Gene‐based and pathway‐based testing for rare‐variant association in affected sib pairs
Bibliographic record
Abstract
Next generation sequencing technologies have made it possible to investigate the role of rare variants (RVs) in disease etiology. Because RVs associated with disease susceptibility tend to be enriched in families with affected individuals, study designs based on affected sib pairs (ASP) can be more powerful than case-control studies. We construct tests of RV-set association in ASPs for single genomic regions as well as for multiple regions. Single-region tests can efficiently detect a gene region harboring susceptibility variants, while multiple-region extensions are meant to capture signals dispersed across a biological pathway, potentially as a result of locus heterogeneity. Within ascertained ASPs, the test statistics contrast the frequencies of duplicate rare alleles (usually appearing on a shared haplotype) against frequencies of a single rare allele copy (appearing on a nonshared haplotype); we call these allelic parity tests. Incorporation of minor allele frequency estimates from reference populations can markedly improve test efficiency. Under various genetic penetrance models, application of the tests in simulated ASP data sets demonstrates good type I error properties as well as power gains over approaches that regress ASP rare allele counts on sharing state, especially in small samples. We discuss robustness of the allelic parity methods to the presence of genetic linkage, misspecification of reference population allele frequencies, sequencing error and de novo mutations, and population stratification. As proof of principle, we apply single- and multiple-region tests in a motivating study data set consisting of whole exome sequencing of sisters ascertained with early onset breast cancer.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.010 | 0.038 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.002 | 0.002 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.002 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".