Campaign run · Parkinson's disease
ideate-parkinson-mechanism-r2
Started as an ideation run, then planned and tested 6 hypotheses of its own, beginning with: Lysosomal-convergence score log2(LRRK2)-log2(GBA1) identifies the most PD-depleted DA subtype in Kamath 2022 SN atlas (AUROC>=0.70, CI>0.5, beats random pair).
Status
- How far it got
- Completed the pipeline
Tested at least one hypothesis and reached the multi-agent review stage. This shows the run went through the whole pipeline, not that its work passed a quality bar.
- Hypotheses
6 nominated; 6 evaluated.
- Recorded status
Done. The run recorded a final status of done.
- Census class
Success. 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
This run started from the ideation brief below, which asked for research directions rather than data analysis. It then went on to plan and test the hypotheses listed on this page.
Full research brief given to the run
Research purpose: understand the MECHANISM of Parkinson's disease (PD) — the molecular, cellular, circuit, and systems-level processes that drive dopaminergic neuron vulnerability and disease progression — and propose PROMISING FUTURE RESEARCH DIRECTIONS that are concrete enough for an autonomous computational pipeline to pursue on PUBLIC data.
Targets:
(1) Survey PD-mechanism evidence broadly: papers (single-cell/spatial atlases, genetics/GWAS, proteomics, alpha-synuclein biology, mitochondrial/lysosomal pathways, neuroinflammation, gut-brain axis), plus stated positions from leading PD researchers and relevant philosophy-of-medicine views on causation/biomarkers.
(2) Propose directions that are NOVEL relative to the campaign's existing topics — do not re-propose work already covered; find the gaps and the cross-cutting syntheses between them.
(3) For each proposed direction, identify CANDIDATE PUBLIC DATASETS (named atlases / accessions / repositories: GEO, SRA, PRIDE, Allen, PPMI-derived public tables, etc.) that the direction would use. Put dataset pointers in the direction's rationale.
This is a survey + proposal task, not a data-analysis task.
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.
| ID | Hypothesis and decision rule | Verdict |
|---|---|---|
| H1Pre-registered | Lysosomal-convergence score log2(LRRK2)-log2(GBA1) identifies the most PD-depleted DA subtype in Kamath 2022 SN atlas (AUROC>=0.70, CI>0.5, beats random pair). | Not testableIn the explorer |
Evidence (verbatim from the run outputs) H1 is INCONCLUSIVE because the Kamath 2022 SN snRNA-seq (GSE178265, approximately 400,000 nuclei) requires dbGaP controlled-access approval Adjudication note dbGaP controlled access; only descriptive surrogate (GSE184950, 4 samples), AUROC never computed. | ||
| H2Pre-registered | TFEB targets (LAMP2A, CTSD, CTSB, ATP6AP1, MCOLN1) >=4/5 down with gene-set FDR<=0.10 in BOTH GBA1-N370S and LRRK2-G2019S iPSC-DA vs isogenic controls (+synergy arm). | Not testableIn the explorer |
Evidence (verbatim from the run outputs) The primary analysis could not be executed as pre-registered because none of the five TFEB target genes appear in the NanoString NS_HS_NEUROPATH_V1.0 panel of GSE167335 Adjudication note Report/analysis label 'NOT SUPPORTED' and graph = refuted, but this rests on a post-hoc V-ATPase surrogate (8/9 up, donor-level permutation p=0.333, N=2 donors). GBA1-N370S arm blocked (no isogenic dataset); synergy arm untestable. | ||
| H3Pre-registered | TFEB-target composite correlates with alpha-syn protein (proteomics) in iPSC-DA (Spearman r>0.40, perm p<0.05) (+ pharmacological reversal arm). | Not testableIn the explorer |
Evidence (verbatim from the run outputs) H3 is BLOCKED: no matched iPSC-DA RNA-seq + lysosomal proteomics dataset with simultaneous measurement of both modalities was accessible. Adjudication note Reversal arm also untested (no treatment data). | ||
| OTF1Proposed on the fly | LRRK2-G2019S iPSC-DA neurons show compensatory upregulation of V-ATPase subunit genes (partially reversed by MLi-2). | InconclusiveIn the explorer |
Evidence (verbatim from the run outputs) this design is fundamentally underpowered for significance testing. Adjudication note 8/9 genes up, mean log2FC +0.485 (CI -0.454 to 1.471), exact donor permutation p=0.333 = minimum achievable at N=2+2. The knowledge-graph node marked supported came from the pseudo-replicated stage 3 analysis; the latest stage 8 node = inconclusive. MLi-2 reversal part never testable (no data). | ||
| OTF2Proposed on the fly | GBA1-N370S cells (exhausted compensation) show V-ATPase DOWNregulation, distinguishing two phases of lysosomal dysfunction. | Not testableIn the explorer |
Evidence (verbatim from the run outputs) The GBA1 N370S arm of H2 could not be tested: no GBA1 N370S isogenic iPSC-DA RNA-seq dataset was found in accessible GEO deposits Adjudication note None recorded. | ||
| OTF3Proposed on the fly | N=2 donors/group NanoString cannot reach significance; a properly powered test needs N>=5 donors with whole-transcriptome LRRK2-G2019S iPSC-DA data. | Not testableIn the explorer |
Evidence (verbatim from the run outputs) N ≥ 5 independent biological replicates at the donor level is necessary Adjudication note Methodological/future-data statement; no suitable dataset fetched. | ||