ABSTRACT
Changes in diagnostic criteria, for example, the various International Classification of Headache Disorders criteria, would lead to changes in the outcomes of epidemiological studies. International Classification of Headache Disorders-1 was based mainly on expert opinion, yet most of the diagnostic criteria were reliable and valid, but it did not include chronic migraine. In its second version, the classification introduced chronic migraine, but this diagnosis resembled more a high-frequency migraine rather than the actual migraine transformation process. It also introduced medication overuse headache, but it necessitated analgesic withdrawal and subsequent headache improvement to be diagnosed as such. Hence patients having medication overuse headache could only be diagnosed in retrospect, which was an awkward situation. Such restrictive criteria for chronic migraine and medication overuse headache omitted a high proportion of patients. International Classification of Headache Disorders-3 allows a diagnosis of medication overuse headache due to combination analgesics if taken for at least 10 days per month for more than three months. Hence the prevalence rate of medication overuse headache and chronic migraine can increase compared to the previous version of the headache classification. Different criteria have been used across studies to identify chronic migraine and medication overuse headache, and therefore the information acquired from previous studies using earlier criteria becomes uncertain. Hence much epidemiological research would need to be interpreted cautiously or repeated with the most updated criteria, since the subjects in studies that apply the latest criteria may be phenotypically different from those in older studies.
ABSTRACT
BackgroundSARS-CoV-2 variants of concern (VOCs) have been associated with higher rate of transmission, and evasion of immunisation and antibody therapeutics. Variant sequencing is widely utilized in the UK. However, only 0.5% (~650k) of the 133 million cumulative positive cases worldwide were sequenced (in GISAID) on 08 April 2021 with 97% from Europe and North America and only ~0.25% (~320k) were variant sequences. This may be due to the lack of availability, high cost, infrastructure and expert staff required for sequencing. Public health decisions based on a non-randomised sample of 0.5% of the population may be insufficiently powered, and subject to sampling bias and systematic error. In addition, sequencing is rarely available in situ in a clinically relevant timeframe and thus, is not currently compatible with diagnosis and treatment patient care pathways. Therefore, we investigated an alternative approach using polymerase chain reaction (PCR) genotyping to detect the key single nucleotide polymorphisms (SNPs) associated with increased transmission and immune evasion in SARS-CoV-2 variants. MethodsWe investigated the utility of SARS-CoV-2 SNP detection with a panel of PCR-genotyping assays in a large data set of 640,482 SARS-CoV-2 high quality, full length sequences using a prospective in silico trial design and explored the potential impact of rapid in situ variant testing on the COVID-19 diagnosis and treatment patient pathway. ResultsFive SNPs were selected by screening the published literature for a reported association with increased transmission and / or immune evasion. 344881 sequences contained one or more of the five SNPs. This algorithm of SNPs was found to be able to identify the four variants of concern (VOCs) and sequences containing the E484K and L452R escape mutations. InterpretationThe in silico analysis suggest that the key mutations and variants of SARS-CoV-2 may be reliably detected using a focused algorithm of biologically relevant SNPs. This highlights the potential for rapid in situ PCR genotyping to compliment or replace sequencing or to be utilized instead of sequences in settings where sequencing is not feasible, accessible or affordable. Rapid detection of variants with in situ PCR genotyping may facilitate a more effective COVID-19 diagnosis and treatment patient pathway. FundingThe study was funded by Primer Design (UK), with kind contributions from all academic partners.
