Outbreak detection of novel pathogens: Is AI the answer?

Amy Carpenter Aquino

July 2020—A machine learning algorithm, used in conjunction with BioFire’s Syndromic Trends, demonstrated a mechanism for near real-time outbreak detection of enterovirus D68, says a study reported in the Journal of Clinical Virology.

To predict an outbreak, the algorithm, called Pathogen Extended Resolution, or PER, identified EV-D68 among respiratory panel data obtained from routine testing of patients with infection.

The authors, reporting in the recently published study, say that using the epidemiology software service Trends in this way “could provide a potential early-warning system of EV-D68 predictions from BioFire RP tests as well as augment public health response through increased situational awareness of novel pathogens” (Meyers L, et al. J Clin Virol. 2020;​124[3]:104262).

Nationwide Children’s Hospital in Columbus, Ohio, was one of six institutions in the United States and Europe to contribute to the creation of the PER algorithm for detection of EV-D68. Amy Leber, PhD, D(ABMM), the hospital’s senior director of clinical laboratories and director of microbiology and immunoserology, shared her experience with Trends and PER at last year’s AMP annual meeting and in a May 22 interview with CAP TODAY about that presentation and SARS-CoV-2.

“The session at AMP was designed to look at artificial intelligence and its impact in the clinical lab, particularly in molecular diagnostics. The example I gave was about predicting EV-D68 from the pattern of results for rhinovirus and enterovirus PCR results” on the BioFire FilmArray respiratory panel version 1.7. “BioFire was able to use machine learning to look at those targets and certain aspects and say, ‘This looks like it would be an EV-D68.’”

In the EV-D68 study evaluating the PER algorithm, one of the first sites to experience a significant increase in EV-D68 during the 2018 monitoring period was Nationwide Children’s, which confirmed the outbreak and put specific testing into place.

Could Trends or PER be useful in the fight against COVID-19? SARS-CoV-2 does not cross-react with any of the four coronavirus targets on the Film­Array respiratory panels. The FDA on May 1 issued emergency use authorization to BioFire for its Film­Array respiratory panel version 2.1 for detection of SARS-CoV-2 and 21 other pathogens. “They’re adding it as a separate, discrete target,” Dr. Leber says, so there could be real-time monitoring of COVID-19 as more laboratories adopt and submit test results to the Syndromic Trends central database.

“Let’s say COVID-19 dies down in its current wave. But if we’re testing for it routinely in all respiratory samples, it may help us during the flu season because there are several common symptoms. There’s no real pathognomonic presentation for COVID-19.”

For SARS-CoV-2, Nationwide Children’s Hospital’s positivity rate for inpatients has remained relatively low, Dr. Leber says. None of the patients thus far has developed the multisystem inflammatory syndrome sometimes linked to the infection in children.

“I’m part of an infectious disease research group that is very interested in that,” she says. “Part of this syndrome is going to inevitably involve the immune response to the virus, so we’re looking at ways to see which genes are turned on and off in these children. If we could develop a model that looks at a number of laboratory tests, and which genes are turned on and off, to try to predict who might develop this syndrome, that’s a very powerful tool for understanding the long-term effects of this.”

It would take a multidisciplinary approach and the use of multiple tools to develop a profile of the syndrome that’s affecting pediatric patients. “The common belief early on was that this was benign in children and we didn’t have to worry,” she says. “But we’re three months into this disease and we have so much more to learn.”

Data sharing can help ensure there is enough pediatric patient data to build an effective predictive tool for the multisystem inflammatory syndrome. “Conceptually, there are examples of sharing of data already with COVID,” Dr. Leber says. Google’s DeepMind, for one, has links to open-access databases to help people use sequences to predict protein structures that can be used to develop vaccines or drugs. “To be successful at this, we have to be able to share the data,” she says.

If Dr. Leber had given her AMP presentation during the pandemic, she says, she would have driven home the importance of predicting and having an early-warning system for new and emerging disease. To that point, “Should metagenomics or next-generation sequencing be used as a standardized test up front for viruses, as opposed to the approach of using a FilmArray that tests for 20 viruses? NGS can test for any virus,” she points out.

In her view, the concerns about the cost and complexity of NGS are outweighed by the need for early warning and detection of emerging viruses, and to be able to share data.

“I think this will change how we think about viral diagnostics because we don’t know what the next emerging pathogen is.” Relying on a pathogen-specific approach, such as PCR for influenza or for RSV, “limits our ability to detect emerging disease.”

Nationwide Children’s Hospital receives real-time, actionable infectious disease outbreak information as a participant in Syndromic Trends. It is one of four clinical sites in Ohio that shares deidentified patient test results from the FilmArray RP v1.7. As of March 2019, “more than a million files have been analyzed,” Dr. Leber said of the tool.

“This is the part where everyone gets paranoid because we’re sending data across the hospital firewall,” she said at the AMP meeting. Clinical site users send their FilmArray respiratory panel test results to a centralized database, and infectious disease trend analyses are fed back to the clinical sites on an individual basis and in aggregate to look at the regions on the BioFire Syndromic Trends website (Meyers L, et al. JMIR Public Health Surveill. 2018;4[3]:e59).

While the IT staff were nervous about transferring patient test results outside the hospital, “We felt secure that we could transmit these data for Trends without compromising protected health information,” Dr. Leber said. “The good thing is it’s safe; the bad thing is it’s hooked to no other information,” such as patient sex, age, or location, that could inform deeper analysis of infectious disease trends.

The BioFire RP v1.7 can detect 17 viral and three bacterial pathogens. The public respiratory panel detection rate chart, on the BioFire Syndromic Trends website, displays pathogen trends across the United States.

“We use it locally for RSV,” Dr. Leber said. “We have vulnerable patient populations and we want to know when it’s a good time to start using palivizumab.” The trigger point for Nationwide Children’s to administer palivizumab (Synagis) to high-risk pediatric patients is a 10 percent RSV detection rate for greater than two weeks. Last year the hospital reached that level in September.

Influenza outbreaks can be tracked by subtype throughout the country or in regions. “This is a powerful tool. The more people are hooked into this network, the more powerful the data.”

PER was created with the goal of diving deeper into all the data generated to determine if FilmArray influenza A targets could be used to predict novel influenza A.