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Dec 1, 2013 (Vol. 33, No. 21)

Genomic Healthcare Solutions

  • Genome Knowledge Platform

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    Genome interpretation systems assist labs in absorbing reads and producing reports. One such system, the knoSYS™100 by Knome, integrates an interpretation application and informatics engine with a high-performance grid computer. The diagram shows the system’s workflow.

    “We have responded to the call for a system to manage the volume and complexity of next-generation sequencing analysis,” says Ben Salisbury, Ph.D., vp of clinical genomics at Knome.

    “We have built the knoSYS™ 100, an end-to-end software and hardware platform for developing, running, and sharing in silico genetic tests.”

    The knoSYS provides a pipeline that includes sequence alignment, variant calling, interpretation, and reporting. Users can set up their own parameters and filters, and add their institutional knowledge to variant annotation. Different regions of the genome may require different querying strategies. As users develop these querying strategies, Knome facilitates the exchange of query panels between users, allowing expertise to be shared.

    The company says that it is recruiting customers and other experts to develop panels that will run on the knoSYS. These panels can then be tailored by recipient labs to reflect their own preferences and adjusted to accommodate differences that arise from variation in production processes.

    Knome’s software runs on a high-performance computing grid, installed directly at the customer site. “We specifically did not pursue the cloud computing option,” says Dr. Salisbury. “Many institutions are wary of putting their sequence data in the cloud. On-site computing also avoids wasting valuable time transferring enormous raw data files to remote servers.”

    The hardware component of the knoSYS is expandable, designed to grow as the lab’s testing volume expands.

    “Another critical feature of our system, and any system that will be successful going forward,” said Dr. Salisbury, “is the ability to re-query stored genomic sequence. That includes capturing information updates that alter interpretation of earlier analyses, and the ability to run new panels, new tests, as new concerns arise for an individual.”

    Currently, the company is focusing on Mendelian diseases and cancer-related somatic variations. Knome has designed the knoSYS as a modular system that can incorporate new databases and align and call solutions. One module that has already been incorporated is the align and call software developed by business partner Real Time Genomics, which uses clever algorithms to accelerate analysis and incorporates joint calling and pedigree information to increase variant calling accuracy.

  • Pharmacogenomic Analysis

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    ARUP Laboratories offers pharmacogenomics testing as part of an extensive list of tests. This display, produced by ARUP using the Integrative Genome Viewer, reveals a single base deletion in about half of the analyzed sequence reads, showing heterozygosity for CYP2D6 *3 (c.775delA).

    “Is whole-genome/exome sequencing ready for clinical pharmacogenomics applications?” asks Elaine Lyon, Ph.D, medical director of molecular genetics at ARUP Laboratories. “Whole-genome sequencing generates results that we are not yet able to interpret in the context of drug efficacy or adverse reactions. A combination of variants in a single gene or across multiple genes may alter the pharmacogenomic response, or it may be affected by genome-independent factors such as age, other medications, clinical status, and diet.”

    ARUP offers pharmacogenomics testing (PGx) as a part of an extensive list of tests. “PGx analysis generated from whole-exome/genome sequencing has a number of challenges,” continues Dr. Lyon. The response is not observed until the individual is challenged with the drug, which doesn’t lend itself to analysis pipelines to filter and prioritize variants for rare diseases. Some PGX genes have pseudogenes, structural variants (gene conversions), and copy-number variants that are difficult to analyze by next-generation technologies.

    Instead of whole-exome sequencing, ARUP scientists focus on individual genes and variants that are known to affect drug metabolism. In addition to tests for drug-metabolizing enzymes, ARUP offers single-gene tests based on opioid receptors, oncoproteins, and host factors affecting treatment for infectious diseases. ARUP is also evaluating larger PGX gene panels by next-generation sequencing.

    Sequencing data is carefully analyzed and annotated using pharmacogenomics databases. “Databases of clinically relevant mutations are continuously updated,” notes Dr. Lyon. “We plan to contribute to and use ClinVar, an NIH-based public archive that combines relationships among human variations and phenotypes, with supporting evidence for or against pathogenicity.”

    ARUP has also developed software to help in prioritizing variants likely to cause particular phenotypes. The program creates a “functional damage score” by assessing whether a variant damages the gene that contains it, and whether the variant is in a gene relevant to the phenotype.

    The software will support the ARUP’s offering of Exome Sequencing with Symptom Guided Analysis. The testing aims to provide the etiology of a medical condition if it is suspected to be genetic in origin. Exome sequencing results are prioritized based on the physiological symptoms. Other incidental findings are also analyzed to identify potential pathogenic mutations leading to associated syndromes consistent with recommendations from the American College of Medical Genetics.

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