By Allison Proffitt 

May 21, 2015 | The CLARITY challenge is back, and calling for entries.

Boston Children’s Hospital is launching the second iteration of the challenge—CLARITY Undiagnosed—focusing on identifying molecular diagnoses for five families with as-yet undiagnosed conditions. Teams have until June 11 to register, and will compete for a $25,000 award sponsored by longtime Boston Children’s Hospital donor Rob Hale, CEO of Granite Telecommunications, his wife Karen, and their family.

Five patients and their families are participating as subjects in CLARITY Undiagnosed. Competing teams will receive whole genome sequences of the consented family members—mostly trios, though one patient doesn’t have living parents and another case involves multiple affected family members, so there will be more than 3 genomes.

Whole genome sequencing will be done on the Illumina HiSeq 2000 platform and donated to the competition by a third party. Medical records have been collected and de-identified. Clinical summaries will be reviewed by domain experts to make sure that all needed medical details are present.

“We would like to think that a doctor making a decision about a patient has not only the whole genome sequence, but would have all the relevant clinical data available for that patient. As we all know, that is the exception rather than the rule. A lot of data is locked away in a variety of different proprietary systems,” said Isaac Kohane, CLARITY co-organizer, professor of pediatrics at Boston Children’s Hospital and inaugural chair of the Department of Biomedical Informatics (DBMI) at Harvard. “In this instance we’re modeling what should happen and what will happen in the future.”

A panel of judges will vet the teams before releasing the de-identified patient data in July. Teams will have two months to conduct their investigations, and winners will be announced in November.

It’s a short timeline, but that’s part of the design of the competition. “Taking half a year to do analysis is grossly inadequate,” Kohane told Clinical Informatics News. “We need to be pushing the frontier on getting much, much faster turnaround… With a combination of human expertise and automated decision support… we should have a meaningful summary diagnoses in a few days.”

Natural Evolution 

In 2012, the first CLARITY challenge (Children’s Leadership Award for the Reliable Interpretation and Appropriate Transmission of Your Genomic Information) focused on identifying mutations underlying rare disorders for three patients at Boston Children’s Hospital. The winning team was led by Shamil Sunyaev of Brigham and Women's Hospital who was assisted by investigators including Heidi Rehm (Harvard Partners), Daniel MacArthur (Mass General Hospital) and Mike Murray (Brigham).

“The first CLARITY captured the moment when there was a great deal of  uncertainty about what were going to be the dominant sequencing platforms, and what were going to be the dominant ways of interpreting and assembling the genome and calling the variants,” Kohane said.

The competition did reveal agreement across the entries. Even though all of the competing teams did not arrive at the same answers, the pipelines they used were remarkably similar. BWA, GATK, Annotate, Filter, SIFT and Polyphen were all commonly-used tools. (The results of the first CLARITY Challenge were published in Genome Biology, doi:10.1186/gb-2014-15-3-r53.)

But even with the same tools, the results were different, reinforcing the need for interdisciplinary expertise, not just the right algorithms.

“In the first Challenge there were a few teams composed exclusively of bioinformaticians, and the judges found that their entries really didn’t fare very well because they came up with a really nice pipelines and pathways and fancy tables. But a table of genes is useless to a clinician. The winning teams were characterized by medical reports,” explained Alan Beggs, Kohane’s CLARITY co-organizer, director of the Manton Center for Orphan Disease Research at Boston Children’s Hospital and professor of pediatrics at Harvard Medical School.

CLARITY Undiagnosed represents a “natural evolution” in clinical genomics, Beggs said.

“CLARITY 2, I think of as focusing much more on medical genomics, decisions about what are validated disease-causing genes; whether or not a patient’s phenotype is reasonably related to a mutation in a particular disease-causing gene; and whether or not a particular variant is actually pathogenic,” he said. “Clinical interpretation and correlation of the variant with the phenotype is really the focus of CLARITY 2.”

Kohane agreed. “Now we find ourselves in an era where… the focus has drifted clinically—and I think importantly—[away] from anxiety about whether we’re doing the assembly and variant calling correctly. We still recognize that there’s room for improvement,… but controversy now is shifting to what’s the right thing to report, and how to report it so it’s effectively used by clinicians.”

Medical Refugees 

Waiting for a sea change in clinical genomics was not the original plan. After Beggs and Kohane announced the results of the first CLARITY challenge in November 2012, they planned to launch a second competition the next year. In an ugly twist, the next competition was delayed by one of the diseases it meant to tackle. The 2013 CLARITY Challenge planned to address cancer genomics, but the lead physician, a pediatric oncologist, was diagnosed with leukemia before the competition could begin.

The whole idea of the challenge was put on hold, Kohane said, until he met a woman with an undiagnosed disease who was documenting several patients searching for answers.

Katia Moritz is a psychologist and co-founder and Clinical Director of the NeuroBehavioral Institute in Weston, Fla. After a routine endoscopy in 2010 she developed an unknown syndrome. The experience opened her eyes to the plight of people with undiagnosed conditions, whom she terms “medical refugees”.

“I never really realized it was possible to be undiagnosed,” she said. About a year and half into her own search for answers, she started to talk more openly about her challenges. “I realized there were people everywhere who were struggling—dying—without diagnoses.”

Moritz was particularly frustrated to learn that the data from undiagnosed patients isn’t kept or archived anywhere. When a patient dies, their data dies as well.

These should be the most interesting patients, Moritz said. We should be learning from these cases.

She partnered with Nicholas Miller and Crystal Shearman, a husband and wife team of filmmakers that owns Crowbait Pictures, a boutique film production company based in Park City, Utah and Vancouver, Canada. The three pooled their own funds and set out to document the lives and journeys of these medical refugees.

Moritz contacted Kohane in his role as Principle Investigator of the Coordinating Center for the Undiagnosed Disease Network. She wanted to discuss the possibility of creating a database of patient records so that undiagnosed patients might be able to find similar patients, even for diseases without a name.

During their conversation, Kohane mentioned the success that crowdsourcing has had in cracking tough cases, explained the CLARITY Challenge, and offered to focus the next Challenge on undiagnosed cases.

“If you had told me someone was going to offer me a million dollars that day, I would have thought it was more likely than this conversation,” Moritz said. Within a week, Moritz had shifted the focus of the film and CLARITY Undiagnosed took off.

The documentary film that Moritz and her team have been working on, Undiagnosed, follows a large group of families struggling with undiagnosed diseases. Some find their diagnosis along the way. Others are still searching. Moritz and the producers chose five of those patients to be part of CLARITY Undiagnosed.

There is selection bias, Moritz admits, but in a negative way. She said they chose the patients who have tried everything, the ones with the most need.

The team has more than 400 hours of film already, but Moritz is excited about the additional component the CLARITY Challenge will bring to the documentary. “When we met with [Kohane], we thought we were almost done shooting. I thought, ‘We have this beautiful advocacy piece that no one is ever going to watch because it’s so sad,’” she said. “Now I’m so excited.”

The film would like to chronicle the CLARITY teams’ efforts, but teams are under no obligation to participate in the film. Success in the Challenge is completely independent of the film.

“This is not a reality show,” Moritz stressed. “It’s not about who’s winning and losing. We’re going to talk about what we’ve learned, how this has benefitted the patients, and how we can take what we’ve learned and move forward… The idea is to show that when people come together and really collaborate, we can impact the future of medicine.”