Genomic sequencing offers great hope for patients to treat their disease in the most specific way possible through precision medicine. But the new frontier in medicine isn't very helpful for patients with diseases that don't have known links to genetic mutations.

To try and solve some of the toughest cases of undiagnosed patients, Douglas Jamison and Katia Moritz assembled the Undx Consortium, a group of companies and academic labs capable of performing different analytical tests beyond sequencing.

Jamison and Moritz conceived the idea after meeting at the Strategic News Service Future In Review conference where Moritz's documentary, "Undiagnosed: Medical Refugees," was being screened. The movie follows six patients with symptoms that can't be explained who hope to be diagnosed via their genomic data through the CLARITY Undiagnosed Challenge, a virtual medical crowdsourcing effort sponsored by Boston Children's Hospital, Harvard Medical School and San Diego-based Illumina Inc.

"We wanted to see if we can test the same six patients to see whether we can provide anything that's not in the sequencing data," Jamison told BioWorld Insight. "Genomes are nice, but what about all the context around the genes."

"Maybe the information comes from one piece of technology, but the body is a system," Jamison said. "Do we find things at the intersection [of the technologies] that lead us down the right path?"

To get the contextual data, the Undx Consortium brought together, Genome Profiling LLC, of Wilmington, Del., which provided epigenetic analysis. Chromosomal imaging to detect chromosomal rearrangements was done by Kromatid Inc., of Fort Collins, Colo. Metabolomic analysis was provided by Durham, N.C.-based Metabolon Inc. Finally, Rob Knight, professor in the department of pediatrics and the department of computer science at the University of California San Diego, who also runs the American Gut Project, performed microbiome analysis in his lab.

Illumina, which did the original sequencing for the CLARITY Undiagnosed Challenge, is also part of the Undx Consortium, offering follow-up sequencing support.

Getting the samples from patients and distributing them out to all the different laboratories was facilitated by Boston-based Orig3n Inc., which also did stem cell analysis on the patients' samples.

Jamison, who is chairman and CEO at the venture capital company Harris & Harris Group Inc., recently help found Interome Inc., which he calls an "information engine company." Interome, which sponsored Undx Consortium, "integrates the datasets together to produce an output that allows patients to take actions," explained Jamison, who also serves as chairman of Interome.

FINDINGS

The consortium met in San Diego last week to go over their findings. While Jamison had to speak in generalities since the information had yet to be presented to the patients through their clinicians, he was able to highlight some interesting findings.

For instance, one patient had cryptic chromosomal inversions that were picked up by chromosomal imaging.

Other patients appeared to have problems with their metabolic pathways picked up by the metabolomics assays. In some cases, it appears that there may be a specific mutation in a gene that codes for an enzyme involved in a metabolic pathway that wasn't picked up by the initial sequencing. For other metabolic issues, analysis of the microbiome determined abnormalities in microbial flora, which could be contributing to the metabolic changes.

The group also found different methylation patterns – typically hypomethylation – compared to control DNA from the patients' relatives, which may contribute to the disease.

"These are hypotheses, so they still need to be tested," Jamison said, pointing out the testing step is the responsibility of the patients' treating physicians.

GOING FORWARD

Like any scientific exercise, there's hope that the first meeting of the Undx Collaboration can produce a scientific paper explaining the process and results, which may help other researchers struggling to diagnose patients.

The physicians at the meeting made it clear that there was some disconnect between the knowledge of the scientists interpreting the results and the knowledge of the clinicians. For example, it's unrealistic for clinicians to recall information about biochemical pathways they learned in a biochemistry course they took back in college. "We have to take these scientific findings and translate them to help clinicians," Jamison said.

Jamison said he hopes the Undx Consortium meeting could become an annual event with a new cohort of patients each year. To bring in new undiagnosed patients, the consortium will have to expand its clinical network.

As the Undx Consortium is able to provide more hypotheses for undiagnosed patients, it should become more clear which assays are the most helpful complement to genomic sequencing. "Some technologies might drop off if they're not useful, and some might be added," Jamison concluded.