Engaging adolescents and young adults in decisions about return of genomic research results: study protocol for a mixed-methods longitudinal clinical trial protocol.

Background: To protect minors' future autonomy, professional organizations have historically discouraged returning predictive adult-onset genetic test results and carrier status to children. Recent clinical guidance diverges from this norm, suggesting that when minors have genomic sequencing performed for clinical purposes, parents and children should have the opportunity to learn secondary findings, including for some adult-onset conditions. While parents can currently opt in or out of receiving their child's secondary findings, the American Society of Human Genetics Workgroup on Pediatric Genetic and Genomic Testing suggests including adolescents in the decision-making process.

Genetic sex validation for sample tracking in next-generation sequencing clinical testing.

Objective: Data from DNA genotyping via a 96-SNP panel in a study of 25,015 clinical samples were utilized for quality control and tracking of sample identity in a clinical sequencing network. The study aimed to demonstrate the value of both the precise SNP tracking and the utility of the panel for predicting the sex-by-genotype of the participants, to identify possible sample mix-ups.

Results: Precise SNP tracking showed no sample swap errors within the clinical testing laboratories.

Selection, optimization and validation of ten chronic disease polygenic risk scores for clinical implementation in diverse US populations.

Polygenic risk scores (PRSs) have improved in predictive performance, but several challenges remain to be addressed before PRSs can be implemented in the clinic, including reduced predictive performance of PRSs in diverse populations, and the interpretation and communication of genetic results to both providers and patients. To address these challenges, the National Human Genome Research Institute-funded Electronic Medical Records and Genomics (eMERGE) Network has developed a framework and pipeline for return of a PRS-based genome-informed risk assessment to 25,000 diverse adults and children as part of a clinical study. From an initial list of 23 conditions, ten were selected for implementation based on PRS performance, medical actionability and potential clinical utility, including cardiometabolic diseases and cancer.

Genetic Sex Validation for Sample Tracking in Clinical Testing.

Objective: Data from DNA genotyping via a 96-SNP panel in a study of 25,015 clinical samples were utilized for quality control and tracking of sample identity in a clinical sequencing network. The study aimed to demonstrate the value of both the precise SNP tracking and the utility of the panel for predicting the sex-by-genotype of the participants, to identify possible sample mix-ups.

Results: Precise SNP tracking showed no sample swap errors within the clinical testing laboratories.

Current Practices in Pharmacogenomics.

Pharmacogenomics, where genomic information is used to tailor medication management, is a strategy to maximize drug efficacy and minimize toxicity. Although pediatric evidence is less robust than for adults, medications influenced by pharmacogenomics are prescribed to children and adolescents. Evidence-based guidelines and drug label annotations are available from the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Pharmacogenomics Knowledgebase (PharmGKB).

Young adults' reasoning for involving a parent in a genomic decision-making research study.

Young adults have increasing genomic testing opportunities; however, little is known about how equipped they feel about making decisions to learn personal genomic information. We conducted qualitative interviews with 19 young adults, ages 18-21 years old, enrolled in a research study where they made decisions about learning personal genomic risk for developing preventable, treatable, and adult-onset conditions and carrier status for autosomal recessive conditions. Participants had the option to include a parent in their study visit and the decision-making process.

Studying the impact of translational genomic research: Lessons from eMERGE.

Two major goals of the Electronic Medical Record and Genomics (eMERGE) Network are to learn how best to return research results to patient/participants and the clinicians who care for them and also to assess the impact of placing these results in clinical care. Yet since its inception, the Network has confronted a host of challenges in achieving these goals, many of which had ethical, legal, or social implications (ELSIs) that required consideration. Here, we share impediments we encountered in recruiting participants, returning results, and assessing their impact, all of which affected our ability to achieve the goals of eMERGE, as well as the steps we took to attempt to address these obstacles.

Adolescent Decision-Making Involvement in the Receipt of Genomic Testing Results.

Objective: To examine hypothesized predictors of adolescent and parent involvement in the decision about which genomic results to receive.

Study Design: We conducted a longitudinal cohort study during phase 3 of the electronic Medical Records and Genomics (eMERGE) Network. Dyads reported on how they preferred to make choices (adolescent only, parent only, or jointly).

Engaging Adolescents and Young Adults in Decisions About Return of Genomic Research Results: a mixed-methods longitudinal clinical trial protocol.

Background: To protect minors' future autonomy, professional organizations have historically discouraged returning predictive adult-onset genetic test results and carrier status to children. Recent clinical guidance diverges from this norm, suggesting that when minors have genomic sequencing performed for clinical purposes, parents and children should have the opportunity to learn secondary findings, including for some adult-onset conditions. While parents can currently opt in or out of receiving their child's secondary findings, the American Society of Human Genetics Workgroup on Pediatric Genetic and Genomic Testing suggests including adolescents in the decision-making process.

Implementation of CYP2D6-guided opioid therapy at Cincinnati Children's Hospital Medical Center.

Purpose: We describe the implementation of CYP2D6-focused pharmacogenetic testing to guide opioid prescribing in a quaternary care, nonprofit pediatric academic medical center.

Summary: Children are often prescribed oral opioids after surgeries, for cancer pain, and occasionally for chronic pain. In 2004, Cincinnati Children's Hospital Medical Center implemented pharmacogenetic testing for CYP2D6 metabolism phenotype to inform codeine prescribing.

Association of genotype predicted phenotypes with oxycodone requirements and side effects in children undergoing surgery.

Background: Oxycodone is a commonly used oral opioid in children for treating postoperative pain. Highly polymorphic gene metabolizes oxycodone into its more potent metabolite, oxymorphone. We hypothesized that altered activity due to polymorphisms will influence oxycodone requirements {relative oxycodone use [oxycodone morphine equivalents (MEq)/total MEq] to maintain analgesia} (primary outcome) and risk for oxycodone induced side-effects such as respiratory depression (RD) and emesis (secondary outcomes).

Developing video education materials for the return of genomic test results to parents and adolescents.

Objective: To describe the development, implementation, and revision of a video to provide information about genomic testing and the return of genomic research results to adolescents and parents.

Methods: Formative, community-engaged research was conducted in three stages: development, implementation, and revision. Existing research participant advisory groups were used for focus groups and convenience sampling was used for interviews.

Outcomes of Returning Medically Actionable Genomic Results in Pediatric Research.

Purpose: The electronic Medical Records and Genomics (eMERGE) Phase III study was undertaken to assess clinical utility of returning medically actionable genomic screening results. We assessed pediatric clinical outcomes following return of pathogenic/likely pathogenic (P/LP) variants in autosomal dominant conditions with available effective interventions.

Methods: The two eMERGE III pediatric sites collected outcome data and assessed changes in medical management at 6 and 12 months.

A retrospective examination of adjunctive L-methylfolate in children and adolescents with unipolar depression.

Background: Adjunctive l-methylfolate is commonly prescribed for children and adolescents with treatment-resistant mood disorders; however, the relationship between l-methylfolate augmentation across methylenetetrahydrofolate reductase (MTHFR) genotypes in youths with depressive symptoms is unclear.

Methods: We retrospectively examined the electronic health records of patients (N = 412) with depressive symptoms associated with unipolar depressive disorders and their MTHFR C677T genotypes from 2013 to 2019. Patients were ≤18 years of age at the time of MTHFR pharmacogenetic testing.

Multiancestral polygenic risk score for pediatric asthma.

Background: Asthma is the most common chronic condition in children and the third leading cause of hospitalization in pediatrics. The genome-wide association study catalog reports 140 studies with genome-wide significance. A polygenic risk score (PRS) with predictive value across ancestries has not been evaluated for this important trait.

The reckoning: The return of genomic results to 1444 participants across the eMERGE3 Network.

Purpose: The goal of Electronic Medical Records and Genomics (eMERGE) Phase III Network was to return actionable sequence variants to 25,084 consenting participants from 10 different health care institutions across the United States. The purpose of this study was to evaluate system-based issues relating to the return of results (RoR) disclosure process for clinical grade research genomic tests to eMERGE3 participants.

Methods: RoR processes were developed and approved by each eMERGE institution's internal review board.

Experiences of adolescents and their parents after receiving adolescents' genomic screening results.

There has been considerable debate over whether adolescents should have the opportunity to learn genetic information about adult-onset disease risk and carrier status without a clinical indication. Adolescents face increasing opportunities to learn more about such genetic risks through the return of secondary findings from clinical genomic testing, direct-to-consumer genetic testing, and research opportunities. However, little is known about the perspectives of adolescents who have received genomic screening results.

Influence of CYP2D6 metabolizer status on ondansetron efficacy in pediatric patients undergoing hematopoietic stem cell transplantation: A case series.

Chemotherapy-induced nausea and vomiting (CINV) is commonly experienced by patients receiving antineoplastic agents prior to hemopoietic stem cell transplant (HSCT). Ondansetron, a 5-HT3 antagonist metabolized by CYP2D6, is an antiemetic prescribed to treat short-term CINV, but some patients still experience uncontrolled nausea and vomiting while taking ondansetron. Adult CYP2D6 ultrarapid metabolizers (UMs) are at higher risk for CINV due to rapid ondansetron clearance, but similar studies have not been performed in pediatric patients.

Do research participants share genomic screening results with family members?

The public health impact of genomic screening can be enhanced by cascade testing. However, cascade testing depends on communication of results to family members. While the barriers and facilitators of family communication have been researched following clinical genetic testing, the factors impacting the dissemination of genomic screening results are unknown.

Facilitating Genetics Aware Clinical Decision Support: Putting the eMERGE Infrastructure into Practice.

This editorial provides context for a series of published case reports in ACI Open by summarizing activities and outputs of joint electronic health record integration and pharmacogenomics workgroups in the NIH-funded electronic Medical Records and Genomics (eMERGE) Network. A case report is a useful tool to describe the range of capabilities that an IT infrastructure or a particular technology must support. The activities we describe have informed infrastructure requirements used during eMERGE phase III, provided a venue to share experiences and ask questions among other eMERGE sites, summarized potential hazards that might be encountered for specific clinical decision support (CDS) implementation scenarios, and provided a simple framework that captured progress toward implementing CDS at eMERGE sites in a consistent format.