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Tumor-derived circulating cell-free DNA (cfDNA) provides critical clues for cancer early diagnosis, yet it often suffers from low sensitivity. Here, we present a cancer early diagnosis approach using tumor fractions deciphered from circulating cfDNA methylation signatures. We show that the estimated fractions of tumor-derived cfDNA from cancer patients increase significantly as cancer progresses in two independent datasets. Employing the predicted tumor fractions, we establish a Bayesian diagnostic model in which training samples are only derived from late-stage patients and healthy individuals. When validated on early-stage patients and healthy individuals, this model exhibits a sensitivity of 86.1% for cancer early detection and an average accuracy of 76.9% for tumor localization at a specificity of 94.7%. By highlighting the potential of tumor fractions on cancer early diagnosis, our approach can be further applied to cancer screening and tumor progression monitoring., (© 2022. The Author(s).)

Congenital heart defects constitute the most common human birth defect, however understanding of how these disorders originate is limited by our ability to model the human heart accurately in vitro. Here we report a method to generate developmentally relevant human heart organoids by self-assembly using human pluripotent stem cells. Our procedure is fully defined, efficient, reproducible, and compatible with high-content approaches. Organoids are generated through a three-step Wnt signaling modulation strategy using chemical inhibitors and growth factors. Heart organoids are comparable to age-matched human fetal cardiac tissues at the transcriptomic, structural, and cellular level. They develop sophisticated internal chambers with well-organized multi-lineage cardiac cell types, recapitulate heart field formation and atrioventricular specification, develop a complex vasculature, and exhibit robust functional activity. We also show that our organoid platform can recreate complex metabolic disorders associated with congenital heart defects, as demonstrated by an in vitro model of pregestational diabetes-induced congenital heart defects., (© 2021. The Author(s).)