Clinically Adjudicated Reference Standards for Evaluation of Infectious Diseases Diagnostics.

Lack of a gold standard can present a challenge for evaluation of diagnostic test accuracy of some infectious diseases tests, particularly when the test's accuracy potentially exceeds that of its predecessors. This approach may measure agreement with an imperfect reference, rather than correctness, because the right answer is unknown. Solutions consist of multitest comparators, including those that involve a test under evaluation if multiple new tests are being evaluated together, using latent class modeling, and clinically adjudicated reference standards. Clinically adjudicated reference standards may be considered as comparator methods when no predefined test or composite of tests is sufficiently accurate; they emulate clinical practice in that multiple data pieces are clinically assessed together.
Competing Interests: Potential conflicts of interest. V. G. F. reports personal fees from Novartis, Novadigm, Durata, Debiopharm, Genentech, Achaogen, Affinium, Medicines Co., Cerexa, Tetraphase, Trius, MedImmune, Bayer, Theravance, Basilea, Affinergy, Janssen, xBiotech, Contrafect, Regeneron, Basilea, Destiny, Amphliphi Biosciences, Integrated Biotherapeutics, C3J, Armata, Valanbio, Akagera, Aridis, Roche, and Pfizer; grants from the National Institutes of Health (NIH), MedImmune, Cerexa/Forest/Actavis/Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Cubist/Merck, Medical Biosurfaces, Locus, Affinergy, Contrafect, Karius, Genentech, Regeneron, Basilea, Janssen, from Green Cross, Cubist, Cerexa, Durata, Theravance, and Debiopharm. Royalties from UpToDate. V. G. F. also reports support for attending meetings and/or travel from Contrafect to present phase 2 data at 2019 ECCMID; patents planned, issued, or pending (Sepsis Diagnostics); a role as Associate Editor, Clinical Infectious Diseases (2017–2022); and stock or stock options from ArcBio and Valanbio. R. P. reports grants from ContraFect, TenNor Therapeutics Limited, and BioFire. R. P. is a consultant to Curetis, PathoQuest, Selux Diagnostics, 1928 Diagnostics, PhAST, Torus Biosystems, Day Zero Diagnostics, Mammoth Biosciences, and Qvella; monies are paid to Mayo Clinic. Mayo Clinic and R. P. have a relationship with Pathogenomix. R. P. has research supported by Adaptive Phage Therapeutics. Mayo Clinic has a royalty-bearing know-how agreement and equity in Adaptive Phage Therapeutics. R. P. is also a consultant to Netflix, Abbott Laboratories, and CARB-X. In addition, R. P. has a patent on Bordetella pertussis/parapertussis polymerase chain reaction issued, a patent on a device/method for sonication with royalties paid by Samsung to Mayo Clinic, and a patent on an antibiofilm substance issued. R. P. receives honoraria from the NBME, Up-to-Date, and the Infectious Diseases Board Review Course. E. L. T. reports grants or contracts from NIAID, DTRA, Sanofi, NIGMS, DARPA, Karius, Department of Veterans Affairs, and Department of Defense. E. L. T. has patents issued or pending for methods for characterizing infections and methods for developing tests for the same; host based molecular signatures of human infection with severe acute respiratory syndrome coronavirus 2; transcriptional signature for candidemia, gene expression signature useful to predict or diagnose sepsis and methods of using the same; methods to diagnose and treat acute respiratory infections; and biomarkers for the molecular classification of bacterial infection; E. L. T. is an employee of Danaher Corp and previously received consulting fees from Biomeme and has stock or stock options for Biomeme and Danaher. S. R. E. reports grant support from NIH; a contract with DeGruyter; royalties from Taylor & Francis; honoraria from the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION); meeting support from the Food and Drug Administration, Deming Conference on Applied Statistics, Clinical Trial Transformation Initiative, Council for International Organizations of Medical Sciences, International Chinese Statistical Association Applied Statistics Symposium, Antimicrobial Resistance and Stewardship Conference; unpaid board membership from the American Statistical Association, Society for Clinical Trials, Frontier Science Foundation; consulting fees from Genentech, AstraZeneca, Takeda, Microbiotix, Johnson & Johnson, Endologix, ChemoCentryx, Becton Dickenson, Atricure, Roivant, Neovasc, Nobel Pharma, Horizon, International Drug Development Institute, and SVB Leerink; data and safety monitoring board or advisory board service for NIH, Breast International Group, University of Pennsylvania, Washington University, Duke University, Roche, Pfizer, Takeda, Akouos, Apellis, Teva, Vir, DayOneBio, Alexion, Tracon, Rakuten, Abbvie, GSK, Eli Lilly, Nuvelution, Clover, FHI Clinical, Lung Biotech, SAB Biopharm, and Advantagene/Candel. S. B. D. reports research funding related to coronavirus disease 2019 (COVID-19) from Gilead, Regeneron, Shinogi, and the NIH and non–COVID-19-related consulting and research funding from Genentech, Basilea, Shinogi, J + J, and the NIH; support for travel from IDSA, and patents issued (WO2006116688A3). All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
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