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Variance of age-specific log incidence decomposition (VALID): a unifying model of measured and unmeasured genetic and non-genetic risks
BACKGROUND: The extent to which known and unknown factors explain how much people of the same age differ in disease risk is fundamental to epidemiology. Risk factors can be correlated in relatives, so familial aspects of risk (genetic and non-genetic) must be considered. DEVELOPMENT: We present a un...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10655167/ https://www.ncbi.nlm.nih.gov/pubmed/37349888 http://dx.doi.org/10.1093/ije/dyad086 |
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author | Hopper, John L Dowty, James G Nguyen, Tuong L Li, Shuai Dite, Gillian S MacInnis, Robert J Makalic, Enes Schmidt, Daniel F Bui, Minh Stone, Jennifer Sung, Joohon Jenkins, Mark A Giles, Graham G Southey, Melissa C Mathews, John D |
author_facet | Hopper, John L Dowty, James G Nguyen, Tuong L Li, Shuai Dite, Gillian S MacInnis, Robert J Makalic, Enes Schmidt, Daniel F Bui, Minh Stone, Jennifer Sung, Joohon Jenkins, Mark A Giles, Graham G Southey, Melissa C Mathews, John D |
author_sort | Hopper, John L |
collection | PubMed |
description | BACKGROUND: The extent to which known and unknown factors explain how much people of the same age differ in disease risk is fundamental to epidemiology. Risk factors can be correlated in relatives, so familial aspects of risk (genetic and non-genetic) must be considered. DEVELOPMENT: We present a unifying model (VALID) for variance in risk, with risk defined as log(incidence) or logit(cumulative incidence). Consider a normally distributed risk score with incidence increasing exponentially as the risk increases. VALID’s building block is variance in risk, Δ(2), where Δ = log(OPERA) is the difference in mean between cases and controls and OPERA is the odds ratio per standard deviation. A risk score correlated r between a pair of relatives generates a familial odds ratio of exp(rΔ(2)). Familial risk ratios, therefore, can be converted into variance components of risk, extending Fisher’s classic decomposition of familial variation to binary traits. Under VALID, there is a natural upper limit to variance in risk caused by genetic factors, determined by the familial odds ratio for genetically identical twin pairs, but not to variation caused by non-genetic factors. APPLICATION: For female breast cancer, VALID quantified how much variance in risk is explained—at different ages—by known and unknown major genes and polygenes, non-genomic risk factors correlated in relatives, and known individual-specific factors. CONCLUSION: VALID has shown that, while substantial genetic risk factors have been discovered, much is unknown about genetic and familial aspects of breast cancer risk especially for young women, and little is known about individual-specific variance in risk. |
format | Online Article Text |
id | pubmed-10655167 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-106551672023-06-22 Variance of age-specific log incidence decomposition (VALID): a unifying model of measured and unmeasured genetic and non-genetic risks Hopper, John L Dowty, James G Nguyen, Tuong L Li, Shuai Dite, Gillian S MacInnis, Robert J Makalic, Enes Schmidt, Daniel F Bui, Minh Stone, Jennifer Sung, Joohon Jenkins, Mark A Giles, Graham G Southey, Melissa C Mathews, John D Int J Epidemiol Methods BACKGROUND: The extent to which known and unknown factors explain how much people of the same age differ in disease risk is fundamental to epidemiology. Risk factors can be correlated in relatives, so familial aspects of risk (genetic and non-genetic) must be considered. DEVELOPMENT: We present a unifying model (VALID) for variance in risk, with risk defined as log(incidence) or logit(cumulative incidence). Consider a normally distributed risk score with incidence increasing exponentially as the risk increases. VALID’s building block is variance in risk, Δ(2), where Δ = log(OPERA) is the difference in mean between cases and controls and OPERA is the odds ratio per standard deviation. A risk score correlated r between a pair of relatives generates a familial odds ratio of exp(rΔ(2)). Familial risk ratios, therefore, can be converted into variance components of risk, extending Fisher’s classic decomposition of familial variation to binary traits. Under VALID, there is a natural upper limit to variance in risk caused by genetic factors, determined by the familial odds ratio for genetically identical twin pairs, but not to variation caused by non-genetic factors. APPLICATION: For female breast cancer, VALID quantified how much variance in risk is explained—at different ages—by known and unknown major genes and polygenes, non-genomic risk factors correlated in relatives, and known individual-specific factors. CONCLUSION: VALID has shown that, while substantial genetic risk factors have been discovered, much is unknown about genetic and familial aspects of breast cancer risk especially for young women, and little is known about individual-specific variance in risk. Oxford University Press 2023-06-22 /pmc/articles/PMC10655167/ /pubmed/37349888 http://dx.doi.org/10.1093/ije/dyad086 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of the International Epidemiological Association. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Methods Hopper, John L Dowty, James G Nguyen, Tuong L Li, Shuai Dite, Gillian S MacInnis, Robert J Makalic, Enes Schmidt, Daniel F Bui, Minh Stone, Jennifer Sung, Joohon Jenkins, Mark A Giles, Graham G Southey, Melissa C Mathews, John D Variance of age-specific log incidence decomposition (VALID): a unifying model of measured and unmeasured genetic and non-genetic risks |
title | Variance of age-specific log incidence decomposition (VALID): a unifying model of measured and unmeasured genetic and non-genetic risks |
title_full | Variance of age-specific log incidence decomposition (VALID): a unifying model of measured and unmeasured genetic and non-genetic risks |
title_fullStr | Variance of age-specific log incidence decomposition (VALID): a unifying model of measured and unmeasured genetic and non-genetic risks |
title_full_unstemmed | Variance of age-specific log incidence decomposition (VALID): a unifying model of measured and unmeasured genetic and non-genetic risks |
title_short | Variance of age-specific log incidence decomposition (VALID): a unifying model of measured and unmeasured genetic and non-genetic risks |
title_sort | variance of age-specific log incidence decomposition (valid): a unifying model of measured and unmeasured genetic and non-genetic risks |
topic | Methods |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10655167/ https://www.ncbi.nlm.nih.gov/pubmed/37349888 http://dx.doi.org/10.1093/ije/dyad086 |
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