Morris JS, Hassan MM, Zohner YE, et al. - This study offers a novel procedure for developing risk scores from circulating biomarkers that give a global biological description of an individual patient’s disease. Researchers prospectively collected plasma samples from 767 hepatocellular carcinoma (HCC) patients and 200 controls. They assessed 317 proteins in a CLIA‐certified biomarker testing laboratory. For each patient, a score between 0 and 1 was developed measuring the degree of aberration of their biomarker panel relative to normal, a circulating biomarker aberration score, referred to as the HepatoScore. Log‐rank tests were used to evaluate its ability to sub‐stratify patients within existing staging systems and prognostic factors. A single‐sample score was developed, HepatoScore‐14, which needed only a subset of 14 representative proteins encompassing the global biological effects. HepatoScore was able to sub‐stratify patients accurately within levels of existing prognostic factors and staging systems. Data revealed that HepatoScore‐14 enhances current HCC staging systems, considerably refining patient assessments of prognosis and therapeutic decision making and clinical trial enrollment. The underlying strategy can be used widely to other disease settings and biological media, offering a global biological characterization of disease.