From bench to bedside: a spotlight on pharmacogenomics at Nemours Children’s Health

ABSTRACT

Nemours Children’s Health (NCH) is a large, multi-state pediatric health system in the United States with hospitals and outpatient locations across Delaware, New Jersey, Pennsylvania, and Florida. NCH has maintained consistent effort in pharmacogenomic (PGx) research through the Center for Pharmacogenomics and Translational Research since 2003. In 2018, NCH funded the development of a dedicated Clinical Pharmacogenomics Service (CPGxS) to support PGx testing and return of results across the NCH enterprise. The CPGxS consultant-based service provides clinical PGx testing and supports PGx-focused research. Over the past seven years, the CPGxS has developed an in-house PGx testing platform, integrated a PGx clinical decision support (CDS) system into the electronic medical record (EHR), established a comprehensive consultant clinic, and provided a broad variety of education opportunities for providers, patients, and trainees. In this institutional profile, we highlight the development of a PGx program and related efforts across a multi-state pediatric-specific healthcare system.

Plain Language Summary

Nemours Children’s Health is a pediatric healthcare system with primary locations in Delaware and Florida, and additional locations in several U.S. states. Since 2003, Nemours has worked to understand how genes affect how children respond to medicines, which is a field called pharmacogenomics. In 2018, Nemours Children’s Health created a special clinical service to help clinicians use genetic information to guide medication use. This service offers genetic testing related to medication use; supports research; and helps educate healthcare providers, patients, and families. Over the past seven years, Nemours has built its own testing system, added tools to help doctors use genetic results in patient care, and created a clinical consultation service for personalized medicine. This article shares how Nemours developed its program to improve care for children using pharmacogenomics.

1. Introduction

Nemours Children’s Health (NCH) is one of the largest integrated pediatric health systems in the United States, including two children’s hospitals, 17 collaborating hospitals, three urgent care centers, 34 specialty care clinics, and 40 primary care locations (Figure 1(A,B)), managing over 1.7 million patient encounters per year [1]. While actionable (testing required, testing recommended, or guidance for dose adjustment or alternative drug use) pharmacogenomic (PGx) information is provided in over 250 U.S. Food and Drug Administration (FDA) drug labels [2], clinical implementation in pediatric populations requires specialized programs equipped to address the challenges of pediatric health care [3]. Since 2003, the Center for Pharmacogenomics and Translational Research (CPTR) at NCH has contributed to PGx research [4,5]. In 2016, Nemours joined the Implementing Genomic Medicine in Practice (IGNITE) Consortium [6] and the Pharmacogenomics Global Research Network (PGRN) to collaborate on clinical trials applying PGx, including the recent National Institutes of Health (NIH)-funded multisite trial, A Depression and Opioid Pragmatic Trial in Pharmacogenetics (ADOPT-PGx) [7,8].

Figure 1.

(A) Map of Nemours Children’s Health Delaware Valley hospital & emergency care, collaborating hospital, specialty care, and primary care locations in Pennsylvania, New Jersey, Maryland, and Delaware. (B) Map of Nemours Children’s Health Florida hospital & emergency care, collaborating hospital, urgent care, specialty care, and primary care locations in Florida.

In 2017, NCH established the Nemours Precision Medicine Program (PMP) and Clinical Pharmacogenomics Service (CPGxS) to bridge PGx efforts enterprise-wide [9]. The CPGxS, comprised of specialty-trained PGx pharmacists, supports in-house and external PGx testing for both clinical and research initiatives, integrates PGx results and recommendations in the electronic health record (EHR) through clinical decision support (CDS) tools and a clinical consult service, and provides PGx-based education to patients, providers, and trainees. Here, we describe the development, clinical implementation, and expansion of the CPGxS and related efforts.

2. Clinical implementation

The Nemours PMP established the CPGxS in 2018 (Figure 2). Over the next two years, pre-launch implementation efforts included the development of an in-house Clinical Laboratory Improvement Amendment (CLIA)-approved PGx panel, integration and implementation of EHR CDS systems, and design of a comprehensive clinical PGx consult service. These efforts culminated in an official service launch for NCH locations in the Delaware Valley (Figure 1(A)) in February 2020. Given delays brought on by the COVID-19 pandemic, the service was expanded to NCH Florida locations (Figure 1(B)) in February of 2022.

Figure 2.

Timeline of Nemours children’s Health precision medicine program and clinical pharmacogenomics service development and implementation.

PMP: precision medicine program; PGx: pharmacogenomics; UF: University of Florida; CDS: clinical decision support; CPGxS: clinical pharmacogenomics service; APPE: advanced pharmacy practice experience; PGY2: post-graduate year 2; IGNITE: Implementing Genomics In Practice; ADOPT-PGx: A Depression and Opioid Pragmatic Trial in Pharmacogenetics.

2.1. In-house PGx testing panel

With a focus on clinical PGx testing, the decision to develop an in-house PGx panel in the CLIA-certified Nemours Molecular Diagnostic Laboratory (MDL) was based on test availability, curation of pediatric-relevant variants, and the capability to trigger CDS. The decision to develop an internal panel also supported a hybrid reactive/preemptive-based testing approach for providing results for specific gene drug pairs when indicated, while also allowing for long-term use of additional PGx results. Gene selection for the panel was based on gene-drug pairs with Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines and/or FDA-labeling at the time of consideration, with a focus on drugs most relevant to the pediatric and young adult patient populations seen at NCH. We also considered the overlap between selected genes and gene-drug pairs relevant to adult populations (e.g., CYP2D6-tamoxifen) to ensure the long-term applicability of the results and to support preemptive use of our panel-based testing. Allele selection within each gene was based on those with established functional value and population frequency (>0.5) as reported within CPIC and the Pharmacogene Variation Consortium (PharmVar). The list of variants was further consolidated based on the capability to call each variant using polymerase chain reaction (PCR) genotyping with copy number assays with commercially available assays, and alignment with pharmacogenetic testing coverage at other leading institutions. Utilizing the ThermoFisher TaqMan® Assay and QuantStudio™ 12K FLEX platform, the customized PGx panel includes 44 genotyping assays, and one copy number assay (CYP2D6), that correspond to 12 unique pharmacogenes (Table 1). After analysis with Genotyper™, CopyCaller®, and AlleleTyper™, results are uploaded as discrete data into the EHR. PGx data uploads are reviewed by a PGx pharmacist.

Table 1.

Genes, alleles, and examples of impacted medications included on the Nemours In-house pharmacogenomics testing panel.

Gene	Alleles	Examples of Impacted Medications±
CYP2B6	*4, *5, *6, *7, *9, *16, *18, *22, *34, *36	Efavirenz, Sertraline
CYP2C19	*2, *3, *4, *6, *8, *10, *17, *35	Amitriptyline, Citalopram, Clopidogrel, Dexlansoprazole, Escitalopram, Lansoprazole, Omeprazole, Pantoprazole, Sertraline, Voriconazole
CYP2C9	*2, *3, *5, *6, *8, *11	Celecoxib, Flurbiprofen, Fluvastatin, Ibuprofen, Meloxicam, Phenytoin, Piroxicam, Warfarin
CYP2D6	*2, *3, *4, *5, *6, *7, *8, *9, *10, *17, *29, *41, CNV	Amitriptyline, Atomoxetine, Codeine, Fluvoxamine, Hydrocodone, Metoprolol, Nortriptyline, Ondansetron, Paroxetine, Tamoxifen, Tramadol, Venlafaxine, Vortioxetine
CYP3A4	*22
CYP3A5	*3, *6, *7	Tacrolimus
TPMT	*2, *3A, *3B, *3C	Azathioprine, Mercaptopurine, Thioguanine
NUDT15	*3
SLCO1B1	*5	Atorvastatin, Fluvastatin, Lovastatin, Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin
CYP4F2	rs2108622	Warfarin
CYP2C Cluster	rs12777823
VKORC1	rs9923231

±Based on gene-drug pairs with Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline recommendations and availability in the United States.

The initial PGx panel was validated against commercially available samples previously characterized either at another CLIA/CAP certified laboratory or previously published datasets [10–12]. During the development phase of the PGx panel, our laboratory tested 100 research samples. The testing genotyping accuracy was evaluated using confirmation of selected star alleles (homozygous wild type; heterozygous; homozygous alternate allele) by traditional PCR and Sanger sequencing. The PGx panel is regularly reviewed and updated as additional genes become relevant to the institution’s targeted patient population. Initially, the panel included 10 pharmacogenes and was expanded to 12 pharmacogenes in 2023, adding CYP2B6 due to updated CPIC antidepressant guidelines [13] and CYP3A4 in anticipation of new tacrolimus guidelines. Additional considerations are given to variant inclusion based on the Association for Molecular Pathology (AMP) genotyping recommendations and other resources. For example, NUDT15 × 3 (rs116855232) is the only Tier 1 “must-test” variant as a nonfunctional NUDT15 allele [14]. Although NUDT15 × 2 (rs116855232 + rs746071566) is also a nonfunctional allele and seen in diverse populations, it is classified based on the presence of the nonfunctional NUDT15 × 3 single nucleotide polymorphism (SNP) and the unknown function NUDT15 × 6 SNP (rs746071566). The targeted genotyping method used is not able to capture the duplications of the rs746071566 SNP (associated with * 2, *6, and * 9) and omission of this SNP does not change the clinical phenotype or treatment of patients that truly carry this variant. While the panel may incorrectly call carriers of the very rare NUDT15 × 9 no function allele as NUDT15 × 1 normal function, we acknowledge this is a limitation of our panel; however, our institution has not seen this variant clinically in the 137 patients with sequenced NUDT15 results as reported in previous work [15]. Furthermore, NUDT15 × 4 is associated with an unknown function at this time and would be treated as a normal function variant until further classified. The program continually reviews guidelines and recommendations for changes in allele coverage or functionality and will update the PGx panel as necessary.

2.2. Integrated clinical decision support

Clinical decision support (CDS) is a vital component of clinical PGx programs to provide clinicians with timely, evidence-based information that can guide prescribing decisions by flagging gene-drug interactions at the time of prescribing [16]. After considering the institution’s capacity to internally develop and maintain PGx CDS, integration of a third-party CDS system was considered optimal to support the program, as previously described [17]. To date, over 50 gene-drug pair posttest PGx CDS alerts have been implemented across the NCH EHR system.

2.3. Clinical pharmacogenomics consult service

A dedicated consultant service with 2 dedicated full-time equivalents (FTE) (three total PGx pharmacists), paid for by the institution, was established to support clinical PGx testing and return of results across NCH. The PGx pharmacists were hired for their specialized residency and fellowship training in precision medicine and pharmacogenetics and experience in implementing PGx services. The service also supports clinical testing for research protocols. The CPGxS includes three specially trained pharmacists covering NCH Delaware Valley region and Nemours Florida locations. Providers may order a PGx consult within the EHR for assistance with test ordering, interpretation, and patient education. When a consult is placed for test ordering, a PGx pharmacist contacts the patient and their caregiver for a pretest consult to provide education on PGx and obtain consent for genetic testing. CPGxS pharmacists may work with the prior authorization team to complete insurance benefit investigations and obtain prior authorizations when appropriate. Upon receipt of the PGx results, a PGx pharmacist provides interpretations and clinical recommendations via a consult note to providers, in addition to reviewing the results with the patient and their caregivers via an individually tailored PGx report during a posttest consult. Patient consultations occur via telephone in order to serve the large clinical footprint of NCH, with pretest consults lasting about 10–20 minutes and posttest consults taking anywhere from 30 to 60 minutes depending on the complexity of the patient case. Of note, pharmacist clinical services are not currently billable; however, efforts to evaluate and implement billing mechanisms are ongoing.

2.4. Clinical implementation and expansion of CPGxS services

The CPGxS’s approach to implementing PGx services across NCH targets clinical specialties on a case-by-case basis through engaging stakeholders and provider champions. The target patient populations are identified based on those using medications with evidenced-based PGx-clinical guidelines and/or FDA drug labeling. Providers are initially targeted for education and engagement based on high use rates of medications with PGx implications. Ultimately, physician champions self-identify by being more engaged with initial education and implementation efforts. These individuals are vital to help create excitement and provide valuable input for different service area workflow creations. The initial CPGxS development focused on patients with depression or acute pain to support the implementation of the ADOPT-PGx study [7,8], which began enrolling patients in 2021. The team identified physician champions to better understand the workflow and needs of each clinic or specialty area. Prescribing data across the enterprise was used to identify additional target areas for implementation. Providers were also identified based on interest and willingness to work with the team to develop workflows for each clinical service area. These same steps were applied to expand implementation efforts to primary care, chronic pain management, developmental medicine (focuses on conditions that affect development, communication, and motor skills, such as autism spectrum disorders), psychiatry, and solid-organ transplant. Over time, the service has evolved by adapting specific workflows to the needs of individual clinical specialties after receiving feedback from providers, including modifying the workflow for kidney transplant patients. Additional improvements include the use of templated consultant notes specific to certain specialties to improve efficiency in documentation. The service has also created provider “cheat sheets” to assist with patient identification for PGx testing and the PGx test ordering process. Finally, the service is working to streamline the use of external PGx testing labs by integrating test order and return of results in the EHR.

3. Building evidence to support and sustain pharmacogenetics implementation

A major component of the CPGxS and CPTR is continual advancement of PGx knowledge through laboratory-based, translational, clinical, and quality improvement research. A comprehensive PGx research program supports the clinical implementation of PGx by incorporating PGx into the research work of clinicians within NCH.

3.1. Discovery

The CPGxS and CPTR support PGx discovery research from bench to bedside. One area of focus has been the identification of variants in CYP2C19 and STAT6 that are associated with response to PPI therapy in children treated for gastric-acid-related conditions. In previous studies, variants in CYP2C19 were associated with a lack of response to PPI therapy [18] and worse asthma control [19] for patients receiving lansoprazole. Further correlative studies demonstrated that variants in CYP2C19 and STAT6 were associated with PPI-nonresponsive eosinophilic esophagitis [20].

3.2. Clinical research

The CPGxS also supports prospective longitudinal studies [21] and randomized pragmatic trials [7,8]. NCH is an NIH-IGNITE affiliate member in prospective PGx clinical trials. In the recently completed ADOPT-PGx study, the CPGxS enrolled more pediatric participants with depressive symptoms than any other site in the trial [7,8]. CPGxS members actively contributed to the design, analysis, and communication of trial results as leaders in the pediatric arm of the study. Collaboration in prospective, multi-center studies for implementing PGx testing for pediatric patients is a priority for the program and the service continues to look for opportunities to support PGx research at Nemours Children’s Health. A clinical research goal of the CPGxS is to maintain the ability to support prospective clinical trials and retrospective cohort studies within NCH and with collaborative working groups.

3.3. Implementation science

To support further acceleration of the clinical implementation of PGx, the CPGxS actively supports clinical implementation research to expand the adoption of PGx use in pediatrics [22,23]. The CPGxS has disseminated surveys to understand pediatrician’s understanding and preferences in utilization of a CPGxS [24]. To tailor implementation of PGx to NCH, the service conducts drug utilization evaluations to determine focus areas for PGx implementation. Most recently, the CPGxS conducted a 10-year analysis of psychiatric medication use across NCH, which identified commonly prescribed drugs with CPIC recommendations across departments and individual providers [25]. With these data, we are able to identify physician champions and further develop our service to meet the specific needs of our population. The CPGxS also provides assessment of implementation tools used for clinical PGx [17]. Finally, CPGxS providers are active members of the CPIC, including participation in guideline writing, PGx focused subgroups for the PGRN and the Pediatric Pharmacy Association (PPA).

3.4. Quality assurance

The CPGxS performs proactive quality assessment analysis. Through prospectively tracking clinical, logistical, and molecular data, we ensure high-quality service is delivered to our patients and identify opportunities for improvement. The CPGxS recently reported on the consistency of genetic testing results between the NCH in-house PGx testing panel and the standard-of-care Sanger sequencing approach for identifying variants in TPMT or NUDT15. It was found that a polymerase chain reaction (PCR)-based test would be able to accurately phenotype 100% of patients included in the study, which allowed for consideration of the in-house PGx panel test patients who required testing for TPMT or NUDT15 variants [15].

4. Educational initiatives

PGx is a complex medical science, incorporating genetics, pharmacology, laboratory science, and medical informatics, and thus, educational initiatives are a common component of PGx testing programs. The CPGxS provides a comprehensive PGx educational program for patients, healthcare providers, and trainees through a variety of educational initiatives.

4.1. Patient education

Patient education is provided through a variety of avenues ranging from community-level education to patient-specific resources. The CPGxS has developed web-based resources, such as the “Pharmacogenetics: How Genetic Testing Can Guide Medicine Decisions” webpage (https://kidshealth.org/en/parents/pharmacogenomics.html) and the “90-Second Summary: Pharmacogenetics” educational videos hosted on the KidsHealth website. To date, this site has been used at institutions across 10 different states. These tools provide on-demand support to patients and their caregivers at NCH and are available to anyone with an internet connection. At the individual patient level, the CPGxS provides counseling prior to testing to discuss the process, benefits, and limitations. Once results are available, the consultant service provides individualized counseling to review results, accompanied by a personalized patient report that includes the patient’s results, with further explanation of affected medications. Generally, counseling sessions are completed with the patient’s parent or caregiver, with the patient attending when interested. Sometimes older adolescents choose to be included in the counseling sessions to review their PGx results.

4.2. Provider education

PGx education is delivered to a variety of healthcare providers with a focus on adapting to the needs of healthcare professionals and the stage of implementation. Our provider education offerings range from classroom format didactic training to individual hands-on education. Where possible, educational efforts include personalized genotyping to increase familiarity with PGx testing [26]. The CPGxS has provided didactic training through a stand-alone Precision Medicine Symposium, as a component of the annual Nemours enterprise-wide research week, and through grand rounds or departmental meeting formats. This approach allows for targeted education based on the therapeutic area of interest while gauging interest in implementing PGx services in a particular clinic. Individual or small group meetings with key stakeholders and physician champions are then held to provide more personalized training for test ordering logistics, clinical interpretation, and customization of workflows to the specific needs of each clinic. We have developed a variety of on-demand educational tools and training materials for providers as an aid for operational and clinical application of PGx. Drugs with PGx implications on NCH’s formulary will link to the PGx recommendations on the drug’s monograph and include the CPGxS contact information. Finally, our team provides continuing education on both the local and national levels.

4.3. Trainee education

The CPGxS provides educational and training opportunities to undergraduate students, professional students, and post-graduate trainees. Through the Nemours Summer Research Program, the CPGxS has provided intensive wet-lab and dry-lab PGx-focused 10-week research internships to undergraduate students. At the University of Florida, the CPGxS faculty provides didactic training in PGx and precision medicine, in addition to research volunteer or elective credit hours. The CPGxS also offers a six-week advanced pharmacy practice experience (APPE) rotation to provide direct patient care experience to PharmD students. The CPGxS provides lectures for physician residents providing didactic education on the clinical application of PGx. The CPGxS also provides clinical rotations for pharmacy residents through its collaboration with the University of Florida in order to provide exposure to the unique challenges in implementing PGx in a pediatric patient population. Additionally, the NCH CPGxS has provided mentorship and support for PGx research for physician fellows.

5. Conclusion

The NCH PMP successfully launched the CPGxS to support PGx testing across NCH. This program is unique in that it provides service to a multi-state, pediatric healthcare system. The CPGxS actively engages providers to expand testing across clinical specialties while supporting research and educational efforts. The CPGxS is committed to furthering the advancement and adoption of PGx application in pediatric patient populations and is working to identify challenges and strategies specific to pediatric PGx implementation. The program is also dedicated to continuing its comprehensive education and training opportunities offered to healthcare professionals and trainees.

6. Future perspectives

The future of PGx in pediatrics holds immense promise. As our understanding of genetic variability in drug metabolism and clinical response continues to grow, we can expect more precise, safe, and effective treatments tailored to individual patients. It is imperative to continue to advocate for pediatric inclusion in PGx research to address gaps in knowledge for an often under-studied population. Continuing improvements in access to and reimbursement for PGx testing is also necessary. The CPGxS is currently working to expand its PGx test offerings to combat this. Beyond its own institution, the NCH PMP and CPGxS will continue to collaborate with others to advance the field.

Funding Statement

This paper was not funded.

Article highlights

Introduction

• Nemours Children’s Health (NCH) has developed a robust pharmacogenomics (PGx) program spanning multiple states, integrating clinical services, research, and education.

Clinical Implementation

• The CPGxS was launched in 2018 to provide enterprise-wide PGx services, including a consult-based model and integration into the electronic health record (EHR).

• A custom in-house PGx testing panel was developed, focusing on pediatric-relevant pharmacogenes and enabling CDS alerts for over 50 gene-drug pairs.

• The consultant service includes three PGx-trained pharmacists who provide pre- and posttest counseling, test interpretation, and clinical recommendations.

Building Evidence to Support and Sustain PGx Implementation

• The CPGxS supports translational and clinical research, including participation in NIH-funded trials like ADOPT-PGx.

• Discovery efforts have identified genetic variants associated with treatment response in pediatric populations.

• The service uses implementation science and quality improvement studies to evaluate provider needs, drug utilization, and workflow optimization.

Educational Initiatives

• Educational initiatives include patient education through web-based tools and personalized counseling, provider education through symposia, grand rounds, and personalized sessions, including genotyping for experiential learning, and trainee education through internships, rotations, and didactic instruction for students and residents across disciplines.

Conclusion and Future Perspectives

• The NCH CPGxS is a pediatric-focused PGx model that integrates clinical care, research, and education.

• Future goals include expanding test offerings and advancing pediatric inclusion in PGx research.

Author contributions

KJC and NDS designed the manuscript. KJC, NDS, BQD, SMK, and EBM wrote and critically reviewed the manuscript. VLF, SL, DW, PHA, and KVB critically reviewed the manuscript.

Disclosure statement

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing assistance

No writing assistance was utilized in the production of this manuscript.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.