“…General limitations of biomarker research include threats to validity, including chance, generalizability, bias, reproducibility, overfi tting, confounding, 7,14 analytical issues, 19 concerns regarding processing/storage, and false-positive fi ndings due to multiple hypothesis testing, as well as failure to establish incremental utility beyond existing markers 15 and other clinical tools. 16,18 Common limitations in pulmonary biomarker literature include small studies, the lack of replication cohorts, and the paucity of systemic infl ammation, including CRP, SP-D, fi brinogen, IL-6, IL-8, and TNF-a , was associated to changes in FEV 1 over time. However, this study did reveal that Clara cell protein-16 levels were signifi cantly associated with the rate of change of FEV 1 , suggesting a role as a biomarker of COPD.…”