Around 5% of the population is affected by a rare genetic disease, yet most endure years of uncertainty before receiving a genetic test. A common feature of genetic diseases is the presence of multiple rare phenotypes that often span organ systems. Here, we use diagnostic billing information from longitudinal clinical data in the electronic health records (EHRs) of 2,286 patients who received a chromosomal microarray test, and 9,144 matched controls, to build a model to predict who should receive a genetic test. The model achieved high prediction accuracies in a held-out test sample (area under the receiver operating characteristic curve (AUROC), 0.97; area under the precision–recall curve (AUPRC), 0.92), in an independent hospital system (AUROC, 0.95; AUPRC, 0.62), and in an independent set of 172,265 patients in which cases were broadly defined as having an interaction with a genetics provider (AUROC, 0.9; AUPRC, 0.63). Patients carrying a putative pathogenic copy number variant were also accurately identified by the model. Compared with current approaches for genetic test determination, our model could identify more patients for testing while also increasing the proportion of those tested who have a genetic disease. We demonstrate that phenotypic patterns representative of a wide range of genetic diseases can be captured from EHRs to systematize decision-making for genetic testing, with the potential to speed up diagnosis, improve care and reduce costs.
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Summary level data on frequency and importance of phecodes in the model are presented in Supplementary Table 3. Summary data on clinical and genetic information are provided throughout the paper. All requests for raw (for example CNV and phenotype) data and materials are reviewed by Vanderbilt University Medical Center to determine whether the request is subject to any intellectual property or confidentiality obligations. For example, patient-related data not included in the paper may be subject to patient confidentiality. Any such data and materials that can be shared will be released via a material transfer agreement. ClinGen data were downloaded from UCSC Genome Browser June 2019 (https://genome.ucsc.edu/cgi-bin/hgGateway). DECIPHER CNV syndromes were extracted from https://www.deciphergenomics.org/disorders/syndromes/list.
All code used to construct and run the model is provided at https://github.com/RuderferLab/chromosomalMicroarray.
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This work was supported by R01MH111776 (to D.M.R.), R01MH113362 (to N.J.C. and D.M.R.), R01LM010685 (to L.B.) and U01HG009068 (to N.J.C.). This study makes use of data generated by the DECIPHER community. A full list of centers that contributed to the generation of the data is available from https://decipher.sanger.ac.uk and via email from email@example.com. Funding for the project was provided by Wellcome. The dataset(s) used for the analyses described were obtained from Vanderbilt University Medical Center’s BioVU, which is supported by institutional funding, private agencies and federal grants. These include the NIH-funded Shared Instrumentation Grant S10RR025141, and CTSA grants UL1TR002243, UL1TR000445 and UL1RR024975. Genomic data are also supported by investigator-led projects that include U01HG004798, R01NS032830, RC2GM092618, P50GM115305, U01HG006378, U19HL065962 and R01HD074711; and additional funding sources listed at https://victr.vanderbilt.edu/pub/biovu/.
The authors declare no competing interests.
Peer reviewer information Nature Medicine thanks Marc Williams and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Michael Basson was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
PheWAS Manhattan plot showing significance of associations from logistic regressions of each of 1,620 phecodes and whether an individual received a CMA vs controls. Triangle points represent direction of effect and points are colored by phecode category. For clarity, only phecodes with uncorrected p-values below 5 × 10−150 are labeled.
Age of patients at the time of their CMA report grouped into the most common syndromic region by combining diagnosis and genomic coordinates of reported abnormal variant. Independent patient numbers within each category: 15q11.2 syndromes (32), 16p11.2 syndromes (14), 1q21.1 syndromes (9), CMT/HNPP (18), DiGeorge/22q11.2 Duplication syndrome (31), Down Syndrome (7), Turner/Klinefelter (14), Williams syndrome (9).
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Morley, T.J., Han, L., Castro, V.M. et al. Phenotypic signatures in clinical data enable systematic identification of patients for genetic testing. Nat Med 27, 1097–1104 (2021). https://doi.org/10.1038/s41591-021-01356-z