Artificial intelligence seen as critical tool in helping to diagnose rare diseases

Machine learning algorithms could make a dramatic difference when it comes to diagnosing children with rare diseases, two CHOC Children’s doctors said in a recent webinar.

Although the use of artificial intelligence (AI) in diagnosing medical conditions is in its infancy stages, the potential is huge, said Dr. Jose Abdenur and Dr. Terence Sanger, speaking on a panel during a two-week summit on rare diseases hosted by Global Genes, an Aliso Viejo-based non-profit that advocates for the rare disease community.

“Human decision making is very, very good,” said Dr. Sanger, vice president for research and chief scientific officer at CHOC. “But we’re not very good at incorporating tens of thousands of pieces of information into making these decisions.”

That’s where machine learning could be of immense value, he and Dr. Abdenur said in the one-hour discussion on Sept. 22, which can be viewed in its entirety here.

Machine learning involves the use of computer algorithms that improve automatically by building mathematical models based on reams of data. This makes AI particularly valuable for improving the rare disease diagnosis process, which remains far from perfect, says Abdenur, chief of the division of metabolic disorders at CHOC and director of CHOC’s metabolic laboratory.

Although great strides are being made in diagnosing rare diseases through such processes as rapid whole genome sequencing, 40 percent of families with sick children still do not have diagnoses, Dr. Abdenur said.

“We’re doing better, but we’re definitely not good enough,” he said. “We hope in the future that artificial intelligence and machine learning will help us (reach diagnoses faster).”

In diagnosing patients, clinicians consider a list of possible conditions or diseases that could be causing symptoms – what’s known as making a differential diagnosis. They consider such things as a patient’s symptoms, his or her medical history, basic lab results, and a physical examination.

With AI, a virtually limitless amount of information beyond that – such as similar symptoms that have occurred in patients around the world, the environment they live in, etc. – could be factored into helping make differential diagnoses.

Dr. Sanger compared the benefits of using AI in diagnosing patients to a standard camera – what’s used now – to a wide-angel lens that can take in much more information, which machine learning would provide.

“If you have an avalanche of information, (physicians) can’t take all of it in themselves,” Dr. Abdenur noted.

But a sophisticated machine-learning program could, he and other panelists said.

An algorithm that gets smarter over time would lead to faster, simpler, accurate, and earlier diagnoses, said panel member Annastasiah Mhaka, co-founder of the Alliance for AI in Healthcare.

“Data is at the heart of (learning more about rare childhood diseases), and AI would help along every step of the way,” said another panelist, Sebastien Lefebvre, an analyst with Alexion Pharmaceuticals.

Both Dr. Abdenur and Dr. Sanger agreed that AI could be used to augment a clinician’s decision, but never replace it.

“(AI) never makes a decision for you,” Sanger said. “It just assists in the decision making.”

Newly emerging technologies such as machine learning in healthcare could lead to lower healthcare costs and better treatment, Mhaka said.

“Diagnosis needs are huge and unmet in the (rare disease) population,” she noted.

Learn more about rare disease research at CHOC.

Wired for hope: deep brain stimulation for dystonia

Every morning when she awakes, Sydney Amato begins her daily battle with her body.

If she’s lucky, the 16-year-old will have gotten a handful of hours of uninterrupted sleep – dreaming, perhaps, of doing what most healthy kids her age take for granted:

Hanging out with friends. Going to school. Learning to drive.

Because of a neurological condition called dystonia, Sydney, who is in excellent cognitive health but speaks and walks with some difficulty, suffers from involuntary and near-constant contraction of muscles in her neck, arms, legs and trunk.

Sydney with her father, Louis

Her mind is unable to control the painful jerking that makes most of her body twist and go rigid, her muscles moving out of normal sequence.

Born a right-hander, she can feed herself with some struggle using her left hand. She wants to dress and put on makeup herself, but those normally simple tasks become lengthy ordeals.

“My body fights me all the time,” says Sydney, trying to distract herself in her hospital bed by watching an old episode of “Keeping Up with the Kardashians.” Listening to her favorite music – Ariana Grande, Lauren Daigle, Drake – can only temporarily transport Sydney away from her debilitating condition.

“She knows what she wants to do,” says her father, Louis. “But her body won’t let her.”

Specialists at CHOC Children’s are working hard to change that.

A first for CHOC

On Aug. 14, 2020, a team led by Dr. Terence Sanger, a physician, engineer, and computational neuroscientist who joined CHOC in January 2020 as its first chief scientific officer, and Dr. Joffre E. Olaya, CHOC’s functional restorative neurosurgeon, implanted several temporary electrodes into Sydney’s brain.

Dr. Terence Sanger, a physician, engineer, and computational neuroscientist and CHOC’s chief scientific officer

The surgery marked the first time a patient with a movement disorder at CHOC underwent a procedure called deep brain stimulation (DBS).

Working in perfect harmony as a team, Dr. Sanger and Dr. Olaya performed the first stage of a three-stage surgery on Sydney. As the surgeon, Dr. Olaya placed the leads following advice from Dr. Sanger, the neurologist, where they should go.

In the procedure, millimeter-thick electrodes were precisely positioned into the basal ganglia region of Sydney’s brain – about three inches deep. The surgery involved the use of the ROSA Robot, the same tool that has been used during brain surgery on epilepsy patients at CHOC since 2015.

Dr. Joffre E. Olaya, CHOC pediatric neurosurgeon

Considered one of the most advanced robotized surgical assistants, ROSA includes a computer system and a robotic arm. It’s a minimally invasive surgical tool that improves accuracy and significantly reduces surgery/anesthesia time.

The ROSA Robot helped with implanting and targeting the electrodes, and a portable operating-room CT scanner confirmed their position.

Turning down the volume

DBS is designed to ease Sydney’s condition by sending electrical currents to jam her malfunctioning brain signals.

Think of turning down the volume on your car radio.

“Nobody really understands the cause of dystonia,” Dr. Sanger explains, “but there’s probably too much electrical stimulation going on in the motor areas of the brain. We’re trying to calm down that extra noise.”

Although DBS dates to the 1960s, it wasn’t until the 1980s that the modern era of using it to treat adult patients with tremor and Parkinson’s disease began.

In 2000, Dr. Sanger, working with engineers, data scientists, neurosurgeons, and others, began implanting electrodes in pediatric patients.

Instead of the established method of placing the leads at predetermined sites and hoping they worked, Sanger and his team, just as they did in Sydney’s case, placed temporary leads to best assess where they should go permanently based on patient response.

In 2016, Dr. Sanger began honing DBS to treat children with dystonia. Before the surgery on Sydney, Dr. Sanger had performed DBS on 26 children using the same three-stage technique. He says 80 percent of those children have seen successful results.

Early signs

Sydney began showing symptoms of dystonia – tremors in her hands — when she was 5 ½ years old.

A year later, she was using a wheelchair. She had her first brain surgery at age 7.

Since then, “she’s been all over the U.S.” seeking the right treatment for her condition after several setbacks, says her father.

But her condition was not improving.

Early this year, a neurologist in Kansas City, Mo., recommended that Sydney see Dr. Sanger.

“I asked him, ‘If Sydney was your kid, where would you go?’ Louis Amato recalls. “He said, ‘Hands down, Dr. Sanger.’”

The COVID-19 pandemic pushed Sydney’s surgery to mid-August.

Sydney already had two electrodes in her brain that were only partially working when she came to CHOC in early August for surgery.

After two extensive run-throughs with their team, Dr. Sanger and Dr. Olaya, in a six-hour procedure that at one point had nearly 20 people in the operating room, implanted more electrodes to give her a total of nine.

On Thursday, Aug. 20, six days after Sydney’s surgery, Dr. Sanger stopped by her room at CHOC Children’s Hospital. The room was decorated in purple, Sydney’s favorite color.

Dr. Sanger greeted her as CHOC staff members, joined by members of Sanger Lab, which conducts research in pediatric movement disorders, prepared to have Sydney walk back and forth down a hallway while connected to electrical equipment programmed to record signals in her brain and muscles.

A thick coil of multicolored wires snaked from under a large white bandage covering Sydney’s head. Extending about 6 feet, the wires were plugged into specialized recording equipment controlled by Jennifer MacLean, a pediatric nurse practitioner whose job was to manipulate the strength of electrical charges affecting the four points of contact on each electrode.

The goal: determine which charges worked best and on which electrodes.

“It could have turned out that the DBS procedure made no difference,” Dr. Sanger says. “But we’ve seen a very good response in Sydney.”

For example, her once mostly useless right hand was working much better.

“It gives you goosebumps,” Louis Amato says.

After taking a bite of a veggie burger and sipping some water, Sydney started to walk.

Following her were seven CHOC and Sanger Lab specialists.

“Go nice and slowly,” Jennifer told Sydney. “You’re going too fast for us!”

Perhaps Sydney was anxious to get back to riding Tigger, a quarter horse, in her hometown of Carthage, Mo. She has been riding him for six months.

Sydney is eager to get back to riding her favorite horse, Tigger.

“Her balance isn’t bad on the horse,” says Louis Amato.

Sydney also loves to tan by her pool and swim.

What she wants most, however, is to be freed from her body so she can return to school and do what most teens enjoy.

“It’s stressful,” says her mother, Angie. “She has a lot of friends her age, but she can’t do a lot of the things they do. She has her days when she can get really upset.”

Now, however, working with Dr. Sanger, Dr. Olaya and the entire team at CHOC, the Amatos are more optimistic than ever.

“We’re hopeful that this is going to be a big life-changer for her,” Angie Amato says. “That would be the best thing that could ever happen – better than winning the lottery.”

‘The A Team’

After crunching numbers for a week to assess which of the nine electrodes proved to be the most effective based on how Sydney responded to varying degrees of electrical currents, Dr. Sanger and his team settled on four electrodes that were permanently used to treat her condition – three new ones, and one existing one.

The team performed this second surgery on Sydney in late August.

In the third and final surgery, successfully completed in early September, a rechargeable generator that powers the DBS leads was implanted in Sydney’s chest.

“As we get better and better at this,” says Dr. Sanger, “and as the technology progresses, we’ll be able to do this on kids who are less sick than Sydney.”

Dr. Sanger and Dr. Olaya are poised to dramatically improve the lives of many more patients like Sydney at CHOC.

“I’m really excited that we will be doing more of these procedures to help pediatric patients with movement disorders and significantly improve their quality of life,” says Dr. Olaya. “I look forward to continuing to provide this type of personalized care.”

Angie and Louis Amato say Sydney has never gotten this much special attention during her 11-year-plus medical journey.

“Here at CHOC,” Louis Amato says, “we feel like we’re with the A Team.”

Says Sydney: “I’ve never felt this much confidence and this good about treatment before.”

Learn more about deep brain stimulation (DBS) surgery at CHOC.

CHOC, University Lab Partners establish unique training program for the next generation of biotech innovators

The CHOC Children’s Research Institute and University Lab Partners (ULP) have jointly developed a new science, technology, engineering, and mathematics (STEM), medical innovation and entrepreneurship program geared toward inspiring Orange County high school students to become the next generation of biotech innovators. 

Through the Medical Innovation and Entrepreneurship program, students will work alongside Orange County’s top leaders in innovation and medicine to gain a real-world view of the multidisciplinary skills needed to thrive in the biotech entrepreneurial world.

The program takes students on a journey from idea to innovation, while gaining the understanding of what is required to implement their vision. Student teams will work with industry mentors to solve real-world unmet clinical needs presented by CHOC clinicians, devising a proof-of-concept, an IP and patent strategy, and exit plan that they will pitch to industry leaders on the final day.

Through pediatric-focused case studies, customized lesson plans, team project work, and mentor opportunities, students will identify real-world solutions to issues that directly impact pediatric patients. Students will learn the role a clinician and engineer play as they navigate unmet clinical needs, hospital systems, care providers, and regulatory trends required for healthcare innovation.

In addition, The Young Entrepreneur OC will foster the next generation of leaders through the transformative experience of building a startup. While teaching the skills to build and lead a company, the program also coaches young people to identify and leverage successful pathways to reach personal and professional goals.

“The CHOC Research Institute is thrilled for the opportunity to help inspire the next generation of leaders in healthcare innovation, potentially laying the groundwork for great strides in translational science, medical device development, and basic science research,”  said Dr. Terence Sanger, CHOC’s vice president of research and chief scientific officer.

During the two-week program delivered through the North Orange County ROP, 60  students from five different school districts will learn the business of medtech and biotech through 50 hours of instruction, 10 hours of dedicated mentorship, and 20 hours of clinical needs assessments, project proposals/presentations, literature reviews, and intellectual property challenges. Students will earn 2.5  UC-transferable credits for their participation.

“By connecting our most precious commodity, our students, to businesses who will invest in them, this partnership benefits us all,” said Dr. Terri Giamarino, superintendent of NOCROP. “We want our students to remain in Orange County and be a part of our growth and sustainability.”

Said Dr. George Tolomiczenko, director of medical innovations at University of California, Irvine: “Clinical needs can take many forms in a healthcare setting. Success in meeting an unmet need relies on understanding the target disease, its underlying etiologies and subgroups. I’m looking forward to teaching these high school students how to refine an unmet clinical need.”

The Medical Innovation and Entrepreneurship High School work-based learning program is one of many projects that will launch from the partnership between the CHOC Research Institute and University Lab Partners. The effort brings together clinical skills, business development skills, hospital management, technology strategy, product ideation, and technology development to help support the larger Orange County biotech and medtech community.

“This partnership is a powerful collaboration that will help generate the energy needed to transform the healthcare industry through leading technology products and platforms. This immersive program transforms career exploration and discovery for Orange County students interested in pursuing an exciting career in innovation” said Karin Koch, ULP’s ecosystem director. 

Learn more about the CHOC Children’s Research Institute.

CHOC study shows reduced risk of emergency department COVID-19 infection

A new CHOC Children’s study that could help calm public fears about contracting COVID-19 shows that asymptomatic healthcare professionals who work in a community with a low prevalence of the disease and who undergo daily health screenings are unlikely to be carriers of the coronavirus that causes the disease.

Findings of the study, one of the first of its kind and conducted during California’s projected peak of coronavirus-related use of hospital resources, shine an encouraging light on a topic where there are currently limited data available.

CHOC’s study tested patient-facing staff at its Julia and George Argyros Emergency Department during a two-week period in April 2020, using a Polymerase chain reaction (PCR) test for COVID-19 viral RNA. Subjects were asymptomatic and had no fever, as all employees undergo daily pre-shift health and temperature screenings prior to entering the hospital. Testing found just one of 145 subjects was positive for COVID-19, and contact tracing showed that this person was not responsible for any further transmission of infection.

With these findings indicating that strict screening measures in a hospital serving a community with a lower prevalence of COVID-19 are effective in preventing the spread of the disease, the study could also offer some comfort to people who may have been reluctant to seek medical care for themselves or their children because they fear contracting COVID-19 in a healthcare setting. 

“We are encouraged by the results of the study and trust that our community will be reassured to know that the chances of acquiring COVID-19 during a visit to a pediatric emergency department can be lower than during routine activities,” said study co-investigator Dr. Terence Sanger, CHOC’s vice president of research and chief scientific officer. “We continue to urge them to seek prompt expert care for themselves and their children when the need arises.”

Hospitals nationwide have reported a significant drop in emergency department visits for major acute conditions. Patients may seek medical attention too late for adequate treatment, which could have serious, even fatal, consequences.

Preliminary data from California suggest that while healthcare workers represent 10% of all known COVID-19 cases in the state, only 18% of those cases were known to be acquired in a healthcare setting. This indicates the workers likely contacted the disease outside of the healthcare setting.

The low rate of infection in CHOC’s emergency department could be attributed to many factors, including the lower percentage of infection in the surrounding community, as well as people in the community following safety guidelines including social distancing and wearing masks.

Additionally, healthcare workers in a pediatric setting might be expected to have a lower risk of infection than those in an adult healthcare setting due to a lower rate of high-risk aerosolization procedures such as intubation in younger patients.

“We take every precaution we can to prevent the spread of COVID-19 in CHOC care settings,” said Dr. Theodore Heyming, medical director of CHOC’s emergency department and study co-investigator. “While the effects of the coronavirus continue to be devastating, this report offers a ray of hope that brave healthcare workers can continue to administer care to their patients without the added burden of putting themselves or the people they care for at further unnecessary risk.”

Also contributing to the study were Aprille Tongol, a CHOC research administrator; Jennifer MacLean, a CHOC nurse practitioner; and multiple staff from the CHOC Children’s Research Institute.

Learn more about the CHOC Children’s Research Institute.

CHOC study aims to determine COVID-19 antibodies present in Emergency department staff

A CHOC Children’s Hospital study could determine how many patient-facing clinicians and staff in its emergency department have COVID-19 fighting antibodies, easing concerns of asymptomatic carriers exposing others to the virus in an acute care setting.

Using rapid serological testing, the monthlong study will determine the prevalence of viral exposure and incidence of new exposure among staff at the Julia and George Argyros Emergency Department at CHOC Children’s Hospital.

Serological blood testing looks for antibodies developed by the body to fight infection. Antibodies indicate the likelihood of past or recent infection or exposure. While researchers are still learning about COVID-19, it is also possible those who have been exposed to the virus and recovered have produced antibodies to protect them from the infection.

“While COVID-19 antibody screening is in its infancy, CHOC Children’s is pleased to help share data and contribute to this important conversation as the world’s scientific community unites in a race toward universal testing, antiviral treatment, and the development of a vaccine in order to permit a scientifically-based return to  normalcy,” said study co-principal investigator Dr. Terence Sanger, CHOC’s vice president of research and chief scientific officer.

Dr. Terence Sanger, study co-principal investigator and CHOC’s vice president of research and chief scientific officer.

Under the study, participants will undergo rapid antibody serology testing for immunoglobin G (IgG) and immunoglobin M (IgM) against COVID-19 novel coronavirus through a simple finger prick once per shift, with results available in three minutes. Additionally, all subjects will undergo viral RNA testing on their first day of the study, as well as on any day that they show IgM positive for antibodies.

In early results, all 107 people tested so far had negative results on reverse transcriptase polymerase chain reaction (RT-PCR) tests, a COVID-19 test, and all were negative for IgGs against COVID-19. Two tested positive for IgM but their viral RNA testing was negative.

As the study progresses, up to 250 subjects are expected to enroll total, with about 100 participants being tested each day.

Secondary outcomes include determining a correlation between antibody serology and DNA testing for acute infection, test-retest reliability of serology testing, evidence for direct transmission of infection between healthcare workers, and potential for reinfection in previously infected convalescent patients. 

Antibody screening could become an additional element of  CHOC’s toolkit in protecting patients, families, physicians and staff against COVID-19. Already, the hospital conducts health screenings, requires appropriate masks and personal protective equipment and practices social distancing, in addition to stringent cleaning practices.

All combined, an additional critically important benefit of the study would be the establishment of a “safe zone” in the emergency department by reducing concerns that an asymptomatic staff member or clinician could transmit the disease to a patient seeking care, or their family, despite CHOC’s strict safety and infection prevention precautions.

Hospitals and health systems nationwide are reporting declining emergency department visits, attributed to patients delaying care out of fear of contracting COVID-19 in the facility. For example, more than half of respondents in a recent NRC Health survey have delayed healthcare for themselves or someone in their home because of the virus, and 60 percent of respondents thought there was an elevated risk when visiting their providers.

Suggesting the national trend has impacted CHOC, its current emergency department volume is about 25 percent less than typical this time of year, yet patient acuity is much higher than typical.

“Seeking prompt and expert care for children in emergent situations is critically important – especially during a pandemic,” said Dr. Theodore Heyming, medical director of CHOC’s emergency department and principal investigator of the study. “We understand how frightening COVID-19 is for parents and children alike. We are excited by the possibility that this study could further prove CHOC as a haven for worried parents, and a source of safe and expert pediatric care during this outbreak – and always.”

Dr. Theodore Heyming, medical director of CHOC’s emergency department and principal investigator of the study.

The study, expected to run through mid-May, is aided by WytCote, an Irvine-based technologies solutions company that has enabled access to testing kits from Jiangsu SuperBio Medical Inc.

“This pandemic is impacting all our communities and WytCote recognized that gaining access to such testing could play a critical role towards limiting the spread of the virus. We are pleased to be partnering with CHOC Children’s to support the testing and use of this new coronavirus antibody test,” said Frank Gomez, WytCote’s CEO/Founder.

Learn more about the CHOC Children’s Research Institute