Two cohorts, a hundred infants each, and opposite answers on which sex does worse
also called sex as a prognostic factor · male sex infant ALL · female sex infant ALL · sex effect contradiction
Two teams on opposite sides of the world each followed about a hundred babies with leukaemia and asked whether boys or girls did worse, and got opposite answers with the same statistics. Nothing in either paper tells you which one is wrong.
The same thing, for a scientist
**ANZCHOG (n = 119, Australia and New Zealand): male sex is an independent adverse factor for EFS, HR 2.40 (95% CI 1.35-4.26), p < 0.01.** In the same Cox model the KMT2A-rearrangement hazard is **2.29 (1.08-4.88)** — so in this cohort being male outranks carrying the fusion this entire project is about. **JPLSG MLL-10 (n = 90, Japan): female sex is a significant factor for poor prognosis** in multivariable analysis, alongside MRD >=0.01% at the end of early consolidation. Same design, same order of magnitude of cohort, opposite sign. This is a contradiction the graph should hold open rather than resolve by picking the convenient one.
The two results, as stated
| ANZCHOG (PMID 37752126) | JPLSG MLL-10 (PMID 32845001) | |
|---|---|---|
| population | infant ALL, 119 patients, 69 KMT2A-rearranged / 38 germline / 12 unknown | infant ALL, 90 eligible, risk-stratified LR 15 / IR 19 / HR 56 |
| adverse sex | male | female |
| effect | HR 2.40 (1.35-4.26), p < 0.01, EFS | 'significant factor for poor prognosis', multivariable; no hazard ratio available to us |
| 5-year EFS by sex | male 32% (21-48), female 58% (48-71) | not extractable from the abstract |
| other independent factors | KMT2A-r HR 2.29, age <6 months HR 2.17 | MRD >=0.01% at end of early consolidation |
| what we read | full text (PMC10522653), Table 1 in full | abstract only — no PMCID, not in Europe PMC |
The asymmetry in the last row is not cosmetic and is stated in the evidence caveats: one side of this contradiction is a read table and the other is a sentence. The ANZCHOG side is therefore the better-characterised one, which is not the same as the correct one.
What could make both true
Neither cohort is a random sample of infant ALL, and there are at least four ways both results could be honest.
- Different composition. ANZCHOG's 119 include 38 KMT2A-germline infants, who do much better (5-year EFS 73% vs 33%). If sex correlated with KMT2A status in that cohort, the sex term could be partly carrying fusion status. The JPLSG multivariable analysis is anchored on the KMT2A-r population. These are not the same estimand.
- Different protocols and eras. Different induction, different transplant policy — JPLSG MLL-10 explicitly restricted HSCT to its high-risk group — and a sex effect mediated by toxicity or by transplant access would differ between them.
- Different populations. Pharmacogenetic variation differs between the Japanese and the Australian/New Zealand populations, and thiopurine and other drug-handling variants have known ancestry-structured frequencies.
- Both are subgroup-sized. At ~50-70 patients per arm, a hazard ratio of 2.4 with a lower bound of 1.35 is compatible with a much smaller true effect, and neither analysis appears to have been pre-specified for sex.
The honest reading is that sex is not established as a prognostic factor in infant ALL in either direction, and that any entry in this graph using sex to stratify risk is resting on one of two mutually exclusive findings.
Why this belongs in a fusion-biology graph at all
Because of the ANZCHOG hazard ordering. In that cohort's own Cox model the sex term (2.40) is larger than the KMT2A-rearrangement term (2.29), and both clear significance. This graph spends its effort on the fusion, correctly, but a covariate of comparable magnitude that nobody can sign is a standing reminder that fusion status is not the only large term in the model — and that the project's habit of treating clinical variables as background while treating molecular variables as foreground is a choice, not a finding.
It is also a test case for ana-reading-depth. Had both sides been taken from abstracts, this would have entered the graph as 'sex is prognostic in infant ALL' with two supporting citations and no visible problem, because each abstract is individually unremarkable. The contradiction is only visible when the two are put side by side, which is the thing a knowledge graph is supposed to be for and the thing find-contradictions.py cannot do, since it keys on shared PMIDs and these two papers share none.
The graph already held both halves and never noticed
This entry was written expecting to add two findings. Both were already here.
concept-anzchog-infant-all-cohort-presenting-featuresE1 already carried male sex (HR 2.40, 1.35-4.26) ... independent for EFS, with the KMT2A and age hazards beside it.concept-pallor-and-anaemia-infant-all-no-infant-figureE4 andconcept-risk-group-cut-points-are-administrative-choices-infant-allE3 each already carried female sex to be the significant prognostic factor from JPLSG MLL-10.
Three entries, two opposite claims about the same quantity, written in different cycles by different agents, each correct about its own source, none linked to the others and none aware there was anything to be aware of. No validator flagged it: every item had a resolving citation, a caveat and published counter-evidence, and coverage stood at 100%.
That is the real finding here, and it is about the instrument rather than about infant leukaemia. Per-entry correctness does not aggregate into whole-graph consistency, and this project's quality measures are all per-entry. The partner-provenance audit reached the same conclusion from the opposite direction in the same cycle — every imported result flagged its own import, and no entry showed the pattern of imports — which suggests the gap is structural and not a pair of coincidences.
- Get the JPLSG hazard ratio. Without it the comparison is a direction against an effect size, and the paper is outside every route this project has — institutional access or a request to the authors would settle it.
- Does Interfant-99 or Interfant-06 report a sex term? Those are the largest infant ALL cohorts in existence and would outweigh both of these. If they report none, that absence should be bounded and recorded.
- Is sex confounded with KMT2A status in the ANZCHOG cohort? The paper gives the marginal counts (51 male, 68 female) but not the cross-tabulation against fusion status, which is what would show whether the sex term is carrying fusion status.
- Generalise the check that found this. A whole-graph pass for pairs of entries making opposite-signed claims about the same quantity from different sources would catch the class that find-contradictions.py cannot see, which keys on shared PMIDs.
- E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
In the ANZCHOG infant ALL cohort (n = 119), Cox regression with EFS as endpoint identified male sex as an independent adverse prognostic factor, HR 2.40 (95% CI 1.35-4.26), p < 0.01, with 5-year EFS 32% (21-48) in males against 58% (48-71) in females. In the same model the KMT2A-rearrangement hazard is 2.29 (1.08-4.88) and age under 6 months is 2.17 (1.12-4.19).
Late effects in survivors of infant acute lymphoblastic leukaemia - a study of the Australian and New Zealand Children's Haematology/Oncology Group · Blood Cancer Journal 2023What this evidence cannot show
Read in full from PMC10522653 on 2026-09-19, Table 1 extracted row by row from the JATS rather than from flattened text — the flattened rendering places the 2.40 adjacent to the KMT2A block and would have supported attributing it to the wrong variable. NCBI efetch returns no abstract for this PMID; the paper is nonetheless open access, which is the corrected unreadable rule doing its job. The cohort mixes KMT2A-rearranged and germline infants, 51 males against 68 females, and sex does not appear to have been a pre-specified analysis.
Evidence that argues against this (2)
- A directly comparable analysis in a cohort of similar size reports the opposite sign: JPLSG MLL-10 found FEMALE sex a significant factor for poor prognosis in multivariable analysis. Two significant multivariable sex effects pointing opposite ways, at ~100 patients each, is better explained by cohort composition or chance than by a real reversing biological effect. Blood 2020
- The paper's stated purpose is late effects in survivors, not prognostic modelling, so this Cox model is a secondary analysis within a survivorship study. A hazard ratio from a model that is not the paper's reason for existing carries the usual multiplicity problem, and the report gives no indication that the sex term was pre-specified or corrected for the five other variables tested. Blood Cancer Journal 2023
- E2moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
In the JPLSG MLL-10 trial (90 eligible infants, stratified LR 15 / IR 19 / HR 56), multivariable analysis found female sex and MRD >=0.01% at the end of early consolidation to be significant factors for poor prognosis. Three-year EFS was 66.2% (SE 5.6) for KMT2A-rearranged patients and 93.3% (SE 6.4) for KMT2A-germline.
A risk-stratified therapy for infants with acute lymphoblastic leukemia: a report from the JPLSG MLL-10 trial · Blood 2020What this evidence cannot show
Abstract only. Checked against the corrected unreadable rule on 2026-09-19: Europe PMC returns inEPMC=N, isOpenAccess=N and no PMCID for this PMID, so no full text is fetchable by this project's routes and **no hazard ratio, confidence interval or sex-stratified EFS figure is available to us**. The claim records that the finding was reported and its direction, and nothing about its size. Confidence is capped at moderate for that reason, not because the trial is weak.
Evidence that argues against this (2)
- The ANZCHOG cohort reports the opposite sign with a full hazard ratio: male sex adverse, HR 2.40 (1.35-4.26), p < 0.01. Since only one of the two can describe a general effect, each is counter-evidence to the other, and the asymmetry in what we can read about them must not be mistaken for an asymmetry in their reliability. Blood Cancer Journal 2023
- The two analyses are not the same estimand, which is the most likely resolution and also the reason neither generalises. JPLSG's multivariable analysis sits on a risk-stratified KMT2A-r trial population with HSCT restricted to the high-risk group; ANZCHOG's sits on a mixed cohort that is 32% KMT2A-germline. A sex term means something different in each. EMBL-EBI 2026
- E3established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
The contradiction is invisible to this project's contradiction detector. `find-contradictions.py` keys on a shared PMID cited as support in one entry and against another, or carried at divergent confidence; these two papers share no identifier and would never be compared. The conflict is only detectable by reading two claims about the same quantity side by side.
What this evidence cannot show
A statement about this repository's tooling as of 2026-09-19, verified by reading the script's own output categories, not a claim about contradiction detection in general. A claim-level semantic detector would in principle catch this and none is implemented.
Evidence that argues against this (1)
- Not every pair of opposite-signed findings is a defect to be detected, and an automated detector keyed on claim similarity would drown in false positives from exactly the scope differences that explain this case. The existing PMID-keyed detector is narrow because narrow is what makes its output worth reading; widening it has a cost. EMBL-EBI 2026
- E4established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.analysis
Both sides of this contradiction were already present in the graph before this entry existed, in three separate entries written in different cycles: the ANZCHOG male-sex hazard in concept-anzchog-infant-all-cohort-presenting-features E1, and the JPLSG female-sex finding in concept-pallor-and-anaemia-infant-all-no-infant-figure E4 and concept-risk-group-cut-points-are-administrative-choices-infant-all E3. None referenced another, and all validator and coverage checks passed.
Cross-entry audit of sex-effect claims in the Oncofusion knowledge graph (coordinator, cycle 50) · Oncofusion knowledge graph (internal audit) 2026What this evidence cannot show
Established by grepping the graph's clinical folder for sex-effect language on 2026-09-19 and reading the matching evidence items. The search was string-based over one folder, so it is a lower bound on how many entries carry a sex claim, not a census.
Evidence that argues against this (2)
- Holding two sourced findings that disagree is not in itself a defect — it is what a literature that disagrees looks like, and a graph that suppressed one side would be worse. The defect is only that nothing connected them, so a reader arriving at either entry would leave with a confident one-sided answer. Oncofusion knowledge graph (internal audit) 2026
- The generalisation may be too strong. Three entries is a small base, and the graph does have a mechanism for exactly this — find-contradictions.py — which failed here only because these papers share no identifier. A single missed class is weaker evidence of a structural gap than the text above implies. Oncofusion knowledge graph (internal audit) 2026