@article{b20d7ccbb9f9416a85e1d5bee2ffbb95,
title = "Sensitive and specific detection of mosaic chromosomal abnormalities using the Parent-of-Origin-based Detection (POD) method",
abstract = "Background: Mosaic somatic alterations are present in all multi-cellular organisms, but the physiological effects of low-level mosaicism are largely unknown. Most mosaic alterations remain undetectable with current analytical approaches, although the presence of such alterations is increasingly implicated as causative for disease.Results: Here, we present the Parent-of-Origin-based Detection (POD) method for chromosomal abnormality detection in trio-based SNP microarray data. Our software implementation, triPOD, was benchmarked using a simulated dataset, outperformed comparable software for sensitivity of abnormality detection, and displayed substantial improvement in the detection of low-level mosaicism while maintaining comparable specificity. Examples of low-level mosaic abnormalities from a large autism dataset demonstrate the benefits of the increased sensitivity provided by triPOD. The triPOD analyses showed robustness across multiple types of Illumina microarray chips. Two large, clinically-relevant datasets were characterized and compared.Conclusions: Our method and software provide a significant advancement in the ability to detect low-level mosaic abnormalities, thereby opening new avenues for research into the implications of mosaicism in pathogenic and non-pathogenic processes.",
keywords = "Autism, Cleft, HapMap, Microarray, Mosaicism, Parent-child, Parent-of-origin, Software, Trio",
author = "Baugher, {Joseph D.} and Baugher, {Benjamin D.} and Shirley, {Matthew D.} and Jonathan Pevsner",
note = "Funding Information: We thank Eric L. Stevens for critical review of the manuscript. We gratefully acknowledge the resources provided by the Autism Genetic Resource Exchange (AGRE) Consortium and the participating AGRE families. The Autism Genetic Resource Exchange is a program of Autism Speaks and is supported, in part, by grant 1U24MH081810 from the National Institute of Mental Health to Clara M. Lajonchere (PI). We thank Dr. Cathy Laurie for providing sample identifiers for previously reported mosaic abnormalities within the cleft lip/palate dataset. We thank Drs. Terri H. Beaty, Alan F. Scott, Ingo Ruczinski, and Robert Scharpf for facilitating access to the cleft dataset. Funding support for the study entitled “International Consortium to Identify Genes and Interactions Controlling Oral Clefts” was provided by several previous grants from the National Institute of Dental and Craniofacial Research (NIDCR). Data and samples were drawn from several studies performed by members of this consortium. Funding to support original data collection, previous genotyping, and analysis was provided to individual investigators from several sources. Funding for individual investigators included: R21-DE-013707 and R01-DE-014581 (Beaty); R37-DE-08559 and P50-DE-016215 (Murray, Marazita); the Iowa Comprehensive Program to Investigate Craniofacial and Dental Anomalies (Murray); R01-DE-09886 (Marazita); R01-DE-012472 (Marazita); R01-DE-014677 (Marazita); R01-DE-016148 (Marazita); R21-DE -016930 (Marazita); and R01-DE-013939 (Scott). Parts of this research were supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Wilcox, Lie). Additional recruitment was supported by the Smile Train Foundation for recruitment in China (Jabs, Beaty, Shi) and a grant from the Korean government (Jee). The genome-wide association study, also known the International Cleft Consortium, is part of the Gene Environment Association Studies (GENEVA) program of the trans-NIH Genes, Environment, and Health Initiative [GEI] supported by U01-DE-018993. Genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health (NIH) to The Johns Hopkins University, contract number HHSN268200782096C. Funds for genotyping were provided by the NIDCR through CIDR{\textquoteright}s NIH contract. Assistance with genotype cleaning, as well as with general study coordination, was provided by the GENEVA Coordinating Center (U01-HG-004446) and by the National Center for Biotechnology Information (NCBI). We sincerely thank all of the patients and families at each recruitment site for participating in this study, and we gratefully acknowledge the invaluable assistance of all clinical, field, and laboratory staff who contributed to this effort over the years.",
year = "2013",
month = may,
day = "31",
doi = "10.1186/1471-2164-14-367",
language = "English (US)",
volume = "14",
journal = "BMC genomics",
issn = "1471-2164",
publisher = "BioMed Central",
number = "1",
}