., markers 1-2) for allele HLA-B*58:02 can 
               
               
                 be assessed and distinguished from the panel of assessed 
               
               
                 markers of Table 4, to provide further specificity for assessing 
               
               
                 ADR risks associated with allele HLA-B*58:01. 
               
            
           
           
               
               
               
               
               
               
            
               
                 Marker 
                 SNP 
                 specificity 
                 sensitivity 
                 ppv 
                 npv 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 1 
                 rs6936478_A 
                 0.997 
                 1 
                 0.878 
                 1 
               
               
                 2 
                 rs111664408_G 
                 0.997 
                 0.972 
                 0.833 
                 0.999 
               
               
                 3 
                 rs12199223_A 
                 0.859 
                 1 
                 0.094 
                 1 
               
               
                 4 
                 rs12189871_T 
                 0.859 
                 1 
                 0.094 
                 1 
               
               
                 5 
                 rs4406273_A 
                 0.858 
                 1 
                 0.093 
                 1 
               
               
                 6 
                 rs12211087_A 
                 0.859 
                 1 
                 0.093 
                 1 
               
               
                 7 
                 rs28894993_T 
                 0.858 
                 1 
                 0.093 
                 1 
               
               
                 8 
                 rs28732138_A 
                 0.861 
                 1 
                 0.094 
                 1 
               
               
                 9 
                 rs78090769_T 
                 0.927 
                 1 
                 0.167 
                 1 
               
               
                 10 
                 rs79815527_A 
                 0.927 
                 0.972 
                 0.163 
                 0.999 
               
               
                 11 
                 rs75412754_C 
                 0.928 
                 0.972 
                 0.165 
                 0.999 
               
               
                 12 
                 rs143527370_TTA 
                 0.927 
                 0.972 
                 0.164 
                 0.999 
               
               
                 13 
                 rs534234550_G 
                 0.881 
                 0.972 
                 0.107 
                 0.999 
               
               
                 14 
                 rs9267184_T 
                 0.881 
                 0.972 
                 0.107 
                 0.999 
               
               
                 15 
                 rs67942473_T 
                 0.881 
                 0.972 
                 0.107 
                 0.999 
               
               
                 16 
                 rs9267202_A 
                 0.881 
                 0.972 
                 0.107 
                 0.999 
               
               
                 17 
                 rs9267212_T 
                 0.881 
                 0.972 
                 0.107 
                 0.999 
               
               
                 18 
                 rs9267214_T 
                 0.881 
                 0.972 
                 0.107 
                 0.999 
               
               
                 19 
                 rs537357246_A 
                 0.882 
                 0.972 
                 0.108 
                 0.999 
               
               
                 20 
                 rs9267217_C 
                 0.881 
                 0.972 
                 0.107 
                 0.999 
               
               
                 21 
                 rs9267218_A 
                 0.882 
                 0.972 
                 0.107 
                 0.999 
               
               
                 22 
                 rs541349280_A 
                 0.884 
                 0.972 
                 0.109 
                 0.999 
               
               
                 23 
                 rs9267271_A 
                 0.861 
                 0.972 
                 0.092 
                 0.999 
               
               
                 24 
                 rs9267280_A 
                 0.881 
                 0.972 
                 0.107 
                 0.999 
               
               
                 25 
                 rs9267283_A 
                 0.875 
                 0.972 
                 0.102 
                 0.999 
               
               
                 26 
                 rs9267289_A 
                 0.881 
                 0.972 
                 0.107 
                 0.999 
               
               
                 27 
                 rs9267296_A 
                 0.881 
                 0.972 
                 0.106 
                 0.999 
               
               
                 28 
                 rs9267301_C 
                 0.882 
                 0.972 
                 0.107 
                 0.999 
               
               
                 29 
                 rs2523460_A 
                 0.881 
                 0.972 
                 0.107 
                 0.999 
               
               
                 30 
                 rs9267315_T 
                 0.881 
                 0.972 
                 0.107 
                 0.999 
               
               
                 31 
                 rs143499322_C 
                 0.997 
                 0.944 
                 0.871 
                 0.999 
               
               
                 32 
                 rs79503523_G 
                 0.951 
                 0.944 
                 0.220 
                 0.999 
               
               
                 33 
                 rs148725606_A 
                 0.908 
                 0.944 
                 0.130 
                 0.999 
               
               
                 34 
                 rs9267133_A 
                 0.908 
                 0.944 
                 0.130 
                 0.999 
               
               
                 35 
                 rs2395031_A 
                 0.906 
                 0.944 
                 0.128 
                 0.999 
               
               
                 36 
                 rs2894220_T 
                 0.907 
                 0.944 
                 0.129 
                 0.999 
               
               
                 37 
                 rs9267135_C 
                 0.907 
                 0.944 
                 0.129 
                 0.999 
               
               
                 38 
                 rs9267136_A 
                 0.907 
                 0.944 
                 0.129 
                 0.999 
               
               
                 39 
                 rs9267137_C 
                 0.907 
                 0.944 
                 0.129 
                 0.999 
               
               
                 40 
                 rs7758090_T 
                 0.891 
                 0.944 
                 0.112 
                 0.999 
               
               
                 41 
                 rs7758267_A 
                 0.891 
                 0.944 
                 0.112 
                 0.999 
               
               
                 42 
                 rs9267141_T 
                 0.891 
                 0.944 
                 0.112 
                 0.999 
               
               
                 43 
                 rs9267142_G 
                 0.891 
                 0.944 
                 0.112 
                 0.999 
               
               
                 44 
                 rs9267143_T 
                 0.891 
                 0.944 
                 0.112 
                 0.999 
               
               
                 45 
                 rs9267145_G 
                 0.891 
                 0.944 
                 0.112 
                 0.999 
               
               
                 46 
                 rs9267146_G 
                 0.891 
                 0.944 
                 0.112 
                 0.999 
               
               
                 47 
                 rs9267147_C 
                 0.891 
                 0.944 
                 0.112 
                 0.999 
               
               
                 48 
                 rs576159127_CT 
                 0.879 
                 0.944 
                 0.102 
                 0.999 
               
               
                 49 
                 rs9267155_G 
                 0.879 
                 0.944 
                 0.102 
                 0.999 
               
               
                 50 
                 rs9267156_T 
                 0.879 
                 0.944 
                 0.102 
                 0.999 
               
               
                 51 
                 rs9267157_T 
                 0.880 
                 0.944 
                 0.103 
                 0.999 
               
               
                 52 
                 rs9267168_A 
                 0.891 
                 0.944 
                 0.112 
                 0.999 
               
               
                 53 
                 rs9267169_T 
                 0.891 
                 0.944 
                 0.112 
                 0.999 
               
               
                 54 
                 rs3828893_A 
                 0.891 
                 0.944 
                 0.112 
                 0.999 
               
               
                 55 
                 rs3749945_T 
                 0.891 
                 0.944 
                 0.112 
                 0.999 
               
               
                 56 
                 rs72459742_A 
                 0.891 
                 0.944 
                 0.112 
                 0.999 
               
               
                 57 
                 rs9267175_T 
                 0.891 
                 0.944 
                 0.112 
                 0.999 
               
               
                 58 
                 rs9267176_T 
                 0.891 
                 0.944 
                 0.112 
                 0.999 
               
               
                 59 
                 rs9267211_T 
                 0.882 
                 0.944 
                 0.104 
                 0.999 
               
               
                 60 
                 rs200587233_G 
                 0.885 
                 0.944 
                 0.107 
                 0.999 
               
               
                 61 
                 rs9267243_T 
                 0.882 
                 0.944 
                 0.104 
                 0.999 
               
               
                 62 
                 rs17197066_A 
                 0.997 
                 0.916 
                 0.846 
                 0.998 
               
               
                 63 
                 rs147200847_A 
                 0.994 
                 0.916 
                 0.717 
                 0.998 
               
               
                 64 
                 rs112928571_G 
                 0.997 
                 0.916 
                 0.846 
                 0.998 
               
               
                 65 
                 rs182979559_T 
                 0.997 
                 0.916 
                 0.846 
                 0.998 
               
               
                 66 
                 rs572558969_G 
                 0.997 
                 0.916 
                 0.846 
                 0.998 
               
               
                 67 
                 rs7752002_T 
                 0.997 
                 0.916 
                 0.868 
                 0.998 
               
               
                 68 
                 rs6934570_G 
                 0.946 
                 0.916 
                 0.201 
                 0.998 
               
               
                 69 
                 rs187331993_T 
                 0.995 
                 0.916 
                 0.767 
                 0.998 
               
               
                 70 
                 rs1793894_A 
                 0.915 
                 0.916 
                 0.136 
                 0.998 
               
               
                 71 
                 rs527277270. 
                 0.921 
                 0.916 
                 0.146 
                 0.998 
               
               
                   
                 rs531277843_G 
               
               
                 72 
                 rs16899682_C 
                 0.952 
                 0.888 
                 0.214 
                 0.998 
               
               
                 73 
                 rs146870705_T 
                 0.997 
                 0.888 
                 0.842 
                 0.998 
               
               
                 74 
                 rs62395345_G 
                 0.971 
                 0.888 
                 0.310 
                 0.998 
               
               
                 75 
                 rs13197153_C 
                 0.946 
                 0.888 
                 0.196 
                 0.998 
               
               
                 76 
                 rs149345291_A 
                 0.891 
                 0.861 
                 0.103 
                 0.997 
               
               
                 77 
                 rs549439680_T 
                 0.985 
                 0.861 
                 0.469 
                 0.997 
               
               
                 78 
                 rs140577688_G 
                 0.997 
                 0.861 
                 0.861 
                 0.997 
               
               
                 79 
                 rs112625334_C 
                 0.974 
                 0.861 
                 0.329 
                 0.997 
               
               
                 80 
                 rs112193896_T 
                 0.974 
                 0.861 
                 0.326 
                 0.997 
               
               
                 81 
                 rs113807067_A 
                 0.988 
                 0.861 
                 0.516 
                 0.997 
               
               
                 82 
                 rs114910910_C 
                 0.988 
                 0.861 
                 0.516 
                 0.997 
               
               
                 83 
                 rs111541554_G 
                 0.990 
                 0.861 
                 0.563 
                 0.997 
               
               
                 84 
                 rs114500081_A 
                 0.988 
                 0.861 
                 0.525 
                 0.997 
               
               
                 85 
                 rs62395767_G 
                 0.978 
                 0.861 
                 0.369 
                 0.997 
               
               
                 86 
                 rs3093667_T 
                 0.997 
                 0.861 
                 0.815 
                 0.997 
               
               
                 87 
                 rs3093669_A 
                 0.987 
                 0.861 
                 0.492 
                 0.997 
               
               
                 88 
                 rs115166054_T 
                 0.989 
                 0.861 
                 0.534 
                 0.997 
               
               
                 89 
                 rs148897498_C 
                 0.988 
                 0.861 
                 0.525 
                 0.997 
               
               
                 90 
                 rs140894428_C 
                 0.988 
                 0.861 
                 0.525 
                 0.997 
               
               
                 91 
                 rs145103532_C 
                 0.997 
                 0.861 
                 0.861 
                 0.997 
               
               
                   
               
            
           
         
       
     
     Example 2: Polymorphic Markers for Pharmacogenetic HLA Risk Alleles 
     Methodology 
     Specific HLA alleles strongly associated with drug toxicities/response with a PharmGKB strength of evidence score of ≥2 were selected from the PharmGKB database (see Whirl-Carrillo, M., et al., Pharmacogenomics knowledge for personalized medicine. Clin Pharmacol Ther, 2012. 92(4): p. 414-7) for subsequent discovery of proxy-single nucleotide polymorphism (proxy-SNP) markers. We identified 2504 samples from the 1000 Genomes (1KG) Project dataset that had both whole genome sequencing and HLA typing data available (discovery cohort) (see Abi-Rached, L., et al., Immune diversity sheds light on missing variation in worldwide genetic diversity panels. PLoS One, 2018. 13(10): p. e0206512; and Genomes Project, C., et al., A global reference for human genetic variation. Nature, 2015. 526(7571): p. 68-74). 
     These multi-ethnic samples represented the five super populations, as defined by the 1KG Project: African Americans (n=661), Europeans (n=503), Hispanics (n=347), East (n=504) and South Asians (n=489). We evaluated the performance of all variants within the MHC region (n=608,256) across the entire discovery cohort to tag the selected pharmacogenetic HLA alleles by assessing their sensitivity, specificity, positive predictive value, and negative predictive value (Erlichster, M., et al., Cross-ethnicity tagging SNPs for HLA alleles associated with adverse drug reaction. Pharmacogenomics J, 2018). The identified proxy-SNPs were ranked based on these performance metrics, which informs the selection of multi-ethnic proxy-SNPs as markers of pharmacogenetic HLA risk alleles. In addition, the initial performance metric estimations of the high ranking proxy-SNPs were refined by experimentally genotyping and/or HLA typing selected samples with potential false positive and/or false negative results based on the low-coverage sequencing data of the 1KG Project. Of note, this analysis also identified some proxy-SNPs that are markers for highly related HLA risk alleles with only recent evolutionary divergence (e.g., B*58:01 and B*58:02). To confirm the performance metrics of the identified top ranking proxy-SNPs, an independent replication cohort of 79 multi-ethnic Coriell samples was analyzed [African Americans (n=20), Europeans (n=27), Hispanics (n=8), East Asians (n=23) and Middle Eastern (n=1)], which included 60 samples confirmed to carry at least one of the pharmacogenetic HLA risk alleles (Abi-Rached, L., et al., PLoS One, 2018. 13(10): p. e0206512; Bettinotti, M. P., et al., Characterization of 108 Genomic DNA Reference Materials for 11 Human Leukocyte Antigen Loci: A GeT-RM Collaborative Project. J Mol Diagn, 2018. 20(5): p. 703-715; and Bykova et al., In Silico Analysis of the Minor Histocompatibility Antigen Landscape Based on the 1000 Genomes Project. Front Immunol, 2018. 9: p. 1819). 
     Results 
     Further analysis was performed to identify smaller panels of the best proxy-SNPs for the HLA alleles. As described above, 2504 samples across super populations from 1000 Genome project dataset with whole genome sequencing and HLA typing data (discovery cohort,  FIG. 1 ). We estimated the carriage sensibility and specificity to assess the HLA allele tagging performance of each variant within MHC region (n=608,256). We typed false positive and false negative samples to confirm the predicted estimations for the best proxy-SNPs. We genotyped those proxy-SNPs on 79 multiethnic samples, 60 of which carry at least one of the four HLA alleles (Replication cohort,  FIG. 1 ) to confirm sensibility and sensitivity of selected SNPs in an independent cohort. 
     The results of this analysis are presented in Tables 6 and 7. Our findings identified a novel multi-ethic proxy-SNP panel that could enable cost-effective and rapid genotype-based screening to predict the four major FDA/EMA recommended pharmacogenomic HLA risk alleles. 
     
       
         
           
               
             
               
                 TABLE 6 
               
             
            
               
                   
               
               
                 Sensitivity (SN) and specificity (SP) of the selected proxy- 
               
               
                 SNPs for HLA-A*31:01, HLA-B*15:02, HLA-B*58:01 and HLA-B*57:01. 
               
            
           
           
               
               
               
            
               
                   
                 Discovery (n = 2504) 
                 Replication (n = 79) 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 Probe name 
                 SN 
                 SP 
                 PPV 
                 NPV 
                 SN 
                 SP 
                 PPV 
                 NPV 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 HLA-A*31:01 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 rs114776910_G 
                 0.976 
                 0.999 
                 0.984 
                 0.999 
                 1.000 
                 1.000 
                 1.000 
                 1.000 
               
               
                 rs138415245_G 
                 0.952 
                 0.999 
                 0.984 
                 0.997 
                 1.000 
                 1.000 
                 1.000 
                 1.000 
               
               
                 rs12665140_A 
                 0.968 
                 0.999 
                 0.984 
                 0.998 
                 1.000 
                 1.000 
                 1.000 
                 1.000 
               
               
                 rs147023494_T 
                 1.000 
                 0.997 
                 0.955 
                 1.000 
                 1.000 
                 1.000 
                 1.000 
                 1.000 
               
               
                 rs148590958_C 
                 0.944 
                 0.998 
                 0.967 
                 0.997 
                 1.000 
                 1.000 
                 1.000 
                 1.000 
               
               
                 rs114716190_G 
                 0.952 
                 0.998 
                 0.968 
                 0.997 
                 1.000 
                 1.000 
                 1.000 
                 1.000 
               
               
                 HLA-B*15:02 
               
               
                 rs144012689_A 
                 1.000 
                 1.000 
                 1.000 
                 1.000 
               
               
                 rs151107659_A 
                 1.000 
                 1.000 
                 1.000 
                 1.000 
                 1.000 
                 1.000 
                 1.000 
                 1.000 
               
               
                 rs188729361_A 
                 0.989 
                 1.000 
                 1.000 
                 1.000 
                 1.000 
                 1.000 
                 1.000 
                 1.000 
               
               
                 rs181377228_A 
                 0.989 
                 0.990 
                 1.000 
                 1.000 
                 1.000 
                 1.000 
                 1.000 
                 1.000 
               
               
                 HLA-B*58:01 
               
               
                 rs78090769_T 
                 0.994 
                 0.996 
                 0.949 
                 1.000 
                 1.000 
                 1.000 
                 1.000 
                 1.000 
               
               
                 rs79815527_A 
                 0.970 
                 0.994 
                 0.926 
                 0.998 
                 0.950 
                 1.000 
                 1.000 
                 0.984 
               
               
                 rs75412754_C 
                 0.970 
                 0.994 
                 0.926 
                 0.998 
                 0.950 
                 1.000 
                 1.000 
                 0.984 
               
               
                 rs6936478_A 
                 1.000 
                 0.996 
                 0.878 
                 1.000 
               
               
                 HLA-B*57:01 
               
               
                 rs115986568_A 
                 1.000 
                 0.998 
                 0.968 
                 1.000 
                 1.000 
                 1.000 
                 1.000 
                 1.000 
               
               
                 rs149663102_T 
                 1.000 
                 0.998 
                 0.968 
                 1.000 
                 1.000 
                 1.000 
                 1.000 
                 1.000 
               
               
                 rs114170382_A 
                 1.000 
                 0.998 
                 0.968 
                 1.000 
                 1.000 
                 1.000 
                 1.000 
                 1.000 
               
               
                 rs114607072_T 
                 0.993 
                 0.998 
                 0.968 
                 1.000 
                 1.000 
                 1.000 
                 1.000 
                 1.000 
               
               
                 rs138099588_G 
                 0.993 
                 0.997 
                 0.955 
                 1.000 
                 1.000 
                 1.000 
                 1.000 
                 1.000 
               
               
                 rs41558312_G 
                 0.993 
                 0.998 
                 0.968 
                 1.000 
                 1.000 
                 1.000 
                 1.000 
                 1.000 
               
               
                 rs58102217_A 
                 1.000 
                 0.986 
                 0.816 
                 1.000 
                 1.000 
                 0.982 
                 0.930 
                 1.000 
               
               
                 rs41543314_G 
                 1.000 
                 0.985 
                 0.812 
                 1.000 
                 1.000 
                 1.000 
                 1.000 
                 1.000 
               
               
                   
               
               
                 PPV positive predictive value. 
               
               
                 NPV negative predictive value. 
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 7 
               
               
                   
               
               
                 Sensitivity (SN) and specificity (SP) by ethnicities (reported 
               
               
                 the number of carriers) of selected proxy-SNPs for HLA- 
               
               
                 A*31:01, HLA-B*15:02, HLA-B*58:01 and HLA-B*57:01. 
               
               
                   
               
             
            
               
                 HLA-A*31:01 
               
            
           
           
               
               
               
               
            
               
                   
                 African Americans 
                 Hispanics 
                 Europeans 
               
               
                   
                 (n = 10) 
                 (n = 32) 
                 (n = 24) 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
            
               
                 probe name 
                 SS 
                 SP 
                 PPV 
                 NPV 
                 SS 
                 SP 
                 PPV 
                 NPV 
                 SS 
                 SP 
               
               
                   
               
               
                 rs114776910_G 
                 0.70 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
               
               
                 rs138415245_G 
                 0.60 
                 1.00 
                 1.00 
                 0.99 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
               
               
                 rs12665140_A 
                 0.60 
                 1.00 
                 1.00 
                 0.99 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
               
               
                 rs147023494_T 
                 1.00 
                 0.99 
                 0.71 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
               
               
                 rs148590958_C 
                 0.60 
                 1.00 
                 1.00 
                 0.99 
                 1.00 
                 1.00 
                 0.97 
                 1.00 
                 0.92 
                 1.00 
               
               
                 rs114716190_G 
                 0.70 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 0.97 
                 1.00 
                 0.92 
                 1.00 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                   
                 Europeans 
                 East Asians 
                 South Asians 
               
               
                   
                 (n = 24) 
                 (n = 36) 
                 (n = 24) 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
            
               
                 probe name 
                 PPV 
                 NPV 
                 SS 
                 SP 
                 PPV 
                 NPV 
                 SS 
                 SP 
                 PPV 
                 NPV 
               
               
                   
               
               
                 rs114776910_G 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 0.92 
                 1.00 
               
               
                 rs138415245_G 
                 1.00 
                 1.00 
                 0.97 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 0.92 
                 1.00 
               
               
                 rs12665140_A 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 0.92 
                 1.00 
               
               
                 rs147023494_T 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 0.92 
                 1.00 
               
               
                 rs148590958_C 
                 1.00 
                 1.00 
                 0.97 
                 1.00 
                 0.97 
                 1.00 
                 1.00 
                 1.00 
                 0.92 
                 1.00 
               
               
                 rs114716190_G 
                 1.00 
                 1.00 
                 0.97 
                 1.00 
                 0.97 
                 1.00 
                 1.00 
                 1.00 
                 0.92 
                 1.00 
               
               
                   
               
            
           
           
               
            
               
                 HLA-B*15:02 
               
            
           
           
               
               
               
               
               
            
               
                   
                 African Americans 
                 Hispanics 
                 Europeans 
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
            
               
                 probe name 
                 SS 
                 SP 
                 PPV 
                 NPV 
                 SS 
                 SP 
                 PPV 
                 NPV 
                 SS 
                 SP 
               
               
                   
               
               
                 rs144012689_A 
               
               
                 rs151107659_A 
               
               
                 rs188729361_A 
               
               
                 rs181377228_A 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                   
                   
                 East Asians 
                 South Asians 
               
               
                   
                 Europeans 
                 (n = 47) 
                 (n = 41) 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
            
               
                 probe name 
                 PPV 
                 NPV 
                 SS 
                 SP 
                 PPV 
                 NPV 
                 SS 
                 SP 
                 PPV 
                 NPV 
               
               
                   
               
               
                 rs144012689_A 
                   
                   
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
               
               
                 rs151107659_A 
                   
                   
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
               
               
                 rs188729361_A 
                   
                   
                 0.98 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
               
               
                 rs181377228_A 
                   
                   
                 0.98 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
               
               
                   
               
            
           
           
               
            
               
                 HLA-B*58:01 
               
            
           
           
               
               
               
               
               
            
               
                   
                 African Americans 
                 Hispanics 
                 Europeans 
                   
               
               
                   
                 (n = 71) 
                 (n = 5) 
                 (n = 8) 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
            
               
                 probe name 
                 SS 
                 SP 
                 PPV 
                 NPV 
                 SS 
                 SP 
                 PPV 
                 NPV 
                 SS 
                 SP 
               
               
                   
               
               
                 rs78090769_T 
                 0.99 
                 0.99 
                 0.90 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
               
               
                 rs79815527_A 
                 0.93 
                 0.98 
                 0.88 
                 0.99 
                 1.00 
                 0.99 
                 0.63 
                 1.00 
                 1.00 
                 1.00 
               
               
                 rs75412754_C 
                 0.93 
                 0.98 
                 0.88 
                 0.99 
                 1.00 
                 0.99 
                 0.63 
                 1.00 
                 1.00 
                 1.00 
               
               
                 rs6936478_A 
                 1.00 
                 0.99 
                 0.87 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                   
                 Europeans 
                 East Asians 
                 South Asians 
               
               
                   
                 (n = 8) 
                 (n = 55) 
                 (n = 28) 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
            
               
                 probe name 
                 PPV 
                 NPV 
                 SS 
                 SP 
                 PPV 
                 NPV 
                 SS 
                 SP 
                 PPV 
                 NPV 
               
               
                   
               
               
                 rs78090769_T 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 0.97 
                 1.00 
               
               
                 rs79815527_A 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 0.97 
                 1.00 
               
               
                 rs75412754_C 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 0.97 
                 1.00 
               
               
                 rs6936478_A 
               
               
                   
               
            
           
           
               
            
               
                 HLA-B*57:01 
               
            
           
           
               
               
               
               
            
               
                   
                 African Americans 
                 Hispanics 
                 Europeans 
               
               
                   
                 (n = 1) 
                 (n = 12) 
                 (n = 42) 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
            
               
                 probe name 
                 SS 
                 SP 
                 PPV 
                 NPV 
                 SS 
                 SP 
                 PPV 
                 NPV 
                 SS 
                 SP 
               
               
                   
               
               
                 rs115986568_A 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 0.92 
                 1.00 
                 1.00 
                 1.00 
               
               
                 rs149663102_T 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 0.92 
                 1.00 
                 1.00 
                 1.00 
               
               
                 rs114170382_A 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 0.92 
                 1.00 
                 1.00 
                 1.00 
               
               
                 rs114607072_T 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 0.92 
                 1.00 
                 0.98 
                 1.00 
               
               
                 rs138099588_G 
                 1.00 
                 1.00 
                 0.50 
                 1.00 
                 1.00 
                 1.00 
                 0.92 
                 1.00 
                 0.98 
                 1.00 
               
               
                 rs41558312_G 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 0.92 
                 1.00 
                 0.98 
                 1.00 
               
               
                 rs58102217_A 
                 1.00 
                 0.96 
                 0.04 
                 1.00 
                 1.00 
                 0.99 
                 0.86 
                 1.00 
                 1.00 
                 0.99 
               
               
                 rs41543314_G 
                 1.00 
                 0.96 
                 0.04 
                 1.00 
                 1.00 
                 0.98 
                 0.67 
                 1.00 
                 1.00 
                 1.00 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                   
                 Europeans 
                 East Asians 
                 South Asians 
               
               
                   
                 (n = 42) 
                 (n = 11) 
                 (n = 85) 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
            
               
                 probe name 
                 PPV 
                 NPV 
                 SS 
                 SP 
                 PPV 
                 NPV 
                 SS 
                 SP 
                 PPV 
                 NPV 
               
               
                   
               
               
                 rs115986568_A 
                 0.98 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 0.99 
                 0.97 
                 1.00 
               
               
                 rs149663102_T 
                 0.98 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 0.99 
                 0.97 
                 1.00 
               
               
                 rs114170382_A 
                 0.98 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 0.99 
                 0.97 
                 1.00 
               
               
                 rs114607072_T 
                 0.98 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 0.99 
                 0.97 
                 1.00 
               
               
                 rs138099588_G 
                 0.95 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 0.99 
                 0.97 
                 1.00 
               
               
                 rs41558312_G 
                 0.95 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 0.99 
                 0.97 
                 1.00 
               
               
                 rs58102217_A 
                 0.93 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 0.99 
                 0.97 
                 1.00 
               
               
                 rs41543314_G 
                 0.95 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 1.00 
                 0.99 
                 0.97 
                 1.00 
               
               
                   
               
               
                 PPV positive predictive value. 
               
               
                 NPV negative predictive value.