TY - JOUR
T1 - Interpretable Clinical Genomics with a Likelihood Ratio Paradigm
AU - UNC Biocuration Core
AU - Robinson, Peter N.
AU - Ravanmehr, Vida
AU - Jacobsen, Julius O.B.
AU - Danis, Daniel
AU - Zhang, Xingmin Aaron
AU - Carmody, Leigh C.
AU - Gargano, Michael A.
AU - Thaxton, Courtney L.
AU - Karlebach, Guy
AU - Reese, Justin
AU - Holtgrewe, Manuel
AU - Köhler, Sebastian
AU - McMurry, Julie A.
AU - Haendel, Melissa A.
AU - Smedley, Damian
N1 - Publisher Copyright:
© 2020 American Society of Human Genetics
PY - 2020/9/3
Y1 - 2020/9/3
N2 - Human Phenotype Ontology (HPO)-based analysis has become standard for genomic diagnostics of rare diseases. Current algorithms use a variety of semantic and statistical approaches to prioritize the typically long lists of genes with candidate pathogenic variants. These algorithms do not provide robust estimates of the strength of the predictions beyond the placement in a ranked list, nor do they provide measures of how much any individual phenotypic observation has contributed to the prioritization result. However, given that the overall success rate of genomic diagnostics is only around 25%–50% or less in many cohorts, a good ranking cannot be taken to imply that the gene or disease at rank one is necessarily a good candidate. Here, we present an approach to genomic diagnostics that exploits the likelihood ratio (LR) framework to provide an estimate of (1) the posttest probability of candidate diagnoses, (2) the LR for each observed HPO phenotype, and (3) the predicted pathogenicity of observed genotypes. LIkelihood Ratio Interpretation of Clinical AbnormaLities (LIRICAL) placed the correct diagnosis within the first three ranks in 92.9% of 384 case reports comprising 262 Mendelian diseases, and the correct diagnosis had a mean posttest probability of 67.3%. Simulations show that LIRICAL is robust to many typically encountered forms of genomic and phenomic noise. In summary, LIRICAL provides accurate, clinically interpretable results for phenotype-driven genomic diagnostics.
AB - Human Phenotype Ontology (HPO)-based analysis has become standard for genomic diagnostics of rare diseases. Current algorithms use a variety of semantic and statistical approaches to prioritize the typically long lists of genes with candidate pathogenic variants. These algorithms do not provide robust estimates of the strength of the predictions beyond the placement in a ranked list, nor do they provide measures of how much any individual phenotypic observation has contributed to the prioritization result. However, given that the overall success rate of genomic diagnostics is only around 25%–50% or less in many cohorts, a good ranking cannot be taken to imply that the gene or disease at rank one is necessarily a good candidate. Here, we present an approach to genomic diagnostics that exploits the likelihood ratio (LR) framework to provide an estimate of (1) the posttest probability of candidate diagnoses, (2) the LR for each observed HPO phenotype, and (3) the predicted pathogenicity of observed genotypes. LIkelihood Ratio Interpretation of Clinical AbnormaLities (LIRICAL) placed the correct diagnosis within the first three ranks in 92.9% of 384 case reports comprising 262 Mendelian diseases, and the correct diagnosis had a mean posttest probability of 67.3%. Simulations show that LIRICAL is robust to many typically encountered forms of genomic and phenomic noise. In summary, LIRICAL provides accurate, clinically interpretable results for phenotype-driven genomic diagnostics.
KW - Human Phenotype Ontology
KW - exome sequencing
KW - genome sequencing
KW - liklihood ratio
KW - phenotype-driven genomic diagnostics
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U2 - 10.1016/j.ajhg.2020.06.021
DO - 10.1016/j.ajhg.2020.06.021
M3 - Article
AN - SCOPUS:85089981782
SN - 0002-9297
VL - 107
SP - 403
EP - 417
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 3
ER -