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Genome-wide association studies, false positives, and how we interpret them

Biedrzycki, Richard J (2018) Genome-wide association studies, false positives, and how we interpret them. Master's Thesis, University of Pittsburgh. (Unpublished)

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Genome-wide association studies (GWAS) identify genetic regions that may play a role in the development of phenotypes. Annotation of these significantly associated “peaks” for their connection to the tested phenotype is an important step in the process of GWAS. However, some of these peaks may be false positives. In this study, we analyzed annotators’ ability to make convincing connections between synthetic GWAS peaks and the phenotype of interest, where synthetic peaks were taken from a GWAS of a trait genetically uncorrelated to the original trait. We provided five annotators with a mix of three original and six synthetic GWAS peaks of three peak significance categories along with relevant literature search results and asked them to annotate these regions. We asked three annotators to record how strong the evidence was at each peak connecting it to the scanned trait as well as the likelihood of the annotator’s further study of that region for its role in the development of the trait. Annotation status was significantly associated with both original/synthetic peak status (p = 0.0034) and peak significance category (p = 0.0112). The proportion of synthetic peaks annotated as having convincing connections was greater than expected of an “ideal” annotator (p <2.2 x 10-16). Annotators rated original peaks as having significantly higher strength of evidence (pBonferroni = 0.0348) and likelihood of further study than synthetic peaks (pBonferroni = 0.0122). Highly significant peaks had significantly higher strength of evidence than suggestively significant peaks (pBonferroni = 0.0441).

This study shows the ease with which annotators are able to make convincing connections between synthetic peaks and tested phenotypes. Because of the amount of resources invested into GWAS, it is essential that these studies are performed with care to reduce wasting resources on follow-up of false positives and ensure effective follow-up of true positives for the benefit of public health.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Biedrzycki, Richard Jrjb67@pitt.edurjb67
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorWeeks, Daniel Eweeks@pitt.eduweeks0000-0001-9410-7228
Committee MemberShaffer, John Rjrs51@pitt.edujrs51
Committee MemberChen, Weiwei.chen@pitt.eduwei.chen
Date: 28 June 2018
Date Type: Publication
Defense Date: 5 April 2018
Approval Date: 28 June 2018
Submission Date: 25 April 2018
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 68
Institution: University of Pittsburgh
Schools and Programs: School of Public Health > Human Genetics
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: genetic epidemiology, GWAS, genome-wide association studies, association studies, false positives, annotation, public health
Date Deposited: 28 Jun 2018 19:59
Last Modified: 30 Jun 2022 15:21


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