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Use of genomic panels to determine risk of developing type 2 diabetes in the general population: a targeted evidence-based review.

ABSTRACT: This evidence review addresses whether type 2 diabetes genomic risk panels improve health outcomes (e.g., reduce rates of developing type 2 diabetes) in low- or high-risk adults; two clinical scenarios promulgated by commercial companies offering such testing. Evidence for the analytic validity of available genomic profiles was inadequate. Clinical validity ranged from inadequate to convincing for 30 variants identified on five type 2 diabetes genomic panels and by genome-wide association studies. Eight common variants were identified for general population use; evidence credibility based on published criteria was strong for two variants, moderate for two variants, and weak for four variants. TCF7L2 had the largest per-allele odds ratio of 1.39 (95% confidence interval 1.33-1.46). Models combining the best four, best eight, and all 30 variants used summary effect sizes, reported genotype frequencies, and assumed independent effects. Areas under the curve were 0.547, 0.551, and 0.570, respectively. In high-risk populations, per-allele odds ratios for TCF7L2 alone were similar to those of the general population. TCF7L2, in combination with other variants, yielded minimal improvement in risk reclassification. Evidence on TCF7L2 clinical validity was adequate. Three studies addressed the clinical utility of intervention effectiveness, stratified by TCF7L2 genotype; none found significant interactions. Clinical utility evidence was inadequate. In addition to analytic validity and clinical utility knowledge gaps, additional gaps were identified regarding how to inform, produce, and evaluate models combining multiple variants.

SUBMITTER: Palomaki GE

PROVIDER: S-EPMC4684162 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Use of genomic panels to determine risk of developing type 2 diabetes in the general population: a targeted evidence-based review.

Palomaki Glenn E GE Melillo Stephanie S Marrone Michael M Douglas Michael P MP

Genetics in medicine : official journal of the American College of Medical Genetics 20130314 8

This evidence review addresses whether type 2 diabetes genomic risk panels improve health outcomes (e.g., reduce rates of developing type 2 diabetes) in low- or high-risk adults; two clinical scenarios promulgated by commercial companies offering such testing. Evidence for the analytic validity of available genomic profiles was inadequate. Clinical validity ranged from inadequate to convincing for 30 variants identified on five type 2 diabetes genomic panels and by genome-wide association studie ...[more]

PMID: 23492876

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Project description:BACKGROUND:The 2015 American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) guidelines for clinical sequence variant interpretation state that "well-established" functional studies can be used as evidence in variant classification. These guidelines articulated key attributes of functional data, including that assays should reflect the biological environment and be analytically sound; however, details of how to evaluate these attributes were left to expert judgment. The Clinical Genome Resource (ClinGen) designates Variant Curation Expert Panels (VCEPs) in specific disease areas to make gene-centric specifications to the ACMG/AMP guidelines, including more specific definitions of appropriate functional assays. We set out to evaluate the existing VCEP guidelines for functional assays. METHODS:We evaluated the functional criteria (PS3/BS3) of six VCEPs (CDH1, Hearing Loss, Inherited Cardiomyopathy-MYH7, PAH, PTEN, RASopathy). We then established criteria for evaluating functional studies based on disease mechanism, general class of assay, and the characteristics of specific assay instances described in the primary literature. Using these criteria, we extensively curated assay instances cited by each VCEP in their pilot variant classification to analyze VCEP recommendations and their use in the interpretation of functional studies. RESULTS:Unsurprisingly, our analysis highlighted the breadth of VCEP-approved assays, reflecting the diversity of disease mechanisms among VCEPs. We also noted substantial variability between VCEPs in the method used to select these assays and in the approach used to specify strength modifications, as well as differences in suggested validation parameters. Importantly, we observed discrepancies between the parameters VCEPs specified as required for approved assay instances and the fulfillment of these requirements in the individual assays cited in pilot variant interpretation. CONCLUSIONS:Interpretation of the intricacies of functional assays often requires expert-level knowledge of the gene and disease, and current VCEP recommendations for functional assay evidence are a useful tool to improve the accessibility of functional data by providing a starting point for curators to identify approved functional assays and key metrics. However, our analysis suggests that further guidance is needed to standardize this process and ensure consistency in the application of functional evidence.

Dataset Information

Use of genomic panels to determine risk of developing type 2 diabetes in the general population: a targeted evidence-based review.

Publications

Use of genomic panels to determine risk of developing type 2 diabetes in the general population: a targeted evidence-based review.

Similar Datasets

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