Apr 17 2014

Studies Find Genes Linked to BMI, Cardiovascular Health

BMITwo recent studies expand the list of genes associated with body fat and body mass index (BMI), and their connection to heart disease, high blood pressure, and diabetes. One study showed higher BMI caused harmful effects on the risk of type 2 diabetes, high blood pressure, and inflammation, while a second investigation found gene signals linked to higher levels of body fat metrics.

According to the CDC, heart disease causes approximately 600,000 deaths each year in the United States, and 67 million adults have high blood pressure (which is associated with increased rates of heart attack, heart failure, and stroke). For its part, diabetes is the 7th most common cause of death, and nearly 12 percent of American adults over 20 years of age are living with diabetes.

“These findings are highly relevant to the obesity pandemic in the United States and many other countries,” said the Center for Applied GenomicsBrendan J. Keating, DPhil, who co-led both studies.

Lowering BMI Could Improve Cardiovascular Health

In the BMI investigation, published recently in the American Journal of Human Genetics, Dr. Keating collaborated with clinical epidemiologist Michael V. Holmes, MD, PhD, of the Perelman School of Medicine at the University of Pennsylvania. That study made use of a recently developed tool called Mendelian randomization (MR) that allows researchers to construct genetic risk scores for specific traits of interest.

The study team analyzed eight population cohorts including over 34,000 individuals of European descent, of whom over 4,400 had type 2 diabetes, over 6,000 had coronary heart disease and over 3,800 had a previous stroke.

“This study is the first to use this emerging MR technique with a combination of genetic markers known to impact BMI, to assess the causal relationship of BMI and a comprehensive repertoire of traits,” said Dr. Holmes.

The authors concluded that their analysis supports the importance of BMI in regulating cardiometabolic traits and the risk of type 2 diabetes. “Our findings suggest that lowering BMI is likely to result in multiple reductions of cardiovascular traits: in blood pressure, inflammation, fasting glucose and insulin, and in the risk of type 2 diabetes,” said Dr. Keating.

Body Fat Genetic Signals Discovered

Dr. Keating also co-led a second study, published in Human Molecular Genetics, that analyzed genes associated with central adiposity. Measures of central adiposity, or body fat, can be derived using waist circumference and waist-to-hip ratio.

Keating’s co-senior author was Kira C. Taylor, PhD, MS, of the University of Louisville. The study team performed a meta-analysis in over 57,000 subjects of European ancestry, then validated their results in even larger numbers from independent studies.

This study discovered three novel genetic signals associated with central adiposity, in the genes TMCC1, HOXC10, and PEMT. In addition, the team found two more novel genetic signals, in the SHC1 and ATBDB4 genes, which were only observed in women.

“Previous research has reported different gene variants operating between men and women related to adiposity,” said Dr. Keating. “This gives us initial clues of the genes involved with sex-specific body shapes. Future research using these findings may yield insight into the actual biological mechanisms that dictate why males and females have different body distributions of fat deposits.”

The adiposity study showed an association, not a causal role, for the genetic signals, with other signals yet to be discovered using even larger sample sizes. Several of the genes are in regulatory regions, Dr. Keating noted. While additional work is needed to tease out the biology of these signals, but the first steps of identifying genes underpinning these traits has been accomplished, Dr. Keating added.

For more information about both studies, see the full press release.

Permanent link to this article: http://www.research.chop.edu/blog/studies-find-genes-linked-bmi-cardiovascular-health/

Apr 16 2014

Investigating Breakthrough Cystic Fibrosis Drug’s Effect on Weight

cystic fibrosis

“What caught our eye with this is as they were doing the clinical trials there was a completely unexpected weight gain … almost every participant was gaining weight,” Dr. Stallings noted.

A new project at The Children’s Hospital of Philadephia seeks to gain a clearer idea of what effect the novel cystic fibrosis drug ivacaftor has on energy balance and weight gain. With the support of the drug’s manufacturer, Vertex Pharmaceuticals, CHOP’s Virginia A. Stallings, MD, will measure the degree to which patients with cystic fibrosis taking ivacaftor — which is sold under the name Kalydeco — experience improvements in nutritional status and growth.

An inherited disease that is chronic, progressive, and often fatal, according to the Cystic Fibrosis Foundation cystic fibrosis affects approximately 30,000 adults and children in the United States and 70,000 worldwide. The disease is characterized by thick mucus that causes respiratory and digestive issues, and is associated with poor growth and weight gain, among other complications. There is currently no cure for cystic fibrosis, and until recently most treatments have focused on alleviating the disease’s symptoms.

Kalydeco is approved to treat CF in patients 6 years of age and older who have specific mutations in their cystic fibrosis gene. Kalydeco was first approved in 2012 on the strength of trials that showed it improved lung function “and other aspects of cystic fibrosis such as increasing weight gain,” according to the FDA. Though the FDA recently expanded the number of mutations for which Kalydeco is approved, because its approval is restricted to particular mutations it can currently only treat a small segment of the overall cystic fibrosis population. Nonetheless, Kalydeco is a “breakthrough” drug, said CHOP’s Dr. Stallings.

With this project, Dr. Stallings will examine Kalydeco’s effect on cystic fibrosis patients’ energy balance and weight gain. Dr. Stallings and her team proposed the study to Vertex after noting the unexpected weight gain observed during Kalydeco’s clinical trials.

Much of Dr. Stallings’ career has been spent working on ways to improve cystic fibrosis patients’ weight and growth, so the approval of Kalydeco — which treats the “primary cellular defect” — was “was a major, exciting, proof-of-principle,” she said.

“What caught our eye with this is as they were doing the clinical trials there was a completely unexpected weight gain … almost every participant was gaining weight,” Dr. Stallings noted.

She proposed a comprehensive study that will investigate what effect Kalydeco has on pancreatic function, how well patients are able to absorb food, and whether taking the drug has any effect on the patients’ appetite and food intake. Over the next 18 months, Dr. Stallings and her team will enroll patients who are about to go on the drug, to measure the effect Kalydeco has on their weight, appetite, and energy intake and needs before, during, and after treatment. The study will make use of innovative “SmartPills” that can measure changes in pH and gastrointestinal motility, Dr. Stallings said.

In a related project supported by the Cystic Fibrosis Foundation, Andrea Kelly, MD, from the Division of Endocrinology and Diabetes, has been working on an investigation of Kalydeco’s effect on insulin and insulin secretion. If the investigators were able to compare findings (not to mention share study participants), “we would have a spectacular look at the whole metabolic change,” said Dr. Stallings.

Saying she was excited about the study, and the promise of novel therapies like Kalydeco, Dr. Stallings said, “we’ve never had a time in CF when we could almost guarantee weight gain … so here we have an experimental design where almost everybody is going to gain weight.”

To learn more about cystic fibrosis, and cystic fibrosis research at The Children’s Hospital of Philadelphia, see the Cystic Fibrosis Center website.

Permanent link to this article: http://www.research.chop.edu/blog/investigating-breakthrough-cystic-fibrosis-drugs-effect-weight/

Apr 15 2014

Study Identifies Risk Factors for Obstructive Sleep Apnea

sleep apneaWhile obstructive sleep apnea syndrome (OSAS) is a relatively common condition, affecting about 2 percent to 4 percent of young children, the scientific community is just opening its eyes to pediatric sleep disorders. Little is known, for example, about the characteristics that increase OSAS severity in children.

OSAS occurs when a child stops breathing during sleep, usually because there is a blockage from enlarged tonsils or adenoids. Many of the pauses, called apneas and hypopneas, cause a brief arousal that increases muscle tone, opens the airway, and allows the child to resume breathing. These repeated disruptions result in restless sleep. Recurrent nightly episodes of obstructive apnea are associated with adverse behavioral, cognitive, quality of life, and health outcomes in children.

Researchers from the Sleep Center at The Children’s Hospital of Philadelphia were involved with a large, multicenter study called the Childhood Adenotonsillectomy Study for Children With OSAS (CHAT), and recently they used the study’s baseline data to perform a cross-sectional screening to analyze which factors predict OSAS severity. They examined data from 421 children ages 5 to 9 years who had undergone sleep testing, known as polysomnography, and evaluated the relationship between their levels of OSAS to sex, race, body mass index, environmental tobacco smoke (ETS), prematurity, socioeconomic variables, and comorbidities.

“If presumably you know some of the risk factors, you might be able to address some of those risk factors and preempt the sleep apnea or at least diagnosis it earlier,” said Carole L. Marcus, MBBCh, director of CHOP’s Sleep Center, who was first author for the CHAT study and also participated in the auxiliary study that appeared in SLEEP in February.

The auxiliary study found that African American race predicted OSAS severity, which supports previous research. This is especially interesting, Dr. Marcus said, because the CHAT study results showed that African American children had less improvement postoperatively, both in terms of polysomnographic changes and behavioral changes. Much debate exists about why African American race would be associated with higher OSAS severity and poorer outcomes after surgery, but some research suggests genetic, craniofacial, and environmental components play a role.

“They have worse disease, but they don’t respond as well to the therapy and possibly have more complications from the treatment,” Dr. Marcus said. “That definitely deserves further research. We also found in another related study that looked at continuous positive airway pressure, which is an alternative therapy for kids who don’t improve following surgical therapy, that they had poor adherence to CPAP. So they’re definitely a more difficult group to treat.”

Study participants’ exposure to secondhand smoke was another significant risk factor for increased OSAS severity that researchers identified.  ETS already has been connected to snoring in children, so this novel finding advances pediatric sleep research by demonstrating its effect on OSAS.

African American race and exposure to ETS were each associated with an approximately 20 percent increase in apnea-hypopnea index. More research is needed, Dr. Marcus said, to define these specific factors and suggest better OSAS screening strategies that focus on African American children and children exposed to ETS.

In the meantime, pediatricians can use this study’s findings to promote awareness of OSAS by asking parents about snoring at their children’s regular healthcare maintenance visits, Dr. Marcus said. It also provides an ideal opportunity to encourage families with smokers to quit and protect their children from secondhand smoke.

Permanent link to this article: http://www.research.chop.edu/blog/study-identifies-risk-factors-obstructive-sleep-apnea/

Apr 14 2014

Forbes Article Features CHOP Gene Therapy Expert

gene therapy

Dr. High is an internationally recognized hematologist and molecular researcher.

A recent Forbes article on the resurrection of the gene therapy business featured The Children’s Hospital of Philadelphia gene therapy expert Katherine A. High, MD. Dr. High is cited as one of a small group of scientists who “kept the field alive” after business interest in gene therapy “dried up” when companies ran into issues bringing gene therapy from the bench to the bedside.

Dr. High felt “gene therapy researchers had been making two mistakes: using a virus that might make the patient very sick (the adenovirus) and not carefully picking the diseases they would treat,” the Forbes article says. “People were choosing targets based on high unmet medical need and the size of the market, not based on the scientific evidence that gene therapy would impact the disease,” Dr. High said.

An internationally recognized hematologist and molecular researcher, Dr. High is a professor of Pediatrics at the University of Pennsylvania, and a Howard Hughes Medical Institute investigator. She has led translational studies in hemophilia, including reporting on the first cure of hemophilia B in a canine model of the disease using gene therapy.

Pointing out that “High’s approach yielded amazing results,” the Forbes article cites Dr. High’s pioneering use of adeno-associated virus as a gene therapy delivery vector and her contribution to a study of RPE65-related inherited retinal dystrophy, a rare retinal disease that progresses to total blindness by adulthood. “In one trial 12 patients, 5 of them kids, had dramatic improvements in their sight. The children were able to move from Braille classrooms to sighted ones. A late-stage study that could result in the treatment’s approval is ongoing,” the Forbes article notes.

The article also mentions the gene therapy company Spark Therapeutics. Based in part on Dr. High’s work, Spark was launched in October 2013 with a $50 million capital commitment from Children’s Hospital. In addition to building on Dr. High’s RPE65-related work, Spark — which received the “Deal of the Year” award at the 2014 Pennsylvania Bio Annual Dinner & Awards Celebration — is also working toward on hemophilia B treatments and neurodegenerative disease programs.

To read more, see the Forbes article, “Gene Therapy’s Big Comeback.”

Permanent link to this article: http://www.research.chop.edu/blog/forbes-article-features-chop-gene-therapy-expert/

Apr 11 2014

New iPad® App Helps Construct Genetic Pedigrees

geneticHuman pedigrees are diagrams similar to a family tree that make it easier to visualize genetic relationships within families and to record how diseases may recur across generations. Genetic counselors use pedigree analysis to study the inheritance of genes and apply this knowledge to patient-care decision making.

Families who have children with developmental delay or mental retardation, birth defects, multisystem medical problems, unusual facial features, or failure to thrive may benefit from genetic counseling to get clues to inheritance patterns.

Traditionally, genetic counselors interview parents and hand-draw pedigrees, but they now have a new app to create those diagrams digitally on an iPad® screen with a few finger taps. The Center for Biomedical Informatics (CBMi) at The Children’s Hospital of Philadelphia created the Proband app as an efficient data collection tool that enables genetic counselors, geneticists, and researchers to construct even the most complex family pedigrees simply and flexibly. It is based on standard pedigree nomenclature and symbols, and users can make edits seamlessly as they gather new information.

“We designed this app for ease of use with options appearing as you need them,” said Jeff Miller, lead analyst at the CBMi. “Our goal is to make those features contextually relevant, and not to overwhelm the user.”

The CBMi development team solicited critiques and feedback from clinical genetics specialists at CHOP. Mindy Li, MD, a clinical genetics and metabolism fellow, tested the app and compared it to reviewing traditional hand-drawn pedigrees. One advantage to the app is that she did not have to decipher someone else’s handwriting or idiosyncratic abbreviations. She also enjoyed the convenience of being able to set the iPad on her lap while conducting an interview.

“It’s a better interaction than if I had to turn toward a computer screen and input the information,” Dr. Li said.

The app can capture any level of detail, without the space limitations of paper. And instead of opening up a file cabinet, users can store the pedigrees in a standardized format and export the diagrams to other applications such as electronic medical records.

“As health technology in general is moving toward electronic data, it’s important to have pedigrees easy to read and easy to integrate,” Dr. Li said.

This application is one example of the many ways in which CBMi helps transform clinical care and research at CHOP and across the industry. Miller and other team members presented Proband at the annual meeting of the American College of Medical Genetics and Genomics, March 28 in Nashville. The National Human Genome Research Institute’s Clinical Sequencing Exploratory Research (CSER) Program grant 5U01HG006546-03 funded this work.

Genetic counselors, clinical genetics specialists, and others can download the app from the iTunes App Store. iPad is a trademark of Apple Inc. App Store is a service mark of Apple Inc.

For more information, read the press release.

Permanent link to this article: http://www.research.chop.edu/blog/new-ipad-app-helps-construct-genetic-pedigrees/

Apr 09 2014

Evaluating How Peer Passengers Affect Teen Drivers

teen driversThe work of Children’s Hospital’s Dennis Durbin, MD, MSCE, scientific director of CHOP’s Center for Injury Research and Prevention (CIRP), figured prominently in a recently published Atlantic article on teen drivers and distracted driving. The article, “How Gender Affects the Behavior of Teen Drivers,” in part reports on the recent Engaged Driving Symposium, held March 31 in Washington, D.C., and sponsored by State Farm and the Association for the Advancement of Automotive Medicine (AAAM).

The Atlantic article is focused on the “surprising differences” between how teen male and female drivers drive, and particularly on how boys’ and girls’ driving is affected by having passengers in the car. For example, boys are “three times more likely to drive recklessly when there was a girl in the car than when they were driving alone, and slightly more likely than with a boy in the car.”

“In the presence of peers, teens will overvalue the short-term rewards of their decisions rather than the long-term consequences,” the article quotes Dr. Durbin as saying at the conference.

Underscoring this, in a paper published in the Annals of Advances in Automotive Medicine to coincide with the Engaged Driving Symposium, citing a recent study the authors (led by Dr. Durbin) note “the rate of crashes and near crashes was nearly twice as high when teens drove with more risk-taking friends.”

Peer passengers “may serve as a source of driver diverted attention, either by diverting the driver’s eyes from the roadway or by engaging the driver in conversation to the extent that a cognitive distraction is created,” the authors write.

And in a recent post on the Center for Injury Research and Prevention blog, Dr. Durbin notes that he prefers the term “engaged driving” to “distracted driving” as “it better describes what we want drivers to do to be safe.”

“Research into how young drivers make decisions about how often and under what circumstances they’re likely to “disengage” from the driving task will help us understand how best to motivate teens to remain fully engaged and prevent crashing, especially in higher risk situations,” Dr. Durbin writes.

To read more, see the Atlantic article and Dr. Durbin’s CIRP blog post. To learn about the pioneering traffic injury prevention research being performed at the Center for Injury Research and Prevention, see the CIRP website.


Permanent link to this article: http://www.research.chop.edu/blog/evaluating-peer-passengers-affect-teen-drivers/

Apr 07 2014

Congress Passes Legislation to Train Pediatric Providers

pediatricLegislation that reauthorizes an important program to ensure that the U.S. has enough doctors trained to treat children cleared final passage in the House and now awaits President Obama’s signature.

The Children’s Hospital GME Support Reauthorization Act of 2013 reauthorizes federal funding to support graduate medical education for freestanding children’s hospitals. Rep. Joseph Pitts (R-PA) and Sen. Robert Casey Jr. (D-PA) sponsored the bill, which will invest $300 million annually in children’s hospitals over the next five years.

“CHOP is grateful for the bipartisan leadership that Sen. Casey and Rep. Pitts provided on this legislation,” said The Children’s Hospital of Philadelphia’s CEO Steven Altschuler, MD. “They recognize the importance of pediatric healthcare and ensuring it is accessible in communities throughout Pennsylvania and beyond. By enabling children’s hospitals to train pediatricians, we can meet the specialized needs of our patients and provide appropriate healthcare for children.”

By 2025, the U.S. will face a shortage of physicians to meet the needs of our U.S. population, according to the American Medical Association. Pediatric subspecialists who train at children’s hospitals are among the more than 20 specialty groups already experiencing severe shortages.  Close to 4 million babies are born annually in the U.S., so it is vital for the nation to maintain a robust pediatric workforce.

First enacted by Congress in 1999, the Children’s Hospital Graduate Medical Education program encourages more young doctors to pursue pediatrics. CHGME provides funding to about 55 freestanding children’s hospitals in 30 states to support the training of more than 6,000 pediatricians and other residents.

“Reauthorizing this program will help some of our country’s best medical centers train physicians and enable families and children to receive better care,” Casey said. “Pennsylvania’s children’s hospitals are some of the best in the country. Passing this bill will allow these hospitals to continue their lifesaving work and remain a driver of our economy.”

In his remarks on the House floor before the vote on the bill April 1, Pitts said, “I am glad that today we will pass a bill that will help keep American children healthy. … Locally in my area of Pennsylvania, the Children’s Hospital of Philadelphia participates in the program. I’ve had the privilege of visiting the hospital a number of times and meeting with the young patients and the doctors learning how to treat them.”

The CHGME program has a proven track record of success. Although they represent 1 percent of all hospitals, freestanding children’s hospitals train more than 45 percent of general pediatricians, 51 percent of all pediatric specialists, and the majority of pediatric researchers.

Permanent link to this article: http://www.research.chop.edu/blog/congress-passes-legislation-train-pediatric-providers/

Apr 04 2014

Advocates Shaky That NIH Funding Remains Steady

NIH fundingAdvocates for biomedical research expressed their disappointment in President Barack Obama’s proposed budget for fiscal year 2015, which includes a slight rise in funding for the National Institutes of Health. This modest boost is expected to support 9,326 new and competing grants, 329 more than this year.

The FY15 budget in­cludes $30.2 billion for NIH to back research at institutions across the U.S. NIH Director Francis Collins, MD, PhD, told the Wall Street Journal that his agency is “grateful that in a tough budget year, the NIH was able to get an increase.” However, he noted that NIH is about $500 million behind where it was in the Obama administration’s proposed fiscal-year 2012 budget.

The research community had hoped that the 2015 budget would help to make up for lost ground following the devastating sequestration last year, which resulted in a 5 percent cut to NIH’s budget. Instead, they continue to worry that keeping funding levels at status quo will not sustain the fast pace of scientific innovation. Several research advocacy groups are calling on the administration and Congress to make a significant investment in NIH funding during their budget negotiations.

“The United States once stood firmly at the forefront of the research revolution, but after a decade of budgets that have not kept pace with inflation and last year’s across-the-board sequestration cuts, NIH has seen a more than 20 percent decline in its purchasing power and can only fund one in every seven research grants it receives,” wrote the United for Medical Research in a statement. “As such, the U.S. is slipping in its position as the global leader in the life sciences.”

The $30.2 billion proposed in the budget, adjusted for inflation, would be $100 million lower than the 2002 funding level for the NIH. Mary Woolley, president and CEO of Research!America, reiterated that insufficient funding levels for federal research and health agencies jeopardize scientific discovery and its capacity to improve health outcomes and stem the explosion of chronic diseases.

“We simply cannot sustain our nation’s research ecosystem, combat costly and deadly diseases like Alzheimer’s and cancer, and create quality jobs with anemic funding levels that threaten the health and prosperity of Americans,” Woolley wrote in a statement.

In his budget message, President Obama emphasized the importance of biomedical research and proposed an Opportunity, Growth, and Security Initiative that would provide an additional $970 million for NIH, which would support about 650 additional new grants. But an analysis of federal policy reported in Inside Higher Ed described this potential windfall as “almost fanciful” because the new initiative would depend on Congress reaching consensus on major changes in the tax code.

While The Science Coalition, a nonprofit, nonpartisan organization of the nation’s leading public and private research universities, appreciated the signs of President Obama’s “commitment to world-class science and research,” it remains wary about the long-term funding trends.

“The result is that we now face an innovation deficit — the gap between needed and actual federal investments in research and higher education,” stated Jon Pyatt, 2014 president of The Science Coalition. “We urge Congress to make investments in research and education a national priority. Only by doing so can we close the innovation deficit and truly put our nation back on a track for long-term economic health, well-being, and security.”


Philip R. Johnson, MD
Director, The Children’s Hospital of Philadelphia Research Institute
Chief Scientific Officer and Executive Vice President

Permanent link to this article: http://www.research.chop.edu/blog/advocates-shaky-nih-funding-remains-steady/

Apr 02 2014

1 in 68: An Interview with CHOP Experts on the CDC’s New Autism Rate

autismThe Centers for Disease Control and Prevention (CDC) recently announced a new prevalence estimate for Autism Spectrum Disorder: 1 in 68 individuals. This is 29 percent higher than the estimate released in 2012 (1 in 88), 64 percent higher than the estimate from 2009 (1 in 110), and a 124 percent increase from the report from 2007 (1 in 150).

Philip R. Johnson, MD, director of The Children’s Hospital of Philadelphia Research Institute, recently interviewed Center for Autism Research experts to get their take on the new CDC numbers.


Dr. Johnson: What could account for such a dramatic rise from the initial reports?

Judith Miller, PhD: There are a few reasons that we can hypothesize that can account for this rise. For one, with each surveillance study, the participating sites get better and better at gathering records from their clinical and educational sources. Secondly, autism spectrum disorder (ASD) awareness has increased dramatically over the last 15 years, so with each year increasing numbers of parents, schools, and clinicians are considering whether a child’s difficulties might be due to autism. Third, the true prevalence may be rising due to real changes in the factors that cause autism.

Dr. Johnson: How are these studies conducted? 

Susan E. Levy, MD, MPH: These studies rely on record reviews rather than in-person evaluations. Records of any child who meets the age criteria, who lives in the specified geographic region, and who has come to the attention of a healthcare or special education agency are included. An anonymous file is compiled of that child’s comprehensive health and education evaluations, which is then reviewed by clinicians using a standard rating procedure.

The studies looking at prevalence of developmental disorders such as ASD are carried out in multiple locations in the United States, funded by U.S. Department of Health and Human Services through the CDC. Sites are awarded the opportunity to participate based on their ability to access the necessary records and conduct the necessary work, and each site works closely with their local healthcare and education agencies to collect the data.


Dr. Johnson: Do these numbers seem to fit with clinicians’ and researchers’ sense of the prevalence?

Dr. Miller: It’s always better to have data than rely on anyone’s impression. I think this is the record review method is a probably the best one possible. However, record review will always have limitations, including the lack of gold standard clinical evaluations. The best approach would be to do a real epidemiological study, basically door to door with expert clinical evaluations but that is so expensive as to probably be impractical in this funding environment.

The CDC, however, did do a small study with in-person assessments, and it showed good correlation to the record-based study. But that was many years ago. I am hopeful the CDC can receive funds needed to continue doing validation studies. With increased awareness in the community, and recent changes to diagnostic criteria it’s important to understand how the diagnosis is being made in the community.

Marsha Gerdes, PhD: It’s probably most important to take a step back from the numbers.  Even if the diagnosis is not 100 percent accurate in all cases, these are children who are coming to the attention of their schools, parents, or healthcare providers. They are struggling in some way with social communication and behaviors. We as a community need to come together around how best to meet their individual needs and to support their families and educators.

Robert Schultz, PhD:  Given the CDC’s methods, there will clearly be errors of diagnosis, including misdiagnosing some children who really don’t have ASD. However, that does not mean that all or nearly all of the children identified don’t have a condition that causes them to struggle much more than a typical child.

It is also important to recognize that diagnostic categories such as ASD mask considerable heterogeneity. It is often said, “If you have seen one child with autism, you have seen one child.”  More recent research is showing that ASD presents on a continuum with typical development, but for certain skills and traits, just on the lower end of some continuous dimension. The point here is that there might not be sharp boundaries and a real category of autism.

The World Health Organization (WHO) and other organizations will report the “true” prevalence of brain based mental disorders is about 20 percent, and these often start at birth or prenatally. I would say 1.5 percent of children who present with ASD on record review very likely have something. The “essence” of what they have however is proving a bit more elusive than we use to understand, and many times cases do not fit neatly in current diagnostic groups. But that does not mean that these kids are not struggling and in need of interventions.

Dr. Gerdes: Let’s put the 1.5 percent in the context of other developmental disorders. The CDC’s report, “Trends in the prevalence of Developmental Disabilities in U.S. children, 1997-2008,” reported learning disabilities at 7.7 percent and ADHD at 6.7 percent, an increase of 33 percent. Many of the same factors of increasing awareness and accessing services may have played a role in increases of other developmental disabilities.


Dr. Johnson: OK, I get all that. But then, how does one define “normal?” If 20 percent of people have brain based mental disorders, then it’s no longer “atypical.”

Dr. Schultz: Yes, it is a value judgment as to where you draw the line and say this kind of problem necessitates special attention. The values most commonly invoked are economic and quality of life. The WHO discusses the impact of mental disorders in terms of both dollars and DALYS (disability-adjusted life years). Where you draw the line affects who gets treatment and ultimately can save both dollars and DALYS.


Dr. Johnson: Sounds reasonable. But still. Let’s say 1 in 68 children have “something.” Did they always have something?

Dr. Miller: At the Center for Autism Research, we see more and more children being referred for mild forms of autism (the group that saw the largest increase in the CDC study). We find that 20-25 percent of children who have been diagnosed with mild forms of ASD in the community don’t meet our gold standard criteria for an autism spectrum disorder. These children are struggling, but their clinical presentation is complex, and doesn’t always fit neatly under ASD.

Dr. Gerdes: Services funded by the community (e.g., Early Intervention, Special Education, Mental Health, etc.) are often, but not always, tied to both a diagnosis and a level of impairment.  This can make it difficult to help those individuals with milder symptoms or a less common presentation of symptoms. Obtaining services for those children and adults can be challenging.

Dr. Schultz: The field has really begun to move away from studying categories of mental disorders, as they don’t map onto to the brain or to the genome in a clean fashion. Tom Insel, MD, Director of the National Institute of Mental Health, has lead the way here, and is pushing for grants to propose studies that cut across diagnostic boundaries, that focus on processes rather than diagnostic categories (e.g., processes such as sociability — which can be linked to reward circuits in the brain, or executive functioning — which can be linked to functions of the frontal lobes). Deficient executive functioning and sociability are features shared by many different disorders. Ultimately profiles of functioning across these and other dimensions will likely prove both more accurate and more helpful in guiding treatment.

Dr. Johnson: Given the efforts to encourage early screening, were you surprised that the average age of diagnosis remained the same?

Dr. Levy: Not at all. The AAP’s recommendations for early screening came out in 2007. The CDC’s data is on children born in 2002 (turned 8 years old in 2010). Pediatricians have been working hard on early identification, but still confront barriers of the “perfect” tool for a busy primary care office and access to appropriate resources for treatment in the community. But early identification (by age alone) is not the only hurdle. Access to care by underserved groups of children is still a major problem. White children were more likely to be identified with autism than black or Hispanic children. High-risk groups such as former premature infants, children with acquired brain injury, genetic disorders and others need to be identified and screened or evaluated more consistently. Environmental exposures and factors need to be investigated carefully, in the context of well-designed studies as potential causes of ASD.

That said, 1 in 68 children probably do have something that deserves our clinical and research attention. Thus, the CDC work always cuts both ways — it is good to have the public’s attention on the welfare of these kids. We agree that more attention can be focused on earlier identification, and also on appropriate evidence based services that can reduce symptoms and the impact of symptoms on functioning at home and school.

To learn more about autism spectrum disorders and ASD research at The Children’s Hospital of Philadelphia, see the Center for Autism Research website.

Permanent link to this article: http://www.research.chop.edu/blog/1-68-interview-chop-experts-cdcs-new-autism-rate/

Apr 02 2014

Prominent Gene Therapy Expert Joins CHOP

gene therapyBeverly L. Davidson, PhD, a nationally prominent expert in gene therapy, joined The Children’s Hospital of Philadelphia on April 1. A member of the Hospital’s Department of Pathology and Laboratory Medicine, Dr. Davidson will serve as the new director of the Center for Cellular and Molecular Therapeutics.

Prior to coming to CHOP, Dr. Davidson — who investigates gene therapy for neurodegenerative diseases — was associate director of the Center for Gene Therapy at the University of Iowa. Dr. Davidson “will greatly enhance our abilities to translate important biological discoveries into pioneering treatments for deadly diseases,” said Robert W. Doms, MD, PhD, CHOP’s pathologist-in-chief.

Dr. Davidson has also assumed the role of director of the Center for Cellular and Molecular Therapeutics (CCMT), succeeding the Center’s inaugural director, Katherine A. High, MD. The CCMT is “dedicated to the understanding, development, and application of gene and related cell and nucleic acid therapies and the promotion of professional public education,” according to its website.

In addition to her roles at CHOP Dr. Davidson is a member of the Scientific Advisory Board of the Hereditary Disease Foundation, and is a scientific co-founder and advisor at the gene therapy company Spark Therapeutics, which launched in late 2013 with a $50 million capital commitment from CHOP.

Research Interests

 Dr. Davidson’s research has been concentrated on inherited genetic diseases that attack the central nervous system, with a particular focus on childhood-onset neurodegenerative diseases such as Batten disease and similar disorders.  According to the NIH, Batten disease and related disorders affect “an estimated 2 to 4 of every 100,000 live births in the United States.”

In these disorders, the lack of an enzyme impairs lysosomes, proteins that perform crucial roles in removing unwanted by-products of cellular metabolism. Toxic waste products then accumulate in the brain and cause progressively severe brain damage. Dr. Davidson has developed novel methods to deliver therapeutic genes to the central nervous system, and her team has succeeded in reversing neurological deficits in animal models of disease, and is working to advance this approach in humans.

She has also studied other inherited neurological diseases such as Huntington’s disease and spino-cerebellar ataxia. In these studies, she has delivered forms of RNA to the brains of animals to silence the activity of disease-causing genes. Although much of Dr. Davidson’s work has centered on delivering beneficial genes to the central nervous system, the viral vectors that she has developed are applicable to other organs and tissues — for example, in gene therapy directed to the lungs or the liver.

For more information about Dr. Davidson and her research, see the Hospital’s press release about her appointment. To learn more about the pioneering gene therapy research being performed at Children’s Hospital, see the CCMT site.




Permanent link to this article: http://www.research.chop.edu/blog/prominent-gene-therapy-expert-joins-chop/

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