The sequencing of the human genome and the subsequent availability of inexpensive, robust methods for "omics" profiling (e.g., genome-wide association studies, gene expression microarrays, and metabolomics) have led to optimism of a new era of biomarkers that would allow for a "precision medicine" approach to critical care. Unfortunately, this promise has yielded few tangible results, as the general biomedical reproducibility crisis (1–3) is particularly troublesome in critical care (4–8) and in omics biomarker studies (9–11). There are two broad problems that lead to seemingly similar studies of biomarkers in critical care producing different results. One problem is traditional nonreproducibility due to false positive biomarker selection or nonrobust statistical models. The other, more importantly, is a lack of generalizability in moving from a narrow study population into broader applications in critical care. We present here a contextual framework for addressing these problems and for assessing new biomarker studies.

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