Rank rare-disease variants for review
Which methods recover causal variants and genes within a realistic laboratory review budget?
Evidence collection plan
Collection plannedEvidence collection is planned for this question. The plan defines a comparison to investigate; it does not establish model performance or suitability.
Comparison question
Does adding a molecular-effect model to phenotype-, pedigree- and frequency-aware analysis improve causal-finding recovery at the same analyst review budget?
Baselines to include
- Conventional filtering and phenotype/pedigree-aware review with pinned versions
- An appropriate pinned Exomiser configuration without the added model
Outcomes to measure
- Case-level recovery of independently adjudicated causal findings within the review budget
- Analyst effort, missed variant classes, unresolved cases and abstention
- Confirmed diagnoses measured separately from ranked candidates
Validation requirements
- Separate families, centres and evaluation time periods.
- Freeze knowledge releases and model training cutoffs; audit predictor-derived labels.
- Retain unresolved cases in workload and coverage denominators.
- Record calling failures separately and include them in end-to-end sensitivity.
- Use independent qualified clinical-genetics adjudication for diagnostic claims.
Next collection task
Build a case-level evidence table separating solved-case ranking, unselected diagnostic evaluation and molecular-effect proxies, with exact versions and same-input comparators.
Your decision and inputs
Choose methods for prioritising variants in an initial exome or genome analysis, using phenotype, pedigree and molecular evidence to focus laboratory review.
- Who this is for
- Diagnostic scientists; Clinical genomicists evaluating interpretation workflows
- Context
- Clinical research
- Inputs
- Quality-controlled variant calls, genome build and calling coverage
- Phenotype terms, pedigree, inheritance and available family sequencing
- Dated population-frequency and gene–disease evidence
- Expected output
- A ranked candidate list with supporting evidence, conflicts, filter reasons and unresolved findings for professional review.
- Biological setting
- Initial ES/GS interpretation in a defined congenital-anomaly or developmental-disorder population. Singleton and family-based analysis require separate comparisons.
Outside this use case
- Variant ranking alone does not establish pathogenicity or a patient diagnosis.
- Balanced pathogenic/benign variant classification does not measure case-level diagnostic performance.
- Reanalysis, cancer-risk estimation and treatment selection are separate questions.
What this establishes for clinical research
Clinical research on interpretation support. Confirmed diagnoses and downstream management outcomes require separate evaluation from candidate retrieval.
Which evaluations inform this question?
No model comparison has been collected for this question yet.
Relevant methods and studies may exist outside this collection.
What evidence is still missing?
- Case-level comparisons using identical inputs and a fixed review budget remain to be collected.
- Independent qualified clinical-genetics adjudication, unresolved cases and variant-calling failures are needed to assess clinical performance.
- Published validation summaries do not establish access to reusable patient-level cohorts.
Sources and review
Automated source review · 2026-09-28 · Codex
Automated review of Rewire's workflow definition and sourced research brief against the agreed exploration and backlog. No human expert approval, model-applicability assessment or clinical validation is claimed.
- Rewire clinical use-case priorities: workflow definitions and evidence plans · Original source ↗
C1 — Rare-disease candidate ranking
Release provenance and downloads
Release 2026-09-28-c7b5ac6d34f2
Use-case input digest a0dd27a5f430ec387d309fd6e8615083250873ce4cff5e882c6fb8458ef80e95
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Question use-case-rare-disease-candidate-ranking. Any numerical results on this page come from this release's existing evaluation records.