Frontiers in Medicine (May 2017)
Defining Disease, Diagnosis, and Translational Medicine within a Homeostatic Perturbation Paradigm: The National Institutes of Health Undiagnosed Diseases Program Experience
- Timothy Gall,
- Timothy Gall,
- Elise Valkanas,
- Christofer Bello,
- Thomas Markello,
- Christopher Adams,
- William P. Bone,
- Alexander J. Brandt,
- Jennifer M. Brazill,
- Lynn Carmichael,
- Mariska Davids,
- Joie Davis,
- Zoraida Diaz-Perez,
- David Draper,
- David Draper,
- Jeremy Elson,
- Elise D. Flynn,
- Rena Godfrey,
- Catherine Groden,
- Cheng-Kang Hsieh,
- Roxanne Fischer,
- Gretchen A. Golas,
- Jessica Guzman,
- Yan Huang,
- Megan S. Kane,
- Elizabeth Lee,
- Chong Li,
- Amanda E. Links,
- Valerie Maduro,
- May Christine V. Malicdan,
- Fayeza S. Malik,
- Michele Nehrebecky,
- Joun Park,
- Paul Pemberton,
- Katherine Schaffer,
- Dimitre Simeonov,
- Murat Sincan,
- Damian Smedley,
- Zaheer Valivullah,
- Colleen Wahl,
- Nicole Washington,
- Lynne A. Wolfe,
- Lynne A. Wolfe,
- Karen Xu,
- Yi Zhu,
- William A. Gahl,
- William A. Gahl,
- Cynthia J. Tifft,
- Cynthia J. Tifft,
- Camillo Toro,
- David R. Adams,
- David R. Adams,
- Miao He,
- Miao He,
- Peter N. Robinson,
- Melissa A. Haendel,
- R. Grace Zhai,
- Cornelius F. Boerkoel
Affiliations
- Timothy Gall
- NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, United States
- Timothy Gall
- National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United States
- Elise Valkanas
- NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, United States
- Christofer Bello
- Department of Molecular and Cellular Pharmacology, University of Miami School of Medicine, Miami, FL, United States
- Thomas Markello
- NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, United States
- Christopher Adams
- NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, United States
- William P. Bone
- NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, United States
- Alexander J. Brandt
- NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, United States
- Jennifer M. Brazill
- Department of Molecular and Cellular Pharmacology, University of Miami School of Medicine, Miami, FL, United States
- Lynn Carmichael
- Appistry, Inc., St. Louis, MO, United States
- Mariska Davids
- NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, United States
- Joie Davis
- NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, United States
- Zoraida Diaz-Perez
- Department of Molecular and Cellular Pharmacology, University of Miami School of Medicine, Miami, FL, United States
- David Draper
- NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, United States
- David Draper
- National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United States
- Jeremy Elson
- MicroSoft Research, Redmond, WA, United States
- Elise D. Flynn
- NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, United States
- Rena Godfrey
- NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, United States
- Catherine Groden
- NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, United States
- Cheng-Kang Hsieh
- MicroSoft Research, Redmond, WA, United States
- Roxanne Fischer
- National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United States
- Gretchen A. Golas
- NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, United States
- Jessica Guzman
- NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, United States
- Yan Huang
- NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, United States
- Megan S. Kane
- NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, United States
- Elizabeth Lee
- NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, United States
- Chong Li
- Department of Molecular and Cellular Pharmacology, University of Miami School of Medicine, Miami, FL, United States
- Amanda E. Links
- NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, United States
- Valerie Maduro
- NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, United States
- May Christine V. Malicdan
- NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, United States
- Fayeza S. Malik
- Department of Molecular and Cellular Pharmacology, University of Miami School of Medicine, Miami, FL, United States
- Michele Nehrebecky
- NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, United States
- Joun Park
- Department of Molecular and Cellular Pharmacology, University of Miami School of Medicine, Miami, FL, United States
- Paul Pemberton
- NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, United States
- Katherine Schaffer
- NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, United States
- Dimitre Simeonov
- NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, United States
- Murat Sincan
- NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, United States
- Damian Smedley
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
- Zaheer Valivullah
- NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, United States
- Colleen Wahl
- NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, United States
- Nicole Washington
- Environmental Genomics and Systems Biology, Lawrence Berkeley National Laboratory, Berkeley, CA, United States
- Lynne A. Wolfe
- NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, United States
- Lynne A. Wolfe
- National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United States
- Karen Xu
- NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, United States
- Yi Zhu
- Department of Molecular and Cellular Pharmacology, University of Miami School of Medicine, Miami, FL, United States
- William A. Gahl
- NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, United States
- William A. Gahl
- National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United States
- Cynthia J. Tifft
- NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, United States
- Cynthia J. Tifft
- National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United States
- Camillo Toro
- NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, United States
- David R. Adams
- NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, United States
- David R. Adams
- National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United States
- Miao He
- Palmieri Metabolic Disease Laboratory, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
- Miao He
- Department of Pathology and Laboratory of Medicine, University of Pennsylvania, Philadelphia, PA, United States
- Peter N. Robinson
- 0The Jackson Laboratory for Genomic Medicine, Farmington, CT, United States
- Melissa A. Haendel
- 1Department of Medical Informatics and Clinical Epidemiology, Oregon Health & Science University, Portland, OR, United States
- R. Grace Zhai
- Department of Molecular and Cellular Pharmacology, University of Miami School of Medicine, Miami, FL, United States
- Cornelius F. Boerkoel
- NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, United States
- DOI
- https://doi.org/10.3389/fmed.2017.00062
- Journal volume & issue
-
Vol. 4
Abstract
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.
Keywords
