Campaign run · Parkinson's disease

parkinson-prs-portability-r1

PDPlanned, no test completedAttempt 1 of 3 at this topic

When a polygenic risk score (PRS) is built from the Kim 2024 multi-ancestry PD GWAS (GCST90275127) via LDpred-funct on a 1000-Genomes LD reference, does its expected liability-scale R² in 1000 Genomes individuals stratified by Saffie-Awad-2025- style super-population ancestry-clusters (EUR, EAS, AMR, AFR, AJ) match the Saffie-Awad-2025-reported AUC values within ±0.05 per ancestry — purely using public sumstats + 1000 Genomes individual genotypes (no UK Biobank, no GP2 individual access)?

Not tested (run did not execute) 5

This run in the hypothesis explorer

Status

How far it got: Planned, no test completed
Wrote pre-registered hypotheses with decision rules, but no hypothesis test was completed. Its hypotheses are listed as not tested (run did not execute).
Hypotheses: 5 nominated; 0 evaluated; 5 not tested because the run did not execute them.
Recorded status: Halted. The run recorded a final status of halted: it was closed without being marked done. A halted run can still have tested hypotheses and written a final report.
Census class: Partial. Census class is a label from an earlier, process-level census of the campaign. It does not map one-to-one onto the stages above. How the classes compare.

Research question

The sentence under the run id is quoted from this brief.

Full research brief given to the run

Saffie-Awad 2025 trained 105 PRSs across 7 ancestries on GP2 R9 individual data and reported AUC by ancestry (EUR 0.621, EAS 0.578, AAC 0.591, AJ 0.67, AFR 0.583, AMR 0.639, CAS 0.612). Reproducing those AUCs requires GP2 access. This proposal asks the methodological question: how close can a summary-statistics-only + 1000-Genomes-only re-implementation get? The answer is itself an informative methodological contribution about what portability benchmarks are possible without IRB-gated cohort access.

Hypotheses (pre-registered):

H1 (primary — EUR portability matches Saffie-Awad): PRS liability-scale R² in 1000 Genomes EUR individuals (CEU+GBR+FIN+IBS+TSI, n ≈ 503) is within ±0.05 of the liability-R² corresponding to Saffie-Awad 2025's Model 2 EUR AUC of 0.621 (translated via Lee 2012 formula given EUR PD prevalence 0.3%).

H2 (secondary — ancestry-decay ratio): Ratio of AUC(EAS) / AUC(EUR) is within ±0.1 of the Saffie-Awad-reported 0.578 / 0.621 = 0.93. (Ancestry-decay must reproduce roughly, not exactly.)

H3 (secondary — protein-MR PRS overlay): Adding the Storm 2025 protein-MR pQTL-instrumented gene-set as a fixed-effect overlay (PROteinMR-PRS) increases EUR liability-scale R² by ΔR² ≥ 0.01 vs. SNP-only PRS. Methodological test of whether protein-MR adds incremental information.

H4 (secondary — multi-ancestry GWAS does not hurt EUR): The Nalls 2019 EUR-only PRS (GCST009325) does NOT significantly outperform the Kim 2024 multi-ancestry PRS in the EUR 1000 Genomes stratum (DeLong p > 0.1). Tests the field concern that multi-ancestry GWAS hurts EUR-stratum performance.

H5 (secondary — bootstrap CI honesty): Per-ancestry bootstrap 95% CI is reported alongside point estimates. For ancestries with n < 200 in 1000 Genomes (e.g., AMR sub-populations), CI width > 0.15 is the expected outcome; this must be reported in analysis summary and negative_results.md, not buried.

Null payoff. If LD-mismatch and small 1000 Genomes per-ancestry sample sizes inflate error bars beyond ±0.05 (H1), the Wang & Visscher 2024 concern about summary-only PRS portability benchmarking is confirmed, and the run would put a quantitative number on it. Either outcome is informative.

The research question comes from the topic's current research brief. All attempts at a topic share it; earlier attempts may have started from an earlier wording.

Hypotheses and verdicts

Each hypothesis was written with its decision rule before any analysis (or, for on-the-fly hypotheses, recorded during execution). AI adjudication agents applied that rule to the run's latest outputs and quoted the evidence verbatim. Where the data did not meet the rule, the verdict follows the data, even if the run's own label or report claimed support.

Each hypothesis as pre-registered (a condensed statement with its decision rule), the adjudicated verdict, the verbatim evidence and the adjudicator's note.
ID	Hypothesis and decision rule	Verdict
H1Pre-registered	EUR 1000G LDpred-funct PRS liability-R2 within ±0.05 of Saffie-Awad 2025 EUR benchmark (AUC 0.621), bootstrap equivalence test	Not runIn the explorer
H2Pre-registered	EAS/EUR ancestry-decay ratio within ±0.10 of Saffie-Awad ratio 0.931	Not runIn the explorer
H3Pre-registered	Storm 2025 protein-MR overlay adds ΔR2 >= 0.01 in EUR	Not runIn the explorer
H4Pre-registered	Kim 2024 multi-ancestry PRS not worse than Nalls 2019 EUR-only PRS in EUR (DeLong p>0.10, Kim>=Nalls)	Not runIn the explorer
H5Pre-registered	Bootstrap AUC-equivalent CI width >0.15 for at least one sub-population with n<200	Not runIn the explorer