An international team led by St. Jude Children’s Research Hospital and the Hopp Children’s Cancer Center developed M‑PACT, a methylation‑based predictive algorithm that classifies difficult pediatric brain tumors using tiny amounts of circulating tumor DNA (ctDNA) from cerebrospinal fluid (CSF). Published in Nature Cancer, M‑PACT achieved 92% identification in a 79‑sample benchmark and 88% in a 58‑sample validation set. The workflow uses low‑input enzymatic methyl sequencing (EM‑Seq), imputation to recover sparse CpG coverage, and tumor fraction deconvolution to separate malignant from nonmalignant signals. CSF offers a higher brain‑specific ctDNA signal versus blood but is more technically challenging to assay. Investigators propose M‑PACT as a tool to subtype tumors, guide treatment strategies, and accelerate trial enrollment for pediatric CNS cancers where tissue biopsies may be limited.