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Genet Epidemiol. 2018 Sep;42(6):528-538. doi: 10.1002/gepi.22130. Epub 2018 Jun 25.

Efficient computation of the joint probability of multiple inherited risk alleles from pedigree data.

Author information

1
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
2
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
3
Department of Biostatistics, Yale School of Public Health, New Haven, Connecticut.

Abstract

The Elston-Stewart peeling algorithm enables estimation of an individual's probability of harboring germline risk alleles based on pedigree data, and serves as the computational backbone of important genetic counseling tools. However, it remains limited to the analysis of risk alleles at a small number of genetic loci because its computing time grows exponentially with the number of loci considered. We propose a novel, approximate version of this algorithm, dubbed the peeling and paring algorithm, which scales polynomially in the number of loci. This allows extending peeling-based models to include many genetic loci. The algorithm creates a trade-off between accuracy and speed, and allows the user to control this trade-off. We provide exact bounds on the approximation error and evaluate it in realistic simulations. Results show that the loss of accuracy due to the approximation is negligible in important applications. This algorithm will improve genetic counseling tools by increasing the number of pathogenic risk alleles that can be addressed. To illustrate we create an extended five genes version of BRCAPRO, a widely used model for estimating the carrier probabilities of BRCA1 and BRCA2 risk alleles and assess its computational properties.

KEYWORDS:

Mendelian risk prediction; family history; germline risk alleles; peeling algorithm

PMID:
29943416
PMCID:
PMC6129424
[Available on 2019-09-01]
DOI:
10.1002/gepi.22130
[Indexed for MEDLINE]

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