Publications and our contributions to PGx community

Publications and our contributions to PGx community

Academic excellence

As recognized leaders in pharmacogenomics (PGx), Dr. Broeckel and the RPRD research team are known for their scientific rigor and academic excellence. We partner with the world’s leading medical institutions to advance PGx research and practice.

View our academic publications and scientific contributions listed below that highlight our academic excellence and commitments in scientific and clinical research.

Dr Broeckel Pharmacogenomics Researcher


Fernandez CA, et al. Concordance of DMET Plus Genotyping Results With Those of Orthogonal Genotyping Methods. Clin Pharmacol Ther. 2012 Sep;92(3):360-5. 

Hicks JK, et al. A Clinician-Driven Automated System for Integration of Pharmacogenetic Interpretations into an Electric Medical Record. Clin Pharmacol Ther. 2012 Nov;92(5):563-6.

Shuldiner AR, et al. The Pharmacogenomics Research Network Translational Pharmacogenetics Program: Overcoming Challenges of Real-world Implementation. Clin Pharmacol Ther. 2013 Aug;94(2):207-10.

Bell GC, et al. Development and Use of Active Clinical Decision Support for Preemptive Pharmacogenomics. J Am Med Inform Assoc. 2014 Feb;21(e1):e93-9.

Hoffman JM, et al. PG4KDS: a Model for the Clinical Implementation of Pre-emptive Pharmacogenetics. Am J Med Genet C Semin Med Genet. 2014 Mar;166C(1):45-55.

Miller AW, et al. Development of Reusable Logic for Determination of Statin Exposure-time from Electronic Health Records. J Biomed Inform. 2014 Jun;49:206-12.

Hicks JK, et al. Voriconazole Plasma Concentrations in Immunocompromised Pediatric Patients Vary by CYP2C19 Diplotypes. 2014 Jun;15(8):1065-78.

Thompson P, et al. Pharmacokinetics and Pharmacogenomics of Daunorubicin in Children: a Report From the Children’s Oncology Group. Cancer Chemother Pharmacol. 2014 Oct;74(4):831-8.

Dunnenberger HM, et al. Preemptive Clinical Pharmacogenetics Implementation: Current Programs in Five US Medical Centers. Annu Rev Pharmacol Toxicol. 2015 Jan;55:89-106.

Pratt VM, et al. Characterization of 137 Genomic DNA Reference Materials for 28 Pharmacogenetic Genes: A GeT-RM Collaborative Project. J Mol Diagn. 2016 Jan;18(1):109-23.

Yang W, et al. Comparison of Genome Sequencing and Clinical Genotyping for Pharmacogenes. Clin Pharmacol Ther. 2016 Oct;100(4):380-8.

Gammal RS, et al. Pharmacogenetics for Safe Codeine Use in Sickle Cell Disease. 2016 Jul;138(1).

Pasternak AL, et al. The Impact of the UGT1A1*60 Allele on Bilirubin Serum Concentrations. 2017 Jan;18(1):5-16.

Bhatt DK, et al. Hepatic Abundance and Activity of Androgen and Drug Metabolizing Enzyme, UGT2B17, are Associated with Genotype, Age, and Sex. Drug Metab Dispos. 2018 Jun;46(6):888-96.

Bhatt DK, et al. Age- and Genotype-Dependent Variability in the Protein Abundance and Activity of Six Major Uridine Diphosphate-Glucuronosyltransferases in Human Liver. Clin Pharmacol Ther. 2019 Jan;105(1):131-41.

Yang JJ, et al. Pharmacogene Variation Consortium Gene Introduction: NUDT15. Clin Pharmacol Ther. 2019 May;105(5):1091-1094.

Click here for selected publications utilizing NGS.

Conference abstracts:

Four Novel NUDT15 Haplotypes Relevant for Treatment of Acute Lymphoblastic Leukemia

Turner A, Aggarwal P, Scharer G, Broeckel U.

Presented at The American Society of Pediatric Hematology/Oncology (ASPHO) 2019.


Genetic variants in TPMT and NUDT15 have been associated with thiopurine-related myelotoxicity requiring dose adjustment during treatment of acute lymphoblastic leukemia (ALL). The frequency of variants in these genes varies across different populations and comprehensive, accurate genotyping, with a short turnaround time (TAT) is critical to adjust thiopurine dosing.


We aim to establish a novel targeted next generation sequencing (NGS) methodology to comprehensively assay TPMT and NUDT15 haplotypes with a TAT that meets thiopurine dose optimization window.


Eight genomic DNA samples from the 1000 Genomes Project were selected as controls for assay validation. Sequencing libraries were prepared using a custom AmpliSeq assay and NGS was performed on the Illumina iSeq™ system. Sequence reads were aligned to the human reference genome (GRCh38). Haplotypes were determined based on overlapping read alignment. Known polymorphisms were further confirmed with real-time qPCR (RT-PCR).


All samples were prepared and sequenced within three days and showed 100% concordance for sequence variants with both the 1000 Genomes data and the confirming RT-PCR in TPMT and NUDT15. Deep NGS allowed the assignment of variants into haplotypes. Interestingly, in addition to identifying two samples with complex heterozygous NUDT15 haplotypes (NUDT15*2/*3) we found six samples with four previously undescribed NUDT15 haplotypes. These included four heterozygous amino acid changes: p.Val93Ile, p.Pro12Leu, p.Gly13Ala, and p.Lys33Asn, two of which protein modeling has predicted to be deleterious to enzyme activity (p.Pro12Leu and p.Lys33Asn, minor allele frequency= 0.01 to 0.20, 0.003 to 0.08 respectively).


Genotyping of TPMT and NUDT15 is recognized as a critical test to assess the risk of thiopurine associated adverse reactions, particularly in ALL patients. Currently, CPIC® and PharmVar have annotated 41 TPMT and 19 NUDT15 haplotypes, including many with reduced function. Our NGS assay accurately captured all regions containing variants known to affect enzyme activity and identified all known TPMT and NUDT15 haplotypes. Notably, we were able to identify four novel NUDT15 haplotypes which may affect enzyme activity. These results support the use of an NGS testing methodology for detection of known and novel TPMT and NUDT15 polymorphisms. This analysis approach is particularly important for genes in which many functional haplotypes have not yet been identified, to avoid enzyme activity misclassification. Importantly, the assay can be performed in a time frame that enables dose adjustment prior to or during treatment of ALL.

Click here to download poster.


Identification of Novel CYP2D6 Haplotypes that Interfere with TaqMan Copy Number Analysis

Turner A, Aggarwal P, Boone EC, Haidar CE, Relling M., Broeckel U, Gaedig, A.

Presented at American Society of Human Genetics (ASHG) 2018. 

Cytochrome P450 2D6 (CYP2D6) is a highly polymorphic gene encoding an enzyme critical in the metabolism of up to 25% of commonly prescribed drugs. There are over 100 described star allele (*) haplotypes, including frequent gene conversions, deletions, duplications and gene-fusions (D6/D7 hybrid), many of which have altered enzyme activity. Accurate copy number (CN) calling is critical in determining patient drug response. TaqMan CNV assays are a commonly used methodology for CN analysis, utilizing specific primers and labeled probes to evaluate the CN state of a genomic region of interest. Polymorphisms within the primer or probe target sequence can generate a false positive for a CN loss. Currently, three CYP2D6 intra-gene regions can be tested using commercially available TaqMan assays: intron 2, intron 6 and exon 9. Gene-fusions or conversions present as discrepant CN calling between the three regions. During clinical testing, we identified samples with CNV inconsistent with known haplotypes. To characterize the haplotypes that lead to these CNV results, we performed long-range PCR, Next-Gen sequencing and allele-specific Sanger sequencing. Sequence analysis of 20 patients identified six novel sub-alleles containing polymorphisms within the TaqMan assay probe binding sites, causing a false-positive copy number loss. In total, four novel haplotypes (sub-alleles) with SNPs within the intron 2 and 6 probes were identified (*1 sub-allele 1: rs770138443, rs78854695; sub-allele 2: rs781257354, rs37522240. *2 sub-allele 1: rs180847475, rs186133763; sub-allele 2: rs370010370). Analysis of samples which showed CN loss in only exon 9, identified new *10 and *17 sub-allele haplotypes. Two additional samples with exon 9 CNV contained hybrid/deletion arrangements within the probe region that affected CN analysis. In summary, performance of widely used TaqMan CNV assays is affected by the presence of sequence variation within the probe-target regions. The identification of these haplotypes and further characterization of these structural variations will be important for clinical interpretation and could directly impact patient care.

Click here to download poster.

Implementation of Affymetrix PharmacoScanTM for Comprehensive Preemptive Clinical Pharmacogenetic Testing

Turner A, Lorier R, Aggarwal, P Matter A, Broeckel U.

Presented at American Society of Human Genetics (ASHG)-Pharmacogenomics Research Network (PGRN) symposium, 2016.

Genotyping of relevant pharmacogenetic (PGx) genes (e.g. single nucleotide polymorphisms, copy number variants) and HLA typing for known associations with drug metabolism and hypersensitivity allows for personalized drug selection and dosing prior to administration. This enables a clinician to provide a patient with an optimized treatment regimen by maximizing drug efficacy and limiting adverse reactions.

Currently, there are over 300 actionable alleles and genes with known dosing recommendations. Affected drugs span a wide range of categories from pain management to heart disease and cancer treatment (e.g. codeine, warfarin, allopurinol). With improved PGx knowledge, such as the identification of new alleles and the dependence of drug metabolism on multi-gene interactions (e.g. warfarin: VKORC1 and CYP2C9), there is a need for an updated and comprehensive PGx genotyping platform. Affymetrix’s PharmacoScanTM enables genotyping of over 4000 markers in 900 pharmacogenetic relevant genes to be done as a single test.

In our CLIA-certified clinical laboratory, we have tested approximately 5,000 samples on a variety of PGx platforms. To address the need for improved PGx testing, we clinically validated the PharmacoScanTM platform as part of our repertoire. We validated the accuracy and detection of critical PGx variants utilizing a diverse reference set of 96 Coriell samples. This set was previously genotyped on multiple PGx platforms by our group, as well as others in a collaborative effort by the CDC. The PharmacoScanTM data generated for this reference set will be available as a public resource.

Data generated on comprehensive platforms can present challenges for interpretation and practical application for both clinicians and patients. As part of our complete diagnostic approach, we developed a workflow to generate quality-assured data that is translated in a meaningful and actionable way. In addition to the raw data, we provide translational reports, which include the patient’s haplotype-specific metabolizer status based on the CPIC dosing guidelines. Downstream inclusion of this data in the EMR will enable clinicians to preemptively make the most informed drug choices and dosing decisions, providing cost-effective and better-individualized patient care.

Click here to download poster.

Our additional contributions to PGx development

Clinical Pharmacogenetics Implementation Consortium (CPIC):

Drs. Broeckel (CEO and founder) and Scharer (CMO) are both long-standing members of the CPIC® since its inception in 2009.  CPIC is a pioneering PGx consortium committed to facilitating the implementation of PGx testing in the clinic by providing actionable clinical guidelines to translate genetic tests results into customized patient-focused prescribing decisions by physicians for certain drugs. The detailed evidence-based, gene/drug clinical recommendations created by CPIC are peer-reviewed and are being increasingly used in the clinical practice. They are regarded as the standard guideline in PGx clinical implementation.

Read more about CPIC.


Amy Turner (Director of Research and Development) is a member of the Pharmacogene Variation (PharmVar) Consortium and serves as a gene expert for CYP2D6, NUDT15, and DPYD.

PharmVar was established in 2018 and funded by the Pharmacogenomics Research Network (PGRN) to serve as repository for PGx gene data and its nomenclature. PharmVar aims to facilitate and develop a standardized PGx gene nomenclature for the entire global PGx community.

Amy Turner’s contribution to the PharmVar NUDT15 gene introduction:

Yang JJ, et al. Pharmacogene Variation Consortium Gene Introduction: NUDT15. Clin Pharmacol Ther. 2018 Dec 4. doi: 10.1002/cpt.1268.

Read more about PharmVar.

Genetic Testing Reference Materials Coordination Program (GeT-RM)

Dr. Broeckel and his research team have been an important contributor to the GeT-RM since 2015. As part of the Clinical Laboratory Improvement Amendments (CLIA) regulations of 1988, the Get-RM program is supported by the Centers for Disease Control and Prevention (CDC). The goal of the GeT-RM is to establish a PGx community dedicated to creating reference materials, quality control measures, and proficiency testing for genetic testing.

Dr. Broeckel’s team has characterized the PGx impact of genomic DNA reference materials utilizing the PharmacoScanTM and its predecessor DMET platform.

Pratt VM, et al. Characterization of 137 Genomic DNA Reference Materials for 28 Pharmacogenetic Genes: A GeT-RM Collaborative Project. J Mol Diagn. 2016 Jan;18(1):109-23.PMID: 26621101 PMCID: 4695224.

Gaedigk A, et al. Characterization of Reference Materials for Genetic Testing of Rare CYP2D6 Alleles: A GeT-RM Collaborative Project. In Progress.

Read more about Get-RM program.

Collaborating Opportunities

As a team primarily driven by passion for science, we are excited to work with the bright minds in the precision medicine community. If you are interested in collaborating with RPRD, please contact Amy Turner, Director of Research and Development to discuss potential opportunities.

Improve Drug R&D

Pharmacogenetics testing is an increasingly important tool to mitigate risks for clinical trials, interpretation of clinical data and retrospective studies.

Improve Patient Outcomes

Through our continued research in advanced PGx technologies and solutions, we help clinicians practice personalized medicine to achieve better outcomes for their patients.