rewire.itbenchmarks

Use caseDNA and genomesResearch and clinical research

Rank rare-disease variants for review

Which methods recover causal variants and genes within a realistic laboratory review budget?

In this release 0 evaluated endpoints · 0 tested configurations · No current evaluated evidence · 3 recorded evidence gaps

Evidence collection plan

Collection planned

Evidence 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.

Question and applicability

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
Research setting

Research and clinical research. See Clinical research scope for what the evidence does not establish.

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.

Inputs and expected output

Inputs you need

  • 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.

Clinical research scope

Clinical research on interpretation support. Confirmed diagnoses and downstream management outcomes require separate evaluation from candidate retrieval.

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.

No model comparison has been collected for this question yet.

Relevant methods and studies may exist outside this collection.

View the evidence plan and next collection task

Limitations and missing evidence

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

  • 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.

Contribute evidence or propose a correction

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.

Release provenance and downloads

Release 2026-09-29-06401fd5b220

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.