fragmentomics-domain

name	fragmentomics-domain
description	cfDNA fragmentomics biology — what each feature measures and how to interpret it for ctDNA detection.

cfDNA Fragmentomics Domain Knowledge

When to use this skill

• Implementing a new feature evaluator
• Interpreting evaluation results
• Writing documentation or exploration cells

Biology Background

Cell-free DNA (cfDNA) in plasma is released during cell death. Cancer cells contribute "circulating tumor DNA" (ctDNA) with distinct fragmentation patterns:

1. Shorter fragments — ctDNA tends to be shorter than normal cfDNA
2. Altered nucleosome positioning — different WPS patterns at regulatory regions
3. Epigenetic signatures — methylation and chromatin states from tissue of origin
4. End motif preferences — DNA cleavage enzymes leave characteristic motifs

Feature Interpretation

Feature	What it measures	Direction in ctDNA+
FSC core_short_ratio	Fraction of 120-150bp fragments	↑ increased
FSR short_long_ratio	Short / Long fragment ratio	↑ increased
MDS score	Global methylation from fragment ends	Variable
OCF z-score	Tissue-of-origin signal strength	↑ if tissue contributing
ATAC z-score	Chromatin accessibility deviation from normal	↑ or ↓ depending on mark
WPS periodicity_score	Regularity of nucleosome spacing	↓ disrupted
EndMotif entropy	Diversity of end motifs	Changed

Confounders

• Sequencing depth (total_fragments) — many features are depth-dependent
• GC bias — addressed by GC correction in FSC.ontarget vs FSC (uncorrected)
• Panel design — XS1 vs XS2 have different target regions and probe designs