Assessing Genomic Sequencing Information for Health Care Decision Making Workshop Summary (2014) / Chapter Skim
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2 How Evidence Is Gathered and Evaluated
2 How Evidence Is Gathered and Evaluated
Pages 5-30
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From page 5... ...
• "Binning" the genome on the basis of clinical validity and clini cal utility and other staged approaches can facilitate pre-test in formed consent, analysis, and post-test return of results. • Given how resource-intensive the process of evaluating variant ev idence is, a collective effort using a standardized assessment ap proach and shared variant databases would be helpful in leading to more efficient variant curation.
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From page 6... ...
Other topics addressed were the gathering, assessment, and evaluation of evidence for use in next-generation sequencing in cancer genomics; how new information is reviewed in the context of existing information; and how variant information can be shared more widely. GATHERING DATA In recent years, many gene panels have been introduced into the clinical setting, noted Madhuri Hegde, professor of human genetics and executive director of the Emory Genetics Laboratory.
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• Clinical validity: the accuracy and reliability of a variant for identifying or predicting an event with biological or medical significance in an asymptomatic individual. • Clinical utility: the usefulness of information in clinical deci sion making and in improving health outcomes.
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-approved drug, that define clinical trial eligibility, or that are plausibly predictive of response to an approved drug which might not otherwise have been chosen. Variants linked to response to an approved drug have already been defined through the companion diagnostic mechanism, though the companion diagnostic development process can be extremely complicated (IOM, 2014; McCormack et al., 2014)
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From page 9... ...
For example, Rehm told of how a patient with the rare disease distal arthrogryposis type 5, a condition related to congenital joint contracture, underwent genome sequencing even though at the time the disorder had no known genetic etiology. Because this patient had unaffected parents, a de novo cause of disease was suspected, Rehm said.
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The Clinical Genome Resource, or ClinGen, is a collaboration among research groups dedicated to combining research data with data from clinical tests as well as expert curation to determine which genetic variants are most relevant to patient care (NIH, 2013)
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Thus Berg and his colleagues have divided the concept of actionability into several specific elements that give a semi-quantitative assessment of actionability for every gene–phenotype pair: • Severity of a disease, which is typically the most severe possible outcome • Likelihood of a severe outcome • Effectiveness of an intervention to mitigate the severe outcome • Acceptability of the intervention, with consideration given to all the hazards of the intervention • State of the knowledge base, including knowledge about the gene–phenotype association, disease manifestations, and inter ventions Each of the 5 elements receives a score from 0 to 3, for a total score of between 0 and 15. Thresholds can be set for dividing variants into bins indicating whether the variants have clinical utility or clinical validity or the clinical implications are unknown (Berg et al., 2011)
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"You can have a __________________________ 1 Following much discussion over the ACMG Genome Sequencing Return of Results guidelines issued in March 2013, ACMG has since updated their recommendations to include an "opt-out" option for patients undergoing whole exome or whole genome sequencing. For more information, see ACMG Updates Recommendation on "Opt Out" for Genome Sequencing Return of Results, https://www.acmg.net.docs/Release_ACMGUpdates Recommendations_final.pdf (accessed June 11, 2014)
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The Medical Exome Project Hegde's group has taken an approach to qualifying evidence that is different from Berg's. The production of a medical exome -- the subset of a human genome consisting of the more than 4,000 genes that have been identified as clinically relevant and that can be adequately covered -- will require evidence about each gene and a technically complete assay, Hegde said.
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or Unlikely: Evidence arguing against unlikely significance role in disease 1 Gene of "uncertain signif- Single or few studies, variants, and icance" (studies available families reported AND segregation not but insufficient to draw established OR no human studies re conclusions) ported but strong animal model data with relevance to human disease 2 Probably disease associated Single or few studies, variants, and families reported AND limited segrega tion observed 3 Definitely an established Multiple studies, variants, and families disease gene reported AND significant segregation and or strong functional evidence SOURCE: Madhuri Hegde, IOM workshop presentation on February 3, 2014.
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From page 15... ...
By working with the Jain Foundation to acquire clinical data from patients, Hegde's group is generating information about the variants, which will be submitted to ClinVar, Hegde said. ACTIONABILITY DETERMINATION Actionability depends on the clinical context in which a genetic test is performed, said Katrina Goddard, senior investigator with the Kaiser Permanente Northwest Center for Health Research, in agreement with Berg.
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While variants that have sufficient clinical actionability should be part of a routine clinical report, consistent with the ACMG recommendations, other classes of conditions that are clinically valid but have insufficient clinical actionability would be subject to more careful consideration on the part of the patient and clinician about whether a patient would prefer to be given such information, Berg said. Genomic testing at Washington University uses a definition of actionability with components that are very similar to those described by Goddard in that practice guidelines for the genetic condition exist and that professional society practice guidelines recommend action for the purposes of patient management, surveillance or screening, family management, and circumstances to avoid.
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This process requires setting a high bar for which variants from a genome-scale test to report; otherwise, reporting variants with unknown clinical validity (see Box 2-1) or unknown implications for the asymptomatic patient's health could potentially have negative impacts, such as patient concern about a test result or unnecessary medical costs for testing that may not be clinically useful.
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. Bin 1 includes variants that meet clinical utility criteria based on the medical literature and are therefore defined as medically actionable; examples include variants that are known or presumed to be deleterious.
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SOURCE: Jonathan Berg, IOM workshop presentation, February 3, 2014. Systematic Evidence Gathering and Actionability Determination The recognition of weaknesses in gene–phenotype associations has led those in Rehm's laboratory to take a more systematic approach to evaluating and scoring the evidence.
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"We hope that by structuring this data, it will allow groups to make cutoffs and decisions about what we think should be returned to individuals." As part of the Clinical Sequencing Exploratory Research (CSER) consortium,3 Goddard said, the NextGen project is integrating wholegenome sequencing into preconception carrier status testing and evaluating the downstream costs and use versus those of the current standard of care.
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In the second stage, an evidence-based process for each specific gene–phenotype pair is documented in a summary report. Reproducible search methods are used to identify studies and data, which are restricted to systematic reviews, evidence-based practice guidelines, or expert consensusbased practice guidelines.
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"If the germline is that difficult, consider how difficult cancer variation data curation could be." A bioinformatics team is needed to analyze the sequencing data after it is generated, Kulkarni said. Even in the case with a 42-cancer gene panel, there is too much information to process manually, so a software system was designed to perform base calling, alignment, variant calling, and genome annotation in a semi-automated way.
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From page 23... ...
For example, more than 50 million genetic variants have been found in the human genome, Rehm said, with many of them unique to individuals, and misinterpretation of these variants can affect clinical care and study outcomes. The vast majority of the variants seen in clinical testing and research studies are rare, which makes it difficult to generate sufficient evidence to make a claim.
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For example, a team of six annotators worked for 6 months on the initial 28-gene-variant curation, sorting out the variants based on given criteria. Additionally, both algorithmic and knowledge-based variant curation methods are necessary for clinical interpretation, and annotating and keeping up with variant management is expensive.
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you can imagine how much time it takes for the lab to go through all those variants and reclassify them. It is a huge help for us if the clinicians actually approach us." The ACMG guidelines require that a testing laboratory make an effort to contact physicians who previously tested patients in the event that new information changes the initial clinical interpretation of the sequence variant, Hegde said.
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Data Quality Related to the issue of updating variant information is a concern over the reproducibility of data in the literature. When published studies do not include complete procedures or the primary data are not accessible, it makes evaluating the quality of the data difficult.
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Rehm said out that no whole-genome sequencing effort today is complete in covering all regions of the genome or detecting all types of variation including substitutions, insertion– deletions, copy number variations, structural variants, and gene fusions. In addition, the bioinformatics techniques applied to raw sequence data in different labs can produce differences in sequences.
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From page 28... ...
. need to address." On the subject of assessing the comparability of genome sequencing results from different laboratories, Hegde observed that the College of American Pathologists has a next-generation sequencing committee that is working on a database for proficiency testing and cross-validation of variant detection.
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From page 29... ...
Only a percentage of the variants in genomic data have been rigorously confirmed, and these can be interpreted and put in a report that goes in the EHR. "The consensus right now is you can update [information]
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