Weck, Karen E.

Context.— As pharmacogenetic testing is incorporated into routine care, it is essential for laboratories to provide accurate and consistent results. Certified laboratories must successfully complete proficiency testing. Objectives.— To understand and examine trends in participation and performance of laboratories participating in the College of American Pathologists pharmacogenetic proficiency testing surveys. Design.— Results from College of American Pathologists pharmacogenetic proficiency testing challenges from 2012 through 2017 were reviewed for concordance with expected genotype and phenotype for each sample (intended responses). Results.— Laboratories correctly reported results for 96.7% to 100% of samples with no variants. Excluding CYP2D6, laboratories correctly detected and reported variant alleles for each gene (93.7%–99.2% correct). CYP2D6 showed lower concordance, with 83.1% of laboratories reporting the intended genotype across all samples; however, in many cases, the laboratories that did not report a variant allele did not test for that allele. Among laboratories reporting the intended genotype, most successfully reported the intended phenotype (85.9%–99.0%). Conclusions.— Although laboratories are generally performing well, there is room for additional improvement, particularly for challenging genes, such as CYP2D6. Efforts in the field of pharmacogenomics to recommend alleles that should be included in clinical tests, identify reference materials, and standardize translation from genotype to phenotype may address some of the remaining variability in results.

Context.— The College of American Pathologists proficiency testing program has been instrumental in identifying problems in clinical testing. Objective.— To describe how this program was used to identify a single-nucleotide polymorphism that affects clinical testing for spinocerebellar ataxia type 3. Design.— A proficiency testing sample with discordant results for spinocerebellar ataxia type 3 analysis was further evaluated by targeted Sanger sequencing and genotype polymerase chain reaction using multiple DNA polymerases. Results.— Of 28 laboratories responding in the spinocerebellar ataxia type 3 Proficiency Survey, 18 reported an incorrect homozygous result and 10 reported the expected heterozygous result. A heterozygous single-nucleotide polymorphism complementary to the 3′ end of a published forward primer was identified in the proficiency testing sample, which may have led to allele dropout. However, this primer was used by only 3 of 18 laboratories (16%) reporting a homozygous result. A new forward primer of identical sequence, except for the 3′ end being complementary to the single-nucleotide polymorphism, showed the expected heterozygous pattern. The possibility of DNA polymerase 3′-5′ exonuclease activity contributing to allele dropout was investigated by testing 9 additional polymerases with and without exonuclease activity. No clear pattern emerged, but enzymes with and without 3′-5′ exonuclease activity yielded both homozygous and expected heterozygous results with the published forward primer. Conclusions.— Proactive systematic primer sequence checking is recommended because single-nucleotide polymorphism interference may result in allele dropout and impact clinical testing. Allele dropout is also influenced by other factors, including DNA polymerase exonuclease activity.

Abstract Objective Clinicians’ ability to use and interpret genetic information depends upon how those data are displayed in electronic health records (EHRs). There is a critical need to develop systems to effectively display genetic information in EHRs and augment clinical decision support (CDS). Materials and Methods The National Institutes of Health (NIH)-sponsored Clinical Sequencing Exploratory Research and Electronic Medical Records & Genomics EHR Working Groups conducted a multiphase, iterative process involving working group discussions and 2 surveys in order to determine how genetic and genomic information are currently displayed in EHRs, envision optimal uses for different types of genetic or genomic information, and prioritize areas for EHR improvement. Results There is substantial heterogeneity in how genetic information enters and is documented in EHR systems. Most institutions indicated that genetic information was displayed in multiple locations in their EHRs. Among surveyed institutions, genetic information enters the EHR through multiple laboratory sources and through clinician notes. For laboratory-based data, the source laboratory was the main determinant of the location of genetic information in the EHR. The highest priority recommendation was to address the need to implement CDS mechanisms and content for decision support for medically actionable genetic information. Conclusion Heterogeneity of genetic information flow and importance of source laboratory, rather than clinical content, as a determinant of information representation are major barriers to using genetic information optimally in patient care. Greater effort to develop interoperable systems to receive and consistently display genetic and/or genomic information and alert clinicians to genomic-dependent improvements to clinical care is recommended.