Methodological biases in Virology: Insights and Lessons from Early SARS-CoV-2 Studies

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Abstract

The objective of this study review is to identify methodological biases in publicly available virological studies, motivated by a review and examination of early SARS-CoV-2. A narrative critical review of virology literature (1930-2024) has been conducted. Literature was identified through targeted keyword searches in PubMed, Scopus, Web o Science, and Google Scholar, refined by AI-assisted tools to detect recurring patterns. Studies were included if they addressed viral isolation, genome sequencing and infectivity testing. After exhaustive search and review, three recurrent methodological weaknesses were identified: Isolation frequently equated with indirect detection of genetic material rather than rigorous purification by density gradients of viral particles; Sequencing reliant on computational assemblies and references genomes, with no direct sequencing from purified particles by gradients of density; Infectivity inferred from cytopathic effects or modelling, with insufficient or incomplete negative controls. The review of the virological studies from 1930 to 2024 illustrate that these weaknesses are systematic. Contemporary virology often relies on indirect evidence. The current viral model has not been empirically verified. Thus, more rigorous isolation, sequencing from purified particles, exhaustive negative controls, and independent replication are essential to restore scientific robustness.

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