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The effect of disease misclassification on the ability to detect a gene-environment interaction: implications of the specificity of case definitions for research on Gulf War illness

BACKGROUND: Since 1997, research on Gulf War illness (GWI) has predominantly used 3 case definitions—the original Research definition, the CDC definition, and modifications of the Kansas definition—but they have not been compared against an objective standard. METHODS: All 3 case definitions were me...

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Autores principales: Haley, Robert W., Dever, Jill A., Kramer, Gerald, Teiber, John F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10659093/
https://www.ncbi.nlm.nih.gov/pubmed/37986147
http://dx.doi.org/10.1186/s12874-023-02092-3
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author Haley, Robert W.
Dever, Jill A.
Kramer, Gerald
Teiber, John F.
author_facet Haley, Robert W.
Dever, Jill A.
Kramer, Gerald
Teiber, John F.
author_sort Haley, Robert W.
collection PubMed
description BACKGROUND: Since 1997, research on Gulf War illness (GWI) has predominantly used 3 case definitions—the original Research definition, the CDC definition, and modifications of the Kansas definition—but they have not been compared against an objective standard. METHODS: All 3 case definitions were measured in the U.S. Military Health Survey by a computer-assisted telephone interview in a random sample (n = 6,497) of the 1991 deployed U.S. military force. The interview asked whether participants had heard nerve agent alarms during the conflict. A random subsample (n = 1,698) provided DNA for genotyping the PON1 Q192R polymorphism. RESULTS: The CDC and the Modified Kansas definition without exclusions were satisfied by 41.7% and 39.0% of the deployed force, respectively, and were highly overlapping. The Research definition, a subset of the others, was satisfied by 13.6%. The majority of veterans meeting CDC and Modified Kansas endorsed fewer and milder symptoms; whereas, those meeting Research endorsed more symptoms of greater severity. The group meeting Research was more highly enriched with the PON1 192R risk allele than those meeting CDC and Modified Kansas, and Research had twice the power to detect the previously described gene-environment interaction between hearing alarms and RR homozygosity (adjusted relative excess risk due to interaction [aRERI] = 7.69; 95% CI 2.71–19.13) than CDC (aRERI = 2.92; 95% CI 0.96–6.38) or Modified Kansas without exclusions (aRERI = 3.84; 95% CI 1.30–8.52) or with exclusions (aRERI = 3.42; 95% CI 1.20–7.56). The lower power of CDC and Modified Kansas relative to Research was due to greater false-positive disease misclassification from lower diagnostic specificity. CONCLUSIONS: The original Research case definition had greater statistical power to detect a genetic predisposition to GWI. Its greater specificity favors its use in hypothesis-driven research; whereas, the greater sensitivity of the others favor their use in clinical screening for application of future diagnostic biomarkers and clinical care. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12874-023-02092-3.
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spelling pubmed-106590932023-11-20 The effect of disease misclassification on the ability to detect a gene-environment interaction: implications of the specificity of case definitions for research on Gulf War illness Haley, Robert W. Dever, Jill A. Kramer, Gerald Teiber, John F. BMC Med Res Methodol Research BACKGROUND: Since 1997, research on Gulf War illness (GWI) has predominantly used 3 case definitions—the original Research definition, the CDC definition, and modifications of the Kansas definition—but they have not been compared against an objective standard. METHODS: All 3 case definitions were measured in the U.S. Military Health Survey by a computer-assisted telephone interview in a random sample (n = 6,497) of the 1991 deployed U.S. military force. The interview asked whether participants had heard nerve agent alarms during the conflict. A random subsample (n = 1,698) provided DNA for genotyping the PON1 Q192R polymorphism. RESULTS: The CDC and the Modified Kansas definition without exclusions were satisfied by 41.7% and 39.0% of the deployed force, respectively, and were highly overlapping. The Research definition, a subset of the others, was satisfied by 13.6%. The majority of veterans meeting CDC and Modified Kansas endorsed fewer and milder symptoms; whereas, those meeting Research endorsed more symptoms of greater severity. The group meeting Research was more highly enriched with the PON1 192R risk allele than those meeting CDC and Modified Kansas, and Research had twice the power to detect the previously described gene-environment interaction between hearing alarms and RR homozygosity (adjusted relative excess risk due to interaction [aRERI] = 7.69; 95% CI 2.71–19.13) than CDC (aRERI = 2.92; 95% CI 0.96–6.38) or Modified Kansas without exclusions (aRERI = 3.84; 95% CI 1.30–8.52) or with exclusions (aRERI = 3.42; 95% CI 1.20–7.56). The lower power of CDC and Modified Kansas relative to Research was due to greater false-positive disease misclassification from lower diagnostic specificity. CONCLUSIONS: The original Research case definition had greater statistical power to detect a genetic predisposition to GWI. Its greater specificity favors its use in hypothesis-driven research; whereas, the greater sensitivity of the others favor their use in clinical screening for application of future diagnostic biomarkers and clinical care. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12874-023-02092-3. BioMed Central 2023-11-20 /pmc/articles/PMC10659093/ /pubmed/37986147 http://dx.doi.org/10.1186/s12874-023-02092-3 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Haley, Robert W.
Dever, Jill A.
Kramer, Gerald
Teiber, John F.
The effect of disease misclassification on the ability to detect a gene-environment interaction: implications of the specificity of case definitions for research on Gulf War illness
title The effect of disease misclassification on the ability to detect a gene-environment interaction: implications of the specificity of case definitions for research on Gulf War illness
title_full The effect of disease misclassification on the ability to detect a gene-environment interaction: implications of the specificity of case definitions for research on Gulf War illness
title_fullStr The effect of disease misclassification on the ability to detect a gene-environment interaction: implications of the specificity of case definitions for research on Gulf War illness
title_full_unstemmed The effect of disease misclassification on the ability to detect a gene-environment interaction: implications of the specificity of case definitions for research on Gulf War illness
title_short The effect of disease misclassification on the ability to detect a gene-environment interaction: implications of the specificity of case definitions for research on Gulf War illness
title_sort effect of disease misclassification on the ability to detect a gene-environment interaction: implications of the specificity of case definitions for research on gulf war illness
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10659093/
https://www.ncbi.nlm.nih.gov/pubmed/37986147
http://dx.doi.org/10.1186/s12874-023-02092-3
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