Documentation / Cohort Analysis / Results and Interpretation

Study Results and Interpretation

A completed Study combines individual classifications with cohort-level genotype, carrier, frequency, and gene evidence. Start by confirming sample membership and QC, then move from the variant matrix to the derived gene-level views.

Results Belong to an Analysis Run

Burden, pLoF, compound-heterozygous, pathway, and candidate-gene results are tied to a Study analysis run. If sample membership or the gene scope changes, run the analysis again and interpret the current run rather than combining values from different cohort states.

Current Result Views

Actionable Findings

Pathogenic and Likely Pathogenic variants from the cohort catalog, with the samples and genotypes in which each variant occurs.

Interpretation boundary: Actionable in this view means classification-based prioritization. It does not establish phenotype fit, penetrance, or a final reportable finding.

Variant Matrix

A deduplicated variant catalog linked to sparse sample-level genotypes, cohort carrier and homozygous counts, cohort allele frequency, and classification-discordance flags.

Interpretation boundary: A cohort summary class does not replace the individual sample classification or its evidence trace.

Gene Burden

Carrier-based rare-variant aggregation by gene, compared with an expected population carrier count and accompanied by corrected statistical results and power context.

Interpretation boundary: Results are sensitive to qualifying-variant rules, population comparability, sample size, and technical batch.

Predicted Loss of Function

Gene summaries for frameshift, stop-gained, splice-donor, and splice-acceptor variants, including carriers and available constraint or clinical context.

Interpretation boundary: A predicted loss-of-function consequence is not automatically disease-causing; transcript relevance and gene mechanism require review.

Frequency Comparison

Variants ordered by the absolute difference between Study allele frequency and the available global population frequency.

Interpretation boundary: The displayed comparison is descriptive and should not be read as an ancestry-adjusted association test.

Compound Heterozygotes

Within-gene pairs observed in the same sample for genes in the Study scope.

Interpretation boundary: The pair is a candidate configuration. Phase, variant significance, gene mechanism, and phenotype fit remain separate questions.

Candidate Genes

A ranked synthesis of available Study evidence, with component evidence retained for review.

Interpretation boundary: Ranking supports triage. Exact internal weighting is proprietary and the score is not a calibrated probability of causality.

Cohort Classification Consensus

When the same variant has more than one classification across samples, the cohort catalog uses the most severe observed class in the order Pathogenic, Likely Pathogenic, Uncertain Significance, Likely Benign, and Benign. A discordance flag is stored when more than one non-null class is present.

This is a display and filtering convention, not a reclassification rule. Review the individual analyses, evidence versions, phenotype context, and any manual reclassification before resolving the difference.

Gene Burden Statistics

The current engine collapses qualifying variants into a carrier state for each gene. It reports a two-sided Fisher exact comparison against the expected population carrier count and a CMC carrier-collapsing result. With the current binary-carrier implementation, the CMC p-value is the same as the Fisher p-value.

Folklore applies Benjamini-Hochberg false-discovery-rate correction across tested genes and also reports a Bonferroni-adjusted value. The default significance flag uses an FDR threshold of 0.05. Minimum detectable odds-ratio context is provided to show when the Study is underpowered for modest effects.

SKAT-O is not currently computed or reported. A missing SKAT-O value must not be interpreted as a negative result.

Pathway Results

The interface can display pathway-enrichment results when a completed analysis run contains them. The current automated pipeline does not load pathway definitions by default, so an absent pathway section normally means that no pathway result was generated, not that every pathway tested negative.

Not Current Study Outputs

Genome-wide association study results are not generated by the current production Study pipeline.

Polygenic risk scores are not generated by the current production Study pipeline.

SKAT-O is not a current burden result.

Principal-component ancestry or batch-effect results are not part of the current production QC view.

Interpretation Checklist

Confirm that the intended samples and latest completed run are selected.

Review FAIL and OUTLIER samples before interpreting carrier or frequency values.

Check reference build, pipeline version, capture design, ancestry, relatedness, and case-control definition.

Inspect qualifying variants and individual classifications behind every gene-level signal.

Use corrected statistical values and the reported power context; do not rank genes by raw p-value alone.

Validate clinically important findings with the appropriate laboratory and clinical review process.

Clinical and Statistical Boundary

Enrichment, frequency difference, and candidate ranking identify evidence worth reviewing. They do not prove causality, exclude confounding, or establish a diagnosis. Final interpretation belongs to qualified professionals using the complete clinical and laboratory context.