Sample Adequacy Control for Negative Molecular Results: An Integrated Specimen-Process Framework to Strengthen Result Interpretation

Sample adequacy control (SAC) is a validated specimen-specific marker or metric, threshold, and reporting rule used to decide whether a negative molecular result is supported by the submitted specimen. SAC is not simply a cell-count or biomass check. Depending on specimen type and target, an unsupported negative result may reflect insufficient or nonrepresentative material, adequacy-marker degradation, inefficient transfer or extraction, matrix-associated inhibition, or mismatch between marker and anatomical compartment. SAC is therefore best understood as an integrated specimen-process adequacy control for negative-result interpretation. Its result should be reported as valid, borderline, or invalid for the intended negative interpretation, not as detected/not detected like the disease-specific biomarker. This perspective synthesizes quantitative polymerase chain reaction (qPCR) control guidance, preanalytical-quality literature, respiratory and enteric sampling studies, human papillomavirus (HPV) evidence, cartridge-assay precedents, and decentralized workflows. Direct prospective evidence that SAC improves patient or epidemiologic outcomes remains limited; available evidence is outcome-adjacent or operational, including HPV cellularity-control associations, Chlamydia trachomatis/Neisseria gonorrhoeae (CT/NG) and Ebola cartridge precedents, respiratory workflows showing lower pathogen positivity at higher SAC quantification cycle (Cq) strata, and reporting rules that change validity or recollection decisions. We propose a risk-based framework for selecting, validating, reporting, and monitoring SAC, with particular value in direct-amplification, point-of-care, and self-collection workflows where preanalytical failures affect negative-result interpretation.