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

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

Figure 1

Flow diagram showing the process by which patients are accepted into and evaluated for a diagnosis within the National Institutes of Health (NIH) Undiagnosed Diseases Program (UDP). The process is divided into five major components listed along the left side. The initial component is patient selection. This is followed by patient admission to the NIH clinical research center (CRC) for phenotyping and, when appropriate, agnostic screening for disturbances of evolutionary, developmental, and biochemical homeostases. These data are then integrated computationally and through discussion to determine if there is a known medical diagnosis. Patients with a diagnosis are given disposition recommendations based on that diagnosis. For those without a diagnosis and without a candidate cause, their data are queued for iterative reanalysis, and they and their referring physician are given disposition recommendations based on what was learned. For those without a diagnosis and with a candidate cause, their data are subjected, as resources allow, to research studies to evaluate the potential causality, and they and their referring physician are given disposition recommendations based on what was learned.