Lessons from the CAGI-4 Hopkins clinical panel challenge

John Marc Chandonia, Aashish Adhikari, Marco Carraro, Aparna Chhibber, Garry R. Cutting, Yao Fu, Alessandra Gasparini, David T. Jones, Andreas Kramer, Kunal Kundu, Hugo Y.K. Lam, Emanuela Leonardi, John Moult, Lipika R. Pal, David B. Searls, Sohela Shah, Shamil Sunyaev, Silvio C.E. Tosatto, Yizhou Yin, Bethany A. Buckley

Research output: Contribution to journalArticlepeer-review


The CAGI-4 Hopkins clinical panel challenge was an attempt to assess state-of-the-art methods for clinical phenotype prediction from DNA sequence. Participants were provided with exonic sequences of 83 genes for 106 patients from the Johns Hopkins DNA Diagnostic Laboratory. Five groups participated in the challenge, predicting both the probability that each patient had each of the 14 possible classes of disease, as well as one or more causal variants. In cases where the Hopkins laboratory reported a variant, at least one predictor correctly identified the disease class in 36 of the 43 patients (84%). Even in cases where the Hopkins laboratory did not find a variant, at least one predictor correctly identified the class in 39 of the 63 patients (62%). Each prediction group correctly diagnosed at least one patient that was not successfully diagnosed by any other group. We discuss the causal variant predictions by different groups and their implications for further development of methods to assess variants of unknown significance. Our results suggest that clinically relevant variants may be missed when physicians order small panels targeted on a specific phenotype. We also quantify the false-positive rate of DNA-guided analysis in the absence of prior phenotypic indication.

Original languageEnglish (US)
Pages (from-to)1155-1168
Number of pages14
JournalHuman mutation
Issue number9
StatePublished - Sep 2017


  • CAGI
  • genetic testing
  • phenotype prediction
  • variant interpretation

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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