The many definitions of multiplicity of infection

Abstract

The presence of multiple genetically different pathogenic variants within the same individual host is common in infectious diseases. Although this is neglected in some diseases, it is well recognized in others like malaria, where it is typically referred to as multiplicity of infection (MOI) or complexity of infection (COI). In malaria, with the advent of molecular surveillance, data is increasingly being available with enough resolution to capture MOI and integrate it into molecular surveillance strategies. The distribution of MOI on the population level scales with transmission intensities, while MOI on the individual level is a confounding factor when monitoring haplotypes of particular interests, e.g., those associated with drug-resistance. Particularly, in high-transmission areas, MOI leads to a discrepancy between the likelihood of a haplotype being observed in an infection (prevalence) and its abundance in the pathogen population (frequency). Despite its importance, MOI is not universally defined. Competing definitions vary from verbal ones to those based on concise statistical frameworks. Heuristic approaches to MOI are popular, although they do not mine the full potential of available data and are typically biased, potentially leading to misinferences. We introduce a formal statistical framework and suggest a concise definition of MOI and its distribution on the host-population level. We show how it relates to alternative definitions such as the number of distinct haplotypes within an infection or the maximum number of alleles detectable across a set of genetic markers. It is shown how alternatives can be derived from the general framework. Different statistical methods to estimate the distribution of MOI and pathogenic variants at the population level are discussed. The estimates can be used as plug-ins to reconstruct the most probable MOI of an infection and set of infecting haplotypes in individual infections. Furthermore, the relation between prevalence of pathogenic variants and their frequency (relative abundance) in the pathogen population in the context of MOI is clarified, with particular regard to seasonality in transmission intensities. The framework introduced here helps to guide the correct interpretation of results emerging from different definitions of MOI. Especially, it excels comparisons between studies based on different analytical methods.

Estimating multiplicity of infection, allele frequencies, and prevalences accounting for incomplete data

“…Usual models to estimate MOI (e.g. [ 3 , 5 , 9 ]) disregard such empty records and assume missingness at random. However, these methods would not account for incomplete information in the remaining observations.…”

“…To determine whether the proposed model is an improvement compared to the original model of [ 3 , 5 , 9 ], we conducted a numerical study, to compare both methods’ performance in terms of bias and variance. It turned out that it is not straightforward which model is superior.…”

“…The statistical properties of some of the existing methods to estimate MOI and lineage frequencies have been studied in detail (e.g. [3][4][5]). However, a common problem in practice is the quality of the molecular data itself-missing information at one or several molecular markers is common.…”

Pregnant women as a sentinel population for genomic surveillance of malaria in the Democratic Republic of Congo

“…For example, levels of complexity of infection, which result from bites of mosquitoes infected with more than one clone and/or multiple bites, were similar in both cohorts, even though women tend to harbor longer-lasting asymptomatic parasite reservoirs. These pronounced levels of heterozygosity suggest that pregnant women can also provide valuable information about changes in transmission intensity 26 , e.g., in response to vaccine deployment.…”

Evolutionary genetics of malaria

“…The presence of multiple genetically distinct parasite haplotypes within an infection is frequently referred to as multiplicity of infection (MOI) or complexity of infections (COI) and considered important in malaria. The terms MOI and COI are ambiguously defined in the literature (see ( Schneider et al, 2022 ) for a comprehensive review). Although, it is unclear whether MOI is affecting the clinical pathogenesis of malaria, or whether different parasite haplotypes are competing within infections (intra-host competition), MOI mediates the amount of meiotic recombination and scales with transmission intensities ( Pacheco et al, 2020 ) (see Figure 3 ).…”