Background
As the SARS-CoV-2 virus, the cause of COVID-19, emerged in early 2020 and quickly spread across the globe, clinical molecular genetics laboratories experienced a dramatic drop in samples referred for clinical testing as non-critical healthcare appointments were postponed. These laboratories, utilizing years of expertise in a field of rapidly evolving new technologies and high throughput testing, as well as clinical technologists trained in high-complexity testing, large genetics laboratories stepped in the fill the gap, a measure that kept laboratories running and staff employed.
Case presentation
Our expertise in high-throughput high-complexity led from requests to perform testing in our genomics laboratory to building new laboratories in both the United Sates (US) and the United Kingdom (UK). These efforts resulted in building three laboratories from an empty space to a functioning, staffed clinical laboratory in approximately eight weeks. In total, these laboratories have employed over 1200 individuals (∼550 US and ∼700 UK). To date, these laboratories have performed over 10 million SARS-CoV-2 assays. Initial challenges included navigating state, federal, and country regulations and rapidly training a large clinical staff while ensuring optimal assay performance. As the pandemic continued, unpredictable decreases and surges in case numbers led to uncertainty in program longevity and staffing needs creating operational challenges. Clinical testing in the US is governed by the Clinical Laboratory Improvement Amendments (CLIA), which provide very specific requirements for personnel, training, proficiency testing and the quality management system. However, high complexity molecular testing for a viral target could fall into the CLIA category of general chemistry (as does molecular genetic testing) or microbiology, subcategory virology. The category chosen has dramatic effects on the specific experience required for technologists, supervisors and the laboratory director. Outside the US, laboratory requirements are dictated by accepted best practices and accrediting agencies, rather than specific laws, sometimes making it difficult to know what requirements need to be met. In the US, regulatory guidance has been dynamic. At the beginning of the pandemic, laboratories were required to use an assay with Food and Drug Administration (FDA) Emergency Use Authorization (EUA) or submit an EUA for their Laboratory Developed Test (EUA). In the fall of 2020, the FDA stopped requiring and declined to review new EUA applications for LDT assays. In November 2021 EUA submissions once again were required for any assay in use without an EUA. This has put unpresented pressure on laboratory operations to identify and hire qualified individuals to navigate the assay validation and subsequent assay management requirements. The FDA has approved EUAs with a wide range of assay sensitivity, ranging from 20 copies/ ml to several thousand copies/ ml. This wide range of assays used by the laboratories led to some unexpected outcomes. For example, individuals who tested positive the laboratory tested negative by another less sensitive assay, resulting in the perception of discrepant results. Further, vaccinated people testing positive, albeit with indication of a low viral load, was also unexpected. The high sensitivity of the assay with lowest copy detection allows the diagnosis of more individuals than less sensitivity assays, which is critical in stopping the spread of a virus that can be asymptomatic. An approach for cost saving is pooling of samples. When case numbers surge, as occurred with the spread of the SARS-CoV-2 Delta variant, a pooling approach is no longer efficient, therefore, a permanent shift to a pooling approach is not feasible.
Conclusion
In conclusion, our experience with high-throughput sequencing is allowing us to pivot quickly to viral genome sequencing, which is proving critical to understanding and combating this pandemic. Rare metabolic diseases, intellectual disabilities and hereditary cancer syndromes will always still need attention and continuous innovation but the innovation in genomics has greatly facilitated the much needed scaling of testing facilities for SARS-CoV2. We will need to learn to balance these activities and continue to support testing needs for these in addition to emerging diseases.