Dataset Information

Description and pilot results from a novel method for evaluating return of incidental findings from next-generation sequencing technologies.

ABSTRACT: The aim of this study was to develop, operationalize, and pilot test a transparent, reproducible, and evidence-informed method to determine when to report incidental findings from next-generation sequencing technologies.Using evidence-based principles, we proposed a three-stage process. Stage I "rules out" incidental findings below a minimal threshold of evidence and is evaluated using inter-rater agreement and comparison with an expert-based approach. Stage II documents criteria for clinical actionability using a standardized approach to allow experts to consistently consider and recommend whether results should be routinely reported (stage III). We used expert opinion to determine the face validity of stages II and III using three case studies. We evaluated the time and effort for stages I and II.For stage I, we assessed 99 conditions and found high inter-rater agreement (89%), and strong agreement with a separate expert-based method. Case studies for familial adenomatous polyposis, hereditary hemochromatosis, and ?1-antitrypsin deficiency were all recommended for routine reporting as incidental findings. The method requires <3 days per topic.We establish an operational definition of clinically actionable incidental findings and provide documentation and pilot testing of a feasible method that is scalable to the whole genome.

SUBMITTER: Goddard KA

PROVIDER: S-EPMC3927794 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Description and pilot results from a novel method for evaluating return of incidental findings from next-generation sequencing technologies.

Goddard Katrina A B KA Whitlock Evelyn P EP Berg Jonathan S JS Williams Marc S MS Webber Elizabeth M EM Webster Jennifer A JA Lin Jennifer S JS Schrader Kasmintan A KA Campos-Outcalt Doug D Offit Kenneth K Feigelson Heather Spencer HS Hollombe Celine C

Genetics in medicine : official journal of the American College of Medical Genetics 20130404 9

<h4>Purpose</h4>The aim of this study was to develop, operationalize, and pilot test a transparent, reproducible, and evidence-informed method to determine when to report incidental findings from next-generation sequencing technologies.<h4>Methods</h4>Using evidence-based principles, we proposed a three-stage process. Stage I "rules out" incidental findings below a minimal threshold of evidence and is evaluated using inter-rater agreement and comparison with an expert-based approach. Stage II do ...[more]

PMID: 23558254

Similar Datasets

Project description:BACKGROUND: We have developed a simulation approach to help determine the optimal mixture of sequencing methods for most complete and cost effective transcriptome sequencing. We compared simulation results for traditional capillary sequencing with "Next Generation" (NG) ultra high-throughput technologies. The simulation model was parameterized using mappings of 130,000 cDNA sequence reads to the Arabidopsis genome (NCBI Accession SRA008180.19). We also generated 454-GS20 sequences and de novo assemblies for the basal eudicot California poppy (Eschscholzia californica) and the magnoliid avocado (Persea americana) using a variety of methods for cDNA synthesis. RESULTS: The Arabidopsis reads tagged more than 15,000 genes, including new splice variants and extended UTR regions. Of the total 134,791 reads (13.8 MB), 119,518 (88.7%) mapped exactly to known exons, while 1,117 (0.8%) mapped to introns, 11,524 (8.6%) spanned annotated intron/exon boundaries, and 3,066 (2.3%) extended beyond the end of annotated UTRs. Sequence-based inference of relative gene expression levels correlated significantly with microarray data. As expected, NG sequencing of normalized libraries tagged more genes than non-normalized libraries, although non-normalized libraries yielded more full-length cDNA sequences. The Arabidopsis data were used to simulate additional rounds of NG and traditional EST sequencing, and various combinations of each. Our simulations suggest a combination of FLX and Solexa sequencing for optimal transcriptome coverage at modest cost. We have also developed ESTcalc http://fgp.huck.psu.edu/NG_Sims/ngsim.pl, an online webtool, which allows users to explore the results of this study by specifying individualized costs and sequencing characteristics. CONCLUSION: NG sequencing technologies are a highly flexible set of platforms that can be scaled to suit different project goals. In terms of sequence coverage alone, the NG sequencing is a dramatic advance over capillary-based sequencing, but NG sequencing also presents significant challenges in assembly and sequence accuracy due to short read lengths, method-specific sequencing errors, and the absence of physical clones. These problems may be overcome by hybrid sequencing strategies using a mixture of sequencing methodologies, by new assemblers, and by sequencing more deeply. Sequencing and microarray outcomes from multiple experiments suggest that our simulator will be useful for guiding NG transcriptome sequencing projects in a wide range of organisms.

Dataset Information

Description and pilot results from a novel method for evaluating return of incidental findings from next-generation sequencing technologies.

Publications

Description and pilot results from a novel method for evaluating return of incidental findings from next-generation sequencing technologies.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets