Two-phase sample selection strategies for design and analysis in post-genome wide association fine-mapping studies
Bibliographic record
Abstract
Abstract Post-GWAS analysis, in many cases, focuses on fine-mapping targeted genetic regions discovered at GWAS-stage; that is, the aim is to pinpoint potential causal variants and susceptibility genes for complex traits and disease outcomes using next-generation sequencing (NGS) technologies. Large-scale GWAS cohorts are necessary to identify target regions given the typically modest genetic effect sizes. In this context, two-phase sampling design and analysis is a cost-reduction technique that utilizes data collected during phase 1 GWAS to select an informative subsample for phase 2 sequencing. The main goal is to make inference for genetic variants measured via NGS by efficiently combining data from phases 1 and 2. We propose two approaches for selecting a phase 2 design under a budget constraint. The first method identifies sampling fractions that select a phase 2 design yielding an asymptotic variance covariance matrix with certain optimal characteristics, e.g. smallest trace, via Lagrange multipliers (LM). The second relies on a genetic algorithm (GA) with a defined fitness function to identify exactly a phase 2 subsample. We perform comprehensive simulation studies to evaluate the empirical properties of the proposed designs for a genetic association study of a quantitative trait. We compare our methods against two ranked designs: residual-dependent sampling and a recently identified optimal design. Our findings demonstrate that the proposed designs, GA in particular, can render competitive power in combined phase 1 and 2 analysis compared to alternative designs while preserving type 1 error control. These results are especially apparent under the more practical scenario where design values need to be defined a priori and are subject to mispecification. We illustrate the proposed methods in a study of triglyceride levels in the North Finland Birth Cohort of 1966. R code to reproduce our results is available at github.com/egosv/TwoPhase_postGWAS .
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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 | 0.045 | 0.082 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.002 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.002 | 0.002 |
| Research integrity | 0.002 | 0.002 |
| Insufficient payload (model declined to judge) | 0.004 | 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".