Oncofusion

start / graph / ana-arid1b-survives-leave-one-out-eleven-of-eleven-and-my-own-pre-registered-threshold-was-uninformative-by-construction

Analysismoderate confidence 3 of 5: One strong study, or several smaller consistent ones.

ARID1B's buffering effect survives leave-one-out in 11 of 11 - even dropping the line whose own effect is -1.2269 leaves -0.2129 at p = 0.00465. But the lineage-concentration test says there was LITTLE confound to remove, cycle 84's headline confirms an absence rather than defeating a threat, and my own pre-registered TVD threshold fired on a measure that is large by construction at n=11

also called the ARID1B leave-one-out · was there a lineage confound to remove at all · a pre-registered threshold that was uninformative by construction

Two checks I had promised and not done, both capable of undermining my own earlier conclusion: dropping each of the eleven relevant cell lines in turn leaves the finding intact every time, including when the most extreme line is removed, so it is not one cell line wearing a statistic. But the second check shows the earlier tissue-of-origin correction was not correcting much - the eleven lines are no more concentrated in particular tissues than a random eleven would be - and one of my own pre-set thresholds turned out to be automatically satisfied at this sample size, so it decided the answer while carrying no information.

The same thing, for a scientist

**Two open questions I named in cycles 81 and 84 and did not run. Both could deflate my own result; one does.** **Q1 — LEAVE-ONE-OUT AT n=11: ROBUST, 11 of 11.** Pre-registered as FRAGILE if dropping any single line moved the difference inside ±0.10 or its p above 0.05. | dropped line | its own gene effect | difference without it | p without it | |---|---:|---:|---:| | ChaGo-K-1 | +0.0550 | −0.3411 | 0.00015 | | … | | | | | SNU-449 | −0.7141 | −0.2642 | 0.00110 | | RL95-2 | −0.7507 | −0.2605 | 0.00165 | | **Karpas-422** | **−1.2269** | **−0.2129** | **0.00465** | **The most deflating possible drop — Karpas-422, whose own ARID1B dependency is −1.2269 — still leaves −0.2129 at p = 0.00465.** No single line carries the effect. **But the group is heterogeneous and that deserves saying.** Individual effects in the 11 mutant lines run from **+0.0550 to −1.2269**. Roughly five of eleven sit near or above zero; the group mean is carried by four or five lines. "ARID1B becomes essential when ARID1A is disrupted" is a statement about a *subset* of ARID1A-mutant lines, not about all of them, and no leave-one-out can show otherwise. **Q2 — WAS THERE A LINEAGE CONFOUND TO REMOVE? Largely no, and this deflates cycle 84.** Cycle 84's own counter-evidence posed exactly this and said the distinguishing number had not been computed. It now is: - **Permutation p = 0.42083.** A random 11-line draw from the pool is at least as lineage-concentrated as the observed mutant group **42% of the time**. - **Largest single lineage share in the mutant group = 0.1818 — two of eleven.** No lineage dominates. - 9 distinct lineages across 11 mutant lines. **So cycle 84's headline — "lineage explains none of it" — is true and much less impressive than it read.** Its stratified permutation had little confound to remove, and the 0.0024 shift it reported is better understood as *confirming an absence* than as *defeating a threat*. That was cycle 84's own deflating alternative and it is the correct reading. **AND MY PRE-REGISTERED THRESHOLD FIRED ON THE WRONG CLAUSE.** I declared, in advance, "TVD ≥ 0.50 **or** permutation p < 0.05 → there was a real confound". Observed TVD is **0.7026**, so the script printed *"THERE WAS A REAL CONFOUND"*. **That verdict is wrong and I am overriding it.** An 11-line sample can occupy at most 11 of 80 lineages, so its total variation distance from the pool is **large by construction regardless of any confound** — the wild-type mass in the 69+ lineages the sample cannot reach guarantees it. The permutation controls for sample size; TVD does not. **The `or` in my own verdict logic let an uninformative measure decide the answer.**

Go deeper
A pre-registration is only as good as the measure it names, and this is the third instance

This project has now recorded three distinct ways a pre-registered criterion can be sound in form and useless in substance, and I have supplied two of them.

  1. Cycle 76: a falsifier whose reagent could not distinguish the thing it was about (MLL1n, an N-terminus antibody, asked to report on the fusion).
  2. Cycle 82/83: a falsifier whose population was never stated, which flipped between cell lines (hyp-q118's FUNCTION ARM, 0.7008 versus 0.9980).
  3. Now: a criterion whose measure is saturated at the sample size it is applied to. TVD between an 11-item and a 1,197-item distribution over 80 categories is near its ceiling whatever the data says.

All three cleared every process rule this project has — declared in advance, numeric, scoreable, with a band. The common failure is that pre-registration disciplines when you choose the threshold, not whether the statistic can answer the question.

The specific lesson for next time: before declaring a threshold on a summary statistic, compute what that statistic does under the null at the actual sample size. Here that is one line of code — permute and look at the distribution — and it is exactly what the permutation clause already did. Had I declared the permutation alone, the pre-registration would have been right. The or was the defect: it let the weaker measure rescue a verdict the stronger one denied.

What survives, stated carefully

Survives and is strengthened: the ARID1B buffering effect itself. It is not one line (11 of 11 leave-one-out), it is not a lineage artefact (cycle 84, and now with the caveat that there was little artefact available to be one), the ARID1A instrument check has passed under two different permutation schemes, and ARID2/SMARCA4 have stayed flat throughout.

Newly qualified: the strength of cycle 84's contribution. Its stratification was a correct test that found little to correct, and its entry should be read as "lineage was checked and was not the explanation" rather than "a lineage confound was removed".

Newly surfaced: heterogeneity. Five of eleven ARID1A-mutant lines have ARID1B effects near or above zero. The interesting question is no longer whether buffering is real but what distinguishes the four or five lines that show it — and the obvious candidate, which this analysis cannot test, is whether those are the lines whose ARID1A mutation is genuinely inactivating. That is cycle 81's underpowered truncating-only stratum returning as the central question rather than a caveat.

Unchanged: zero leukaemia lines are in any of this. Buffering is a pan-cancer cBAF result and remains an inference, not a measurement, in KMT2A-rearranged cells.

Facts and figures
Q1 leave one out verdictROBUST - 11 of 11 stay outside the band and significant
Q2 verdict as scored by the scriptTHERE WAS A REAL CONFOUND - fired on the TVD clause
Q2 verdict after overriding a bad thresholdLITTLE CONFOUND TO REMOVE. Cycle 84's 'lineage explains none of it' is TRUE but confirms an ABSENCE rather than defeating a threat - which was cycle 84's own deflating alternative and is the correct reading.
the defect in my own pre registrationI declared 'TVD >= 0.50 OR permutation p < 0.05'. The OR let a measure that is saturated at n=11 decide a verdict the sample-size-controlled measure denied. Had I declared the permutation alone, the pre-registration would have been right.
the prescriptionbefore declaring a threshold on a summary statistic, compute what that statistic does UNDER THE NULL AT THE ACTUAL SAMPLE SIZE. Here that is one line of code and the permutation clause already did it.
what becomes the central questionwhat distinguishes the 4-5 ARID1A-mutant lines that show the effect from the 5-6 that do not. The obvious candidate is whether their ARID1A mutation is genuinely inactivating - which is cycle 81's underpowered truncating-only stratum returning as the main question rather than a caveat.
absence classmeasured-not-analysed
absence class noteBoth tests in this entry were named as open questions by me - Q1 in cycle 81, Q2 in cycle 84 - and both cost one script run against data already public. Q1 went unrun for four cycles. Not never-measured; the data exists and the analysis is arithmetic on it.
seed20260923
n permutations20000
depmap releaseNOT STATED BY THE OPEN TARGETS API
pulled2026-09-23
open targets dataVersion26.06, fetched live in cycle 86 via {meta{dataVersion{year month iteration}}}. This is the OPEN TARGETS PLATFORM release and NOT a DepMap release name - the DepMap release itself is genuinely not stated, which is what the 'release not stated' caveats in these entries correctly mean. Recording it because it is the only version anchor available and these entries were omitting it.
full contrast
mean_mutant-0.371mean_mutant: -0.3709difference-0.298difference: -0.2985mean_wt-0.072mean_wt: -0.0724perm_p0.000perm_p: 0.0002
full contrast — the numbers behind the chart
{
  "difference": -0.2985,
  "perm_p": 0.0002,
  "mean_mutant": -0.3709,
  "mean_wt": -0.0724
}
most deflating drop
{
  "line": "Karpas-422",
  "depmap_id": "ACH-000315",
  "its_own_gene_effect": -1.2269,
  "difference_without_it": -0.2129,
  "perm_p_without_it": 0.00465
}
heterogeneity in the mutant group
{
  "range_of_individual_effects": "+0.0550 (ChaGo-K-1) to -1.2269 (Karpas-422)",
  "note": "roughly 5 of 11 sit near or above zero, so the group mean is carried by 4-5 lines. 'ARID1B becomes essential when ARID1A is disrupted' is a statement about a SUBSET of ARID1A-mutant lines."
}
Q2 lineage concentration
{
  "permutation_p": 0.42083,
  "interpretation": "a random 11-line draw is at least this lineage-concentrated 42% of the time",
  "largest_single_lineage_share": 0.1818,
  "n_distinct_lineages_mutant": 9,
  "n_distinct_lineages_wild_type": 80,
  "observed_tvd": 0.7026,
  "tvd_is_uninformative_here": "an 11-line sample can occupy at most 11 of 80 lineages, so TVD from the pool is near its ceiling by construction. The measure is saturated at this sample size."
}
third instance of a sound but useless criterion
[
  "cycle 76: a falsifier whose REAGENT could not distinguish the thing it was about (MLL1n, an N-terminus antibody, asked to report on the fusion)",
  "cycle 82/83: a falsifier whose POPULATION was never stated and which flipped between cell lines (hyp-q118 FUNCTION ARM, 0.7008 vs 0.9980)",
  "cycle 85: a criterion whose MEASURE is saturated at the sample size it is applied to (TVD at n=11 against 80 categories)"
]
Still open
  1. Leave-TWO-out, or a bootstrap over the 11 mutant lines. A single-drop test cannot detect an effect carried jointly by two or three lines, and with 5 of 11 near zero that is the live possibility rather than a hypothetical.
  2. Re-run the lineage concentration on a COARSE CURATED lineage ontology rather than an over-splitting disease string. If 80 categories are too fine to see a tissue-level confound, the threat cycle 84 tested for could be real and invisible to this measure - which would restore it.
  3. What distinguishes the 4-5 responding lines? If it is truncating versus missense ARID1A, then DepMap's own functionally-annotated mutation calls would both answer this and lift cycle 81's pre-registered primary stratum above its minimum group size. That single route now addresses the two largest remaining limits at once.
Every source behind this entry (1)
  1. E1moderate confidence 3 of 5: One strong study, or several smaller consistent ones.analysis

    Dropping each of the 11 ARID1A-mutant DepMap lines in turn, ARID1B's gene-effect difference against the 1,197 wild-type screens stays outside the pre-registered plus-or-minus 0.10 band and significant in all 11 cases; the most deflating drop, Karpas-422 whose own effect is -1.2269, leaves -0.2129 at 20,000-permutation p = 0.00465. Individual effects in the mutant group range from +0.0550 to -1.2269. The mutant group's lineage distribution is NOT unusually concentrated: permutation p = 0.42083 against random 11-line draws, largest single lineage share 0.1818 (two of eleven), 9 distinct lineages.

    What this evidence cannot show

    THE PRE-REGISTERED VERDICT ON Q2 IS WRONG AND IS OVERRIDDEN IN THIS ENTRY. I declared 'TVD >= 0.50 OR permutation p < 0.05 -> there was a real confound'; TVD came in at 0.7026 so the script printed 'THERE WAS A REAL CONFOUND'. An 11-line sample can occupy at most 11 of 80 lineages, so its TVD from the pool is near its ceiling by construction whatever the data says - the measure is saturated at this sample size and carries no information. The permutation clause (p = 0.42083) is the one that controls for sample size and it says the opposite. Reporting the script's verdict would have been reporting an artefact of my own threshold choice. Otherwise: the leave-one-out shares every limit of the underlying contrast - it inherits the ANY-mutation stratum because the truncating-only primary had 4 usable lines, ZERO leukaemia lines are in the test, and the DepMap release is not stated by the Open Targets API (figures carry the pull date 2026-09-23). A leave-one-out also cannot detect an effect carried jointly by two or three lines, only by one.

    Evidence that argues against this (3)
    • A leave-one-out is the weakest robustness check available and I should not present 11 of 11 as strong. It removes ONE line at a time, so an effect carried jointly by two or three of the eleven would survive every single-drop run while still resting on a quarter of the group. Given the observed heterogeneity - five of eleven lines near or above zero - that is not a hypothetical: a leave-TWO-out or a bootstrap over the mutant group is the test that would actually bound this, and neither was run.
    • The Q2 result cuts at cycle 84 but it also weakens the motivation for cycle 84's own existence, which makes me the wrong person to have scored it. Having discovered that the stratified test had little to correct, the tidy conclusion is 'the effect was never at risk from lineage' - but the equally available reading is that the lineage proxy (a disease string, over-splitting into 80 categories) was too fine to detect a real tissue-level confound, and that a coarse curated lineage ontology would show concentration this measure cannot see. That would restore the threat, and no curated ontology was tried.
    • Karpas-422 surviving as a drop is reassuring for robustness and troubling for interpretation: it is a germinal-centre B-cell lymphoma line with a very strong ARID1B dependency (-1.2269), and its presence in an 'ARID1A-mutant' group rests on the same Cellosaurus free-text call as the rest. If that single call is wrong the group mean moves by 0.085 - and a leave-one-out precisely cannot distinguish 'the effect survives without this line' from 'this line's mutation call is the most consequential unverified datum in the analysis'.
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