Selecting Clinical Populations for Studies of Qualitative Fibrinogen Phenotypes: A proposed framework integrating molecular plausibility analytical feasibility confounding and falsifiability

This methodological article proposes a framework for selecting the first clinical population in studies of qualitative fibrinogen phenotypes. It compares chronic kidney disease, diabetes mellitus, a defined acute inflammatory condition undergoing resolution, and rheumatoid arthritis according to molecular plausibility, analytical feasibility, clinical comparability, temporal information, recruitment, resources, and experimental falsifiability. The framework separates four questions: whether the measurements are feasible, whether fibrinogen preparations differ functionally under standardized conditions, whether a nominated molecular modification contributes to that difference, and whether an altered state is autonomously maintained. Minimum requirements precede comparative weighting, preventing theoretical appeal from compensating for inadequate assays or unavailable infrastructure. Any weighted assessment requires documented assumptions and sensitivity analysis rather than a universal disease ranking. Stable non-dialysis chronic kidney disease is developed as a conditional worked example centered on fibrinogen carbamylation. The proposed pilot prioritizes feasibility and estimation, with direct-plasmin clot-lysis time at standardized final fibrinogen concentration serving as an exploratory biological readout. The article addresses molecular specificity, purification quality, associated components, comparator selection, technical replication, and interpretation of invalid or noncrossing lysis curves. Mechanistic extensions include orthogonal purification, crossed fibrinogen–plasma reconstitution, and exposure of a common reference substrate to different plasma environments. Four tables and two planning instruments support transparent selection and progression decisions. This is a proposed methodological framework, not a validated selection instrument, approved clinical protocol, or report of original results. Persistent modification during continuing exposure is explicitly distinguished from autonomous pathological maintenance.