Research highlights at Michigan Medicine C.S. Mott Children's Hospital (2018)

Searching for Answers RESEARCH HIGHLIGHTS FROM C.S. MOTT CHILDREN’S HOSPITAL

Our minds race with questions.

And we lead the search for answers.

1 3D PRINTING TECHNOLOGY: How can we use 3D printing to improve care for children?

2 COLLABORATIVE QUALITY IMPROVEMENT: What strategies can we implement to prevent pediatric cardiac arrest?

4 DIABETES: Can we improve on the “gold standard” in

blood glucose testing?

5 COUNTERING PREMATURE BIRTH RISKS: Could an artificial womb

help extremely premature babies survive?

6 PREVENTIVE CARE: Are we doing enough to lower the risks for

children with sickle cell anemia?

7 RESEARCH INFORMATICS: How can we maximize the value of

electronic medical records?

As one of the nation’s leading children’s hospitals, our specialists care for children with rare and complex conditions requiring coordination across multiple subspecialties.

8 BRAIN CANCER: Can a new alternative and two tried-and-true drugs

finally help us beat DIPG? 10 SLEEP MEDICINE: If a child snores, is surgery the answer?

We care for kids with common conditions that are seen in pediatrician offices everywhere, every day.

11 DEVICE DEVELOPMENT: How can we make surgical devices move

And we ask questions.

12 HEALTH COMMUNICATIONS: How should we talk with our young

Because we know things can be better.

Research can be more efficient. Accelerated.

Diagnosis can be made sooner and with greater accuracy.

like a surgeon’s hand? patients about the tough stuff?

14 METABOLISM: How does the brain control the body’s

energy balance?

15 PARENTING STRATEGIES: What’s the best way to encourage kids

to eat healthy?

Care can be more patient-centered. Precise. Individualized.

Surgical tools can be refined to work better for pediatric applications.

16

Patients can thrive, decades after conquering even the most challenging diagnoses.

18 ENDOCRINOLOGY: How does sex impact obesity-associated

We imagine a better future for our patients and our colleagues.

N EPHROLOGY: Could genetics hold the key to a better future

for children with Nephrotic Syndrome? inflammation, and how early in life does it arise?

And we’re helping create it.

19 NEUROLOGY: How long should anti-seizure medicines be continued

Learn more about the nationally ranked clinical services and programs of C.S. Mott Children’s Hospital at www.mottchildren.org

20 GENETICS: What can the intersection of a genetic condition and

after neonatal seizures? a vitamin deficiency teach us about hearing and balance?

21 DEVELOPMENTAL BEHAVIORAL PEDIATRICS: How do tablet apps

compare with traditional “low tech” toys for parent/child play?

3 D PRINTING TECHNOLOGY

How can we use 3D printing to improve care for children?

When Michigan Medicine physicians became the first in the world to treat a lifethreatening case of tracheobronchomalacia by implanting a 3D printed bioresorbable splint in the child’s airway, they didn’t just revolutionize treatment for kids with the rare airway condition. They kicked off a new frontier of innovation using 3D printing to advance care for children.

to practice the high-risk procedure on an exact 3D printed replica of the patient’s anatomy and tumor — which had two parts, one the size of an egg and the other roughly the size of a kiwi. Their 3D modeling allowed them to test alternative approaches and confirm that the tumor could be safely removed minimally invasively.

The 3D splint procedure, which has now been performed on more than 10 children and is in pre-clinical testing to pave the way for a clinical trial, successfully restored breathing for children whose windpipe periodically collapses.

Zopf and Green have begun exploring 3D printing for use in other applications including scaffolds for auricular reconstruction and microtia repair, as well as nasal scaffolds for partial and total nasal reconstruction. In addition, they’re working on an artificial rib model for surgical simulation of auricular reconstruction.

Since the procedure was first performed in 2012, U-M physicians, led by Glenn Green, M.D., and David Zopf, M.D., M.S., both pediatric otolaryngologists, have used 3D printing to break ground in a number of other areas as well.

In 2016, they used 3D modeling to plan a road map for resecting a tumor lodged deep within the skull of a 15-year-old patient. The size and position of the tumor left surgeons unable to visualize it with regular endoscopy. The team was able

Outside the clinical realm, Zopf and his colleagues are also creating high fidelity surgical simulation tools, which will allow trainees to practice complex airway procedures that may only be encountered a few times a year at many medical centers and in other countries with less access to minimally invasive surgical training capabilities.

1

COLL ABOR ATI V E QUALIT Y IMPROV EMENT

What strategies can we implement to prevent pediatric cardiac arrest?

While C.S. Mott Children’s Hospital is one of the nation’s most established pediatric heart programs, congenital and acquired cardiovascular diseases are still rare. One way to ensure that these fragile patients benefit from the latest treatment advances is to share outcomes and best practices with pediatric cardiac critical care specialists at other institutions.

2

In 2009, with funding from the National Institutes of Health, pediatric cardiologist and cardiac intensivist Michael Gaies, M.D., led a team of Michigan Medicine investigators in establishing an international consortium of pediatric cardiac intensive care units and developing a clinical registry as a platform to study quality and outcomes for pediatric cardiac patients.

Now including leaders in pediatric cardiac critical care, cardiac surgery and cardiology from more than 30 of the nation’s top children’s hospitals, the Pediatric Cardiac Critical Care Consortium (PC4) aims to improve the quality of care for patients with critical pediatric and congenital cardiovascular diseases.

After nearly five years of data collection, PC4 has launched its first collaborative-wide, multi-institutional quality improvement project, focused on one of the most significant complications in pediatric intensive care: cardiac arrest.

Pediatric cardiac arrest, often resulting from shock or respiratory failure, is associated with a hospital mortality rate approaching 50 percent, and surviving patients can experience significant neurological and physical morbidity.

Reducing the incidence of pediatric cardiac arrest would be tremendously beneficial for the survival and long-term health of these vulnerable children.

Analyzing registry data on cardiac arrest, a PC4 team found significant variation in outcomes, including up to a tenfold difference in cardiac arrest incidence.

Their hypothesis: if the best practices and organizational factors from the collaborative’s top performers can be transmitted to poorer performers, a reduction in cardiac arrest rates should result. PC4 members from high performing centers, along with members who have successfully implemented cardiac arrest reduction programs at their hospitals, compiled a bundle of best practices aimed at reducing cardiac arrest in the highest risk patient populations. In the months ahead, the bundle will be implemented in more than 25 PC4-member hospitals by multidisciplinary teams of cardiac ICU clinicians, nurses, respiratory therapists and pharmacists. Frequency of cardiac arrest and other outcomes will be measured before and after implementation.

If successful at improving outcomes and quality of care in cardiac arrest prevention, the project’s collaborative learning model will form the foundation for improving cardiac arrest outcomes at centers across the U.S. and around the world.

3

DIABE TE S

Can we improve on the “gold standard” in blood glucose testing?

The epidemic of childhood overweight and obesity has led to increased rates of pediatric prediabetes and diabetes, and a corresponding need to screen more children for these conditions.

The established “gold standard,” the fasting plasma glucose test (FPG), is tried and true, but it is not always convenient, since it requires at least eight hours of fasting prior to the blood draw.

Research led by pediatric endocrinologist Joyce Lee, M.D., M.P.H., is assessing the performance of alternatives to the FPG to identify prediabetes and insulin resistance, specifically biomarkers previously validated in adults but not yet evaluated for pediatric use.

4

Lee’s multidisciplinary team, including investigators in pediatric obesity and diabetes, diabetes epidemiology, metabolomics, human nutrition and biostatistics, is evaluating the performance of an array of glycemia biomarkers in

a cohort of overweight and obese children. Included in the test set are both conventional biomarkers like Hemoglobin A1c and several novel metabolomic biomarkers.

The biomarkers of glycemia will be evaluated for their ability to predict progression of glucose tolerance (from normal to prediabetes or from prediabetes to diabetes) and insulin resistance over time. Although similar studies have been conducted in adults, this is one of the first to evaluate a comprehensive set of conventional and novel biomarkers for identifying prediabetes in children.

The findings will help guide future recommendations for testing, and yield insights about the pathogenesis of prediabetes in adolescence. They will also provide new information on specific dietary interventions and their impact on a patient’s metabolomic “at risk” profiles.

COUNTERING PREM AT URE BIR TH RISK S

Could an artificial womb help extremely premature babies survive?

About 30,000 babies are born each year in the U.S. at less than 28 weeks gestational age. Severely immature lungs cannot provide the brain, heart and other organs with the oxygen needed to survive, placing these extremely premature babies at higher risk of death or profound disabilities including chronic lung disease and brain injury.

Led by pediatric and fetal surgeon George Mychaliska, M.D., Michigan Medicine researchers have developed an extraordinary new artificial womb technology they hope will one day help the tiniest premature babies with the greatest risks of disability or death continue critical organ development outside the mother’s womb until their bodies are ready to breathe air regularly.

Mychaliska’s artificial placenta is a novel application of ECMO technology. The lungs are filled with simulated amniotic fluid and fetal circulation is maintained.

Oxygenated blood flows into the umbilical vein, and deoxygenated blood drains from the right heart.

The technology is advancing rapidly.

The latest milestone: Mychaliska’s team recently demonstrated that the out-ofbody artificial placenta saved premature lambs from lung failure and protected their brain development until they transitioned to mechanical ventilation. In recent experiments, the lambs have survived for 2–3 weeks on the artificial placenta.

This technology is particularly significant because respiratory distress is the most common problem for premature babies, and their underdeveloped lungs are too fragile for even the gentlest forms of mechanical ventilation. The U-M technology simulates the intrauterine environment and provides gas exchange without mechanical ventilation, allowing the baby to grow and thrive while avoiding the many complications associated with conventional treatment.

The technology has the potential to revolutionize the care of premature infants.

Based on the program’s recent advances, Mychaliska anticipates a human clinical trial of the artificial placenta within five years.

The artificial placenta project, funded by the National Institutes of Health, is taking place in the lab of U-M’s Dr. Robert Bartlett, known as the “father of ECMO” for developing the extracorporeal membrane oxygenation technology that works as a heart and lung machine for a prolonged period in patients with heart and lung failure.

5

PR E V ENTI V E C A R E

Are we doing enough to lower the risks for children with sickle cell anemia?

Sickle cell anemia is the most common inherited blood disorder. Predominantly affecting racial and ethnic minority populations in the U.S., one in 375 AfricanAmerican infants is diagnosed with it.

Sickle cell anemia patients live with the constant threat of pain crises, acute chest syndrome, and eye problems. Moreover, these children are 100 times more likely to get a potentially-fatal bacterial infection and 300 times more likely to have a stroke than other children.

Long-standing recommendations call for 1) daily antibiotics for the first five years of life — shown to reduce infection risk by 84 percent; and 2) yearly transcranial Doppler screening from age two to 16 to monitor stroke risk.

Despite the proven life-saving benefits of these recommendations, they are not always followed. Pediatric epidemiologist Sarah Reeves, Ph.D., M.P.H., led two recent studies to assess adherence.

The results indicated a significant compliance gap.

6

In a study of 2,821 children with sickle cell anemia ages three months to five years, just 18 percent received the recommended daily antibiotics.

Further, in a study of 4,775 sickle cell patients ages two to 16 (half of whom were enrolled for two or more consecutive years of the six-year study), the highest annual transcranial Doppler screening rate recorded was 44 percent (in year six, up from 22 percent in year one). With each year of increasing age, a child was three percent less likely to be screened.

While the studies did not explore specific reasons for non-compliance, Reeves notes that both interventions present numerous logistical challenges for families. For example, the antibiotics are in a solution form requiring bi-weekly pharmacy trips for refills, and transcranial Doppler screening often requires a separate outpatient appointment.

These can be significant barriers for families already burdened by substantial caregiving challenges. Children in the Doppler study, for instance, averaged 20 outpatient visits, four ER visits and two inpatient admissions each year. The fact

that sickle cell anemia disproportionately strikes families with lower socioeconomic status and health literacy adds another layer of complexity.

Further study is needed to understand and address the barriers to compliance. But Reeves believes successful strategies will leverage the numerous healthcare touch points already part of managing sickle cell disease, and will involve shared responsibility and collaboration between families, doctors and pharmacists.

RE SE A RCH INFOR M ATIC S

How can we maximize the value of electronic medical records?

Pediatrician, researcher and informatician David Hanauer, M.D., M.S., was looking for a way to get more clinical data from electronic medical records (EMRs). In particular, he wanted access to the “free text,” dictated or typed by providers into the “notes” section of the EMR. As a clinician, Hanauer knows how frequently doctors include clinically important details as notes rather than using diagnostic codes.

Over more than 10 years, Hanauer has worked with a team of U-M developers to create, test and refine EMERSE — the Electronic Medical Record Search Engine.

This powerful, intuitive, user-friendly tool makes it possible to “google” an institution’s entire volume of free text medical records for information and insights never before available.

In the case of Michigan Medicine, that means access — in seconds — to the more than 12 billion words locked in the approximately 130 million clinical notes made on 2.3 million patients.

EMERSE has features not found in a typical search engine. A library of more than 400,000 synonyms, acronyms, abbreviations, and other terminology, including generic and brand names of medications, helps users capture more relevant data points.

And search results can be displayed and sorted in a variety of ways.

In addition to general data abstraction, researchers rely on EMERSE for identifying cohorts and adverse events in clinical trials.

For those studying rare pediatric diseases, EMERSE can retrieve rare references like mentions of genes and biomarkers that would not otherwise be coded in the EMR.

EMERSE is a secure system with access limited to those who have been granted permission for clinical, operational, or research needs. The system is available to other institutions free of charge, along with technical documentation and training.

Michigan Medicine and five other collaborating sites recently received a grant from the National Cancer Institute (NCI) for further development and dissemination to academic medical centers.

To date, more than 1,000 studies and 170 peer-reviewed publications have arisen from its use.

EMERSE has clinical applications, as well.

For example, a doctor or patient might recall discussing a slight heart murmur detected during a previous office visit, but not recall specific details. The clinician can simply search “murmur” and EMERSE will highlight every appearance of the word in the patient’s notes.

7

BR AIN C ANCER

Can a new alternative to biopsy and two tried-and-true drugs finally help us beat DIPG? Brain tumors are the leading cause of death from childhood cancer. The most devastating type is diffuse intrinsic pontine glioma (DIPG), which develop in the region of the brain that controls breathing and heart rate. More than 90 percent of children diagnosed with DIPG die within 18 months.

Recent history has recorded few breakthroughs in the treatment of DIPG. But investigators in Michigan Medicine’s newly established Pediatric Brain Tumor Research Initiative are bucking that trend, as evidenced by two recent advances from the lab of neurooncologist Carl Koschmann, M.D.

8

Genetic sequencing is the vital first step in designing targeted molecular therapies to combat brain tumors. Traditionally, a tissue biopsy has been required to harvest tumor cells for sequencing, which means open brain surgery. Koschmann’s team is exploring a less invasive option.

The trial targets PDGFR, one of the more frequently identified mutations in DIPG tumors, with a set of drugs already used to treat different conditions. Dasatininb has successfully treated leukemia and some sarcomas and Everolimus is a treatment for noncancerous brain tumors.

Evidence of tumor DNA has been found in the cerebrospinal fluid of some adult brain tumor patients. Koschmann is evaluating the use of spinal fluid rather than tumor tissue to diagnose DIPG and create and monitor individualized treatment plans. Because spinal fluid collection is minimally invasive, it could make it possible to retest the tumor at various points during treatment to observe how DIPG responds to therapy.

The team hopes that a combination of precision medicine (dasatininb targeting PDGFR in the individual patient’s tumor) and blood-brain barrier delivery (everolimus blocking the efflux of dasatininb from the brain) may be effective for children with DIPG and high-grade glioma with these identified mutations.

In addition to validating the use of spinal fluid sampling, Koschmann’s lab is also working to identify a screening panel for cerebrospinal fluid tumor DNA. A screening panel could quickly identify common genetic alterations in newly diagnosed DIPG, greatly improving the efficacy of molecular targeted therapies without the need for repeat surgeries.

The trial will build on Koschmann’s research evaluating cerebral spinal fluid for genetic tumor profiling. Spinal fluid will be used to evaluate how well the drugs are permeating the blood-brain barrier and whether the tumors are responding.

Koschmann is also the lead investigator on a separate but related initiative — a phase 2 clinical trial for children with high-grade glioma and DIPG that has opened at Michigan Medicine, followed by expansion to other sites.

9

SLEEP MEDICINE

If a child snores, is surgery the answer?

Physicians often remove tonsils and adenoids in children to help treat habitual snoring and mild sleep-disordered breathing. However, the impact of surgery on mild sleep-disordered breathing is still not clear.

Performed more than 500,000 times annually on children in the United States, adenotonsillectomy is the most common surgery under general anesthesia in that age group. And, more often than not, the procedure is performed to treat obstructed breathing rather than repeated infections.

A new NIH-funded multicenter clinical study known as the Pediatric Adenotonsillectomy Trial for Snoring (PATS) is underway to determine whether surgery or watchful waiting best improves symptoms.

Pediatric pulmonologist Fauziya Hassan, M.B.B.S., M.S., alongside a team of multidisciplinary sleep specialists from U-M, are collaborating with physicians from five other prominent children’s hospitals to enroll children who snore and have mild sleep-disordered breathing.

10

The multicenter PATS study is a follow-up to the Childhood Adenotonsillectomy Trial (CHAT), in which U-M specialists also participated. The CHAT study found that such surgery was highly effective in improving quality of life and behavior for children with obstructive sleep apnea, a condition characterized by repeated obstruction of airflow during sleep causing night time awakenings or drop in oxygen levels.

But the CHAT study also found that 46 percent of untreated children with obstructive sleep apnea saw breathing

improve naturally, without surgery, during seven months of watchful waiting. Many sleep specialists were left asking, if a symptomatic child really does not have prominent sleep apnea, is surgery still helpful?

Hassan and her colleagues hope the PATS trial will help physicians and families make evidence-based recommendations for children with mild sleep disorders.

DE V ICE DE V ELOPMENT

How can we make surgical devices move like a surgeon’s hand?

In an era of spiraling health care cost concerns, a new low-cost surgical instrument is vying to take the place of a $2 million robot for certain minimally invasive procedures, and at the same time bring the benefits of minimally invasive surgery to patients all around the world.

It’s the result of efforts by pediatric surgeon James Geiger, M.D., to find ways to make robotic-supported surgery techniques more accessible, and better suited for use in pediatric surgery.

Laparoscopic procedures are much less traumatic than traditional open surgeries, allowing for quicker recovery and smaller incisions. But the instruments available for surgeons were generally designed for use on adult patients. Geiger and his colleagues found them cumbersome in operations on smaller children.

In addition, the expense of robotic surgery platforms are prohibitive.

Geiger teamed up with Shorya Awtar, Ph.D., from the College of Engineering at U-M to design a simple, ergonomic and intuitive “needle driver” for stitching inside the body.

The resulting FlexDex device mounts to the surgeon’s arm and uses a unique engineering approach to enable the tip of the instrument to mimic the direction of movement of the surgeon’s hand.

The fully mechanical system provides the functionality of robots at the cost of traditional hand-held laparoscopic instruments.

The technology began as basic research at U-M, funded by the National Science Foundation, and has since been spun out into a commercial enterprise, raising almost $15 million through National Science Foundation SBIR grants and Series A and B private investments.

Michigan Medicine surgeons have used the needle driver in several types of laparoscopic and thoracic procedures, with expected applications for a long list of operations including hernia repairs, hysterectomies and prostatectomies at U-M and beyond. FlexDex is already in use in Japan and Brazil, and will soon be available in most of Europe.

With momentum gaining behind them, Geiger and the FlexDex team are on a mission to disrupt the paradigm where surgeons and hospitals have to choose between high cost/high function and low cost/low function.

11

HE ALTH COM M UNIC ATIONS

How should we talk with our young patients about the tough stuff?

12

Pediatric psychologist Melissa Cousino, Ph.D., is interested in how providers communicate with young patients and families, and how those conversations impact health outcomes. Her work with pediatric organ transplant patients focuses on navigating difficult conversations about prognosis, changes in health status and end-of-life care planning.

Cousino’s anecdotal experience challenges the assumption that when it comes to medical decision making, young children should be shielded and young adults consulted. In her clinic she has met both pre-teens who want to be heavily involved in their care and legal adults who prefer to delegate all medical decisions to their parents.

Past research on children and medical decision making has focused on parental preferences; virtually no work has been conducted from the young person’s point of view. Cousino’s novel research attempts to complete the picture. She is documenting the communication preferences of adolescents and young adults ages 12 to 24 who are transplant candidates, transplant recipients and patients living with advanced cardiac disease.

These extremely difficult choices are frequently made under duress, often without the involvement of the young adult patient.

Cousino’s innovative NIH-funded research is designed to characterize the unique decision-making preferences of this population and to examine associations between patient involvement and health-related quality of life.

She is also studying the provider side of the communication equation. Her team has surveyed providers who work with patients facing end-stage organ disease and pre- and post-transplant patients with serious complications. The findings confirm that providers are not regularly discussing treatment or palliative care options with young patients, and that about half feel uncomfortable doing so.

The long-term goal of this work is to develop evidencebased interventions that help adolescents and young adults increase their involvement in decisions while respecting their values, preferences and needs, as well as interventions for providers, including early career provider education.

The Institute of Medicine recently highlighted a critical need to address the medical communication needs of adolescents and young adults with serious illnesses like heart failure.

Given the unpredictable nature of heart failure, many adolescents reach health crises suddenly, without ever having explored their preferences and wishes about transplantation, palliative care and advance care planning.

13

ME TABOLISM

How does the brain control the body’s energy balance?

The brain plays a key role in regulating metabolism and body weight, as evidenced by patients who exhibit profound changes in blood glucose levels and weight after brain injuries. Yet science has yet to fully describe signals the brain uses to control how energy is stored and expended.

Pediatric endocrinologist David Olson, M.D., Ph.D., is attempting to unravel the brain-metabolism connection at a cellspecific level. The Olson lab is using next-generation technologies in mouse models to engineer precise changes in defined neuron populations in specific brain regions in order to determine the role of these cell types in metabolism and energy balance.

A brain region of particular interest is the paraventricular nucleus of the hypothalamus. Cells in this region are important regulators of the feeding, pituitary function and the autonomic nervous system which controls energy expenditure. Using molecular tools to control neuron function, the Olson lab is determining the biological roles of

14

individual cell types within the paraventricular nucleus. As part of a larger collaboration with other U-M investigators, Olson has also been exploring the mechanisms by which leptin (a critical signal of energy stores) alters hypothalamic function to maintain energy balance. When leptin binds its receptor (LepRb), it changes gene expression in LepRbexpressing neurons. Because LepRb cells make up a relatively small percentage of neurons in the hypothalamus, defining the changes that occur upon leptin binding has been difficult.

Using a tool called Translating Ribosome Affinity Purification (TRAP), Olson and his collaborators were able to determine important changes in gene expression specifically in LepRb cells following leptin

treatment. The ability to determine the transcriptional signature of LepRb cells is an important first step in identifying new potential therapeutic targets for obesity and diabetes.

Olson is interested in pursuing pediatric studies that build on this knowledge, learning more about when and how these tiny and powerful brain cell pathways evolve, and whether abnormalities arising during brain development might contribute to obesity syndromes.

This innovative, highly-targeted research approach holds great promise for a wide range of research applications and, hopefully, for the eventual development of therapeutic targets to combat metabolic diseases in children and adults.

PARENTING S TR ATEGIE S

What’s the best way to encourage kids to eat healthy?

“How can I get my child to stop eating junk food, or to eat smaller portions?”

Pediatricians like Megan Pesch, M.D., M.S., hear questions like this every day, as they partner with parents to counteract the epidemic of childhood obesity. Moms and dads are looking for guidance about whether and how to restrict their children’s intake of unhealthy foods.

The few published studies on the subject indicate that parental attempts to restrict eating may contribute to poor body image or disordered eating later on in adolescence. While important cautions to consider, saying nothing seems just as risky.

Parents — and providers — need proven strategies to help kids navigate tough, tempting choices.

To find out what works and what doesn’t, Pesch began studying how moms communicate with children about food, focusing on both what they say and how they say it.

In one project, she videotaped more than 200 mother-child dyads (both with and without obesity, with a mean age of 5.9 years) participating in a standardized

laboratory eating protocol during which they were presented with several servings of cupcakes. Statements made by the mothers aimed at limiting their children’s consumption were coded as restriction with positive affect (gentle, supportive statements) and restriction with negative affect (harsh, judgmental statements).

Statements were also classified as either direct imperatives or more indirect suggestions.

Results indicated that mothers of children with obesity (vs. those without) had higher levels of restriction overall, and significantly higher rates of both restriction with negative affect and direct imperatives.

This indicates that despite guidelines to the contrary, mothers are restricting their children’s intake of unhealthy foods, and that there are different approaches to do so.

In a similar videotaped laboratory study, Pesch explored the stigma faced by children with obesity; specifically, the stereotype that people with overweight are “sloppy eaters” or have poor table manners. Counter to the stereotype, her work did not find an association between

children’s table manners and obesity. She concluded that obesity interventions based on improving table manners may also be counterproductive, perpetuating unfavorable stereotypes and stigma.

Pesch plans additional research she hopes will lead to the development and testing of tools and interventions pediatricians can share with parents.

15

NEPHROLOGY

Could genetics hold the key to a better future for children with Nephrotic Syndrome?

Children diagnosed with nephrotic syndrome face an uncertain future. The cause of most nephrotic syndrome is unknown, and there are no accurate prognostic tools for it. Existing treatments, including steroids, were not developed for use in nephrotic syndrome, and are non-specific and highly toxic.

Moreover, they do not work for every child.

16

Frustrated by the lack of accurate prognostic tools and targeted therapies for nephrotic syndrome , pediatric nephrologist and genetic epidemiologist Matthew Sampson, M.D., M.S.C.E., formed a research program focused on understanding the genetic origins of the disease.

Much of Sampson’s work to date has focused on a high-risk variant of the gene APOL1, occurring only in African American patients. The variant developed in Africa about 8,000 years ago as a means to protect against certain parasites. Individuals with the APOL1 variant face a dramatically increased risk of developing nephrotic syndrome, and of developing more severe nephrotic syndrome.

Sampson’s lab played a leading role in research published in 2015 that revealed several clinically-relevant characteristics about the high risk APOL1 genotype. Patients presented with significantly lower kidney function and significantly more kidney inflammation. They were also far less likely to respond to immunosuppressive therapy. And surprisingly, they were three to four times more likely to have been born prematurely.

In an initial study of 90 African American children with nephrotic syndrome, more than 60 percent of cases could be tied to the high-risk genotype. Children in that group had significantly lower kidney function at baseline, and progressed more rapidly to diminished renal function or kidney failure. This study’s high-risk cohort was five times more likely to have been born prematurely, again highlighting the need to further investigate this aspect of the genotype.

Sampson hopes this work will eventually lead to targeted treatments and screening protocols for nephrotic syndrome, and that his program’s approach represents a paradigm shift toward genomics discovery in pediatric research. To lay the groundwork, he recently launched the Biobank to Illuminate the Genetic Basis of Rare Diseases (BIGBRD), a biorepository to foster further genomic discoveries in nephrotic syndrome and other understudied pediatric diseases.

Following the study, Sampson’s team was able to compile a list of genes and genetic networks that were activated in the kidneys of the high risk APOL1 group. Current initiatives are focused on characterizing the high risk APOL1 genotype in pediatric patients.

17

EN DOCRINOLOGY

How does sex impact obesityassociated inflammation, and how early in life does it arise?

Bountiful basic science and clinical research confirms the link between high-fat diet-induced obesity and chronic lowgrade metabolically driven inflammation (metainflammation); a hallmark of diabetes, cardiovascular and other non-metabolic diseases. There is also scientific evidence that demonstrates that when it comes to these inflammation-related conditions, men and women face different risks.

The lab team of Michigan Medicine pediatric endocrinologist Kanakadurga Singer, M.D., is tackling how gender differences impact obesity-induced inflammation, and when those events occur in childhood development.

In one recent project, the Singer lab investigated obesity-associated inflammation in mouse models, comparing and contrasting the effects of high-fat diet-induced obesity on glucose metabolism and leukocyte activation in both sexes.

18

They demonstrated that male and female leukocytes and hematopoietic stem cells have sex-specific differences in their response to obesity that contribute to greater immune response in males than in females, promoting impaired metabolism in males.

The Singer lab is also building on the evidence suggesting that obesityassociated metabolic dysfunction is a disease of childhood in which growth, development, environment, and genetic predisposition are intertwined. She is particularly interested in how metainflammation is triggered in the arc of child development.

As a starting point, Singer and fellow Michigan Medicine pediatrician Carey Lumeng, M.D., Ph.D., conducted

a comprehensive review of published research on the subject, concluding that: • T he initiating events of metainflammation occur in the prenatal environment and the postnatal setting.

• W hile metainflammation in the immediate postnatal period needs much more study, it is clearly a sensitive window for the patterning of nutritional and inflammatory responses.

By building an understanding of how — and how soon — metainflammation develops and how early life events influence disease risk in adulthood, Singer hopes to identify clinical targets and windows of opportunity to prevent metabolic diseases in patients of all ages.

NEUROLOGY

How long should anti-seizure medicines be continued after neonatal seizures?

About three in 1,000 babies will experience a seizure soon after birth, with 80 percent occurring in the first week of life. Most neonatal seizures resolve within days or weeks, with no repeat occurrence.

Unfortunately, there is little or no evidencebased information to help predict which children are at risk of future seizures (epilepsy) or developmental problems later in life.

Babies are prescribed anticonvulsant medication to treat their seizures, with phenobarbital the most frequent choice.

Parents are directed to continue to administer the anticonvulsants until the doctor approves stopping. But here too, providers and families lack reliable research to guide decisions about how long to continue medication.

Pediatric neurologist RenĂŠe Shellhaas, M.D., M.S., along with co-principal investigator Hannah Glass, M.D., M.S., of the University of California, San Francisco, have launched a multi-center observational study of the treatment of neonatal seizures.

Funded by the Patient-Centered Outcomes Research Institute (PCORI), the study has enrolled more than 300 families whose children were born at or transferred to one of the nine participating study centers.

Children who survived neonatal seizures are now being observed for 24 months to assess their development and risk for later consequences. Because parents of children with medical complexities face a high risk of stress, anxiety and depression, the study is also evaluating parent well-being as their children grow and develop. Parent partners at every study center played a central role in guiding study design and recruitment.

Even before the study concludes, Shellhaas has a recommendation for other pediatric researchers: Make parents your partners in research. From study objectives, design and approach to grant applications and project execution, parental input is invaluable in keeping focused on the most important issues.

After following the infants and their families for two years, the team will learn how neonatal seizures and their treatment influence child development, later seizures and family well-being. Their findings and recommendations will help providers and parents make treatment decisions and know what to expect in the future.

19

GENE TIC S

What can the intersection of a genetic condition and a vitamin deficiency teach us about hearing and balance?

CHARGE syndrome is a multiple birth defect condition affecting one in 10,000 people worldwide. Named for the constellation of clinical features that can arise from it (ocular coloboma, heart defects, atresia of the choanae, retarded growth and development, genital hypoplasia, and ear defects), CHARGE syndrome was established as a genetic disorder in 2004 when it was determined to be caused in most cases by disruptions in the gene CHD7.

From that day to this, Michigan Medicine genetic researchers led by Donna Martin, M.D., Ph.D., have been at the forefront of studying CHD7’s role in CHARGE syndrome.

Recently, Martin and her group were the first to study similarities between birth defects arising from CHARGE syndrome and those associated with deficiency or excess of vitamin A or retinoic acid (RA) during pregnancy. The parallels in clinical features suggested that CHD7 and RA might share common target genes or signaling pathways.

To explore this hypothesis, Martin and her group focused on embryonic development of the inner ear. The inner ear is particularly sensitive to CHD7 levels and is the most commonly affected organ in CHARGE syndrome.

Testing three potential mechanisms of CHD7 and RA interaction, Martin and her team were able to demonstrate that the RA synthesizing enzyme ALDH1A3 interacts with CHD7 in a common genetic pathway to regulate inner ear development.

This significant finding provides an important clue about the genetic underpinnings of CHARGE syndrome; however, many questions remain. Why do more than 90 percent of individuals with CHARGE syndrome have hearing loss when the major hearing components of the ear do not appear to be disrupted? Might the same CHD7-associated genes affecting the ear also play a role in development of the eye, heart, gut and brain?

Ultimately, Martin and her team hope that this investigative path will help solve these mysteries, and lead to the identification of novel therapeutic strategies and interventions to either treat the defects associated with CHARGE syndrome or prevent them from occurring in the first place.

20

DE V ELOPMENTAL BEHAV IOR AL PEDIATRIC S

How do tablet apps compare with traditional “low tech” toys for parent-child play?

Unstructured play is one of the most developmentally productive activities of early childhood, helping children explore social interactions, hone new skills and engage creatively. Parent-child play offers opportunities for young children to learn more than they would playing on their own, as well as cultural participation and bonding.

The research of Jenny Radesky, M.D., a developmental behavioral pediatrician, focuses on how the rise in digital media use impacts both the parent-child relationship and childhood socialemotional development.

Previous studies conducted by Radesky and others indicate that technology has the potential to both enhance and displace parent-child play. In her most recent project, she examined the ways the design features of toys influenced parent-child

play, comparing one-on-one play with digital toys — specifically, applications (apps) on a tablet — and traditional “analog” toys like Lego™ bricks.

The observational lab study examined 15 parent-child pairs (children age four to six) as they responded to and played with both tablet apps and analog toys. Families were asked to bring both a tablet with the child’s favorite games or apps installed and a collection of the child’s favorite toys (board games, cards, blocks, etc.) to the session.

Because bringing many apps to the session was easier than bringing many physical toys, and to ensure a variety of available options, the lab was also stocked with a collection of age-appropriate analog toys.

The study generally confirmed prior findings that parent-child play in digital spaces is both possible and rewarding, as illustrated by instances of collaboration,

Executive Officers of Michigan Medicine: Marschall S. Runge, M.D., Ph.D., executive vice president for medical affairs, dean, University of Michigan Medical School, CEO, Michigan Medicine; David A. Spahlinger, M.D., president, UMHS, and executive vice dean for clinical affairs, University of Michigan Medical School; Patricia D. Hurn, Ph.D., dean, School of Nursing.

Regents of the University of Michigan: Michael J. Behm, Mark J. Bernstein, Shauna Ryder Diggs, Denise Ilitch, Andrea Fischer Newman, Andrew C. Richner, Ron Weiser, Katherine E. White, Mark S. Schlissel (ex officio)

taking turns, building on each other’s ideas and expressing affection. However, these moments were the exception rather than the rule.

Parents and children were less likely to engage with each other or to respond to each other’s bids for attention during play with tablets versus play with toys.

These differences can be attributed to specific design features of tablet devices and children’s apps, such as interfaces designed to be one-sided rather than supporting parallel interaction, and games that demand continual attention.

The University of Michigan, as an equal opportunity/affirmative action employer, complies with all applicable federal and state laws regarding nondiscrimination and affirmative action. The University of Michigan is committed to a policy of equal opportunity for all persons and does not discriminate on the basis of race, color, national origin, age, marital status, sex, sexual orientation, gender identity, gender expression, disability, religion, height, weight, or veteran status in employment, educational programs and activities, and admissions. Inquiries or complaints may be addressed to the Senior Director for Institutional Equity, and Title IX/Section 504/ADA Coordinator, Office for Institutional Equity, 2072 Administrative Services Building, Ann Arbor, Michigan 48109-1432, 734-763-0235, TTY 734-647-1388, institutional.equity@umich.edu. For other University of Michigan information call 734-764-1817. © 2018 , The Regents of the University of Michigan

www.mottchildren.org Michigan Medicine C.S. Mott Children’s Hospital 1540 E. Hospital Dr. Ann Arbor, MI 48109 PATIENTS & FAMILIES

877-475-MOTT (877-475-6688) @MottChildren PHYSICIANS

800-962-3555 @MottDocs Learn more about supporting U-M pediatric research at www.mottchildren.org/giving