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modkit probability threshold

Aperta
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Valutazione

Difficoltà
5/5
Tempo stimato
Più di una settimana
Idoneità per principianti
25/100
Tipo di issue
Documentazione
Chiarezza
Da chiarire
Stato di attività
Attiva
Stack tecnologico
rust
Ambito
bioinformatics

Direzione di ricerca

The issue names no source files, tests, or entry points. Start by reviewing modkit v0.6.4 pileup threshold behavior and the context described in issue #611; this would be complete when maintainers establish and document guidance for replicate thresholds and rare-modification cutoffs.

Scritto dal modello di indicizzazione a partire dal testo della issue.

Descrizione

Hi everyone,

I'm working on 5mC/5hmC methylation analysis in a plant and a fungus using modkit v0.6.4, and I'm having trouble settling on a good threshold-setting approach.
Canonical cytosines seem to benefit from a moderate threshold, but the same doesn't apply to modified bases or naturally sparse sequence contexts — especially sparser marks like fungal modifications, 5hmC or CHH methylation contexts.
Furthermore, modkit's pileup default thresholds are not generated per modification individually and can vary across replicates.

Based on issue #611, I tested finding the methylation probability at the 10th-percentile rank individually for each canonical base, type (5mC/5hmC), and context (CG, CHG, CHH), both per-sample and pooled across biological replicates:
However, the results leave me unsure:

  • For sparse modifications like fungal 5mC/5hmC specifically, the values come out around ~0.45, which feels way too low.

  • Canonical cytosines: Fungal thresholds jump to ~0.99, while plant CG canonical sits at ~0.65.

I also tested default modkit pileup per context (CG, CHG, CHH). While the thresholds slightly differ between biological replicates, the difference doesn't seem massive (the biggest difference across replicates is a max spread of around ~0.04).

This brings me to my core questions:

  • When modkit default pileup thresholds slightly differ across biological replicates (by a max spread of ~0.04), is it better to use each replicates's individual threshold and accept the minor variation, or is it better to take the mean across replicates' default threshold to establish a single, unified threshold for the group to make comparisons clean and acceptable?

  • For rare modifications (like 5hmC) and sparse contexts (like CHH), automated 10th-percentile retention drops the threshold down to ~0.45, whereas modkit's default pileup threshold sits higher (>0.7). Is it better to follow modkit's standard default pileup threshold, or should an even stricter manual floor be enforced (e.g., >0.85)?

  • Are there generally accepted threshold ranges considered strict vs. lenient — e.g., 0.7–0.8 being "moderate" and >0.85 being "strict" — when applied to rarer modifications or sparse contexts?

Right now, I am leaning toward trusting default modkit thresholds evaluated individually for each context and then applying the mean across biological replicates to make them comparable, but I am very open to other suggestions or corrections.

Any advice or guidance would be greatly appreciated!

Lingua principale
Rust
Stelle
276
Fork
33
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