Background Genetic surveillance of the Plasmodium falciparum parasite shows great promise for helping National Malaria Control Programmes (NMCPs) assess parasite transmission. Genetic metrics such as the frequency of polygenomic (multiple strain) infections, genetic clones, and the complexity of infection (COI, number of strains per infection) are correlated with transmission intensity. However, despite these correlations, it is unclear whether genetic metrics alone are sufficient to estimate clinical incidence. Methods This study examined parasites from 3147 clinical infections sampled between the years 2012–2020 through passive case detection (PCD) across 16 clinic sites spread throughout Senegal. Samples were genotyped with a 24 single nucleotide polymorphism (SNP) molecular barcode that detects parasite strains, distinguishes polygenomic (multiple strain) from monogenomic (single strain) infections, and identifies clonal infections. To determine whether genetic signals can predict incidence, a series of Poisson generalized linear mixed-effects models were constructed to predict the incidence level at each clinical site from a set of genetic metrics designed to measure parasite clonality, superinfection, and co-transmission rates. Results Model-predicted incidence was compared with the reported standard incidence data determined by the NMCP for each clinic and found that parasite genetic metrics generally correlated with reported incidence, with departures from expected values at very low annual incidence ( 10‰), parasite genetics can be used to accurately infer incidence and is consistent with superinfection-based hypotheses of malaria transmission. When transmission was < 10‰, many of the correlations between parasite genetics and incidence were reversed, which may reflect the disproportionate impact of importation and focal transmission on parasite genetics when local transmission levels are low.
