Use caseDNA and genomesResearch and clinical research

Select a patient-RNA splicing-variant validation workflow

Which DNA/RNA evidence workflow identifies splice-altering variants for inherited-disorder follow-up when patient RNA and tissue-specific context are available?

In this release 1 evaluated endpoint · 1 tested configuration · Direct evidence for the stated endpoint · 3 recorded evidence gaps

Question and applicability

Inspect the FRASER known pathogenic-event recovery curve and the sequence-classification proxy evidence before selecting a workflow and designing patient-RNA follow-up for the intended cohort size.

Who this is for: Clinical researchers scoping the available diagnostic-genomics evidence
Computational researchers comparing exact evaluated configurations
Research setting: Research and clinical research. See Clinical research scope for what the evidence does not establish.
Biological setting: FRASER, applied to a retrospective Kremer rare-mitochondrial-disorder skin-fibroblast RNA cohort (119 samples/105 individuals, 13 known pathogenic splicing events), recovers a mean 85% (11 of 13) of known events at a reduced 30-sample subsample. A separate, proxy sequence-classification AUC for DNA foundation-model embeddings (Feng et al. 2025, Table 1 Acceptor/Donor) is also linked, scoped as a different endpoint.

Outside this use case

Diagnostic yield in patients without a known pathogenic event (this is recovery of already-known events, not discovery)
Full-cohort outlier-gene workload counts (12/7/10 genes/sample), a different population from the 30-sample recovery evaluation and not ingested here
Blinded pathogenicity adjudication or VUS reclassification

Inputs and expected output

Inputs you need

Patient skin-fibroblast (or matched tissue) RNA-seq aligned reads
The number of samples available for a FRASER-style aberrant-splicing cohort

Expected output

A sourced recovery curve (fraction of known pathogenic splicing events recovered as cohort size grows) and a separate sequence-classification proxy; no diagnostic-yield claim for unknown cases.

Clinical research scope

Clinical applicability is not established beyond known-event recovery. This does not demonstrate prospective diagnostic yield, blinded adjudication, or general tissue transfer.

Evaluated evidence

Evidence is grouped by its protocol. Relevance refers to the stated endpoint and context; it is separate from clinical validation and from the review method. Limits specific to each evaluation are listed with it.

FRASER Kremer cohort known pathogenic-event subsampling

Current source-reviewed mapping

Direct evidence for the stated endpoint

Direct patient-RNA evidence measuring recovery of known pathogenic splicing events bears on the declared decision, scoped narrowly to known-event recovery rather than diagnostic yield in unknown cases.

Assessed endpoint

Mean recovery of 13 known pathogenic splicing events at reduced cohort size (30 of 119 patient RNA samples) using FRASER on patient skin-fibroblast RNA

Evaluation protocol

FRASER Kremer cohort known pathogenic-event subsampling

Computational task

A reviewed task relationship is not recorded for this protocol.

Input and population constraints

Inspect every linked evaluation's source locator and preserved conflicts before citing a result.
Do not combine this mapping's evaluations with any other protocol's results.

Limits on interpretation

Direct patient-RNA known-event recovery does not establish prospective diagnostic accuracy or patient outcome benefit.
Known pathogenic-event ascertainment and same-cohort retrospective selection can bias recovery.
30 is RNA sample subset size; do not silently equate to 30 independent patients.
No blinded pathogenicity adjudication, general tissue transfer, VUS reclassification sensitivity or transcriptome-wide precision established by this endpoint.
Subsampling repeats, exact score aggregation and numeric uncertainty unavailable from inspected main-text endpoint; supplementary PDF DNS retrieval failed.
FRASER author correction 2022 changes GTEx version V7 to V6p; patient-Kremer endpoint not affected according to correction search result; exact correction bytes not retrieved.

Automated source review · 2026-10-07 · Claude Sonnet AMP-integration worker, bounded transcription of Codex-checked primary values; independently reviewed by Codex (workbench/amp-supervision/primary-review.md, integration-review-corrections.md)

Bounded primary-source transcription, independently Codex-checked. No new model execution, independent experimental reproduction, qualified human scientific review or clinical validation.

Evaluated configurations

Each configuration below belongs to this protocol. Inspect its inputs, population and scoring conditions before comparing it with another evaluation.

FRASER (2021 article implementation)

Author-reported evaluation · Source checked

FRASER (2021 article implementation) evaluation; bounded primary-source AMP candidate.

Inspect results, conditions and reproduction (2 recorded results)

Population and split: 13 known events within 119 samples/105 individuals · retrospective sample-size subsampling
Inputs and adaptation: patient skin-fibroblast RNA aligned BAM · Not reported
Evaluation budget: Not reported
Runtime and memory: Runtime and memory measurements are not reported in this evaluation. A study budget is not a runtime or memory measurement.

Recorded results for this configuration
Metric	Value	Coverage	Uncertainty and source
mean known pathogenic splicing-event recovery at 30 samples	85% % · higher	Not reported scored / Not reported eligible	Not reported Result provenance Detection of aberrant splicing events in RNA-seq data using FRASER · Original source ↗`Results subsection rare disease cohort, paragraph Par18; Supplementary Fig. S20 referenced`
mean recovered known pathogenic events at 30 samples	11 events · higher	Not reported scored / Not reported eligible	Not reported Result provenance Detection of aberrant splicing events in RNA-seq data using FRASER · Original source ↗`Results Par18; Supplementary Fig. S20 referenced`

Evaluation methods, evidence and reproduction

No execution recipe has been verified for this exact configuration and evaluation. Inspect its methods and original run documentation before attempting reproduction.

Open the protocol's results and comparison checks →

Mapping sources and review metadata

Detection of aberrant splicing events in RNA-seq data using FRASER · Original source ↗See clinical/claims.csv and clinical/sources.md in data/omics/use-case-coverage-amp-20261007/

Mapping use-case-mapping-amp-20261007-issue12-fraser-kremer · revision 1

Add Codex-checked primary-source protocol evidence from the bounded AMP intake (rewire.it#365).

Reviewed evidence fingerprint bf9ed2b271943fe5d0a2622184d310ada3400f2318ed1728280fda8feaffa630

Limitations and missing evidence

These gaps apply to the question as a whole. Absence of evidence is not a zero score.

No numeric confidence interval is reported for the 85% recovery figure in the inspected main text.
Subsampling repeat count and exact score-aggregation method are unextracted.
The sequence-classification proxy mapping (Feng Table 1) measures AUC on a different population (DNABERT-2/NT benchmark splice-site datasets), not minigene reporter exon inclusion or patient RNA, and must not be pooled with the FRASER recovery figure.

Planned work

These plans do not contribute measured results or evaluated winners above.

Focused benchmark/run task for rewire-benchmark-data issue #12 ↗

Planned · Reviewed literature evidence is bounded (see evidence_gaps); closing the remaining decision gap needs a dedicated protocol/run task with frozen population and matched controls, tracked in rewire-benchmarks.

Contribute evidence or propose a correction

Evidence collection plan

Collecting evidence

Mapped evidence already covers 1 evaluated endpoint, in the evaluated evidence above. The status above describes only the specific comparison in this plan, which remains open; it does not mean no evidence has been collected. The plan defines a comparison to investigate; it does not establish model performance or suitability.

Comparison question

Which DNA/RNA evidence workflow identifies splice-altering variants for inherited-disorder follow-up when patient RNA and tissue-specific context are available?

Baselines, outcomes and validation requirements

Baselines to include

The conventional/author-introduced workflow measured in the linked primary source(s).

Outcomes to measure

The declared endpoint in this use case's active mapping(s); see evidence_gaps for what remains open.

Validation requirements

Independent held-out population matched to the intended clinical setting.
Qualified human scientific review before any clinical-validation claim.

Next collection task

A dedicated rewire-benchmarks protocol/run task with a prospective, blinded patient-RNA cohort including cases without a pre-known pathogenic event.

Sources and review

Bounded primary-source transcription, independently Codex-checked. No new model execution, independent experimental reproduction, qualified human scientific review or clinical validation.

Detection of aberrant splicing events in RNA-seq data using FRASER · Original source ↗See data/omics/use-case-coverage-amp-20261007/clinical/sources.md

Release provenance and downloads

Release 2026-10-07-1448159e6a81

Use-case input digest d60fd7f669bfec7bd34ec6e5080d8e1cb4e8186f8286ead60888848f1e20e001

Download questions, collection plans and review metadata (JSON) · Verify release checksums

Question use-case-patient-rna-splicing-validation. Any numerical results on this page come from this release's existing evaluation records.