Author: Nancy Fliesler

Tool helps interpret subtle DNA variants from genome-wide association studies

Genome-wide association studies are huge undertakings that compare the genomes of large populations. They can turn up thousands to tens of thousands of genetic variants associated with disease. But which GWAS variants really matter?

That question becomes exponentially harder when the variants lie in the vast stretches of DNA that don’t encode proteins, but instead have regulatory functions.

“It’s hard to know which hits are causal hits, and which are just going along for the ride,” says Vijay Sankaran, MD, PhD, a pediatric hematologist/oncologist at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and an associate member of the Broad Institute.

Reporting in Cell, Sankaran’s team and two other groups at the Broad Institute describe a new tool that can looks at hundreds of thousands of genetic elements at once to pinpoint variants that truly affect gene expression or function. Called the massively parallel reporter assay (MPRA), it could help reveal subtle genetic influences on diseases and traits.

In Sankaran’s case, the MPRA is helping him understand how common variants contribute to blood disorders in children. “Most of the common variation is just tuning genetic function,” he says. “Just slightly, not turning it on or off, but actually just tuning it like a dimmer switch.”

The above video explains how the assay works – via DNA “barcodes.” Read more on the Broad Institute’s blog, Broad Minded.

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Detecting shunt failure in hydrocephalus without imaging or surgery: ShuntCheck

shunts hydrocephalus
Antonio helped test a device that can tell whether a shunt is still working. (Photos: Katherine Cohen)

Antonio Venus-Reeve, 14, had his first shunt surgery for hydrocephalus when he was 2½ months old. Born at 25 weeks’ gestation, weighing less than two pounds, he had a serious brain bleed seven days later.

As Antonio’s head began to swell with excess fluid, neurologists at Boston Children’s Hospital told his mother, Joanne Venus-Williams, that Antonio probably would not be able to walk, talk or develop major motor skills. “Neurosurgery got involved and the team did daily spinal taps to draw out the fluid in his brain,” says Venus-Williams. “They were hoping he wouldn’t need a shunt, but we got to the point where we knew it was the way to go.”

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Why can’t a walker be more like an all-terrain vehicle?

Child innovator Sadie with Amazing Curb Climber
Photo: Patrick McCallum

Sadie McCallum’s own life led her to become an inventor. She’s 9, has cerebral palsy, for which she’s seen at Boston Children’s Hospital, and relies on a walker to get around. “It would be SO much easier if my walker was more like an all-terrain vehicle and could go over curbs or stairs,” she says.

This year, in third grade, Sadie took part in her school’s annual Invention Convention and designed and built the Amazing Curb Climber. She sketched the design, and her family helped her with the planning, drilling, sawing and assembly. The end product combined two of Sadie’s old walkers and six lawn mower wheels (three on either side) to create an all-terrain design, plus two smaller wheels in back. Her dad helped build a portable curb for testing and demo purposes.

The invention won first place for Best Use of a Wheel and second place for Kids’ Choice. Sadie went on to the regional Invention Convention, where she took the first place for the Special Needs Award as well as the Microsoft Technology Award.

Read Sadie’s post on our sister blog, Thriving.

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Plugging gaps in Zika surveillance with online news reports

Zika surveillance
Zika virus disease reports as of May 31, 2016 (click to enlarge)

As the Zika epidemic continues to unfold, most affected countries are flying blind: they have limited government disease surveillance systems in place to track new cases. That leaves public health officials unable to estimate how fast Zika is spreading, where the hotspots are and when the outbreak will peak — much less contain it and prepare for cases of microcephaly and Guillain-Barré syndrome, both now presumed to be caused by the Zika virus.

“One of the things we really struggled with in the early days of Zika was a lack of official data sources,” says research fellow Maia Majumder, MPH, of the Computational Epidemiology Group at Boston Children’s Hospital. “Surveillance has been really lagging. When we don’t know how many cases there are day to day, week to week, it’s really hard to characterize how bad an outbreak is.”

A study this week led by Majumder suggests a readily available data source for estimating actual case counts on the ground: online local news reports, adjusted using data from Google search trends.

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Moving one step closer to smartphone-like, interoperable EHR apps

Medical app buttons croppedToday, most people’s clinical records remain siloed at a single hospital or health network. For the most part, health apps can’t tap into these data, nor can medicine learn from them. Also, most electronic health records (EHRs) are unable to import the biometric data people are collecting from their own devices, much less interpret them.

In 2009, Kenneth Mandl, MD, MPH, and Isaac Kohane, MD, PhD, of Boston Children’s Hospital published a manifesto in The New England Journal of Medicine calling for health care information systems to have iPhone functionality. This would entail several key attributes: liquidity of data, modularity of applications, accommodation of both open-source and closed-source software through open standards, and the ability to support diverse applications.

In short, they envisioned a “plug and play” health IT platform.

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Stem cells and birth defects: Could gastroschisis be treated in utero?

gastroschisis birth defects
Although Gianna was treated surgically, Dario Fauza, MD, hopes to someday use stem cells from the amniotic fluid, multiplied and returned to the womb, to naturally heal gastroschisis and other birth defects. (Courtesy Danielle DeCarlo)

Except when spreading awareness about her condition, 6-year-old Gianna DeCarlo prefers not to wear two-piece bathing suits because of the long vertical scar on her stomach. “Even though nobody’s said anything, she feels like she’ll be made fun of,” says her mother, Danielle. “I do what I can to make her love her body.”

Gianna doesn’t remember her three surgeries or the nasogastric tube she needed as an infant, before she was able to eat normally. She was born with gastroschisis, a striking birth defect in which the abdominal wall doesn’t seal fully during fetal development. As a result, her intestines developed outside her body. She was fed through an IV for several weeks, and was finally stitched fully shut at age 2.

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Science Seen: Worms give a clue to how the nervous system stays organized

nervous system tiling
Courtesy Candice Yip

To the eye, nervous systems look like a tangled mess of neurons and their tree-like branches known as dendrites, but it’s really organized chaos. How the system finds order has intrigued but eluded scientists. In the worm C. elegans, Max Heiman, PhD and graduate student Candice Yip found an elegant system to help explain how neurons each maintain their own space.

Normally, worms have just one neuron of a certain type on either side of their bodies. Yip did a “forward genetic screen” — mutating genes at random to find factors important for neuron wiring. One mutation caused the worm to grow not one set of neurons but five. By engineering the neurons to make a color-changing signal — as shown above — Yip showed that these extra neurons didn’t overlap with each other, but instead carved out discrete territories — a phenomenon known as tiling. How?

Acting on a hunch, Yip and Heiman, of Harvard Medical School and Boston Children’s Hospital’s Division of Genetics and Genomics, showed that C. elegans, faced with an increase in neurons, pressed a molecule called netrin into service to enforce boundaries between them. Netrin is better known for helping nerve fibers navigate to their destinations. When Yip took netrin out of action, the dendrites from the five neurons crossed the invisible borders and grew entangled.

The findings, published today in Cell Reports, could provide insight into neuropsychiatric diseases, believes Heiman, also part of Boston Children’s F.M. Kirby Neurobiology Center. “It’s fundamental to neuropsychiatric disease to make sure brain wiring goes right,” he says. “This is also story about how new features evolve, and how you can form something as complicated as a nervous system. There are pathways that bring everything into order.”

Read more in this feature from Harvard Medical School and learn more about Heiman’s research.

 

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An inner ear in a dish

lab-grown inner ear organs
Images courtesy Eri Hashino

Could regenerative techniques restore hearing or balance by replacing lost sensory cells in the inner ear? Lab-created inner-ear organs, described today in Nature Communications, could provide helpful three-dimensional models for testing potential therapies.

The lab-built sac-like structure above, about 1 millimeter in size, contains fully-formed balance organs resembling the utricle and saccule, which sense head orientation and movement and send impulses to the brain. The tiny organs were built from mouse embryonic stem cells in a 3-D tissue culture in work led by Jeffrey Holt, PhD, of the F.M. Kirby Neurobiology Center at Boston Children’s Hospital and Eri Hashino, PhD, of the University of Indiana.

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Science Seen: Poverty and accidental death, 1999-2012

Unintentional injuries are the fifth largest cause of death in the U.S., and these mortalities have been rising over the past decade. At the same time, more people are living in areas with high poverty levels. Are these trends connected?

An analysis published last week in PLOS One gives evidence that the answer is “yes.” Emergency medicine physician Eric Fleegler, MD, MPH, and colleagues crunched U.S. Census Bureau data against mortality data from the National Center for Health Statistics for 1999 to 2012 — providing resolution down to the county level.

Not only did fatalities increase in tandem with the level of poverty in a county, the study found, but this effect worsened over time, especially for deaths from certain causes such as poisonings, shown here. Read the details in our sister blog, Notes. (Interactive image: Erin Horan)

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Real-time influenza tracking with electronic health records

influenza tracking
Data captured from healthcare visits could be a tool for medical surveillance.

Early influenza detection and the ability to predict outbreaks are critical to public health. Reliable estimates of when influenza will peak can help drive proper timing of flu shots and prevent health systems from being blindsided by unexpected surges, as happened in the 2012-2013 flu season.

The Centers for Disease Control and Prevention collects accurate data, but with a time lag of one to two weeks. Google Flu Trends began offering real-time data in 2008, based on people’s Internet searches for flu-related terms. But it ultimately failed, at least in part because not everyone who searches “flu” is actually sick. As of last year, Google instead now sends its search data to scientists at the CDC, Columbia University and Boston Children’s Hospital.

Now, a Boston Children’s-led team demonstrates a more accurate way to pick up flu trends in near-real-time — at least a week ahead of the CDC — by harnessing data from electronic health records (EHRs).

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