Determining seropositivity—A review of approaches to define population seroprevalence when using multiplex bead assays to assess burden of tropical diseases.

Background: Serological surveys with multiplex bead assays can be used to assess seroprevalence to multiple pathogens simultaneously. However, multiple methods have been used to generate cut-off values for seropositivity and these may lead to inconsistent interpretation of results. A literature review was conducted to describe the methods used to determine cut-off values for data generated by multiplex bead assays. Methodology/Principal findings: A search was conducted in PubMed that that included articles published from January 2010 to January 2020, and 291 relevant articles were identified that included the terms "serology", "cut-offs", and "multiplex bead assays". After application of exclusion of articles not relevant to neglected tropical diseases (NTD), vaccine preventable diseases (VPD), or malaria, 55 articles were examined based on their relevance to NTD or VPD. The most frequently applied approaches to determine seropositivity included the use of presumed unexposed populations, mixture models, receiver operating curves (ROC), and international standards. Other methods included the use of quantiles, pre-exposed endemic cohorts, and visual inflection points. Conclusions/Significance: For disease control programmes, seropositivity is a practical and easily interpretable health metric but determining appropriate cut-offs for positivity can be challenging. Considerations for optimal cut-off approaches should include factors such as methods recommended by previous research, transmission dynamics, and the immunological backgrounds of the population. In the absence of international standards for estimating seropositivity in a population, the use of consistent methods that align with individual disease epidemiological data will improve comparability between settings and enable the assessment of changes over time. Author summary: Serological surveys can provide information regarding population-level disease exposure by assessing immune responses created during infection. Multiplex bead assays (MBAs) allow for an integrated serological platform to monitor antibody responses to multiple pathogens concurrently. As programs adopt integrated disease control strategies, MBAs are especially advantageous since many of these diseases may be present in the same population and antibodies against all pathogens of interest can be detected simultaneously from a single blood sample. Interpreting serological data in a programmatic context typically involves classifying individuals as seronegative or seropositive using a 'cut-off', whereby anyone with a response above the defined threshold is considered to be seropositive. Although studies increasingly test blood samples with MBAs, published studies have applied different methods of determining seropositivity cut-offs, making results difficult to compare across settings and over time. The lack of harmonized methods for defining seropositivity is due to the absence of international standards, pathogen biology, or assay-specific methods that may impact resulting data. This review highlights the need for a standardized approach for which cut-off methods to use per pathogen when applied to integrated disease surveillance using platforms such as MBAs. [ABSTRACT FROM AUTHOR]