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Front Med (Lausanne). 2017 May 26;4:62. doi: 10.3389/fmed.2017.00062. eCollection 2017.

Defining Disease, Diagnosis, and Translational Medicine within a Homeostatic Perturbation Paradigm: The National Institutes of Health Undiagnosed Diseases Program Experience.

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NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, United States.
National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United States.
Department of Molecular and Cellular Pharmacology, University of Miami School of Medicine, Miami, FL, United States.
Appistry, Inc., St. Louis, MO, United States.
MicroSoft Research, Redmond, WA, United States.
William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
Environmental Genomics and Systems Biology, Lawrence Berkeley National Laboratory, Berkeley, CA, United States.
Palmieri Metabolic Disease Laboratory, Children's Hospital of Philadelphia, Philadelphia, PA, United States.
Department of Pathology and Laboratory of Medicine, University of Pennsylvania, Philadelphia, PA, United States.
The Jackson Laboratory for Genomic Medicine, Farmington, CT, United States.
Department of Medical Informatics and Clinical Epidemiology, Oregon Health & Science University, Portland, OR, United States.


Traditionally, the use of genomic information for personalized medical decisions relies on prior discovery and validation of genotype-phenotype associations. This approach constrains care for patients presenting with undescribed problems. The National Institutes of Health (NIH) Undiagnosed Diseases Program (UDP) hypothesized that defining disease as maladaptation to an ecological niche allows delineation of a logical framework to diagnose and evaluate such patients. Herein, we present the philosophical bases, methodologies, and processes implemented by the NIH UDP. The NIH UDP incorporated use of the Human Phenotype Ontology, developed a genomic alignment strategy cognizant of parental genotypes, pursued agnostic biochemical analyses, implemented functional validation, and established virtual villages of global experts. This systematic approach provided a foundation for the diagnostic or non-diagnostic answers provided to patients and serves as a paradigm for scalable translational research.


diploid alignment; distributed cognition; glycome; human phenotype ontology; rare disease

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