Semiautomated approach focused on new genomic information results in time and effort-efficient reannotation of negative exome data.

Most rare disease patients (75-50%) undergoing genomic sequencing remain unsolved, often due to lack of information about variants identified. Data review over time can leverage novel information regarding disease-causing variants and genes, increasing this diagnostic yield. However, time and resource constraints have limited reanalysis of genetic data in clinical laboratories setting. We developed RENEW, (REannotation of NEgative WES/WGS) an automated reannotation procedure that uses relevant new information in on-line genomic databases to enable rapid review of genomic findings. We tested RENEW in an unselected cohort of 1066 undiagnosed cases with a broad spectrum of phenotypes from the Mayo Clinic Center for Individualized Medicine using new information in ClinVar, HGMD and OMIM between the date of previous analysis/testing and April of 2022. 5741 variants prioritized by RENEW were rapidly reviewed by variant interpretation specialists. Mean analysis time was approximately 20 s per variant (32 h total time). Reviewed cases were classified as: 879 (93.0%) undiagnosed, 63 (6.6%) putatively diagnosed, and 4 (0.4%) definitively diagnosed. New strategies are needed to enable efficient review of genomic findings in unsolved cases. We report on a fast and practical approach to address this need and improve overall diagnostic success in patient testing through a recurrent reannotation process.

Implementation of genomic medicine for rare disease in a tertiary healthcare system: Mayo Clinic Program for Rare and Undiagnosed Diseases (PRaUD).

BACKGROUND: In the United States, rare disease (RD) is defined as a condition that affects fewer than 200,000 individuals. Collectively, RD affects an estimated 30 million Americans. A significant portion of RD has an underlying genetic cause; however, this may go undiagnosed. To better serve these patients, the Mayo Clinic Program for Rare and Undiagnosed Diseases (PRaUD) was created under the auspices of the Center for Individualized Medicine (CIM) aiming to integrate genomics into subspecialty practice including targeted genetic testing, research, and education. METHODS: Patients were identified by subspecialty healthcare providers from 11 clinical divisions/departments. Targeted multi-gene panels or custom exome/genome-based panels were utilized. To support the goals of PRaUD, a new clinical service model, the Genetic Testing and Counseling (GTAC) unit, was established to improve access and increase efficiency for genetic test facilitation. The GTAC unit includes genetic counselors, genetic counseling assistants, genetic nurses, and a medical geneticist. Patients receive abbreviated point-of-care genetic counseling and testing through a partnership with subspecialty providers. RESULTS: Implementation of PRaUD began in 2018 and GTAC unit launched in 2020 to support program expansion. Currently, 29 RD clinical indications are included in 11 specialty divisions/departments with over 142 referring providers. To date, 1152 patients have been evaluated with an overall solved or likely solved rate of 17.5% and as high as 66.7% depending on the phenotype. Noteworthy, 42.7% of the solved or likely solved patients underwent changes in medical management and outcome based on genetic test results. CONCLUSION: Implementation of PRaUD and GTAC have enabled subspecialty practices advance expertise in RD where genetic counselors have not historically been embedded in practice. Democratizing access to genetic testing and counseling can broaden the reach of patients with RD and increase the diagnostic yield of such indications leading to better medical management as well as expanding research opportunities.

Nine-gene pharmacogenomics profile service: The Mayo Clinic experience.

PURPOSE: The Pharmacogenomics (PGx) Profile Service was a proof-of-concept project to implement PGx in patient care at Mayo Clinic. METHODS: Eighty-two healthy individuals aged 18 and older underwent genotyping of CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, SLCO1B1, HLA-B*58:01, and VKORC1. A PGx pharmacist was involved in ordering, meeting with patients, interpreting, reviewing, and documenting results. RESULTS: Ninety three percent were CYP1A2 rapid metabolizers, 92% CYP3A4 normal metabolizers, and 88% CYP3A5 poor metabolizers; phenotype frequencies for CYP2C19 and CYP2D6 varied. Seventy-three percent had normal functioning SLCO1B1 transporter, 4% carried the HLA-B*58:01 risk variant, and 35% carried VKORC1 and CYP2C9 variants that increased warfarin sensitivity. CONCLUSION: Pre-emptive PGx testing offered medication improvement opportunity in 56% of participants for commonly used medications. A collaborative approach involving a PGx pharmacist integrated within a clinical practice with regards to utility of PGx results allowed for implementation of the PGx Profile Service. KEY POINTS: The Mayo Clinic PGx (PGx) Profile Service was a proof-of-concept project to utilize PGx testing as another clinical tool to enhance medication selection and decrease serious adverse reactions or medication failures. Over one-half of participants in the pilot using the PGx Profile Service were predicted to benefit from pre-emptive PGx testing to guide pharmacotherapy. PGx pharmacists played a crucial role in the PGx Profile Service by educating participants, identifying medication-gene interactions, and providing evidence-based (CPIC and DPWG) PGx recommendations for past, current, and future medication us.

Implementation of preemptive DNA sequence-based pharmacogenomics testing across a large academic medical center: The Mayo-Baylor RIGHT 10K Study.

PURPOSE: The Mayo-Baylor RIGHT 10K Study enabled preemptive, sequence-based pharmacogenomics (PGx)-driven drug prescribing practices in routine clinical care within a large cohort. We also generated the tools and resources necessary for clinical PGx implementation and identified challenges that need to be overcome. Furthermore, we measured the frequency of both common genetic variation for which clinical guidelines already exist and rare variation that could be detected by DNA sequencing, rather than genotyping. METHODS: Targeted oligonucleotide-capture sequencing of 77 pharmacogenes was performed using DNA from 10,077 consented Mayo Clinic Biobank volunteers. The resulting predicted drug response-related phenotypes for 13 genes, including CYP2D6 and HLA, affecting 21 drug-gene pairs, were deposited preemptively in the Mayo electronic health record. RESULTS: For the 13 pharmacogenes of interest, the genomes of 79% of participants carried clinically actionable variants in 3 or more genes, and DNA sequencing identified an average of 3.3 additional conservatively predicted deleterious variants that would not have been evident using genotyping. CONCLUSION: Implementation of preemptive rather than reactive and sequence-based rather than genotype-based PGx prescribing revealed nearly universal patient applicability and required integrated institution-wide resources to fully realize individualized drug therapy and to show more efficient use of health care resources.

Participant-perceived understanding and perspectives on pharmacogenomics: the Mayo Clinic RIGHT protocol (Right Drug, Right Dose, Right Time).

PURPOSE: To examine predictors of understanding preemptive CYP2D6 pharmacogenomics test results and to identify key features required to improve future educational efforts of preemptive pharmacogenomics testing. METHODS: One thousand ten participants were surveyed after receiving preemptive CYP2D6 pharmacogenomics test results. RESULTS: Eighty-six percent (n = 869) of patients responded. Of the responders, 98% were white and 55% were female; 57% had 4 years or more of post-secondary education and an average age of 58.9 ± 5.5 years. Twenty-six percent said that they only somewhat understood their results and 7% reported they did not understand them at all. Only education predicted understanding. The most common suggestion for improvement was the use of layperson's terms when reporting results. In addition, responders suggested that results should be personalized by referring to medications that they were currently using. Of those reporting imperfect drug adherence, most (91%) reported they would be more likely to use medication as prescribed if pharmacogenomic information was used to help select the drug or dose. CONCLUSION: Despite great efforts to simplify pharmacogenomic results (or because of them), approximately one-third of responders did not understand their results. Future efforts need to provide more examples and tailor results to the individual. Incorporation of pharmacogenomics is likely to improve medication adherence.Genet Med advance online publication 05 January 2017.

Multidisciplinary model to implement pharmacogenomics at the point of care.

PURPOSE: Despite potential clinical benefits, implementation of pharmacogenomics (PGx) faces many technical and clinical challenges. These challenges can be overcome with a comprehensive and systematic implementation model. METHODS: The development and implementation of PGx were organized into eight interdependent components addressing resources, governance, clinical practice, education, testing, knowledge translation, clinical decision support (CDS), and maintenance. Several aspects of implementation were assessed, including adherence to the model, production of PGx-CDS interventions, and access to educational resources. RESULTS: Between August 2012 and June 2015, 21 specific drug-gene interactions were reviewed and 18 of them were implemented in the electronic medical record as PGx-CDS interventions. There was complete adherence to the model with variable production time (98-392 days) and delay time (0-148 days). The implementation impacted approximately 1,247 unique providers and 3,788 unique patients. A total of 11 educational resources complementary to the drug-gene interactions and 5 modules specific for pharmacists were developed and implemented. CONCLUSION: A comprehensive operational model can support PGx implementation in routine prescribing. Institutions can use this model as a roadmap to support similar efforts. However, we also identified challenges that will require major multidisciplinary and multi-institutional efforts to make PGx a universal reality.Genet Med 19 4, 421-429.

Implementing individualized medicine into the medical practice.

There is increasing recognition that genomic medicine as part of individualized medicine has a defined role in patient care. Rapid advances in technology and decreasing cost combine to bring genomic medicine closer to the clinical practice. There is also growing evidence that genomic-based medicine can advance patient outcomes, tailor therapy and decrease side effects. However the challenges to integrate genomics into the workflow involved in patient care remain vast, stalling assimilation of genomic medicine into mainstream medical practice. In this review we describe the approach taken by one institution to further individualize medicine by offering, executing and interpreting whole exome sequencing on a clinical basis through an enterprise-wide, standalone individualized medicine clinic. We present our experience designing and executing such an individualized medicine clinic, sharing lessons learned and describing early implementation outcomes.

Diagnostic yield of exome and genome sequencing after non-diagnostic multi-gene panels in patients with single-system diseases.

BACKGROUND: Though next-generation sequencing (NGS) tests like exome sequencing (ES), genome sequencing (GS), and panels derived from exome and genome data (EGBP) are effective for rare diseases, the ideal diagnostic approach is debated. Limited research has explored reanalyzing raw ES and GS data post-negative EGBP results for diagnostics. RESULTS: We analyzed complete ES/GS raw sequencing data from Mayo Clinic's Program for Rare and Undiagnosed Diseases (PRaUD) patients to assess whether supplementary findings could augment diagnostic yield. ES data from 80 patients (59 adults) and GS data from 20 patients (10 adults), averaging 43 years in age, were analyzed. Most patients had renal (n=44) and auto-inflammatory (n=29) phenotypes. Ninety-six cases had negative findings and in four cases additional genetic variants were found, including a variant related to a recently described disease (RRAGD-related hypomagnesemia), a variant missed due to discordant inheritance pattern (COL4A3), a variant with high allelic frequency (NPHS2) in the general population, and a variant associated with an initially untargeted phenotype (HNF1A). CONCLUSION: ES and GS show diagnostic yields comparable to EGBP for single-system diseases. However, EGBP's limitations in detecting new disease-associated genes underscore the necessity for periodic updates.

Development of Competency-based Online Genomic Medicine Training (COGENT).

The fields of genetics and genomics have greatly expanded across medicine through the development of new technologies that have revealed genetic contributions to a wide array of traits and diseases. Thus, the development of widely available educational resources for all healthcare providers is essential to ensure the timely and appropriate utilization of genetics and genomics patient care. In 2020, the National Human Genome Research Institute released a call for new proposals to develop accessible, sustainable online education for health providers. This paper describes the efforts of the six teams awarded to reach the goal of providing genetic and genomic training modules that are broadly available for busy clinicians.

Pharmacogenomics education and perceptions: is there a gap between internal medicine resident and attending physicians?

Aim: To determine if differences in self-reported pharmacogenomics knowledge, skills and perceptions exist between internal medicine residents and attending physicians. Materials & methods: Forty-six internal medicine residents and 54 attending physicians completed surveys. Thirteen participated in focus groups to explore themes emerging from the surveys. Results: Resident physicians reported a greater amount of pharmacogenomics training compared with attending physicians (48 vs 13%, p < 0.00012). No differences were found in self-reported knowledge, skills and perceptions. Conclusion: Both groups expressed pharmacogenomics was relevant to their current clinical practice; they should be able to provide information to patients and use to guide prescribing, but lacked sufficient education to be able to do so effectively. Practical approaches are needed to teach pharmacogenomics concepts and address point of care gaps.

An assessment of patient perspectives on pharmacogenomics educational materials.

Aim: Pharmacogenomics (PGx) holds potential to improve patient treatment; yet, effective patient educational materials are limited. Materials & methods: Using a 'think aloud' technique, we sought to understand comprehension and perceptions of a multimedia PGx results packet including a cover letter with QR code to an educational video, brochure and prototype report in the context of PGx case vignettes. Results: The cover letter and video components were viewed less favorably due to excess detail, complex jargon and technology challenges. Recommendations were to enhance comprehension and utility and to customize materials to each patient's medications or disease conditions. Conclusion: Educational materials were revised to improve comprehension and usability, and diminish concerns to better prepare patients to understand the importance of discussing test results with their provider.

Education and Knowledge in Pharmacogenomics: Still a Challenge?

A number of barriers exist for adoption of pharmacogenomics into practice. Physicians, pharmacists, and nurses report limited knowledge about pharmacogenomics and its use in patient care. Lack of pharmacogenomics education curricula as part of professional schools or postgraduate training programs has been reported as a potential cause. Understanding pharmacogenomics is further complicated by a complex and nonstandard lexicon, limited medication guidelines, rapidly changing evidence, and insufficient awareness of test availability and utility.

Healthcare provider education to support integration of pharmacogenomics in practice: the eMERGE Network experience.

Ten organizations within the Electronic Medical Records and Genomics Network developed programs to implement pharmacogenomic sequencing and clinical decision support into clinical settings. Recognizing the importance of informed prescribers, a variety of strategies were used to incorporate provider education to support implementation. Education experiences with pharmacogenomics are described within the context of each organization's prior involvement, including the scope and scale of implementation specific to their Electronic Medical Records and Genomics projects. We describe common and distinct education strategies, provide exemplars and share challenges. Lessons learned inform future perspectives. Future pharmacogenomics clinical implementation initiatives need to include funding toward implementing provider education and evaluating outcomes.

Pharmacokinetic Pharmacogenetic Prescribing Guidelines for Antidepressants: A Template for Psychiatric Precision Medicine.

Antidepressants are commonly prescribed medications in the United States, and there is increasing interest in individualizing treatment selection for more than 20 US Food and Drug Administration-approved treatments for major depressive disorder. Providing greater precision to pharmacotherapeutic recommendations for individual patients beyond the large-scale clinical trials evidence base can potentially reduce adverse effect toxicity profiles and increase response rates and overall effectiveness. It is increasingly recognized that genetic variation may contribute to this differential risk to benefit ratio and thus provides a unique opportunity to develop pharmacogenetic guidelines for psychiatry. Key studies and concepts that review the rationale for cytochrome P450 2D6 (CYP2D6) and cytochrome P450 2C19 (CYP2C19) genetic testing can be delineated by serum levels, adverse events, and clinical outcome measures (eg, antidepressant response). In this article, we report the evidence that contributed to the implementation of pharmacokinetic pharmacogenetic guidelines for antidepressants primarily metabolized by CYP2D6 and CYP2C19.

Integrating Pharmacogenomics into Clinical Practice: Promise vs Reality.

BACKGROUND: Limited information is available regarding primary care clinicians' response to pharmacogenomic clinical decision support (PGx-CDS) alerts integrated in the electronic health record. METHODS: In February 2015, 159 clinicians in the Mayo Clinic primary care practice were sent e-mail surveys to understand their perspectives on the implementation and use of pharmacogenomic testing in their clinical practice. Surveys assessed how the clinicians felt about pharmacogenomics and whether they thought electronic PGx-CDS alerts were useful. Information was abstracted on the number of CDS alerts the clinicians received between October 2013 and the date their survey was returned. CDS alerts were grouped into 2 categories: the alert recommended caution using the prescription, or the alert recommended an alternate prescription. Finally, data were abstracted regarding whether the clinician changed their prescription in response to the alert recommendation. RESULTS: The survey response rate was 57% (n = 90). Overall, 52% of the clinicians did not expect to use or did not know whether they would use pharmacogenomic information in their future prescribing practices. Additionally, 53% of the clinicians felt that the alerts were confusing, irritating, frustrating, or that it was difficult to find additional information. Finally, only 30% of the clinicians that received a CDS alert changed their prescription to an alternative medication. CONCLUSIONS: Our results suggest a lack of clinician comfort with integration of pharmacogenomic data into primary care. Further efforts to refine PGx-CDS alerts to make them as useful and user-friendly as possible are needed to improve clinician satisfaction with these new tools.

Practical considerations for implementing genomic information resources. Experiences from eMERGE and CSER.

OBJECTIVES: To understand opinions and perceptions on the state of information resources specifically targeted to genomics, and approaches to delivery in clinical practice. METHODS: We conducted a survey of genomic content use and its clinical delivery from representatives across eight institutions in the electronic Medical Records and Genomics (eMERGE) network and two institutions in the Clinical Sequencing Exploratory Research (CSER) consortium in 2014. RESULTS: Eleven responses representing distinct projects across ten sites showed heterogeneity in how content is being delivered, with provider-facing content primarily delivered via the electronic health record (EHR) (n=10), and paper/pamphlets as the leading mode for patient-facing content (n=9). There was general agreement (91%) that new content is needed for patients and providers specific to genomics, and that while aspects of this content could be shared across institutions there remain site-specific needs (73% in agreement). CONCLUSION: This work identifies a need for the improved access to and expansion of information resources to support genomic medicine, and opportunities for content developers and EHR vendors to partner with institutions to develop needed resources, and streamline their use - such as a central content site in multiple modalities while implementing approaches to allow for site-specific customization.

Evaluation of the use of clinical decision support and online resources for pharmacogenomics education.

AIM: To assess impact and value of using clinical decision support (CDS) to drive providers toward online pharmacogenomics education. MATERIALS & METHODS: CDS was used to target prescribers of codeine/tramadol, send an educational email, display alert/inbox and provide links to an online resource. Providers were surveyed to assess impact. RESULTS: Of the methods used to target providers, educational email was more effective (7.2%). Survey response rate was 29.2% (n = 528/1817). Of respondents, 57.4% reported opening the email and 27.1% accessed the online resource. Of those accessing the resource, 89% found it useful and learned something new about pharmacogenomics. CONCLUSION: The impact of using CDS to target pharmacogenomics education was limited. However, providers accessing the online resource found it useful and educational.

Development and initial validation of a project-based rubric to assess the systems-based practice competency of residents in the clinical chemistry rotation of a pathology residency.

CONTEXT: Systems-based practice (SBP) is 1 of 6 core competencies required in all resident training programs accredited by the Accreditation Council for Graduate Medical Education. Reliable methods of assessing resident competency in SBP have not been described in the medical literature. OBJECTIVE: To develop and validate an analytic grading rubric to assess pathology residents' analyses of SBP problems in clinical chemistry. DESIGN: Residents were assigned an SBP project based upon unmet clinical needs in the clinical chemistry laboratories. Using an iterative method, we created an analytic grading rubric based on critical thinking principles. Four faculty raters used the SBP project evaluation rubric to independently grade 11 residents' projects during their clinical chemistry rotations. Interrater reliability and Cronbach α were calculated to determine the reliability and validity of the rubric. Project mean scores and range were also assessed to determine whether the rubric differentiated resident critical thinking skills related to the SBP projects. RESULTS: Overall project scores ranged from 6.56 to 16.50 out of a possible 20 points. Cronbach α ranged from 0.91 to 0.96, indicating that the 4 rubric categories were internally consistent without significant overlap. Intraclass correlation coefficients ranged from 0.63 to 0.81, indicating moderate to strong interrater reliability. CONCLUSIONS: We report development and statistical analysis of a novel SBP project evaluation rubric. The results indicate the rubric can be used to reliably assess pathology residents' critical thinking skills in SBP.