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101. Additional Copies of the Proteolipid Protein Gene Causing Pelizaeus-Merzbacher Disease Arise by Separate Integration into the X Chromosome

Author

Hodes, M. E., Woodward, Karen, Spinner, Nancy B., Emanuel, Beverly S., Enrico-Simon, Agnes, Kamholz, John, Stambolian, Dwight, Zackai, Elaine H., Pratt, Victoria M., Thomas, I. T., Crandall, Kerry, Dlouhy, Stephen R., and Malcolm, Sue

Subjects
Proteolipids -- Research, Genetic disorders -- Causes of, Chromosome abnormalities -- Research, Biological sciences
Published
2000

102. The Spectrum of Clinical Utilities in Molecular Pathology Testing Procedures for Inherited Conditions and Cancer

Author

Joseph, Loren, primary, Cankovic, Milena, additional, Caughron, Samuel, additional, Chandra, Pranil, additional, Emmadi, Rajyasree, additional, Hagenkord, Jill, additional, Hallam, Stephanie, additional, Jewell, Kay E., additional, Klein, Roger D., additional, Pratt, Victoria M., additional, Rothberg, Paul G., additional, Temple-Smolkin, Robyn L., additional, and Lyon, Elaine, additional

Published
2016
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103. Characterization of 137 Genomic DNA Reference Materials for 28 Pharmacogenetic Genes

Author

Pratt, Victoria M., primary, Everts, Robin E., additional, Aggarwal, Praful, additional, Beyer, Brittany N., additional, Broeckel, Ulrich, additional, Epstein-Baak, Ruth, additional, Hujsak, Paul, additional, Kornreich, Ruth, additional, Liao, Jun, additional, Lorier, Rachel, additional, Scott, Stuart A., additional, Smith, Chingying Huang, additional, Toji, Lorraine H., additional, Turner, Amy, additional, and Kalman, Lisa V., additional

Published
2016
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105. Contributors

Author

Aarsand, Aasne K., Abbott, April N., Adeli, Khosrow, Anderson, Neil W., Apple, Fred S., Ayling, Ruth M., Babady, Esther, Badminton, Michael N., Badrick, Tony, Bais, Renze, Bazydlo, Lindsay A.L., Bechtel, Laura K., Bertholf, Roger L., Best, D. Hunter, Bjarnason, Ingvar, Block, Darci R., Blum, Lee M., Bossuyt, Patrick M.M., Boyd, James C., Brown, Sarah M., Buchan, Blake W., Burnett, David, Burnett, Leslie, Bystrom, Cory, Cappellini, Maria Domenica, Caulfield, Adam J., Ceriotti, Ferruccio, Chabot-Richards, Devon, Chen, Derrick J., Chen, Dong, Cheng, Steven, Cheung, Nai-Kong V., Chiu, Rossa W.K., Clarke, Nigel J., Cole, Timothy J., Cooper, Mark, Dayspring, Thomas D., Delaney, Michael P., Dietzen, Dennis J., Doern, Christopher D., D’Orazio, Paul, Eisenhofer, Graeme, Ellervik, Christina, Florkowski, Christopher M., Forbes, Betty A., Fraser, Callum G., Fraser, William D., Freedman, Danielle B., Genzen, Jonathan R., George, Tracy I., Gettings, Katherine B., Glasziou, Paul, Goetze, Jens Peter, Grant, Russell P., Grebe, Stefan, Green, Ralph, Gronowski, Ann M., Guder, Walter G., Hage, David S., Halsall, David, Haverstick, Doris M., Hawker, Charles D., Heaton, Phillip, Higgins, Russell A., Hilmarsdóttir, Ingibjörg, Holstege, Chris, Hoofnagle, Andrew N., Hoon, Dave, Horowitz, Gary, Horvath, Andrea Rita, Howe, John Greg, Humphries, Romney M., Jaffe, Allan S., Jones, Graham R.D., Jones, Patricia M., Jungheim, Emily, Kelley, Todd W., Kitchen, Steve, Kricka, Larry J., Kushnir, Mark M., Lamb, Edmund J., Landers, James P., Langman, Loralie J., Laterza, Omar, Lau, Anna F., Lianidou, Evi, Liesman, Rachael M., Linnet, Kristian, Lo, Stanley F., Lo, Y.M. Dennis, Longo, Nicola, Mackay, Mark, Makrigiorgos, G. Mike, Manis, John P., Mardis, Elaine R., Marshall, William J., McCormack, Ann, McMillin, Gwendolyn A., Meier, Brenton M., Miller, W. Greg, Milone, Michael C., Moons, Karel G.M., Nerenz, Robert D., Nieuwesteeg, Michelle, Nikolac, Nora, Nolte, Frederick S., Panteghini, Mauro, Park, Jason Y., Pasquali, Marzia, Patel, Jay L., Patel, Robin, Podini, Daniele S., Pratt, Victoria M., Price, Christopher P., Pritt, Bobbi S., Quillen, Karen, Rappold, Brian A., Rashidi, Hooman H., Remaley, Alan T., Rifai, Nader, Roberts, Norman B., Rockwood, Alan L., Rosenberg, William, Sacks, David B., Sandberg, Sverre, Sardh, Eliane, Sarno, Mark J., Schindler, Emily I., Schuetz, Audrey N., Scott, Mitchell G., Sethi, Amar A., Shapiro, Howard M., Shaw, Leslie M., Sherwood, Roy A., Simundic, Ana-Maria, Sodi, Ravinder, St John, Andrew, Stout, Molly, Strathmann, Frederick G., Sturgeon, Catharine, Swinkels, Dorine W., Tanwar, Sudeep, Taylor, Andrew, Thatcher, Stephanie A., van Solinge, Wouter W., van Wijk, Richard, Vaught, Jim, Vnencak-Jones, Cindy L., Wadelius, Mia, Walsham, Natalie E., Warnick, G. Russell, Weedn, Victor W., Wells, David A., Wengenack, Nancy L., Whatley, Sharon D., Winter, William E., Wittwer, Carl T., Yarbrough, Melanie L., and Zhang, Qian-Yun

Published
2018
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106. Multisite Investigation of Strategies for the Implementation of CYP2C19 Genotype‐Guided Antiplatelet Therapy.

Author

on behalf of the IGNITE Network, Empey, Philip E., Stevenson, James M., Coons, James C., Owusu Obeng, Aniwaa, Peterson, Josh F., Petry, Natasha, Pratt, Victoria M., Scott, Stuart A., Skaar, Todd C., Stouffer, George A., Wilke, Russell A., Lee, Craig R., Tuteja, Sony, Weitzel, Kristin W., Johnson, Julie A., Cavallari, Larisa H., Angiolillo, Dominick J., Franchi, Francesco, and Rollini, Fabiana

Subjects
PLATELET aggregation inhibitors, GENOTYPES, PERCUTANEOUS coronary intervention, PHARMACOGENOMICS, AROMATASE
Abstract

CYP2C19 genotype‐guided antiplatelet therapy following percutaneous coronary intervention is increasingly implemented in clinical practice. However, challenges such as selecting a testing platform, communicating test results, building clinical decision support processes, providing patient and provider education, and integrating methods to support the translation of emerging evidence to clinical practice are barriers to broad adoption. In this report, we compare and contrast implementation strategies of 12 early adopters, describing solutions to common problems and initial performance metrics for each program. Key differences between programs included the test result turnaround time and timing of therapy changes, which are both related to the CYP2C19 testing model and platform used. Sites reported the need for new informatics infrastructure, expert clinicians such as pharmacists to interpret results, physician champions, and ongoing education. Consensus lessons learned are presented to provide a path forward for those seeking to implement similar clinical pharmacogenomics programs within their institutions. [ABSTRACT FROM AUTHOR]

Published
2018
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107. Recommendations for Clinical CYP2C9Genotyping Allele Selection

Author

Pratt, Victoria M., Cavallari, Larisa H., Del Tredici, Andria L., Hachad, Houda, Ji, Yuan, Moyer, Ann M., Scott, Stuart A., Whirl-Carrillo, Michelle, and Weck, Karen E.

Abstract

The goals of the Association for Molecular Pathology Pharmacogenomics (PGx) Working Group of the Association for Molecular Pathology Clinical Practice Committee are to define the key attributes of PGx alleles recommended for clinical testing and a minimum set of variants that should be included in clinical PGx genotyping assays. This document provides recommendations for a minimum panel of variant alleles (Tier 1) and an extended panel of variant alleles (Tier 2) that will aid clinical laboratories when designing assays for CYP2C9testing. The Working Group considered the functional impact of the variants, allele frequencies in different populations and ethnicities, the availability of reference materials, and other technical considerations for PGx testing when developing these recommendations. Our goal is to promote standardization of testing PGx genes and alleles across clinical laboratories. These recommendations are not to be interpreted as restrictive but to provide a reference guide. The current document will focus on CYP2C9testing that can be applied to all CYP2C9-related medications. A separate recommendation on warfarin PGx testing is being developed to include recommendations on CYP2C9alleles and additional warfarin sensitivity–associated genes and alleles.

Published
2019
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109. Report of New Haplotype for ABCC2 Gene

Author

Pratt, Victoria M., primary, Beyer, Brittany N., additional, Koller, Daniel L., additional, Skaar, Todd C., additional, Flockhart, David A., additional, Levy, Kenneth D., additional, and Vance, Gail H., additional

Published
2015
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112. Recommendations for Clinical CYP2C19Genotyping Allele Selection

Author

Pratt, Victoria M., Del Tredici, Andria L., Hachad, Houda, Ji, Yuan, Kalman, Lisa V., Scott, Stuart A., and Weck, Karen E.

Abstract

This document was developed by the Pharmacogenomics (PGx) Working Group of the Association for Molecular Pathology Clinical Practice Committee, whose aim is to recommend variants for inclusion in clinical pharmacogenomic testing panels. The goals of the Association for Molecular Pathology PGx Working Group are to define the key attributes of PGx alleles recommended for clinical testing and to define a minimum set of variants that should be included in clinical PGx genotyping assays. These recommendations include a minimum panel of variant alleles (tier 1) and an extended panel of variant alleles (tier 2) that will aid clinical laboratories when designing PGx assays. The Working Group considered variant allele frequencies in different populations and ethnicities, the availability of reference materials, and other technical considerations for PGx testing when developing these recommendations. These CYP2C19genotyping recommendations are the first of a series of recommendations for PGx testing. These recommendations are not to be interpreted as restrictive, but they are meant to provide a helpful guide.

Published
2018
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114. Opportunities and Challenges Associated with Clinical Diagnostic Genome Sequencing

Author

Schrijver, Iris, primary, Aziz, Nazneen, additional, Farkas, Daniel H., additional, Furtado, Manohar, additional, Gonzalez, Andrea Ferreira, additional, Greiner, Timothy C., additional, Grody, Wayne W., additional, Hambuch, Tina, additional, Kalman, Lisa, additional, Kant, Jeffrey A., additional, Klein, Roger D., additional, Leonard, Debra G.B., additional, Lubin, Ira M., additional, Mao, Rong, additional, Nagan, Narasimhan, additional, Pratt, Victoria M., additional, Sobel, Mark E., additional, Voelkerding, Karl V., additional, and Gibson, Jane S., additional

Published
2012
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119. Genetically Characterized Positive Control Cell Lines Derived from Residual Clinical Blood Samples

Author

Bernacki, Susan H, primary, Beck, Jeanne C, primary, Stankovic, Ana K, primary, Williams, Laurina O, primary, Amos, Jean, primary, Snow-Bailey, Karen, primary, Farkas, Daniel H, primary, Friez, Michael J, primary, Hantash, Feras M, primary, Matteson, Karla J, primary, Monaghan, Kristin G, primary, Muralidharan, Kasinathan, primary, Pratt, Victoria M, primary, Prior, Thomas W, primary, Richie, Kristy L, primary, Levin, Barbara C, primary, Rohlfs, Elizabeth M, primary, Schaefer, Frederick V, primary, Shrimpton, Antony E, primary, Spector, Elaine B, primary, Stolle, Catherine A, primary, Strom, Charles M, primary, Thibodeau, Stephen N, primary, Cole, Eugene C, primary, Goodman, Barbara K, primary, and Stenzel, Timothy T, primary

Published
2005
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120. Developing a Sustainable Process to Provide Quality Control Materials for Genetic Testing

Author

Chen, Bin, primary, O'Connell, Catherine D., additional, Boone, D Joe, additional, Amos, Jean A., additional, Beck, Jeanne C., additional, Chan, Maria M., additional, Farkas, Daniel H., additional, Lebo, Roger V., additional, Richards, Carolyn Sue, additional, Roa, Benjamin B., additional, Silverman, Lawrence M., additional, Barton, David E., additional, Bejjani, Bassem A., additional, Belloni, Dorothy R., additional, Bernacki, Susan H., additional, Caggana, Michele, additional, Charache, Patricia, additional, Dequeker, Elisabeth, additional, Ferreira-Gonzalez, Andrea, additional, Friedman, Kenneth J., additional, Greene, Carol L., additional, Grody, Wayne W., additional, Highsmith, William Edward, additional, Hinkel, Cecelia S., additional, Kalman, Lisa V., additional, Lubin, Ira M., additional, Lyon, Elaine, additional, Payne, Deborah A., additional, Pratt, Victoria M., additional, Rohlfs, Elizabeth, additional, Rundell, Clark A., additional, Schneider, Erasmus, additional, Willey, Ann M., additional, Williams, Laurina O., additional, Willey, James C., additional, Winn-Deen, Emily S., additional, and Wolff, Daynna J., additional

Published
2005
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121. Detection of 677CT/1298AC “double variant” chromosomes: Implications for interpretation of MTHFR genotyping results

Author

Brown, Nicholas M., primary, Pratt, Victoria M., additional, Buller, Arlene, additional, Pike-Buchanan, Lisa, additional, Redman, Joy B., additional, Sun, Weimin, additional, Chen, Rebecca, additional, Crossley, Beryl, additional, McGinniss, Matthew J., additional, Quan, Franklin, additional, and Strom, Charles M., additional

Published
2005
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122. Cystic fibrosis population carrier screening: 2004 revision of American College of Medical Genetics mutation panel

Author

Watson, Michael S., primary, Cutting, Garry R., additional, Desnick, Robert J., additional, Driscoll, Deborah A., additional, Klinger, Katherine, additional, Mennuti, Michael, additional, Palomaki, Glenn E., additional, Popovich, Bradley W., additional, Pratt, Victoria M., additional, Rohlfs, Elizabeth M., additional, Strom, Charles M., additional, Richards, C. Sue, additional, Witt, David R., additional, and Grody, Wayne W., additional

Published
2004
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123. CYP3A4and CYP3A5Genotyping Recommendations

Author

Pratt, Victoria M., Cavallari, Larisa H., Fulmer, Makenzie L., Gaedigk, Andrea, Hachad, Houda, Ji, Yuan, Kalman, Lisa V., Ly, Reynold C., Moyer, Ann M., Scott, Stuart A., van Schaik, R.H.N., Whirl-Carrillo, Michelle, and Weck, Karen E.

Abstract

The goals of the Association for Molecular Pathology Clinical Practice Committee's Pharmacogenomics (PGx) Working Group are to define the key attributes of pharmacogenetic alleles recommended for clinical testing and a minimum set of variants that should be included in clinical PGx genotyping assays. This document series provides recommendations for a minimum panel of variant alleles (tier 1) and an extended panel of variant alleles (tier 2) that will aid clinical laboratories when designing assays for PGx testing. The Association for Molecular Pathology PGx Working Group considered functional impact of the variant alleles, allele frequencies in multiethnic populations, the availability of reference materials, and other technical considerations for PGx testing when developing these recommendations. The goal of this Working Group is to promote standardization of PGx gene/allele testing across clinical laboratories. This document will focus on clinical CYP3A4and CYP3A5PGx testing that may be applied to all CYP3A4- and CYP3A5-related medications. These recommendations are not to be interpreted as prescriptive but to provide a reference guide.

Published
2023
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133. Development and Characterization of Reference Materials for MTHFR, SERPINA1, RET, BRCA1, and BRCA2Genetic Testing

Author

Barker, Shannon D., Bale, Sherri, Booker, Jessica, Buller, Arlene, Das, Soma, Friedman, Kenneth, Godwin, Andrew K., Grody, Wayne W., Highsmith, Edward, Kant, Jeffery A., Lyon, Elaine, Mao, Rong, Monaghan, Kristin G., Payne, Deborah A., Pratt, Victoria M., Schrijver, Iris, Shrimpton, Antony E., Spector, Elaine, Telatar, Milhan, Toji, Lorraine, Weck, Karen, Zehnbauer, Barbara, and Kalman, Lisa V.

Abstract

Well-characterized reference materials (RMs) are integral in maintaining clinical laboratory quality assurance for genetic testing. These RMs can be used for quality control, monitoring of test performance, test validation, and proficiency testing of DNA-based genetic tests. To address the need for such materials, the Centers for Disease Control and Prevention established the Genetic Testing Reference Material Coordination Program (GeT-RM), which works with the genetics community to improve public availability of characterized RMs for genetic testing. To date, the GeT-RM program has coordinated the characterization of publicly available genomic DNA RMs for a number of disorders, including cystic fibrosis, Huntington disease, fragile X, and several genetic conditions with relatively high prevalence in the Ashkenazi Jewish population. Genotypic information about a number of other cell lines has been collected and is also available. The present study includes the development and commutability/genotype characterization of 10 DNA samples for clinically relevant mutations or sequence variants in the following genes: MTHFR; SERPINA1; RET; BRCA1; and BRCA2. DNA samples were analyzed by 19 clinical genetic laboratories using a variety of assays and technology platforms. Concordance was 100% for all samples, with no differences observed between laboratories using different methods. All DNA samples are available from Coriell Cell Repositories and characterization information can be found on the GeT-RM website.

Published
2009
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134. CYP2C8, CYP2C9and CYP2C19characterization using Next Generation Sequencing and Haplotype Analysis: A GeT-RM Collaborative Project

Author

Gaedigk, Andrea, Boone, Erin C., Scherer, Steven E., Lee, Seung-been, Numanagić, Ibrahim, Sahinalp, Cenk, Smith, Joshua D., McGee, Sean, Radhakrishnan, Aparna, Qin, Xiang, Wang, Wendy Y., Farrow, Emily G., Gonzaludo, Nina, Halpern, Aaron L., Nickerson, Deborah A., Miller, Neil A., Pratt, Victoria M., and Kalman, Lisa V.

Abstract

Pharmacogenetic tests typically target selected sequence variants to identify haplotypes that are often defined by star (*) allele nomenclature. Due to their design, these targeted genotyping assays are unable to detect novel variants that may change the function of the gene product and thereby affect phenotype prediction and patient care. In the current study, 137 DNA samples that were previously characterized by the Genetic Testing Reference Material (GeT-RM) Program using a variety of targeted genotyping methods were recharacterized using targeted and whole genome sequencing analysis. Sequence data were analyzed using three genotype calling tools to identify star allele diplotypes for CYP2C8, CYP2C9and CYP2C19.The genotype calls from next-generation sequencing (NGS) correlated well to those previously reported, except when novel alleles were present in a sample. Six novel alleles and 38 novel suballeles were identified in the three genes due to identification of variants not covered by targeted genotyping assays. In addition, several ambiguous genotype calls from a previous study were resolved using the NGS and/or long read NGS data. Diplotype calls were mostly consistent between the calling algorithms, although several discrepancies were noted. This study highlights the utility of NGS for pharmacogenetic testing and demonstrates that there are many novel alleles that are yet to be discovered, even in highly characterized genes such as CYP2C9and CYP2C19.

Published
2022
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135. Consensus Characterization of 16 FMR1Reference Materials: A Consortium Study

Author

Amos Wilson, Jean, Pratt, Victoria M., Phansalkar, Amit, Muralidharan, Kasinathan, Highsmith, W. Edward, Beck, Jeanne C., Bridgeman, Scott, Courtney, Ebony M., Epp, Lidia, Ferreira-Gonzalez, Andrea, Hjelm, Nick L., Holtegaard, Leonard M., Jama, Mohamed A., Jakupciak, John P., Johnson, Monique A., Labrousse, Paul, Lyon, Elaine, Prior, Thomas W., Richards, C. Sue, Richie, Kristy L., Roa, Benjamin B., Rohlfs, Elizabeth M., Sellers, Tina, Sherman, Stephanie L., Siegrist, Karen A., Silverman, Lawrence M., Wiszniewska, Joanna, and Kalman, Lisa V.

Abstract

Fragile X syndrome, which is caused by expansion of a (CGG)nrepeat in the FMR1gene, occurs in approximately 1:3500 males and causes mental retardation/behavioral problems. Smaller (CGG)nrepeat expansions in FMR1, premutations, are associated with premature ovarian failure and fragile X-associated tremor/ataxia syndrome. An FMR1-sizing assay is technically challenging because of high GC content of the (CGG)nrepeat, the size limitations of conventional PCR, and a lack of reference materials available for test development/validation and routine quality control. The Centers for Disease Control and Prevention and the Association for Molecular Pathology, together with the genetic testing community, have addressed the need for characterized fragile X mutation reference materials by developing characterized DNA samples from 16 cell lines with repeat lengths representing important phenotypic classes and diagnostic cutoffs. The alleles in these materials were characterized by consensus analysis in nine clinical laboratories. The information generated from this study is available on the Centers for Disease Control and Prevention and Coriell Cell Repositories websites. DNA purified from these cell lines is available to the genetics community through the Coriell Cell Repositories. The public availability of these reference materials should help support accurate clinical fragile X syndrome testing.

Published
2008
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136. Detection of 677CT/1298AC “double variant” chromosomes: Implications for interpretation of MTHFRgenotyping results

Author

Brown, Nicholas M., Pratt, Victoria M., Buller, Arlene, Pike-Buchanan, Lisa, Redman, Joy B., Sun, Weimin, Chen, Rebecca, Crossley, Beryl, McGinniss, Matthew J., Quan, Franklin, and Strom, Charles M.

Abstract

Purpose: Genotyping 37,026 individuals as part of a thrombophilia evaluation, we determined and analyzed the genotypic frequencies of the 677CT and 1298AC mutations in the methylenetetrahydrofolate reductase (MTHFR) gene.

Published
2005
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137. Report of New Haplotype for ABCC2 Gene rs17222723 and rs8187718 in cis

Author

Pratt, Victoria M., Beyer, Brittany N., Koller, Daniel L., Skaar, Todd C., Flockhart, David A., Levy, Kenneth D., and Vance, Gail H.

Abstract

The ATP-binding cassette, subfamily C [CFTR/MRP], member 2 (ABCC2) gene is a member of the ATP-binding cassette transporters and is involved in the transport of molecules across cellular membranes. Substrates transported by ABCC2 include antiepileptics, statins, tenofovir, cisplatin, irinotecan, and carbamazepine. Because of the pharmacogenomics implications, we developed a clinical laboratory–developed assay to test for seven variants in the ABCC2 gene: c.3563T>A (p.V1188E, rs17222723), c.1249G>A (p.V417I, rs2273697), c.3972C>T (p.I1324I, rs3740066), c.2302C>T (p.R768W, rs56199535), c.2366C>T (p.S789F, rs56220353), c.-24C>T (5′UTR, rs717620), and c.4544G>A (p.C1515Y, rs8187710). During the validation process, we noted several DNA samples, obtained from the Coriell Cell Repository, that contained both c.3563T>A, c.4544G>A, and a third variant, suggesting that c.3563T>A and c.4544G>A are in cis on the chromosome in some individuals. We obtained DNA samples from a trio (father, mother, and child), tested their ABCC2 variants, and confirmed that c.3563T>A and c.4544G>A were in cis on the same chromosome. Here, we report a new haplotype in ABCC2.

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138. Revisiting Oversight and Regulation of Molecular-Based Laboratory-Developed Tests A Position Statement of the Association for Molecular Pathology

Author

Ferreira-Gonzalez, Andrea, Emmadi, Rajyasree, Day, Stephen P., Klees, Robert F., Leib, Jennifer R., Lyon, Elaine, Nowak, Jan A., Pratt, Victoria M., Williams, Mary S., and Klein, Roger D.

Subjects
health care economics and organizations
Abstract

Since 2006, the US Food and Drug Administration, Congress, and other policymakers have explored the appropriate way to guarantee the clinical and analytical validity of laboratory-developed tests. In the past, the Association for Molecular Pathology has publicly urged the Food and Drug Administration to exercise caution in implementing regulatory changes that could potentially hinder innovation or interfere with the practice of medicine. In 2012, the Association for Molecular Pathology Professional Relations Committee chose to develop this paper with the goal of outlining the best methods for ensuring appropriate oversight and validation of molecular diagnostic procedures. At the conclusion of this process, the workgroup reaffirmed the Association’s previous position that the Centers for Medicare and Medicaid Services Clinical Laboratory Improvement Amendments program can provide the appropriate level of oversight for the vast majority of diagnostic tests.

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139. Opportunities and Challenges Associated with Clinical Diagnostic Genome Sequencing A Report of the Association for Molecular Pathology

Author

Schrijver, Iris, Aziz, Nazneen, Farkas, Daniel H., Furtado, Manohar, Gonzalez, Andrea Ferreira, Greiner, Timothy C., Grody, Wayne W., Hambuch, Tina, Kalman, Lisa, Kant, Jeffrey A., Klein, Roger D., Leonard, Debra G.B., Lubin, Ira M., Mao, Rong, Nagan, Narasimhan, Pratt, Victoria M., Sobel, Mark E., Voelkerding, Karl V., and Gibson, Jane S.

Abstract

This report of the Whole Genome Analysis group of the Association for Molecular Pathology illuminates the opportunities and challenges associated with clinical diagnostic genome sequencing. With the reality of clinical application of next-generation sequencing, technical aspects of molecular testing can be accomplished at greater speed and with higher volume, while much information is obtained. Although this testing is a next logical step for molecular pathology laboratories, the potential impact on the diagnostic process and clinical correlations is extraordinary and clinical interpretation will be challenging. We review the rapidly evolving technologies; provide application examples; discuss aspects of clinical utility, ethics, and consent; and address the analytic, postanalytic, and professional implications.

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141. Implementing a pragmatic clinical trial to tailor opioids for chronic pain on behalf of the IGNITE ADOPT PGx investigators.

Author

Skaar TC, Myers RA, Fillingim RB, Callaghan JT, Cicali E, Eadon MT, Elwood EN, Ginsburg GS, Lynch S, Nguyen KA, Obeng AO, Park H, Pratt VM, Rosenman M, Sadeghpour A, Shuman S, Singh R, Tillman EM, Volpi S, Wiisanen K, Winterstein AG, Horowitz CR, Voora D, Orlando L, Chakraborty H, Van Driest S, Peterson JF, Cavallari LA, Johnson JA, and Dexter PR

Subjects
Adult, Female, Humans, Male, Middle Aged, Pain Management methods, Pain Measurement, Pharmacogenomic Testing, Precision Medicine methods, Analgesics, Opioid therapeutic use, Analgesics, Opioid adverse effects, Chronic Pain drug therapy, Cytochrome P-450 CYP2D6 genetics, Cytochrome P-450 CYP2D6 metabolism
Abstract

Chronic pain is a prevalent condition with enormous economic burden. Opioids such as tramadol, codeine, and hydrocodone are commonly used to treat chronic pain; these drugs are activated to more potent opioid receptor agonists by the hepatic CYP2D6 enzyme. Results from clinical studies and mechanistic understandings suggest that CYP2D6-guided therapy will improve pain control and reduce adverse drug events. However, CYP2D6 is rarely used in clinical practice due in part to the demand for additional clinical trial evidence. Thus, we designed the ADOPT-PGx (A Depression and Opioid Pragmatic Trial in Pharmacogenetics) chronic pain study, a multicenter, pragmatic, randomized controlled clinical trial, to assess the effect of CYP2D6 testing on pain management. The study enrolled 1048 participants who are taking or being considered for treatment with CYP2D6-impacted opioids for their chronic pain. Participants were randomized to receive immediate or delayed (by 6 months) genotyping of CYP2D6 with clinical decision support (CDS). CDS encouraged the providers to follow the CYP2D6-guided trial recommendations. The primary study outcome is the 3-month absolute change in the composite pain intensity score assessed using Patient-Reported Outcomes Measurement Information System (PROMIS) measures. Follow-up will be completed in July 2024. Herein, we describe the design of this trial along with challenges encountered during enrollment., (© 2024 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Published
2024
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142. Implementing a pragmatic clinical trial to tailor opioids for acute pain on behalf of the IGNITE ADOPT PGx investigators.

Author

Cavallari LH, Cicali E, Wiisanen K, Fillingim RB, Chakraborty H, Myers RA, Blake KV, Asiyanbola B, Baye JF, Bronson WH, Cook KJ, Elwood EN, Gray CF, Gong Y, Hines L, Kannry J, Kucher N, Lynch S, Nguyen KA, Obeng AO, Pratt VM, Prieto HA, Ramos M, Sadeghpour A, Singh R, Rosenman M, Starostik P, Thomas CD, Tillman E, Dexter PR, Horowitz CR, Orlando LA, Peterson JF, Skaar TC, Van Driest SL, Volpi S, Voora D, Parvataneni HK, and Johnson JA

Subjects
Humans, Codeine administration & dosage, Cytochrome P-450 CYP2D6 genetics, Cytochrome P-450 CYP2D6 metabolism, Hydrocodone administration & dosage, Practice Patterns, Physicians', Prospective Studies, Tramadol administration & dosage, Acute Pain diagnosis, Acute Pain drug therapy, Analgesics, Opioid administration & dosage, Pain, Postoperative diagnosis, Pain, Postoperative drug therapy
Abstract

Opioid prescribing for postoperative pain management is challenging because of inter-patient variability in opioid response and concern about opioid addiction. Tramadol, hydrocodone, and codeine depend on the cytochrome P450 2D6 (CYP2D6) enzyme for formation of highly potent metabolites. Individuals with reduced or absent CYP2D6 activity (i.e., intermediate metabolizers [IMs] or poor metabolizers [PMs], respectively) have lower concentrations of potent opioid metabolites and potentially inadequate pain control. The primary objective of this prospective, multicenter, randomized pragmatic trial is to determine the effect of postoperative CYP2D6-guided opioid prescribing on pain control and opioid usage. Up to 2020 participants, age ≥8 years, scheduled to undergo a surgical procedure will be enrolled and randomized to immediate pharmacogenetic testing with clinical decision support (CDS) for CYP2D6 phenotype-guided postoperative pain management (intervention arm) or delayed testing without CDS (control arm). CDS is provided through medical record alerts and/or a pharmacist consult note. For IMs and PM in the intervention arm, CDS includes recommendations to avoid hydrocodone, tramadol, and codeine. Patient-reported pain-related outcomes are collected 10 days and 1, 3, and 6 months after surgery. The primary outcome, a composite of pain intensity and opioid usage at 10 days postsurgery, will be compared in the subgroup of IMs and PMs in the intervention (n = 152) versus the control (n = 152) arm. Secondary end points include prescription pain medication misuse scores and opioid persistence at 6 months. This trial will provide data on the clinical utility of CYP2D6 phenotype-guided opioid selection for improving postoperative pain control and reducing opioid-related risks., (© 2022 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Published
2022
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143. Multisite Investigation of Strategies for the Implementation of CYP2C19 Genotype-Guided Antiplatelet Therapy.

Author

Empey PE, Stevenson JM, Tuteja S, Weitzel KW, Angiolillo DJ, Beitelshees AL, Coons JC, Duarte JD, Franchi F, Jeng LJB, Johnson JA, Kreutz RP, Limdi NA, Maloney KA, Owusu Obeng A, Peterson JF, Petry N, Pratt VM, Rollini F, Scott SA, Skaar TC, Vesely MR, Stouffer GA, Wilke RA, Cavallari LH, and Lee CR

Subjects
Clinical Decision-Making, Clopidogrel adverse effects, Cytochrome P-450 CYP2C19 metabolism, Genotype, Humans, Interdisciplinary Communication, Patient Care Team, Patient Selection, Phenotype, Platelet Aggregation Inhibitors adverse effects, Predictive Value of Tests, Program Development, Program Evaluation, United States, Clopidogrel therapeutic use, Cytochrome P-450 CYP2C19 genetics, Percutaneous Coronary Intervention adverse effects, Pharmacogenetics methods, Pharmacogenomic Testing, Pharmacogenomic Variants, Platelet Aggregation Inhibitors therapeutic use, Precision Medicine methods
Abstract

CYP2C19 genotype-guided antiplatelet therapy following percutaneous coronary intervention is increasingly implemented in clinical practice. However, challenges such as selecting a testing platform, communicating test results, building clinical decision support processes, providing patient and provider education, and integrating methods to support the translation of emerging evidence to clinical practice are barriers to broad adoption. In this report, we compare and contrast implementation strategies of 12 early adopters, describing solutions to common problems and initial performance metrics for each program. Key differences between programs included the test result turnaround time and timing of therapy changes, which are both related to the CYP2C19 testing model and platform used. Sites reported the need for new informatics infrastructure, expert clinicians such as pharmacists to interpret results, physician champions, and ongoing education. Consensus lessons learned are presented to provide a path forward for those seeking to implement similar clinical pharmacogenomics programs within their institutions., (© 2018 American Society for Clinical Pharmacology and Therapeutics.)

Published
2018
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144. Codeine Therapy and CYP2D6 Genotype

Author

Pratt VM, Scott SA, Pirmohamed M, Esquivel B, Kane MS, Kattman BL, and Malheiro AJ

Abstract

Codeine is used to relieve mild to moderately severe pain, and it belongs to the drug class of opioid analgesics. Codeine has also been prescribed to prevent coughing, though the antitussive administration is most often in liquid formulations and in conjunction with other medications. (1, 2) The hepatic CYP2D6 enzyme metabolizes a quarter of all prescribed drugs, including codeine. The CYP2D6 enzyme converts codeine into its active metabolite, morphine, which provides its analgesic effect. Consequently, pain relief may be inadequate in individuals who have 2 inactive copies of CYP2D6 (“poor metabolizers”, PMs), because of reduced morphine levels. In contrast, individuals who have more than 2 normal-function copies of the CYP2D6 gene (“ultrarapid metabolizers”, UMs) are able to metabolize codeine to morphine more rapidly and more completely. As a result, even with therapeutic doses of codeine, these individuals may experience the symptoms of morphine overdose, which include extreme sleepiness, confusion, and shallow breathing, which in some instances can be fatal. Nursing mothers with ultrarapid CYP2D6 metabolism may also produce breast milk containing higher than expected levels of morphine that can lead to severe adverse events in their infants. (3) The FDA-drug label for codeine states that even at labeled dosage regimens, individuals who are UMs may have life-threatening or fatal respiratory depression or experience signs of overdose (Table 1). The label also contains a boxed warning, which states that respiratory depression and death have occurred in children who received codeine following tonsillectomy, adenoidectomy, or both, and had evidence of being CYP2D6 UMs. The Clinical Pharmacogenetics Implementation Consortium (CPIC) recommends that for an individual identified as a CYP2D6 UM, another analgesic should be used to avoid the risk of severe toxicity with a “normal” dose of codeine. CPIC also recommends avoiding codeine in individuals identified as CYP2D6 PMs due to the possibility of lack of effect (Table 2). (4) The Dutch Pharmacogenetics Working Group (DPWG) have published codeine dosing recommendations based on CYP2D6 genotype, and condition being treated (cough or pain), typical dosing, and additional risk factors, such as reduced kidney function or co-medication with CYP3A4 inhibitors. For UMs, the DPWG recommends an alternative to codeine for the treatment of pain (for example, oxycodone) (Table 3). (5)

Published
2012

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