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From DNA to PDF: Harnessing the Genome and Phenome to Make Better Diagnoses

By Matt Luchette 
May 28, 2013 | When doctors like Marc Williams need to analyze thousands of variants in a patient’s genome to make a diagnosis, a little help can go a long way.
Williams, the director of the Genomic Medicine Institute at the Geisinger Health System, won a Bio-IT World Best Practices award in Informatics at the Bio-IT World Conference & Expo this past month for his project testing the effectiveness of SimulConsult’s “Genome-Phenome Analyzer,” a tool to help clinicians analyze a patient’s genome. His goal for the project was to “test the impact of bringing the power of genome analysis to clinical practice.” 
“If we were able to pull this off, it was going to dramatically improve my ability as a clinician to help diagnose my patients.” Williams told Bio-IT World.
In the decade since the Human Genome Project, the cost of whole-genome sequencing has plummeted from nearly $100 million per genome in 2001 to almost $1,000 per genome today. And with costs continuing to fall, many researchers think genome analysis may soon become a common clinical tool—like taking a patient’s blood pressure or pulse—to help doctors make more accurate diagnoses. The issue now, for physicians and researchers alike, is no longer sequencing the genome, but rendering clinically-actionable recommendations based on the data. 
Currently when a doctor needs to analyze a patient’s genome, the sequence may be given to a number of geneticists who try to correlate some 30,000 possible genetic variants with the patient’s reported symptoms. “That’s great if you’re at a large academic center,” says Williams, but if it’s going to be useful in the clinic, doctors will need programs that improve the efficiency of the interpretive process.
SimulConsult’s “Genome-Phenome Analyzer” hopes to do just that: it combines a patient’s sequenced genome with the physician’s clinical findings to help determine a diagnosis. The program calculates the severity of thousands of genetic variants, based on peer-reviewed genetic articles from GeneReviews’ and GeneTests’ online databases, and correlates the relevant variants with the patient’s signs and symptoms. The result is a differential diagnosis ranked by the likelihood that each disease is the culprit, with links to GeneReviews and GeneTests for published studies on the genes of interest.
The program “takes a process that was once 10-40 hours down to 10 minutes,” said Lynn Feldman, CEO of SimulConsult who first became involved with the company four years ago as an angel investor. Feldman said what drew her most to SimulConsult was her desire to “lower the cost and improve diagnoses in health care,” a goal she hopes to achieve with the Analyzer.
For his Best Practices study, Williams wanted to show just how powerful the Analyzer could be for geneticists and physicians alike. He used the program to test three genetic “trios,” a  patient’s genome along with the parents’ genomes. The test analyzed the patients’ genomes for homozygosity, inheriting the same defective gene from each parent, compound heterozygosity, inheriting a different defective gene from each parent that together create a disease phenotype, or novel genetic variants not found in either parent. Williams then assessed whether the Analyzer was able to select the relevant variants and assign an appropriate diagnosis for each of the patients. In all three trios, the Analyzer correctly identified 100% of the relevant genes, and for one of the patients, ranked the correct diagnosis and pertinent gene as the most probable. For the other two patients, the pertinent genes were ranked among the top three.
In addition to finding known genetic variants, the Analyzer may even help researchers discover new variants. “There’s 80% of the genome that we don’t know anything about,” Feldman said, “so there’s still so much we don’t know.” By analyzing genetic trios, the Analyzer can identify diseases caused by heterozygous genes, where only homozygous cases have been documented, or vice versa. Furthermore, for variants that have no documented human cases, the Analyzer can search for articles on similar variants seen in animal or human studies to help doctors render an appropriate diagnosis.
One novelty of the Analyzer, according to Feldman, is that “it turns the testing paradigm on its head.” When a doctor requests a cholesterol test, for example, the test is typically analyzed once, and may be administered repeatedly to follow trends over time. With the Genome-Phenome Analyzer, “the test is administered once, and can be reanalyzed repeatedly as a patient develops new symptoms.”
To help streamline the program for doctors, Williams hopes that future editions of the Analyzer will integrate seamlessly with electronic health records and pick out relevant symptoms from the doctor’s notes. Feldman hopes to improve communication in the other direction as well, from the Analyzer to the doctor, by including brief summaries on each report that explain the most relevant clinical findings.
“Clinicians want information presented to them in a medical way, not in a PhD way,” she explained.
Winning the Best Practice award may have given SimulConsult the momentum to continue making such improvements. “Staying front and center is very helpful,” Feldman said, and the increased recognition may convince potential clients to trust the program and sign on. “People are afraid to take the first step.” 
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