Clinical OMICS

JUL-AUG 2019

Healthcare magazine for research scientists, labs, pathologists, hospitals, cancer centers, physicians and biopharma companies providing news articles, expert interviews and videos about molecular diagnostics in precision medicine

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22 Clinical OMICs July/August 2019 www.clinicalomics.com final variant list," Scott noted. QIAGEN, he points out, was one of the first companies to standardize and commercialize secondary analysis pipelines for both research and clinical applications to support standards, while providing robust pipelines and tool sets for their customization. Those prod- ucts are CLC Biomedical Workbench for research and QIA- GEN Clinical Insight (QCI)-Analyze for clinical applications. There are also plenty of open-source tools. The Broad Institute, for example, has the Burrows Wheeler Aligner (BWA) for short reads and the variant caller Genome Anal- ysis Toolkit (GATK). The University of Maryland provides another short-read aligner, Bowtie. But without bioinfor- matics expertise, using open-source tools can be daunting. Commercial makers of such tools typically provide support and, as a result, these have gained in popularity. The advent of some industry standards (e.g. ACMG) have also helped. Accurate variant interpretation for tertiary analysis requires high-quality curated content and is one of the most challenging steps in delivering a diagnosis. Two of the most popular sources for such content are the Human Gene Mutation Database (HGMD) and ClinVar. "These are the gold standards for interpretation," says Scott. Because of this, many commercial interpretation platforms incorporate both databases, including QIAGEN Clinical Insight, which also comprises QIAGEN's Ingenuity Knowledge Base. Fabric Genomics is another analysis platform that has gained traction in the past couple of years. It can perform analysis all the way from sequence to the creation of a physician-ready report, but the entry point "depends on the customer," said Francisco M. De La Vega, senior vice president of research and development. "Sometimes the customer wants to assemble the reads and identify genomic variants themselves, and then go to our secure cloud platform to use our proprietary genome interpretation tools for the rest of the process." Fabric has compiled a database of 50,000 genomes and exomes from private sources to train algorithms to perform analysis. The company's leading algorithms are VAAST and Phevor, which were co-developed with Mark Yandell, Ph.D., professor of human genetics at The University of Utah. VAAST ranks genes based on how likely they are to cause disease. Pheevor uses Human Phenotype Ontology (HPO) terms describing the patient phenotype to re-rank those genes. "Over 50 publications have found that VAAST can find new genes and Phevor improves the prioritization of genes involved in any monogenic disease phenotype," he said. Clinicians are also finding utility in the analysis of struc- tural variants (SVs), including deletions, insertions, dupli- cations, inversions, and translocations at least 50 base pairs long. "We used to use microarrays and other technologies to find structural variants, but now whole-genome sequencing is proving to be more sensitive and robust," said Stephen Kingsmore, M.D., president and CEO of Rady Children's Institute for Genomic Disease. But groups are using different algorithms to do structural variant calls. "There is no gold standard yet," he added. "But the genomics com- munity is working to help establish the right stan- dards and benchmarks." A recent paper in Genome Biology seeks to tame that Wild West. Five research- ers from RIKEN Center for Integrative Medical Sci- ences in Yokohama, Japan published a "Comprehen- sive evaluation of SV detec- tion algorithms for whole genome sequencing" in which they evaluated 69 existing structural variant detection algorithms using multiple sim- ulated and real whole-genome sequencing datasets. Their (continued from previous page) (continued on page 24) David Fabrizio, VP of product de- velopment, Foundation Medicine Foundation Medicine sequences thousands of genomes every week and its FoundationCORE clinico-genomic database contains data of more than 300,000 cases. "Thus far, the majority of sequencing has been disproportionately performed on the Caucasian population." —Stephen Kingsmore, M.D., president and CEO, Rady Children's Hospital

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