ARCHCODE: A Falsification-First Framework for Evaluating 3D Chromatin Structural Scores in Variant Interpretation — A β-Thalassemia Case Study (v3 Corrected)

Q: What does this research mean for the field?

The ARCHCODE framework demonstrates that 3D chromatin structural scores perform at chance level (AUC ≈ 0.52) for variant interpretation when controlling for consequence-category distribution artifacts. Novelty: ClaimNovelty.METHODOLOGICAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

Sergey V. Boyko

doi:10.5281/zenodo.20552712

June 5, 2026Open Access

ARCHCODE: A Falsification-First Framework for Evaluating 3D Chromatin Structural Scores in Variant Interpretation — A β-Thalassemia Case Study (v3 Corrected)

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Key Points

This research aims to assess a framework for evaluating 3D chromatin structural scores in relation to genetic variant interpretation in β-thalassemia.
Falsification-first framework designed to examine chromatin structural scores.
Evaluation involved correcting earlier claims regarding variant classification and performance metrics.
Audit conducted to reassess the performance of chromatin scores based on matched control data.
Initial claims of AUC 0.977 were corrected to an approximated AUC of 0.52, indicating chance-level performance.
Proposed reclassification of HBB variants from VUS to Likely Pathogenic was removed due to lack of ACMG-compliant evidence.
Exclusion of mock data highlighted previous inconsistencies in reported findings.

Implication

Evaluates chromatin scores for variant interpretation in β-thalassemia, suggesting improvements in assessment methods.

Abstract

CORRECTION NOTICE (v3, 2026-06-05): This version corrects earlier deposits (v1: Feb 2026; v2: Mar 2026) which contained: (1) phantom reference "Sabaté et al., Nature Genetics 2025" (DOI 404 — paper does not exist) — corrected to Sabaté et al. bioRxiv 2024 (DOI: 10.1101/2024.08.09.605990); (2) clinical reclassification recommendation "we propose reclassifying 3 HBB variants from VUS to Likely Pathogenic" — removed, no ACMG-compliant evidence (PS3) exists; (3) AUC 0.977 overclaim — a June 2026 matched-control audit showed this is a consequence-category distribution artifact (within-category AUC ≈ 0.52, chance level); (4) AlphaGenome inconsistency — mock data excluded from all claims. Full correction details: CORRECTION_NOTE.md.

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Cite This Study

Sergey V. Boyko (2026) studied this question.

synapsesocial.com/papers/6a27ad11a963992e162676bd https://doi.org/10.5281/zenodo.20552712

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ARCHCODE: A Falsification-First Framework for Evaluating 3D Chromatin Structural Scores in Variant Interpretation — A β-Thalassemia Case Study (v3 Corrected)

Key Points

Implication

Abstract

Discussion

Cite This Study

ARCHCODE: A Falsification-First Framework for Evaluating 3D Chromatin Structural Scores in Variant Interpretation — A β-Thalassemia Case Study (v3 Corrected)

Key Points

Implication

Abstract

Discussion

Cite This Study

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