title: Variant priorization and analysis incorporating problematic regions of the genome.
abstract: In case-control studies of rare Mendelian disorders and complex diseases, the power to detect variant and gene-level associations of a given effect size is limited by the size of the study sample. Paradoxically, low statistical power may increase the likelihood that a statistically significant finding is also a false positive. The prioritization of variants based on call quality, putative effects on protein function, the predicted degree of deleteriousness, and allele frequency is often used as a mechanism for reducing the occurrence of false positives, while preserving the set of variants most likely to contain true disease associations. We propose that specificity can be further improved by considering errors that are specific to the regions of the genome being sequenced. These problematic regions (PRs) are identified a-priori and are used to down-weight constitutive variants in a case-control analysis. Using samples drawn from 1000-Genomes, we illustrate the utility of PRs in identifying true variant and gene associations using a case-control study on a known Mendelian disease, cystic fibrosis (CF).
authors.affiliation: Personalis Inc., 1350 Willow Road, Suite 202, Menlo Park, CA, 94025, USA. apatwardhan@personalis.com.
authors.forename: Anil
authors.initials: A
authors.lastname: Patwardhan
authors.forename: Michael
authors.initials: M
authors.lastname: Clark
authors.forename: Alex
authors.initials: A
authors.lastname: Morgan
authors.forename: Stephen
authors.initials: S
authors.lastname: Chervitz
authors.forename: Mark
authors.initials: M
authors.lastname: Pratt
authors.forename: Gabor
authors.initials: G
authors.lastname: Bartha
authors.forename: Gemma
authors.initials: G
authors.lastname: Chandratillake
authors.forename: Sarah
authors.initials: S
authors.lastname: Garcia
authors.forename: Nan
authors.initials: N
authors.lastname: Leng
authors.forename: Richard
authors.initials: R
authors.lastname: Chen
mesh_terms: D016022:Case-Control Studies; D019295:Computational Biology; D003550:Cystic Fibrosis / Q000235:genetics; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics; D030541:Databases, Genetic / Q000706:statistics & numerical data; D059472:Exome; D056726:Genetic Association Studies / Q000706:statistics & numerical data; D014644:Genetic Variation; D015894:Genome, Human; D015698:Genomic Library; D016045:Human Genome Project; D006801:Humans; D057285:Precision Medicine / Q000706:statistics & numerical data; D018401:Sample Size; D016415:Sequence Alignment / Q000706:statistics & numerical data
chemical_list: C505032:CFTR protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator