Inference of gene-environment interaction from heterogeneous case-parent trios
Bibliographic record
Abstract
Introduction: In genetic epidemiology, log-linear models of population risk may be used to study the effect of genotypes and exposures on the relative risk of a disease. Such models may also include gene-environment interaction terms that allow the genotypes to modify the effect of the exposure, or equivalently, the exposure to modify the effect of genotypes on the relative risk. When a measured test locus is in linkage disequilibrium with an unmeasured causal locus, exposure-related genetic structure in the population can lead to spurious gene-environment interaction; that is, to apparent gene-environment interaction at the test locus in the absence of true gene-environment interaction at the causal locus. Exposure-related genetic structure occurs when the distributions of exposures and of haplotypes at the test and causal locus both differ across population strata. A case-parent trio design can protect inference of genetic main effects from confounding bias due to genetic structure in the population. Unfortunately, when the genetic structure is exposure-related, the protection against confounding bias for the genetic main effect does not extend to the gene-environment interaction term. Methods: We show that current methods to reduce the bias in estimated gene-environment interactions from case-parent trio data can only account for simple population structure involving two strata. To fill this gap, we propose to directly accommodate multiple population strata by adjusting for genetic principal components (PCs). Results and Discussion: Through simulations, we show that our PC adjustment maintains the nominal type-1 error rate and has nearly identical power to detect gene-environment interaction as an oracle approach based directly on population strata. We also apply the PC-adjustment approach to data from a study of genetic modifiers of cleft palate comprised primarily of case-parent trios of European and East Asian ancestry. Consistent with earlier analyses, our results suggest that the gene-environment interaction signal in these data is due to the self-reported European trios.
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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 | 0.070 | 0.141 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.003 |
| Bibliometrics | 0.002 | 0.002 |
| Science and technology studies | 0.001 | 0.002 |
| Scholarly communication | 0.002 | 0.001 |
| Open science | 0.002 | 0.002 |
| Research integrity | 0.002 | 0.002 |
| Insufficient payload (model declined to judge) | 0.005 | 0.001 |
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".