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Can multiple SNP testing in BRCA2 and BRCA1 female carriers be used to improve risk prediction models in conjunction with clinical assessment?
BACKGROUND: Several single nucleotide polymorphisms (SNPs) at different loci have been associated with breast cancer susceptibility, accounting for around 10% of the familial component. Recent studies have found direct associations between specific SNPs and breast cancer in BRCA1/2 mutation carriers...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4197237/ https://www.ncbi.nlm.nih.gov/pubmed/25274085 http://dx.doi.org/10.1186/1472-6947-14-87 |
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author | Prosperi, Mattia CF Ingham, Sarah L Howell, Anthony Lalloo, Fiona Buchan, Iain E Evans, Dafydd Gareth |
author_facet | Prosperi, Mattia CF Ingham, Sarah L Howell, Anthony Lalloo, Fiona Buchan, Iain E Evans, Dafydd Gareth |
author_sort | Prosperi, Mattia CF |
collection | PubMed |
description | BACKGROUND: Several single nucleotide polymorphisms (SNPs) at different loci have been associated with breast cancer susceptibility, accounting for around 10% of the familial component. Recent studies have found direct associations between specific SNPs and breast cancer in BRCA1/2 mutation carriers. Our aim was to determine whether validated susceptibility SNP scores improve the predictive ability of risk models in comparison/conjunction to other clinical/demographic information. METHODS: Female BRCA1/2 carriers were identified from the Manchester genetic database, and included in the study regardless of breast cancer status or age. DNA was extracted from blood samples provided by these women and used for gene and SNP profiling. Estimates of survival were examined with Kaplan-Meier curves. Multivariable Cox proportional hazards models were fit in the separate BRCA datasets and in menopausal stages screening different combinations of clinical/demographic/genetic variables. Nonlinear random survival forests were also fit to identify relevant interactions. Models were compared using Harrell’s concordance index (1 - c-index). RESULTS: 548 female BRCA1 mutation carriers and 523 BRCA2 carriers were identified from the database. Median Kaplan-Meier estimate of survival was 46.0 years (44.9-48.1) for BRCA1 carriers and 48.9 (47.3-50.4) for BRCA2. By fitting Cox models and random survival forests, including both a genetic SNP score and clinical/demographic variables, average 1 - c-index values were 0.221 (st.dev. 0.019) for BRCA1 carriers and 0.215 (st.dev. 0.018) for BRCA2 carriers. CONCLUSIONS: Random survival forests did not yield higher performance compared to Cox proportional hazards. We found improvement in prediction performance when coupling the genetic SNP score with clinical/demographic markers, which warrants further investigation. |
format | Online Article Text |
id | pubmed-4197237 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-41972372014-10-16 Can multiple SNP testing in BRCA2 and BRCA1 female carriers be used to improve risk prediction models in conjunction with clinical assessment? Prosperi, Mattia CF Ingham, Sarah L Howell, Anthony Lalloo, Fiona Buchan, Iain E Evans, Dafydd Gareth BMC Med Inform Decis Mak Research Article BACKGROUND: Several single nucleotide polymorphisms (SNPs) at different loci have been associated with breast cancer susceptibility, accounting for around 10% of the familial component. Recent studies have found direct associations between specific SNPs and breast cancer in BRCA1/2 mutation carriers. Our aim was to determine whether validated susceptibility SNP scores improve the predictive ability of risk models in comparison/conjunction to other clinical/demographic information. METHODS: Female BRCA1/2 carriers were identified from the Manchester genetic database, and included in the study regardless of breast cancer status or age. DNA was extracted from blood samples provided by these women and used for gene and SNP profiling. Estimates of survival were examined with Kaplan-Meier curves. Multivariable Cox proportional hazards models were fit in the separate BRCA datasets and in menopausal stages screening different combinations of clinical/demographic/genetic variables. Nonlinear random survival forests were also fit to identify relevant interactions. Models were compared using Harrell’s concordance index (1 - c-index). RESULTS: 548 female BRCA1 mutation carriers and 523 BRCA2 carriers were identified from the database. Median Kaplan-Meier estimate of survival was 46.0 years (44.9-48.1) for BRCA1 carriers and 48.9 (47.3-50.4) for BRCA2. By fitting Cox models and random survival forests, including both a genetic SNP score and clinical/demographic variables, average 1 - c-index values were 0.221 (st.dev. 0.019) for BRCA1 carriers and 0.215 (st.dev. 0.018) for BRCA2 carriers. CONCLUSIONS: Random survival forests did not yield higher performance compared to Cox proportional hazards. We found improvement in prediction performance when coupling the genetic SNP score with clinical/demographic markers, which warrants further investigation. BioMed Central 2014-10-01 /pmc/articles/PMC4197237/ /pubmed/25274085 http://dx.doi.org/10.1186/1472-6947-14-87 Text en © Prosperi et al.; licensee BioMed Central Ltd. 2014 This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Article Prosperi, Mattia CF Ingham, Sarah L Howell, Anthony Lalloo, Fiona Buchan, Iain E Evans, Dafydd Gareth Can multiple SNP testing in BRCA2 and BRCA1 female carriers be used to improve risk prediction models in conjunction with clinical assessment? |
title | Can multiple SNP testing in BRCA2 and BRCA1 female carriers be used to improve risk prediction models in conjunction with clinical assessment? |
title_full | Can multiple SNP testing in BRCA2 and BRCA1 female carriers be used to improve risk prediction models in conjunction with clinical assessment? |
title_fullStr | Can multiple SNP testing in BRCA2 and BRCA1 female carriers be used to improve risk prediction models in conjunction with clinical assessment? |
title_full_unstemmed | Can multiple SNP testing in BRCA2 and BRCA1 female carriers be used to improve risk prediction models in conjunction with clinical assessment? |
title_short | Can multiple SNP testing in BRCA2 and BRCA1 female carriers be used to improve risk prediction models in conjunction with clinical assessment? |
title_sort | can multiple snp testing in brca2 and brca1 female carriers be used to improve risk prediction models in conjunction with clinical assessment? |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4197237/ https://www.ncbi.nlm.nih.gov/pubmed/25274085 http://dx.doi.org/10.1186/1472-6947-14-87 |
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