Discovering the digital biomarker of hepatocellular carcinoma in serum with SERS-based biosensors and intelligence vision

By its many virtues, non-biomarker-reliant molecular detection has recently shown bright prospects for cancer screening but its clinical application is hindered by the shortage of measurable criteria that are analogous to biomarkers. Here, we report a digital biomarker, as a new-concept serum biomarker, of hepatocellular carcinoma (HCC) found with SERS-based biosensors and a deep neural network “digital retina” for visualizing and explicitly defining spectral fingerprints. We validate the discovered digital biomarker (a collection of 10 characteristic peaks in the serum SERS spectra) with unsupervised clustering of spectra from an independent sample batch comprised normal individuals and HCC cases; the validation results show clustering accuracies of 95.71% and 100.00%, respectively. Furthermore, we find that the digital biomarker of HCC shares a few common peaks with three clinically applied serum biomarkers, which means it could convey essential biomolecular information similar to these biomarkers. Accordingly, we present an intelligent method for early HCC detection that leverages the digital biomarker with similar traits as biomarkers. Employing the digital biomarker, we could accurately stratify HCC, hepatitis B, and normal populations with linear classifiers, exhibiting accuracies over 92% and area under the receiver operating curve values above 0.93. It is anticipated that this non-biomarker-reliant molecular detection method will facilitate mass cancer screening.