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The impact of imprecise case definitions in electronic health record research: a melanoma case-study from the Million
Lee Wheless1,2,3, Dominique Mosley4, Daniel Dochtermann5
1Tennessee Valley Healthcare System VA Medical Center, 719 Thompson Lane, Suite 26300, Nashville, TN, 37215, USA. lee.e.wheless@vumc.org.
Abstract:
Cases for a disease can be defined broadly using diagnostic codes, or narrowly using gold-standard confirmation that often is not available in large administrative datasets. These different definitions can have significant impacts on the results and conclusions of studies. We conducted this study to assess how using melanoma phecodes versus histologic confirmation for invasive or in situ melanoma impacts the results of a genome-wide association study (GWAS) using the Million Veteran Program. Melanoma status was determined three ways: (1) by the presence of two or more phecodes, (2) histologically-confirmed invasive melanoma, and (3) histologically-confirmed melanoma in situ. We conducted a GWAS for variants with minor allele frequencies of 1% or greater. There were 45,665 cases in the phecode cohort, 5364 cases in the confirmed invasive melanoma cohort, and 4792 cases in the confirmed melanoma in situ cohort. There were 20,457 variants significant at the genome-wide level in the phecode cohort, 2582 in the invasive melanoma cohort, and 1989 in the melanoma in situ cohort. Most of the variants identified in the phecode cohort did not replicate in the histologically-confirmed cohorts. The different case definitions led to large differences in sample size and variants associated at the genome-wide level. Unvalidated and imprecise case definitions can lead to less accurate results. Investigators should use validated phenotypes when gold-standard definitions are not available.
Insights
Using broad melanoma phecodes in genetic studies inflates case numbers and identified variants. Histologic confirmation is crucial for accurate genome-wide association study (GWAS) results, ensuring reliable genetic discoveries.
Area of Science:
- Genetics
- Epidemiology
- Bioinformatics
Background:
- Defining disease cases broadly using diagnostic codes versus narrowly with gold-standard confirmation significantly impacts study outcomes.
- Large administrative datasets often lack gold-standard confirmation, necessitating careful consideration of case definition methods in genetic research.
Purpose of the Study:
- To evaluate the impact of using melanoma phecodes versus histologic confirmation on genome-wide association study (GWAS) results.
- To compare the number of significant variants and sample sizes across different melanoma case definitions in the Million Veteran Program.
Main Methods:
- Conducted a genome-wide association study (GWAS) on melanoma cases defined by phecodes, histologically-confirmed invasive melanoma, and histologically-confirmed melanoma in situ.
- Analyzed variants with minor allele frequencies of 1% or greater within the Million Veteran Program cohort.
- Compared the number of genome-wide significant variants and replication rates between the different case definition cohorts.
Main Results:
- The phecode cohort (45,665 cases) identified 20,457 genome-wide significant variants.
- Histologically-confirmed invasive melanoma (5364 cases) yielded 2582 significant variants, and melanoma in situ (4792 cases) yielded 1989 significant variants.
- Most variants identified using phecodes did not replicate in the histologically-confirmed cohorts, indicating significant discrepancies.
Conclusions:
- Different case definitions for melanoma lead to substantial variations in sample size and the number of associated genetic variants.
- Unvalidated and imprecise case definitions, such as broad phecodes, can result in less accurate and non-replicable findings in genetic studies.
- Validated phenotypes are essential for accurate results, especially when gold-standard confirmation is unavailable for large datasets.
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