Abstract There is a pressing and strong unmet need to develop noninvasive biomarkers of advancing fibrosis and disease severity in pediatric liver disease. This is particularly important for cholestatic disorders like biliary atresia, where the pace of development of fibrosis is remarkable. Current measures are able with varying degrees of precision to distinguish advanced fibrosis/cirrhosis from minimal to no fibrosis. Unfortunately, they are not able to differentiate intermediate stages of fibrosis, nor are they reproducible enough for use as endpoints in the evaluation of investigation products on liver disease progression. The field of noninvasive testing of hepatic disease, which is complex and unresolved in the liver disease of adults, is especially difficult in pediatrics. Given the invasive nature of liver biopsy most studies of biomarkers in pediatrics cannot be securely associated with histologic measures of fibrosis. The patterns of fibrosis in pediatric liver disease are distinct from diseases in adults. Preliminary analysis of the baseline FibroScan in Pediatric Cholestatic Liver Disease (FORCE -NCT 02922751) study performed by ChiLDReN supports the concept that fibrosis is distinct in biliary atresia, α-1 antitrypsin deficiency and Alagille syndrome. A paradigm shift in the development of noninvasive markers of pediatric liver disease is warranted. The shift should include unbiased nontargeted approaches to the identification of biomarkers and innovative correlation with reproducible parameters of liver disease progression. The current proposal seeks to leverage the discovery features of the protein-capture slow off-rate modified aptamer reagents that are part of SOMAscan assay developed by SomaLogic in the context of the FORCE study. Plasma samples from 255 FORCE participants will be analyzed using the SOMAscan. Robust analytical techniques will be used to assess the correlation of individual and combinations of plasma proteins with clinical characteristics, laboratory parameters and biomarker indices. This analysis will lead to the identification of a unique set of proteins that associate with features of advancing liver disease, like liver stiffness, platelet count, albumin and growth parameters. These findings have a very high probability of accelerating fundamental advances in our noninvasive assessment and understanding of pediatric cholestatic liver disease.