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Publications

Journal Article Review Ahead of print 1 citation

PubMed: 42501868 DOI: 10.1016/j.jhep.2026.07.016

A framework and shared vocabulary to identify actionable protein biomarkers and enable optimal precision medicine: Myth-Busting with Unicorn Biomarkers.

J Hepatol

Authors: Morten A Karsdal, Anne-Christine Bay-Jensen, Daniel Guldager Kring Rasmussen, Aleksander Krag, Stine Johansen, Quentin M Anstee, Diana J Leeming, Federica Genovese, Arun J Sanyal, Cecilie L Bager, Robert J Benschop, Salvador Augustin, Darren Ruane, Neeraj Adya, Jörn M Schattenberg, Ali Mobasheri, Veronica Miller, Maja Thiele, Roberto A Calle, Patrick Bossuyt, Adam Platt, Signe H Larsen, Kim Henriksen, Vincent Bonneau, Bruno Golding, Mohamed Hassanein, Sumanta Mukherjee, Sarah Harris, Zoltan Derdak, Suneil Hosmane, Paresh Thakker, Virginia B Kraus

Affiliations

  • Nordic Bioscience, Herlev, Denmark.
  • Nordic Bioscience, Herlev, Denmark.
  • Medical & Translational Science, Novo Nordisk A/S, Søborg, Denmark.
  • Fibrosis, Fatty Liver and Steatohepatitis Research Center Odense (FLASH), Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark; Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.
  • Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, 4th Floor, William Leech Building, Framlington Place, Newcastle upon Tyne, NE2 4HH, United Kingdom; Newcastle NIHR Biomedical Research Center, Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, NE7 7DN, United Kingdom.
  • Virginia Commonwealth University, Richmond, VA, USA.
  • Eli Lilly and Company, Indianapolis, IN, USA.
  • Boehringer Ingelheim International GmbH, Ingelheim, Germany.
  • Johnson & Johnson, Innovative Medicine, Immunology, Translational Sciences & Medicine, La Jolla, CA, USA.
  • Department of Internal Medicine II, Saarland University Medical Center, Homburg, Germany.
  • Research Unit of Health Sciences and Technology, Physics and Technology, University of Oulu, Oulu, Finland; Department of Regenerative Medicine, State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania; Faculté de Médecine, Université de Liège, Liège, Belgium; Department of Joint Surgery, Sun Yat-sen University, Guangzhou, China.
  • Berkeley School of Public Health; Forum for Collaborative Research, University of California, Berkeley, USA.
  • GSK, Waltham, MA, USA; New York Medical College, Department of Medicine, Valhalla, NY, USA.
  • Department of Epidemiology & Data Science, Amsterdam UMC, University of Amsterdam, The Netherlands.
  • Translational Science and Experimental Medicine, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom.
  • Roche Diagnostics International, Rotkreuz, Switzerland.
  • Translational and Clinical Biomarkers, Pfizer Inc. Pearl River, NY, USA.
  • GSK, Collegeville, PA, USA.
  • Bristol Myers Squibb, San Diego, CA, USA.
  • Takeda Development Center Americas, Inc. Cambridge, MA, USA.
  • Diagnostic Strategy, Medical Affairs, Madrigal Pharmaceuticals, West Conshohocken, PA, USA.
  • Duke Molecular Physiology Institute, Duke University School of Medicine, Duke University, Durham, NC, USA.

Abstract

Not all biomarkers are equal, and some should not be termed biomarkers. Despite an explosion in putative biomarker discoveries from high-throughput proteomic technologies, very few advance beyond initial excitement to become validated, clinically actionable tools. Most stall in a "biomarker valley of death," where promising signals fail to meet robust technical, scientific, and regulatory standards for clinical use. We propose a framework to distinguish between unvalidated protein findings and validated biomarkers with specific utility. We highlight the need to separate exploratory protein measurements from biomarkers that meet predefined analytical criteria and progress through validation, including qualification as Reasonably Likely Surrogate Endpoints (RLSE) or Validated Surrogate Endpoints (VSE). This expert opinion delineates differences between biomarker discovery, development, regulatory qualifications and commercialization pathways, emphasizing nomenclature according to BEST Resource (Biomarkers, EndpointS, and other Tools), analytical validation (CLSI guidelines), clinical relevance, and alignment with frameworks of the US Food and Drug Administration (FDA), specifically Premarket Approval (PMA) or Biomarker Qualification Program (BQP), and the EU's IVDR and Drug Development Tool (DDT) programs. We introduce the concept of the "Unicorn Biomarker" - an extremely rare class of biomarkers with validated multipurpose utility (diagnostic, prognostic, and pharmacodynamic/monitoring) to exemplify their value in decision-making. We propose that minimum technical and biological standards must be met before a molecular measurement can be designated a "biomarker", beyond minimal criteria of association between biological signal and disease state. By raising the bar with Unicorn Biomarkers, this framework aims to guide researchers, regulators, and industry stakeholders in identifying actionable biomarkers and advancing precision medicine.

MeSH

Liver Diseases, Research Design, Liver, Biomarkers, Proteomics, Precision Medicine, Vocabulary