Systems diagnostics: anticipating the next generation of diagnostic tests based on mechanistic insight into disease

•Diagnoses often based on phenotypic presentation, not on mechanisms driving disease.•Treatments have become highly selective, molecularly focused.•Mismatch between diagnoses and treatment creates ineffective therapies.•Mismatch imperils drug discovery and development and efficient/effective health care.•Create ‘systems diagnostics’ to define disease-driving mechanisms in patients. Societal demand for faster and more accurate assignment of treatments is based in both patient care needs and in health economics. From a patient care standpoint, there needs to be a transformation from the empiric method of therapeutic decision making to avoid unwanted side effects from inefficacious treatments. For health economics, the delay in effective therapy and expenditures for ineffective therapies add to the burden of care. To accomplish this transformation, we need to modify our current method of classifying disease from a phenotypic description to one that incorporates the different molecular drivers that created the observed phenotype. To do so, a deeper, systems-based understanding of these disease drivers is required, which will yield a new generation of diagnostic tests, or systems diagnostics.