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. 2015 Nov 5:2015:824-32.
eCollection 2015.

Contrasting Association Results between Existing PheWAS Phenotype Definition Methods and Five Validated Electronic Phenotypes

Joseph B Leader  1 , Sarah A Pendergrass  2 , Anurag Verma  3 , David J Carey  4 , Dustin N Hartzel  1 , Marylyn D Ritchie  3 , H Lester Kirchner  1
Affiliations

Contrasting Association Results between Existing PheWAS Phenotype Definition Methods and Five Validated Electronic Phenotypes

Joseph B Leader et al. AMIA Annu Symp Proc. .

Abstract

Phenome-Wide Association Studies (PheWAS) comprehensively investigate the association between genetic variation and a wide array of outcome traits. Electronic health record (EHR) based PheWAS uses various abstractions of International Classification of Diseases, Ninth Revision (ICD-9) codes to identify case/control status for diagnoses that are used as the phenotypic variables. However, there have not been comparisons within a PheWAS between results from high quality derived phenotypes and high-throughput but potentially inaccurate use of ICD-9 codes for case/control definition. For this study we first developed a group of high quality algorithms for five phenotypes. Next we evaluated the association of these "gold standard" phenotypes and 4,636,178 genetic variants with minor allele frequency > 0.01 and compared the results from high-throughput associations at the 3 digit, 5 digit, and PheWAS codes for defining case/control status. We found that certain diseases contained similar patient populations across phenotyping methods but had differences in PheWAS.

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Figures

Figure 1.
Figure 1.
Venn diagram demonstrating the overlap of cases by phenotype method for T2DM
Figure 2.
Figure 2.
Venn diagram demonstrating the overlap of cases by phenotype method for Obesity
Figure 3.
Figure 3.
Venn diagram demonstrating the overlap of cases by phenotype method for ACS
Figure 4.
Figure 4.
Manhattan-plots of all results. These are the results for the 5-digit ICD-9 code defined case/control diagnoses. Supplementary figures show the results for the 3-digit and PheWAS Code defined case/control status and are available online. The points in gold show the significance of the association result for the ICD-9 based diagnoses most similar to the gold-standard defined phenotype, for example the ICD-9 code 250.00 is the ICD-9 code for T2DM.
Figure 5.
Figure 5.
Sun Plot of association results for SNP rs7127254, coded allele T, present across the three methods of identifying case/control status used for these analyses. This SNP was associated with the gold standard phenotype of obesity in our study with p-value 6.19×10−7, and the array of metabolic syndrome comorbidities also associated with SNP notable. The most significant association for this SNP was with the 5 digit ICD-9 of T2DM.
Figure 6.
Figure 6.
Sun Plot of results for SNP rs2277251, coded allele T. This SNP was associated with the gold standard phenotype of T2DM with p-value 7.08×10−7. SNP-phenotype associations (p < 0.01) that were also present for this SNP across the 3 methods of identifying case/control status. The spectrum of other comorbidities related to T2DM also associated with this SNP is notable.
Figure 7.
Figure 7.
Sun Plot of results for SNP rs10009355, coded allele T. This SNP was associated with the gold standard phenotype of obstructive CAD with p-value 8.24×10−7. SNP-phenotype associations (p < 0.01) that were also present for this SNP across the 3 methods of identifying case/control status. Additional comorbidities related to CAD are associated with this SNP.
See this image and copyright information in PMC

References

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