TY - JOUR AU - Gall, Timothy AU - Valkanas, Elise AU - Bello, Christofer AU - Markello, Thomas AU - Adams, Christopher AU - Bone, William P. AU - Brandt, Alexander J. AU - Brazill, Jennifer M. AU - Carmichael, Lynn AU - Davids, Mariska AU - Davis, Joie AU - Diaz-Perez, Zoraida AU - Draper, David AU - Elson, Jeremy AU - Flynn, Elise D. AU - Godfrey, Rena AU - Groden, Catherine AU - Hsieh, Cheng-Kang AU - Fischer, Roxanne AU - Golas, Gretchen A. AU - Guzman, Jessica AU - Huang, Yan AU - Kane, Megan S. AU - Lee, Elizabeth AU - Li, Chong AU - Links, Amanda E. AU - Maduro, Valerie AU - Malicdan, May Christine V. AU - Malik, Fayeza S. AU - Nehrebecky, Michele AU - Park, Joun AU - Pemberton, Paul AU - Schaffer, Katherine AU - Simeonov, Dimitre AU - Sincan, Murat AU - Smedley, Damian AU - Valivullah, Zaheer AU - Wahl, Colleen AU - Washington, Nicole AU - Wolfe, Lynne A. AU - Xu, Karen AU - Zhu, Yi AU - Gahl, William A. AU - Tifft, Cynthia J. AU - Toro, Camillo AU - Adams, David R. AU - He, Miao AU - Robinson, Peter N. AU - Haendel, Melissa A. AU - Zhai, R. Grace AU - Boerkoel, Cornelius F. PY - 2017 M3 - Methods TI - Defining Disease, Diagnosis, and Translational Medicine within a Homeostatic Perturbation Paradigm: The National Institutes of Health Undiagnosed Diseases Program Experience JO - Frontiers in Medicine UR - https://www.frontiersin.org/articles/10.3389/fmed.2017.00062 VL - 4 SN - 2296-858X N2 - 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. ER -