OmiCairn

Campaign run · Parkinson's disease

parkinson-da-vulnerability-r3

PDStopped before planningAttempt 3 of 5 at this topic

This OmiCairn run formally tests whether the AGTR1+ vulnerable DA subtype is recoverable, and whether it shows the same PD-specific depletion + TP53/NR2F2 upregulation …

Status

How far it got
Stopped before planning

Stopped before writing any hypotheses: a dry-run test, a launch superseded by an immediate relaunch, a usage limit or a process failure.

Why it stopped

This run stopped before the planning stage for an operational reason, not a scientific one. Runs in this group are dry-run tests, launches superseded by an immediate relaunch, runs that hit a usage limit, or one process failure. The released data do not say which of these applies to an individual run. No run in the campaign stopped before planning because data were unavailable.

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

Early stop. 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

Kamath, Macosko et al. (Nat Neurosci 25:588, 2022; DOI 10.1038/s41593-022-01061-1) reported that a single AGTR1+ ventral-tier substantia-nigra pars compacta (SNpc) dopaminergic (DA) neuronal subtype is selectively lost in Parkinson's disease (PD), and that residual AGTR1+ DA cells upregulate TP53 and NR2F2 target programs. The finding was derived from 10 PD/LBD + 8 control donors (387,483 nuclei; 22,048 DA-restricted nuclei) and spatially anchored by Slide-seqV2 to the ventral tier of SNpc. It is the most-cited cellular finding in PD single-cell biology, but has never been formally replicated against three subsequent independent SNpc snRNA-seq atlases under a single re-analysis pipeline.

This OmiCairn run formally tests whether the AGTR1+ vulnerable DA subtype is recoverable, and whether it shows the same PD-specific depletion + TP53/NR2F2 upregulation, in:

  • Wang et al. (Sci Adv 10:eadi8287, 2024; GEO GSE184950) — 23 idiopathic PD + 9 control / 315,867 SNpc nuclei.
  • Adams L., Song M.K. et al. (Nat Aging 4:364, 2024; GEO GSE193688 + dbGaP phs002819.v1.p1) — 9 young + 8 aged + 14 PD / 69,289 SN nuclei, 10x Multiome.
  • Fullard / N M et al. (Sci Data 11:1274, 2024; CELLxGENE collection d5d0df8f-4eee-49d8-a221-a288f50a1590) — 100 donors (75 PD + 25 ctrl), 2,096,155 nuclei across 5 regions; this proposal uses the SNpc slab only.
  • Martirosyan et al. (Mol Neurodegen 19:7, 2024; GEO GSE243639) — 15 PD + 14 ctrl / ~84,000 SNpc nuclei; held out for blind external validation in H3.

Hypotheses (pre-registered):

H1 (primary — vulnerable-subtype depletion replicates): The Kamath AGTR1+ DA subtype (defined by the published Kamath top-30 marker panel — AGTR1, SLC6A3, TH, KCNJ6, etc.; full list lifted from GSE178265 supplementary table) recovers as a contiguous cluster in each of Wang (A3), Adams (A4), and Fullard SNpc (A8) atlases at our chosen clustering resolution. The log-fold-change of (AGTR1+ DA cells / total DA cells) PD vs. matched-age control is negative (depletion) in all 3 replication atlases, with FDR < 0.05 (Benjamini–Hochberg). Effect-size requirement: the magnitude of depletion is within ±50% of the Kamath reference (≈3-fold loss → our log2FC ∈ [-2.6, -0.95]).

H2 (secondary — TP53 / NR2F2 program upregulation): Within retained AGTR1+ DA cells, the TP53 target module and NR2F2 target module (lifted directly from Hallmark TP53 signaling + the Kamath-cited NR2F2 ChIP-seq targets) show positive PD-vs-control fold-change at FDR < 0.05 in ≥ 2 of 3 replication atlases.

H3 (secondary — blind-replication out-of-cohort): A "consensus AGTR1+ marker panel" (intersection of the marker-gene sets across Kamath + Wang + Adams + Fullard SNpc, re-derived from our own DE analysis) scored as a per-donor pseudobulk signature stratifies the Martirosyan A5 PD vs. control donors with ROC AUC ≥ 0.75 (95% bootstrap CI excluding 0.5).

H4 (secondary — cluster-resolution sensitivity): We report the sensitivity of H1 to clustering resolution (Leiden / Louvain γ ∈ {0.3, 0.5, 0.8, 1.0, 1.5, 2.0}). H1's sign and FDR pass are stable across at least 4 of the 6 resolutions. (A finding that AGTR1+ depletion is observed only at γ ≈ Kamath's published resolution would itself be biologically informative and must be reported.)

H5 (secondary — spatial vs. proportional vs. expression decomposition): We decompose PD-vs-control DA loss into: (a) total nuclei recovered per donor (sequencing depth / dissection artifact) (b) DA-cluster fraction within total nuclei (c) AGTR1+ subcluster fraction within DA (d) per-cell AGTR1 expression within AGTR1+ DA and report each of (a)–(d) separately. Honest replication of Kamath requires the effect to be predominantly in (c), not in (a) or (b). A dominant (a) effect would indicate the original finding is partly a dissection or doublet artifact.

A negative or partial-replication result is fully informative. This OmiCairn run must report cluster-merging, marker-gene-loss, or resolution-instability findings as the headline rather than tune clustering until H1 passes.

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.