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 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.

CHOC rare disease expert stresses importance of newborn screening

From just a tiny sample of blood, a lab can test for 35 rare diseases in newborns that, if left undetected, could lead to seizures, developmental delays, permanent brain damage or death.

If results are positive for a metabolic disorder, these labs turn to the experts at CHOC metabolic laboratory for further analysis and treatment of newborns just days old.

September is Newborn Screening Awareness Month, and Dr. Jose Abdenur, director of CHOC’s metabolic laboratory, stresses the importance of these newborn screenings in order to prevent such grim scenarios from playing out.

Dr. Jose Abdenur, director of pediatric metabolic disorders at CHOC

Newborn screening is a public health program that screens all babies for many serious but treatable genetic disorders, and CHOC is one of the state’s largest referral centers for the program. All babies born in California are required to get screened soon after birth, but the diseases babies are screened for varies by state. In Orange County alone, some 38,000 babies are born every year.

CHOC is the only location on the West Coast for children who need cutting-edge treatment for certain metabolic diseases that can be detected from newborn screenings. Further, CHOC’s metabolics program is a leading destination for children from around the world afflicted with certain metabolic disorders, which are rare genetic disorders that result from a missing or defective enzyme in the body. These include disorders such as galactosemia, which impairs the body’s ability to process and produce energy from the sugar galactose, and adrenoleukodystrophy, which causes the buildup of very long-chain fatty acids in the brain.

“There are many, many very good success stories at CHOC, but there are still many things we can improve,” Abdenur says, citing too many false positives for some conditions that make families feel anxious and worried. “But we continue to get better at this.”

Newborn screening began in the 1980s. Over the decades, the Department of Health and Human Services has added recommended disorders for states to screen for in their newborn screening (NBS) programs. There now are 35 core conditions on the so-called Recommended Universal NBS Panel, as well as an additional 26 secondary conditions.

In addition to metabolic disorders, newborn screening can detect disorders related to hematology and immunology — such as sickle cell disease — as well as endocrine disorders, pulmonary diseases including cystic fibrosis, and such neurological conditions as spinal muscular atrophy.

CHOC Specialists Discover New Metabolic Condition

CHOC metabolic disorders division has discovered a previously unreported condition that could provide answers for parents of children experiencing unexplained liver failure.

Led by Dr. Jose Abdenur, the division’s medical director, the team has coined the genetic condition Mitochondrial Transcription Factor A (TFAM) deficiency and has published its findings this month in the journal Molecular Genetics and Metabolism.

Dr. Jose Abdenur
Dr. Jose Abdenur in the metabolics lab at CHOC.

The condition affects mitochondria, the energy-producing part of cells. If this transcription factor, a protein that binds to mitochondrial DNA, isn’t working, the body cannot maintain its mitochondrial DNA, which is essential to creating energy.

The infant patient described in the paper died from liver failure as a result from the mitochondrial DNA depletion. Subsequent testing concluded that her older brother also died previously from the same cause at 2 months of age.

Patient history

The 12-week-old patient presented at CHOC in 2015 after her newborn screening detected elevated levels of tyrosine, an abnormality that may indicate liver disease.

Blood tests revealed elevated liver enzymes, abnormal bilirubin levels and low blood sugar levels. She was soon diagnosed with cirrhosis.

CHOC worked with UCLA to perform whole exome sequencing of the patient. The laboratory found two mutations on TFAM, a gene that had never previously been associated with human disease. However, previous studies had shown that a mouse model with mutations in this gene developed lethal mitochondrial depletion.  This information was a clue to pursue research studies at CHOC’s laboratory in the patient’s fibroblasts for energy metabolism, which proved the pathogenicity of the mutation.

Additional molecular testing found the same homozygous variants in blood samples from the deceased sibling. While this genetic work was underway and about 10 days after the baby’s original admission to CHOC, the patient’s condition deteriorated further.

The team deemed the patient an unsuitable transplant candidate due to her condition being multisystemic. Because her liver had deteriorated so significantly and her muscles were also becoming affected, her family, in agreement with clinicians, opted not to pursue further heroic measures. They received palliative support care and the baby died at about 4 months old.

Future impact

Though this discovery will not bring back their children, the family is grateful to CHOC for providing answers and is hopeful that the discovery will lead to early diagnosis and treatment of this condition in other infants.

Dr. Abdenur expects the discovery and publication will lead liver centers to look at their samples for mitochondrial defects. CHOC’s team will also continue to work on the cells to potentially develop an experimental treatment in the future.

The full paper can be read in the journal Molecular Genetics and Metabolism.

Meet CHOC’s Specialists: Metabolic Disorders

It should come as no surprise that Dr. Jose Abdenur’s favorite fictional M.D. is Gregory House, television’s sleuthing physician known for deducing elusive diagnoses.

After all, Dr. Abdenur serves as chief of CHOC Metabolic Disorders Division, which specializes in diagnosing rare conditions that reMetabolic groupquire hours of unraveling symptoms, researching cases and analyzing data to give parents long-sought answers to what’s ailing their child.

“What we do often begins a life-long treatment,” says Dr. Abdenur. “These conditions create a bond with the family and our staff.”

Dr. Abdenur leads a group of about 20, including himself and two other physicians: Richard Chang, M.D. and Raymond Wang, M.D. Comprised of a clinical team and laboratory team, CHOC’s metabolic disorders division is large compared to other similar divisions at other hospitals, and remains in high clinical demand, the physicians say.

The division’s most commonly treated conditions are glycogen storage diseases, mitochondrial disorders, urea cycle defects, fatty acids oxidation defects and organic acidemias. CHOC metabolics is also the largest referral center in California for metabolic diseases detected by newborn screening.

And the division continues to expand: In mid-January, the division opened a new laboratory focusing on energy metabolism. There, researchers will study patients who have defects in energy production, underscoring the division’s commitment to broadening its understanding of metabolic disorder subsections.

A team- and family-centered approach

A core principle for the division is teamwork. No matter their position, each member of the division plays a vital role in diagnosing and caring for children with rare, often lifelong conditions, Dr. Abdenur says.

“We can’t do what we do without dieticians, genetic counselors and case managers for every single case,” he says. “We need everyone.”

Weekly, the team sees about 45 patients on an outpatient basis, operating several clinics, including the multidisciplinary lysosomal and neurometabolic clinics. The division treats between five and 10 patients a week on an in-patient basis.

Persistence is a chief value for the division. Tenacity is essential because the path to diagnosing a metabolic disorder can be a long and hard, and sometimes a dead end, says Dr. Abdenur.

“I never tell a family that for sure I’ll find out what’s wrong, but for sure, we will look as hard as we can,” he says.

Metabolic disorders physicians are sometimes charged with telling parents nothing more can be done for their child’s condition. And though not ideal, that news can bring solace to a parent, Dr. Abdenur says.

“Even when they know there is nothing more to do, there is a relief,” he says. “That way, they’re not still always wondering if they’re missing something.”

Recognizing that, the division places a keen focus providing family-centered care: Close parental involvement is key during diagnosis and treatment, which often lasts a lifetime. The division also hosts regular family events to provide education and activities for patients and families, as well as nutritionally appropriate treats and recipes.

A focus on research and education

While patient care is the top priority for the division, research and education also remains a central focus for the division.

CHOC metabolics partners with UCLA, Cedars Sinai and Harbor UCLA in a post-graduate program that offers genetics research training opportunities and is supported in part by a grant from the National Institutes of Health. Dr. Abdenur serves as its program director for medical biochemical training programs, and training director for clinical biochemical genetics.

The division also has a relatively new fellowship program. The program is designed to help train future metabolic disorders specialists, says Dr. Chang, noting that in the last round of metabolics certifications, fewer than 20 specialists earned the distinction nationally.

“Metabolics is a specialty that not all children’s hospitals have, and we’re trying to help improve access by training people in the field,” says Dr. Chang. “We’re trying to compensate for the shortage of metabolics physicians.”

The division is also working to broaden metabolics knowledge for CHOC nurses. An upcoming one-day conference made possible by the donation of a family of a metabolics patient will offer nurses more information about various metabolics disorders, as well as insight into the plights of patients and their families.

This is one in an occasional series introducing CHOC specialists. Learn more about how to refer patients to CHOC.