Patient Care Genetics and Genomics: Nationwide Children's at the Forefront - Nationwide Children's Hospital
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A N AT I O N W I D E C H I L D R E N ’ S H O S P I TA L P U B L I C AT I O N | VO LU M E 3 8 I S S U E 1 | W I N T E R 2021
Everything Matters In
Patient Care Genetics and Genomics:
Nationwide Children's
at the Forefront
Bimal Chaudhari, MD, MPH,
uses rapid genome sequencing to
create Best Outcomes for patients. Contents
Features
5
The Steve and Cindy Rasmussen Institute for Genomic
Medicine: An Overview
Richard K. Wilson, PhD Executive Director, The Steve and Cindy
Rasmussen Institute for Genomic Medicine
Elaine R. Mardis, PhD Co-executive Director, The Steve and Cindy
Rasmussen Institute for Genomic Medicine
13
Precision Medicine and Next Generation
Clinical Care in Pediatric Neuro-Oncology
Prajwal Rajappa, MD, MS, Assistant Professor of Pediatrics and
Neurological Surgery Member, Translational Therapeutics Program,
The James Comprehensive Cancer Center, The Ohio State
University College of Medicine Director, Translational
Neuro-Oncology Laboratory, Institute for Genomic Medicine
Articles
4 Where Passion Meets Purpose
Lee Ann Wallace, MBA, BSN, RN, NEA-BC, Senior Vice President, Patient Care Services, Chief Nursing Officer
9 Genomics and Privacy
Natasha Davis, JD/MBA and Nikki Pryor, MSN, RN, CNOR, CPN BH
10 The Need for Speed: Rapid Genome Sequencing
Bimal P. Chaudhari, MD, MPH and Catherine E. Cottrell, PhD
12 Sustaining Our Drive for 5!
Sherri Watts, MSN, RN, Professional Development
17 Pharmacogenetics and the Controversy on Medication Choices
Susan Colace, MD, MSCI
18 Genetic Counseling and Translational Medicine
Theresa Mihalic Mosher, MS, CGC
20 Crisscross Applesauce: Our Journey to Genetic Answers
Kellynne Werner, Parent
22 Opportunity Out of Crisis: Telehealth Implementation in Response to COVID-19
Jennifer B. Reese, PsyD and Ujjwal Ramtekkar, MD, MBA, MPE, DFAACAP
24 In Recognition
Editorial Staff:
Editor: Vicki von Sadovszky | Managing Editor: Marcie Rehmar | Editorial Board: Margaret Carey,
Jo Ann Davis, Cindy Iske, Tanica Jeffries, Marissa Larouere, Megan Lewis, Nancy Noyes, Paige Shalter Bruening,
Danielle Worthington | Editorial Assistant: Joanna Kinner | Editorial Support: Heather Lofy
Photography: Brad Smith | Art Direction/Design: John Ordaz
2 | IN PATIENT CARE IN PATIENT CARE | 3
The Steve and Cindy Rasmussen Institute
Where Passion Meets Purpose for Genomic Medicine: An Overview
A
s part of the 2017-2022 become a cancer cell. Developing a better
Strategic Plan, Nationwide understanding of the cancer location and Richard K. Wilson, PhD, Executive Director, The Steve and Cindy Rasmussen Institute for Genomic Medicine,
The Abigail Wexner Research Institute at Nationwide Children’s Hospital
Children's Hospital committed causes of these over-expressed genes, we
Elaine R. Mardis, PhD, Co-executive Director, The Steve and Cindy Rasmussen Institute for Genomic Medicine,
to Best Outcomes for all children. This will increase our successful outcomes for
The Abigail Wexner Research Institute at Nationwide Children’s Hospital
commitment includes developing cancer therapies. The ability to translate
cures for rare diseases and a better their research into treatment using
understanding of the treatment of whole-exome sequencing allowing for
genetic conditions in children. diagnosis of pediatric conditions that
traditional tests and investigation would
Genomics is one of the areas of focus not be able to identify. Through genome
Lee Ann Wallace that we believe will accelerate our sequencing, targeted therapies, and
MBA, BSN, RN, NEA-BC Journey to Best Outcomes. At the Abigail
medications based on the identification
Senior Vice President, Wexner Research Institute at Nationwide of genetic errors will be developed,
Patient Care Services, Children’s Hospital, our world-renowned
Chief Nursing Officer all leading to improved outcomes.
research teams are breaking new ground
in genomics, gene therapy, and tissue While work has been focused on
engineering. This research will provide rare genetic conditions and cancer,
transformational work in understanding the future is wide open. Other
the genetic causes of disease, an ability areas of future expansion include
to more rapidly sequence genomes, as diagnosis and treatment of seizure
well as reducing the cost of this state-of- disorders and the ability for rapid
the-art medical science and technology. identification of neonatal conditions.
As care team providers, we need to
Rather than a one size fits all approach, continue to expand our knowledge
individualized treatment care plans and understanding of genomics in our
can be developed using high precision own areas of practice, while identifying
diagnostics. Large research studies are the impact of these discoveries on
taking place on the identification of our patients and their families.
cancer tumor DNA while understanding
what processes cause a normal cell to
2017-2022
JOURNEY TO BEST OUTCOMES
VISION
One Team GOAL BEST OUTCOMES
Values for Kids Everywhere
Pre-eminent Clinical &
Research Programs
CORE
STRATEGIES
Growth & Operational
Partnerships Excellence
ACCELERATORS
Education
Quality, Wellness/
Safety & Population
Service Behavioral Genomics Health
Health
4 | IN PATIENT CARE IN PATIENT CARE | 5
W
hen Nationwide Children’s Hospital to the single gene testing performed at most children’s
leadership completed their strategic hospitals which often results in a very long diagnostic
planning process in 2013, they identified odyssey for the patients and their families.
genomics as an accelerator for the hospital that would
differentiate its health care in significant and impactful Recognizing this potential of genomics to improve our
ways as compared to other children’s hospitals. What understanding, diagnosis and treatment of childhood
is genomics and why was it considered a critical diseases, Nationwide Children’s established the
accelerator? How did this aim of the strategic plan Steve and Cindy Rasmussen Institute for Genomic
manifest itself and what has happened since then? Medicine in 2016. The Institute represents a very
unique fusion of capabilities including advanced
Genomics can be simply defined as the study of genomics-centered research and development, clinical
the genome, which is the instruction set encoded molecular diagnostic testing and high-performance
by the DNA inside of our cells and inherited from analytical computing. The intersection of these
our parents. This DNA-based instruction set is capabilities enables our mission of interdisciplinary
interpreted during development as a carefully and collaborative research across multiple service lines
orchestrated process that builds cells, organs and with a goal of including genomics-based evidence as
ultimately an entire human body. Changes to the a critical component of medical practice. Achieving
DNA code of an individual can result in disruptions this mission has become manifest in a series of clinical
of this process, resulting in altered development translational protocols, each of which studies patients
and human disease. The ability to rapidly discover across a number of childhood disease phenotypes. For
and interpret these changes in individual patients example, children who are diagnosed with a brain or
across a variety of pediatric diseases has been other CNS tumor undergo comprehensive analysis
accelerated in recent years by several factors. of the genome in their cancer cells, in collaboration
with our colleagues from Neuro-oncology,
First and foremost, complete sequencing of the first Neurosurgery, Pathology, Radiology and Radiation
human genome (the Human Genome Project, 1990- Oncology who directly care for these patients. The
2003) provided us with the fundamental instruction results of our analyses are discussed during a weekly
set in our DNA - namely the location and structure tumor board attended by care providers from all of
of the protein-coding genes that are shared by all these specialties, with an aim to identify genomic
members of the human population. Second, the advent features that may indicate new treatments or predict
of rapid and relatively inexpensive DNA sequencing outcome. The same protocol has evaluated patients
technology, combined with advanced computational with sarcomas, with blood cancers of various types tissue and may reflect changes that emerged not from may provide clues to the disorder or help identify the
analysis has enabled genome sequencing to become a and more recently, with overgrowth syndromes that inheritance but instead from DNA copying errors syndrome. A clear determination of genetic cause is
high-resolution form of diagnostic laboratory testing. often are caused by mutations in cancer-related during normal development and growth in utero. identified for around 33% of patients evaluated by
Third, a series of “big science” efforts that catalyzed genes. In total, more than 230 patients have been This protocol has evaluated over 40 patients to-date, this clinical test. In the event of a negative result, we
the study of thousands of individual human genome studied on this protocol since January 2018 and over with a return of medically relevant information in may offer these families the option of enrollment onto
sequences and permitted the association of DNA-based 93% of those studied had one or more medically 35% of the patients studied. In most cases, this our rare disease genomics protocol, which performs
changes within those genomes with many conditions meaningful results identified by our analyses. information will not impact patient care, but there is sequencing of the complete genomes of the patient
including cancer, cardiovascular disease, autism and
an intangible value in parents being able to understand and parents, and in some cases includes individuals
other behavioral disorders, epilepsy, craniofacial, Similarly, children with treatment-refractory epilepsy
the underlying cause of their child’s seizures. from the family pedigree that are also affected. Using
cardiac, and other birth defects and various without a known inheritance pattern often undergo
this comprehensive approach, we have uncovered
syndromic metabolic and developmental diseases. brain activity mapping and surgery to remove affected In collaboration with Nationwide Children’s medical complex changes to the DNA of affected individuals
tissues and thereby eliminate or reduce the intensity genetics providers, we annually study more than 300
Building upon these critical factors, the inclusion of that explains their disorder or syndromic difficulties
and frequency of their seizures. Working with our children with undiagnosed syndromic or complex
genome-based diagnostics now enables comprehensive yet could not have been identified by the clinical test
colleagues in Neurosurgery, Neurology and Pathology, disorders thought to have underlying genetic causes.
molecular testing for individual patients with complex which only evaluates about 1.5% of the genome.
we have studied the genome from tissue removed This test, which can be ordered through our clinical
and otherwise undiagnosed disease by evaluating at surgery to identify and characterize genomic laboratory, evaluates the patient’s protein coding genes Our successes in the rare disease genomics protocol
the entire genome in an unbiased fashion to identify changes associated with the cause of their disease. in comparison to those of both parents, when possible, have led to a new effort that also focuses on whole
causative changes. This approach is in stark contrast Many of these changes are unique to the affected to identify changes unique to the child’s genes that genome sequencing of child and parents, but in this
6 | IN PATIENT CARE IN PATIENT CARE | 7
Genomics and Privacy
Natasha Davis, JD/MBA, Senior Associate General Counsel Legal Department
Nikki Pryor, MSN, RN, CNOR, CPN, BH Clinical Risk Manager Legal Department
L
arge scale data breaches are in the news for research. The research subject should have a
frequently, hitting many different types of good understanding of what the consent entails
institutions, such as banks, corporate companies and have the opportunity to ask questions.
and even hospitals. In the digital age, it leads people
to wonder about the security of their information and Privacy concerns with genomics impact not only
how data remains private. This is especially true in the initial research subject, but also siblings, current
the world of genomics, where this sensitive data has a or future children, and other family members. The
unique need to be shared for research, public health, institutional review board (IRB) and/or privacy
clinical interpretation and medical practice support. board is designed to ensure maximum privacy
As this information is shared for current and future protection while sharing the minimum amount
research or treatment of genetic conditions, it is more of data, specimens, etc. Federal law requires
valuable to cybercriminals than traditional protected adherence to these core procedures established by the
case involves tiny newborns in our neonatal intensive psychiatric genomics and autism genomics research health information (PHI) because of its ability to Common Rule including the appropriate informed
care unit with a variety of failure-to-thrive related to study pediatric patients and their families who illuminate generational family health. The balance to consent and the mandated review by the IRB.
difficulties, including metabolic and developmental have been diagnosed with autism, with depression keep it private and secure is paramount while at the Genomics data has the potential to impact denial of
problems. The big difference in this procedure is leading to suicidality and with bipolar disorder. Long- same time remaining cognizant of the importance medical treatment, eligibility for healthcare insurance
our goal to return information about these babies term we anticipate our work in behavioral genomics of sharing for advances in genomic research. and qualifying for job opportunities. The Genetic
to our neonatal ICU providers in only 48 hours! will transition to the setting of genomic testing as a
Information Non-Discrimination Act (GINA) was
This time-to-results goal is a technical and logistical component of medical diagnosis for these children. In the 1950s, cells were used from a developed to protect against discrimination in the
challenge that we are still tackling, yet we have
While strong progress has been made toward our
cancer patient named Henrietta Lack workplace and healthcare insurance but there are still
already made significant progress, having returned
mission at the Rasmussen Institute, it is clear that and were utilized in multiple research unprotected gaps, such as disability, life and long-term
information on our most recent case in only 4 days.
additional medical service lines will benefit from projects. care insurance. GINA also does not apply to small
Two other areas of collaborative study have emerged the integration of genomics into both research and employers and the U.S. military. The uncertainty and
in the past year. One area focuses on the relationship clinical practice. To better identify and define these It became known as the HeLa cell line. This was variability of what privacy protection is available can
between our health and our microbiome, which is opportunities, a critical activity involves education of done without her or her family’s consent, which was impact the participation of needed participants.
defined as the bacteria and viruses that naturally clinical providers regarding the application of genomics not uncommon at the time. When discovered, this
It is imperative that the privacy laws and regulations
live in and on our bodies. Research has illustrated - what it can and cannot address. Similarly, we benefit led to discussions about consent, patient privacy,
match the rapid pace of which science and the study
that this close relationship between humans and from understanding the challenges and unanswered ethics, property rights and others. Those discussions
of genomics evolve. Typically, deidentified data is
microbes shapes our illness and health in ways questions in these different areas of pediatric medical continue today as the boundaries of privacy,
absolved of federal and state privacy requirements but
that had not previously been appreciated and has practice and using this information to shape study patient understandings of consents, and precedence
as technology advances, even the best deidentified data
sparked further study in the pediatric realm. These design, patient accrual and other important aspects set on regulations or legal outcomes evolve.
can be reidentified with accuracy. Future regulations
studies include gaining a better understanding of that maximize the yield of information we obtain. Informed consent is a large component of research
will need to focus on addressing this to meet the needs
the impact of vaccines and antibiotics on the normal With a basic understanding of each other’s vocabulary, and testing. This consent should be written, clear
of scientific advancements and privacy protection.
gastrointestinal flora, adverse effects on normal flora strengths and challenges, we can better define the on the risks and benefits of participation and
caused by anti-anxiety medications and how microbes way by which genomics can help answer the difficult include whether data or specimens will be used
impact childhood neuronal development. Most questions that clinicians must address when diagnosing
recently we have opened a collaborative protocol with and treating their patients. This is the essence of team
researchers and care providers in a new focus area science in precision medicine and why genomics is an
at Nationwide Children’s Behavioral Health. Here accelerator for our hospital and its important focus
we will use the body of knowledge emerging from on providing the best care possible for our patients.
8 | IN PATIENT CARE IN PATIENT CARE | 9
a massive amount of data which needs to be accurately,
but rapidly processed into a human interpretable
form. Dr. Peter White, an Institute co-investigator, and DEFINITIONS
his bioinformatics team have combined automation
and cloud computing to enable rapid analysis. Once
initial data are available, a collaborative team including
researchers, variant scientists and analysts, genetic
counselors and laboratory directors gather to review the
results under the direction of Institute co-investigator
Dr. Catherine Cottrell and Principal Investigator,
Dr. Bimal Chaudhari. During this multidisciplinary The human genome includes all coding and noncoding DNA
review, data from the genome analysis are discussed to sequences. DNA encodes more than 20,000 genes in humans,
but most of the more than 3.2 billion base pairs that comprise
determine if any genetic variants are consistent with the the human genome are repetitive DNA or noncoding sequences
patient’s symptoms, or to reassure clinicians that certain and have not been linked to specific inherited disorders.
suspected diagnoses are unlikely. In the first 6 months, Portions of our genes known as exons encode the genetic in-
the recruitment phase of the study, the team was able to structions for making proteins which are fundamental compo-
The Need for Speed: Rapid Genome Sequencing reduce the time to provide a preliminary interpretation to
under five days. While researchers have many additional
nents of our cellular makeup and biological functions.
Bimal P. Chaudhari, MD, MPH investigations in mind, including using artificial
Principal Investigator, The Steve and Cindy Rasmussen Institute for Genomic Medicine, Assistant
intelligence to further speed up the process, the biggest
Professor of Pediatrics, Divisions of Neonatology, Genetic and Genomic Medicine
impact on care will come when the test is transitioned
Assistant Professor, Department of Pediatrics, The Ohio State University College of Medicine
out of the research setting and into clinical care.
Catherine E. Cottrell, PhD
Senior Director, Clinical Laboratory, The Steve and Cindy Rasmussen Institute for Genomic Medicine The translational nature of the rapid genome
Associate Professor (Clinical), The Departments of Pathology and Pediatrics, The Ohio State University College of Medicine
sequencing protocol was designed to enable The human exome includes all coding DNA sequences
A
rare disease is one that affects fewer than The current standard of care requires sending a sample to an efficient transition toward offering (exons). Comprising only 1%-2% of the human genome, the
exome nonetheless contains the majority of currently recognized
200,000 Americans. However, because there an external laboratory where results take up to two weeks. genome analysis as a validated test within disease-causing variants in the genome.
are more than 7,000 rare diseases, they are the Institute’s Clinical Laboratory.
collectively common, affecting more than 10% of Expediting a genetic diagnosis on a time scale that is
all Americans. More than half of rare diseases have a relevant to critically ill children and their caregivers Because many steps within the translation protocol
genetic basis and disproportionately affect children. At requires multiple service lines acting as one team. were thoughtfully laid out, including provider
Nationwide Children’s Hospital, many children with Investigators at the Steve and Cundy Rasmussen education, transport and handling of the specimens
rare genetic diseases are diagnosed and managed on Institute for Genomic Medicine are partnering and data, as well as results analysis, the study team
an outpatient basis by providers in the Division of with clinicians in Genetic and Genomic Medicine, and laboratory personnel gained critical hands-
Genetic and Genomic Medicine. Historically, patients Neonatology, Critical Care and the Heart Center to on experience. The knowledge gained during the Exome sequencing is a laboratory test designed to identify and
would undergo a series of genetic tests until a diagnosis understand how to deliver a genomic diagnosis in a translational study allows for further refinement in the analyze the sequence of all protein-coding nuclear genes in the
was reached. The process was time consuming and timely manner and to study the impact this change in overall workflow, with the ultimate goal of providing a genome. Approximately 95% of the exome can be sequenced
frustrating for patients and families, often taking practice has on patients, families and clinicians. The time-sensitive and comprehensive result for improved with currently available techniques.
many years to reach a diagnosis. Within the Steve and process begins when the Clinical Genetics consult diagnosis and management in our most critically ill
Cindy Rasmussen Institute for Genomic Medicine at service is asked to evaluate an inpatient. When the patients. Validation efforts in the clinical laboratory are
Nationwide Children’s Hospital, exome sequencing primary service and the clinical geneticist agree that thoroughly considered to ensure that a test is designed
has been available since 2017. Exome sequencing is a rapid result may improve care, families are offered to be highly robust, accurate, and reproducible, while
a clinical test that allows the portions of our genes the standard of care as well the opportunity to enroll meeting necessary standards set forth by professional
which code for protein to be studied for genetic in an IGM translational protocol designed to rapidly societies, and accreditation organizations. Once a
variation which may be associated with disease. Exome sequence the patient’s genome. Blood is drawn from the test is clinically validated, the results can be directly
patient as well as both parents and sent to the lab for Genome sequencing is a laboratory test designed to identify
sequencing has shortened this diagnostic odyssey for shared with clinical providers to inform care, as well and analyze the sequence of all coding and noncoding DNA.
many patients from years to months or even weeks. analysis. In parallel, the patient’s clinical information as documented in the patient’s medical record. With
However, for our sickest patients requiring intensive is summarized and transmitted to the lab. Once researchers, clinicians, laboratory faculty and staff
care, patients, families and doctors do not have the DNA has been extracted, sequencing is completed in jointly focusing on best outcomes for our patients,
luxury of waiting even a few weeks for a diagnosis. a process designed under the leadership of IGM co- the clinical realization of rapid genome sequencing
investigator Dr. Vincent Magrini. This process generates at Nationwide Children’s is soon to be a reality.
10 | IN PATIENT CARE IN PATIENT CARE | 11
Sustaining Our Drive for 5! Precision Medicine and Next Generation
Sherri Watts, MSN, RN, Professional Development
Clinical Care in Pediatric Neuro-Oncology
T
he American Nurses Credentialing Center Program Director and story author transition details,
Prajwal Rajappa, MD, MS
(ANCC) Magnet Recognition Program® evidence and data into a Magnet Worksheet, followed
Assistant Professor of Pediatrics and Neurological Surgery Member, Translational Therapeutics Program, The James Comprehensive Cancer
application criteria are revised every four by a Magnet Narrative Draft and final e-submission
Center, The Ohio State University College of Medicine Director, Translational Neuro-Oncology Laboratory, Institute for Genomic Medicine
years. Health care organizations apply Donabedian’s document. A second structure linked to employees
structure + process = outcome framework to submitting a potential Magnet story is the new
demonstrate the current state of nursing excellence. Magnet Recognition Program. All employees who
submit a potential Magnet story will receive a heartfelt
Approximately 7% of all registered hospitals are Magnet Steering Committee Thank You. As soon
bestowed Magnet® designation by the ANCC as the story becomes a narrative draft, employees
Commission on Magnet Recognition. A much smaller will receive a frameable Certificate of Completion
percentage of these hospitals have sustained Magnet highlighting the story and team. And finally, when the
designation for more than four consecutive journeys. Magnet story is submitted into the final document,
The current state of Nationwide Children’s Hospital employees will receive an ANCC lapel pin.
Magnet status is as an elite member of hospitals who Process: A silver lining process recognized during
are applying for a fifth consecutive ANCC Magnet the pandemic included endless digital workspace
recognition. Nationwide Children’s is in year two of applications which facilitated continual acquisition
the four-year Drive for 5 themed Magnet Journey. of Magnet stories. Similarly acclaimed, was the
The unprecedented times of virtual meetings, pivoting training afforded by Vickie Bennett, DNP, RN-
and welcoming several new hospital leaders has only BC, who transitioned into a new role of eLearning
strengthened our agile and innovative approach. Two Educator. Vickie and her team expanded use of
employees new to their roles, Lee Ann Wallace MBA, virtual programs such as; IdeaBoardz, Adobe Spark,
BSN, RN, NEA-BC Senior VP Patient Care Services and Mentimeter. These new engagement platforms
and Chief Nursing Officer and Vicki von Sadovszky, have become the foundation for brainstorming
PhD, RN, FAAN, Director Professional Development during virtual Magnet Story touch base meetings.
have supported numerous innovative structures and
processes to sustain our Magnet redesignation efforts. Outcomes: With 43 of the 82 required Magnet
stories assigned, Nationwide Children’s is well
Structure: One new structure is an automated positioned for a successful fifth Magnet document.
potential Magnet story submission process available Our agile and innovative methodology to bumps
to all Nationwide Children’s employees. Once vetted along the road has made this journey one to cherish.
and assigned to a Magnet criterion, the Magnet
Drive for 5
2023
NATIONWIDE
CHILDREN'S
12 | IN PATIENT CARE IN PATIENT CARE | 13
I
n the United States alone, approximately technology and personalized medicine and take advantage providers that molecular characterization of diseases could
4,500 children are diagnosed each year with of the precipitous fall in cost of using these platforms. help identify clinically useful data. Despite a national
Central Nervous System (CNS) tumors. emphasis and rationale for NGS integration into health
To that end, large scale genomic studies on a national care delivery systems, widespread genomics programs have
Pediatric CNS tumors are classified as scale have started to enhance our knowledge base as it yet to be incorporated in standard of care practice on the
both malignant and non-malignant pertains to the genomic and molecular characteristics of grass roots level. Additionally, we lack longitudinal data
tumors of the brain and spinal cord. these disparate tumors. Programs such as the Precision with regards to incorporating precision sequencing and
Medicine Initiative (PMI), All of Us and the Cancer its association to clinical management and outcomes.
There are two main types of CNS tumors: gliomas Moonshot have placed an emphasis and value in genomic
and medulloblastomas. Gliomas, tumors of glial profiling to better understand complex disease entities. At Nationwide Children’s Hospital however, we are
origin, contribute to around half of all pediatric These national programs have long and short-term goals. at the forefront of next generation clinical care in
and adolescent CNS tumors, making them the most These short-term goals include building a knowledge base Pediatric Neuro-Oncology in our journey to best
common CNS tumor in this population. There are two of genetics and cancer biology in order to enhance drug outcomes. Given the seamless integration of genomic
main types of gliomas: astrocytomas and ependymomas. discovery while the long-term goals focus on bringing medicine as an addition to the standard of care in our
Astrocytomas, tumors of astrocytes, are the most accessible precision medicine health care delivery to all Pediatric Neuro-Oncology service, we are starting to
common type of glioma. Low-grade astrocytomas are areas of health care infrastructure. With the rollout of appreciate the important implications of precision
classified into pilocytic astrocytoma (grade I), which these programs, there is a drive for participants to provide medicine and genomics-based approaches to complex
are usually benign and diffuse astrocytoma (grade biological samples, personal health information, and disease entities. The Pediatric Neuro-Oncology Tumor
II). Low grade astrocytomas account for roughly genetic information. This cohort of patients serves as a Board engages in a weekly conversation with neuro-
15% of all gliomas. High grade astrocytomas can be platform for researchers to understand disease process oncologists, neurosurgeons, radiation oncologists,
divided into anaplastic astrocytoma (grade III), diffuse and mechanisms. From a policy standpoint, these new neuropathologists, and genomics experts from Steve
intrinsic pontine gliomas (DIPG), and glioblastomas programs underscore a growing consensus among policy and Cindy Rasmussen Institute for Genomic Medicine
(GBMs, grade IV). Grade II astrocytomas exhibit makers and government officials, industry and health care at Nationwide Children’s Hospital who all have one
better prognosis (median survival of six to eight years)
compared to aggressive high grade GBM (median
survival rate of 12 to 18 months). Ependymomas are
tumors of ependymal cells, derived from primitive
glia, that predominantly occurs in the brain. In
addition to these, germ cell tumors, meningiomas and
X-ray of a child's head, side view lymphomas of the brain demonstrate variability with
regards to tumor and molecular heterogeneity. The
disparate nature and histology of these tumors pose
significant treatment challenges and variable outcomes.
These pose significant challenges for children diagnosed
with multiple recurrent, high-grade, inoperable and
infiltrative disease. The current standard of care for
infiltrative disease consists of maximal safe resection
From a policy standpoint, these new
followed by adjuvant therapy, including chemotherapy,
programs underscore a growing radiation therapy or combination chemoradiation
consensus among policy makers and therapy, but these treatments are fraught with
government officials, industry and comorbidities and toxicities ranging from surgical
health care providers that molecular complications, endocrine dysfunction, neurocognitive
characterization of diseases could delay, and impaired neurologic function associated with
help identify clinically useful data. multimodality therapies. Overall, current treatment
approaches in this high-risk population has been
problematic as demonstrated by poor five-year survival
rates. These poor outcomes have served as a driving
force and rationale to start expanding various multi-
faceted approaches. These modern approaches now
aim to leverage Next Generation Sequencing (NGS)
14 | IN PATIENT CARE IN PATIENT CARE | 15
goal in mind: to improve outcomes for our patients by which limits the adaptive immune system’s ability to
Pharmacogenetics and the Controversy on
integrating precision medicine approaches as an addition
the standard of care. Led by world renown genomics
fight the tumor. Numerous studies and therapeutic
strategies are now emerging to selectively deplete or
Medication Choices
experts Drs. Richard Wilson and Elaine Mardis, the Steve reprogram myeloid cells in cancer. These cellular based Susan Colace, MD, MSCI Assistant Professor of Pediatrics Co-Director for the Program in Personalized Medicine and
Pharmacogenomics Pediatric Hematology/Oncology/BMT
M
and Cindy Rasmussen Institute for Genomic Medicine. strategies and tumor extrinsic approaches in addition
is at the forefront of genomic medicine and translation. to genomic medicine will define the next iteration of ost medications we use to treat childhood the way they are processed in the body. Therefore, not
From a programmatic standpoint, all patients with rare precision medicine. It is this next iteration that should diseases are chosen based on a variety of factors: every patient will benefit from genetic testing for selection
and refractory disease are nominated onto the Cancer also emphasize the critical need for longitudinal follow the type of disease, whether the patient has or dosing of medications. Genetic testing is beneficial
protocol. Here tumor tissue and matching normal up of patient care that involved precision medicine any allergies, whether the drug comes in liquid or tablet for those who are going to be taking medications that
control blood samples may undergo germline analyses in along with tumor intrinsic and extrinsic approaches. We form, the experience of the health care provider with that have a known, actionable, drug-gene interaction.
addition to whole exome and RNA sequencing along with need to evaluate the association of precision medicine medication and so on. Once the medication is chosen,
we typically calculate a dose based on the child’s weight One misconception regarding pharmacogenomic
methylation profiling. The resulting data is reviewed in with clinical outcomes and appreciate the benefits in testing is that it will allow the provider to choose the
concert with the clinical course for each patient during a more systematic fashion. For example, evaluating and height and we may even adjust the dose by measuring
drug levels. Usually, this time-tested method works well, best medication for the patient. Pharmacogenomic
and the chosen medicine works at the prescribed dose. testing cannot identify an individual medication as the
best choice for a patient. Rather, it identifies whether
At Nationwide Children’s Hospital however, we are at the forefront of next generation clinical care For some patients and some diseases, however, this process there are medications that a patient is less likely to
is far more challenging. Patients may try medication respond to, more likely to have side effects from or
in Pediatric Neuro-Oncology in our Journey to Best Outcomes. Given the seamless integration
after medication, only to find that one medication has more likely to have trouble finding the right dose.
of genomic medicine as an addition to the standard of care in our Pediatric Neuro-Oncology terrible side effects, and another doesn’t work at all.
service, we are starting to appreciate the important implications of precision medicine and Another patient may have multiple drug levels drawn The other challenge with pharmacogenomic testing is
genomics-based approaches to complex disease entities. over weeks and months, never quite able to find the dose finding the right time to test for variants in genes that might
that works for them. Patients, families and providers all affect medication choice or dosing. Most pharmacogenomic
end up frustrated and discouraged that a medication testing takes several weeks to get results. For patients who
simply isn’t working the way it is supposed to, and may need to start a drug very quickly, it can be difficult to have
each tumor board meeting. Of note, the sequencing the standard of care approaches as a control arm in start to wonder: is there a better way to do this? results back in time to be useful. Once a patient has started
results are returned in a timely fashion so the data can comparison to precision medicine protocols will serve a medication, pharmacogenomic testing is less useful, as
be incorporated into clinical decision making and this is as a method to evaluate outcomes with respect to Pharmacogenomics is the study of how our genes interact the patient will have already experienced side effects or
just one aspect of our program at Nationwide Children’s utilized techniques. We must also continue to develop with medications, also known as drug-gene interactions. a need for dose adjustment. Therefore, the best time to
that is exemplary. Overall, this multi-disciplinary electronic medical record (EMR) capture tools in order to Our genes are like an instruction manual for our whole perform pharmacogenomic testing is before a patient starts
approach brings together a broad range of expertise to evaluate clinical parameters (radiographic and histologic) body. That includes instructions on how our bodies process any medications for a particular disease or problem.
answer challenging clinical questions and design novel along with laboratory and basic research findings. medications. Some genes control how medications are
treatment strategies based on targeted therapies. absorbed, broken down and removed from the body, while There are currently multiple commercial tests available
While the last few years have seen an increase in others control how medications are moved around the body that test for variants in a large number of pharmacogenes,
There is value in also understanding that the overarching clinical sequencing studies in pediatric oncology, we to the places they need to go. Small changes in these genes, some of which can even be ordered for testing at home,
concept of precision medicine is evolving. While the still need to evaluate the impact longitudinally on called genetic variants, can cause two people to process the without a health care provider. While these can be
initial emphasis has primarily focused on defining tumor patient care and outcomes. Various precision oncology same medication very differently. They may be the same size, interesting and sometimes helpful, most of these large
intrinsic driver mutations, there is a growing body of basket trials also have shown preliminary progress and have the same disease, but need very different doses or panels test for variants which primarily affect drugs
data that suggests that the tumor microenvironment but need further evaluation in refractory or relapsed used in adults, and often the interpretation of the
respond very differently because of differences in their genes.
and extrinsic factors including infiltrating immune cells cancers. Ultimately, a collective analysis of clinical and results is aimed at adults, rather than children. In some
play a role in facilitating cancer progression. To that end, laboratory research data in conjunction with genomic We are constantly learning about drug-gene interactions and cases, the interpretation may lead a provider to avoid
the growing field of immunogenomics within precision findings will accelerate better opportunities for precision how they can be useful to patients. Currently, there are more a medication which could be safely tried in a patient,
medicine is defining mechanisms by which innate and medicine in children diagnosed with cancer. Overall, than 375 unique drug-gene pairs in a database frequently thus unnecessarily eliminating a medication choice.
adaptive immune cells play a critical role in promote our goal in the field of pediatric neuro-oncology is updated by the Clinical Pharmacogenetics Implementation
angiogenesis, invasion and chemotherapy resistance and to improve the outcomes of these complex disease Consortium (CPIC). Not every drug-gene pair is actionable. Every patient’s situation is unique, and it can be helpful
treatment response. Furthermore, various studies in solid entities leveraging precision medicine so we leave a An actionable drug-gene pair means that finding a genetic to discuss options for testing, as well as interpretation
tumors have associated innate immune myeloid cells meaningful impact on patients and their families. variant would change the way a provider prescribes the of test results with an expert in pharmacogenomics.
and tumor associated macrophages as indicators of poor drug. Some drug-gene pairs are informative and simply Experts at Nationwide Children’s Hospital can help
prognosis in addition to their role in T-cell exhaustion give us a better of understanding of why two individuals determine whether pharmacogenomic testing would
might respond to the same drug in different ways. Some be helpful in a particular child’s case or can assist in
drugs do not have any known genetic variants that affect interpretation of pharmacogenomic testing results.
16 | IN PATIENT CARE IN PATIENT CARE | 17
Genetic Counseling and Translational Medicine
Theresa Mihalic Mosher, MS, CGC, Licensed Genetic Counselor, The Steve and Cindy Rasmussen Institute for Ge-
nomic Medicine
G
enetic counseling has been around since the of their medical decision making; giving them the
1970s, but the field has grown and become information needed to help them decide whether or
more visible to the public in recent years. not genetic testing is right for their families. If they
However, what genetic counseling is and how it can do undergo testing, genetic counselors coordinate and
be beneficial to patients and families continues to facilitate testing, and then explain what the results
evolve over time. Genetic counseling is defined by the mean in the context of the family health history and
National Society of Genetic Counselors as “a process to patient’s personal medical history. Whether positive or
evaluate and understand a family’s risk of an inherited negative, genetic test results are complex, and helping
medical condition.” In practice, this can mean many individuals understand the relevant information
things. Genetic counselors are involved in a variety of can have implications for their health and decision
settings, from hospitals and obstetric offices, to cancer making–treatments to use, treatments to avoid and
centers and laboratories. You might even talk to one what the risks to other family members might be. While
on the phone or by video chat if you order a genetic testing might not be the right path for
direct-to-consumer test like 23andMe™. everyone, many individuals and families are
increasingly finding the results useful to
At Nationwide Children’s Hospital, them, not only for their personal health
genetic counselors wear many hats or the health of their child, but also for
to serve our (primarily) pediatric finding their own support community.
population in very specific ways. We
work all across the institution, in While genetic testing technology has
the general genetics clinic, Division improved exponentially over the years
of Genetic and Genomic Medicine, and people are able to be diagnosed
specialty sections like Cardiology, more rapidly, there are still many patients
Neurology, Neuromuscular and Hematology with rare, undiagnosed diseases. Based on the
and in the clinical laboratory. We are increasingly National Institute of Health’s definition of a rare
becoming involved in translational research with the disease, about one in 10 people in this country are
Abigail Wexner Research Institute and the newly affected by one. Despite the fact that about 80% new presentations of established genetic diseases. In about 30% of our rare disease research cases, patients are also
dedicated Steve and Cindy Rasmussen Institute for of rare diseases are thought to be genetic, we don’t receiving information that ultimately leads to a diagnosis via clinical genetic testing guided by research findings.
Genomic Medicine at Nationwide Children’s Hospital. yet know the genetic cause for all these diseases.
This allows for a true bench-to-bedside approach While knowing your genetic diagnosis doesn’t always change your medical care, it does provide a name and
to genomic medicine, giving genetic counselors the The Steven and Cindy Rasmussen Institute for an explanation for the condition. It allows family members who might be at risk to be more easily tested, and
ability to literally translate genomic research results Genomic Medicine is uniquely situated in the gap couples who are at risk to have child with the disease to better understand what their reproductive options
and data into informative and actionable clinical between diagnostic clinical testing and the world of are. In a world where patients can connect across the globe, finding a genetic diagnosis often provides the
information for patients. Some genetic counselors genomic research. The Institute has created a model patients and families with the opportunity to find a community where they can meet and connect with
now hold dual roles, seeing patients in the clinic for translational genomic medicine that allows patients others with the same condition. For many patients, finding these communities can be an important tool for
part-time and working on research projects the rest in the clinic with rare undiagnosed diseases who have coping with a rare disease. In the future, the research being done to diagnose rare diseases may help aid in the
of the time, thus allowing for patients at Nationwide reached the end of their clinical genetic testing road development of treatments and therapies, such as gene therapy, that up until now, has we’ve only dreamed of.
Children’s to take full advantage of genomic to be considered for newer types of diagnostic testing
testing available on their journey to diagnosis. that have yet to be rolled out in the clinical arena. As a genetic counselor, it’s my job to help guide patients and families on their journey to best outcomes
Patients who receive genomic sequencing or other types as they navigate the world of genetic testing, and to help them find the most up to date information and
The goal of a genetic counseling session is never to of genomic analyses on a research basis are helping to support resources for a rare disease. With the translational testing model at the Institute, the ability of genetic
tell people what to do with the genetic information, advance science. We are learning more about genes that counselors to provide patients and families with that information has greatly increased, and will continue
but to empower patients and families to take control have an unknown function in the body and describing to grow in the years to come as our technology and understanding of genomics increases even more.
18 | IN PATIENT CARE IN PATIENT CARE | 19Crisscross Applesauce: Our Journey to Genetic Answers We are forever grateful for the opportunities the clinical genetics and research genomics
Kellynne Werner, Parent
teams provided to Collins and our family. Had it not been for their continued persistence to
W
” e have a problem over here!” Those were wasn’t until my mid-twenties and a visit to a podiatrist
the words that followed the statements after a foot injury that I was told I had Nail-Patella
get the right answer, we would still be using our working diagnosis.
of congratulations from the nurses and Syndrome. The podiatrist made this diagnosis based on my
doctors of the operating room when we delivered our family and medical history and my physical presentation.
second operation in just a few weeks. It was around Patella Syndrome as a working diagnosis that fit some of
first born, Collins Avery, via C-section six years ago. Because I had doubts about Nail-Patella Syndrome,
that time that we heard back from the Department Collins’ symptoms, we figured we had nothing to lose
As many first-time parents are, we were both terrified I enlisted my mother’s help in researching all available
of Genetics with some shocking news. Collins’ test by participating and consented for the research study.
and ecstatic when we conceived. It felt even more information about it. The pictures alone were shocking.
came back negative for Nail-Patella Syndrome. “How
exciting for us, as early on in our marriage we had Not only did the issues seem similar to the ones my family In the fall of 2018, we were contacted by Genetics
could this be?” we thought. The Genetics team
suffered a first trimester miscarriage. Heartbroken from had, but the accompanying text served as support of this with information that would forever change us. The
explained that the testing for this particular syndrome
the loss, our main focus became making it through diagnosis. After all of these years, we had the answer to research study had produced a result: a variant with
was new and our Nail-Patella gene could still have
this pregnancy and giving birth to a healthy baby. so many of the issues my father, his siblings and I have Collins’ FLNB gene. The same variant was also found
a mutation that wasn’t picked up by the test, or it
experienced. So, when Collins was born with orthopedic in myself and my father. Shocked and surprised didn’t
About halfway through our pregnancy, we knew that could be a completely different condition. Though it
issues, we assumed that she too had Nail-Patella Syndrome. even begin to describe the emotions we felt at that
it was anything but typical. Collins was breech, with wasn’t the answer we wanted to hear, we knew that
Nail-Patella Syndrome checked enough boxes to be moment. An answer? A real answer to everything
her bottom down and her legs up. Some parents like to It wasn’t long after Collins was born that we had
a working diagnosis to utilize moving forward. we have gone through? It almost seemed unreal.
give their babies cute names like Bunny or Pea during our first visit with Matthew Beran, MD, from the
the pregnancy process. We, however, affectionately Orthopedics team at Nationwide Children’s Hospital. Shortly thereafter, we met with Scott Hickey, MD,
As the years passed, Collins quickly learned to
referred to her as our fold in half baby. Not only We were quick to tell him our family history and the and genetic counselor, Betsy Schmalz, MS, LGC of
navigate and adapt to her environment despite her
did she keep to one position, she also made herself diagnosis I had been given some years before. During the Genetics team at Nationwide Children’s, where we
abilities being slightly different than those of other
comfortable on my right side and rarely moved. This our initial appointment, Dr. Beran listened and validated learned that the FLNB gene is commonly linked to
kids. Both of her legs were corrected to give her a
always made her easy for the doctors to find during our thoughts and suspicions, but mostly played and a known genetic condition called Larsen Syndrome.
90-degree bend, allowing her to walk and run. She
examinations and gave the nurses and technicians a chatted with Collins while he examined her. He shared It is a congenital disorder associated with large joint
seemed to run using her hips and waddle like a
good laugh when it came time to check her heartbeat. with us plans for future surgeries that would need to dislocation that also affects connective tissue. They
penguin when she walked. She worked with physical
take place to correct Collins’ legs. He also thought provided us with a multitude of information about
On the day of my C-section, there was never a thought therapists to build quad strength, so she could climb
it best for us to work with the Genetics department it. The team also spoke with us about additional
for concern. Collins had simply made herself comfortable stairs and use the equipment at the playground.
for additional answers. So, that’s what we did. abnormalities it could include, and set up additional
and was too stubborn to move. Though the C-section Collins may have done things differently from
other kids, but she continued to amaze us daily. testing to rule out further complications. We
went smoothly and Collins came out screaming with all Not long after our visit with orthopedics, we met
We were consistently seen by the Departments of were happy to later find out that Collins did not
her might, it was quickly realized that Collins’ fold in Annemarie Sommer MD from the Division of Genetics
Orthopedics Genetics on a maintenance basis. suffer from any of the rare abnormalities and her
half position wasn’t just for her comfort, it was due to her at Nationwide Children’s which has since been renamed
condition was primarily orthopedics related.
physical development. My husband said “her feet are up by to the Division of Genetic and Genomic Medicine. Dr.
It wasn’t until 2018 that we were contacted by the
her head!” I said “I’m sure they’re fine. She’s been in that Sommer was eager to hear our story and very interested in Today, Collins is a bright and bouncy 6-year-old.
Rare Disease research team, genetic counselors, Theresa
position for five months.” But I was wrong. Both of her Collins’ case. We told her everything we knew about my She continues to struggle with issues related to her
Mihalic Mosher, MS, CGC, and Erin Crist, MMSc,
knees were dislocated and her feet stayed right up by her pregnancy, my family history and my previous diagnosis. knees and legs, but if you asked her, the only thing
CGC, from the Institute for Genomic Medicine at
head. Not believing it was permanent, we figured she had She was fascinated to hear about how my diagnosis she can’t do is sit crisscross applesauce. Though
Nationwide Children’s, about the possibility of Collins
been in that position for so long her muscles just needed came about, the plans the Department of Orthopedics information about Larsen Syndrome is limited, Collins’
being a part of a new genetics research study. This study
to relax. We even had a staff doctor tell us to “swaddle had for Collins and what she could do to help. She medical team is now able to research and work with
was called “Genome Sequencing to Identify Causes
her legs down” until they relaxed. But by day three in the suggested we go a step further and have Collins tested leading experts to get her the best care possible.
of Rare Birth Defects and Birth Disorders.” It would
hospital, we knew that her legs would need more than for Nail-Patella Syndrome. It was a simple blood test
involve looking at the genes of multiple members We are forever grateful for the opportunities the
time and gravity; she needed an orthopedic doctor. and could be done during Collins’ first leg correction
of our family, including myself, my husband, my clinical genetics and research genomics teams provided
surgery at six months old. Perfect! We had a plan.
Our family has a history with orthopedics, as most of father and other extended family members who had to Collins and our family. Had it not been for their
my childhood was spent in some sort of brace. I had After Collins’ first leg surgery, we spent several weeks orthopedic issues similar to Collins. The study was not continued persistence to get the right answer, we would
shoe braces for club feet, a back brace for scoliosis and caring for her as she adjusted to her new leg— fit with a guaranteed answer to Collins’ issues. It could take up still be using our working diagnosis. Knowing that
underwent countless knee surgeries. Throughout the years, cast accessory. We modified seats, toys and beds in order to a year to hear back and there was a chance it would Collins has Larsen Syndrome allows us to plan for
multiple members of my father’s side of the family have to increase her comfort. It was a learning process that we produce no further answers. Knowing we had Nail- her future and the potential obstacles she may face.
been impacted by and carried on orthopedic issues. It tried our best to master, as Collins was scheduled for a
20 | IN PATIENT CARE IN PATIENT CARE | 21You can also read
