Klinik Varyant Sınıflandırma Platformlarının Erken Organizasyonel Aşamalarında Gerçek Dünya Performans Çalışmaları İçin Metodolojik Bir Çerçeve

Özet (abstract)

Automated platforms that classify sequence variants under the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) framework are increasingly used in rare-disease genomics, yet methodology for characterizing their performance at an early organizational stage is underdeveloped. The two framings most common in the literature are poorly suited to this stage: single-source comparison treats one peer laboratory or curated set as ground truth, which is difficult to defend at evidence depths where qualified laboratories disagree 25%–35% of the time; and formal regulatory adjudication requires multi-adjudicator panels and quality-management infrastructure that small or single-founder developers do not yet have. This paper proposes a methodological framework for Real-World Performance Studies that occupies the space between informal in-house testing and formal regulatory adjudication. The framework has four components: a three-layer performance model that separates analytical, classification, and clinical performance and forces every observation to a locus of attribution; a multi-source ground-truth construction with an explicit, evidence-strength-ordered weighting hierarchy; a six-category methodological-disposition taxonomy that resolves platform-versus-comparator disagreement into characterized categories with distinct action implications, only one of which denotes a classifier defect; and a phased pathway that carries early-stage evidence forward toward eventual regulatory submission. The framework is demonstrated, not validated, on three real-world cohorts (97 scored cases across three classifier versions) of a variant classification platform developed by Helena Bioinformatics. The demonstration illustrates how the method is operationalized. It does not test, validate, or claim superiority for any system. The framework is non-proprietary and is offered for independent adoption and adaptation. Its principal limitations - single-platform demonstration, single peer comparator, a taxonomy developed on the same cohorts that illustrate it, and structurally challenging conflicts of interest - are stated explicitly and are the reason the paper claims a method, not a result. The proposed framework is a conceptual methodology operationalized as a structured human-in-the-loop protocol; it is not a turnkey software package, and empirical use requires version-locked automated outputs plus documented expert review.

Yazarların özeti; kaynağından alınmıştır. Frontiers in Genetics, 2026 · DOI ↗