Target product profiles of laboratory and data analytical frameworks for genotyping to monitor antimalarial efficacy

Therapeutic efficacy studies (TESs) are the standard to evaluate antimalarial drug efficacy and guide malaria treatment policy. TESs are particularly relevant now, with resistance to first-line regimens emerging in sub-Saharan Africa. For TESs, a range of parasite genotyping and data analyses are available for genotype correction, a process to distinguish whether recurrent parasitemia after therapy is due to recrudescence of initially infecting parasites (treatment failure) or a new infection. The choice of methods for laboratory genotyping and data analyses can have a large effect on how outcomes are classified, and thereby on trial results. The currently recommended and most widely used laboratory and analytical methods for TES genotyping do not incorporate recent methodological advances and can produce biased results. As such current TES results can be difficult to interpret, especially in areas with high malaria transmission, such as much of sub-Saharan Africa. Thus, improving the accuracy and reliability of TES genotyping and data analysis are a major priority. To that end, we present target product profiles that outline key specifications for genetic data generation, processing, and data analysis, with the goal of creating rigorous and consistent community standards. Primary recommended specifications for laboratory methods include high sensitivity, specificity, and reproducibility, and guidance on the number and genetic diversity of targets; criteria which are best and likely only met by amplicon sequencing. Primary recommendations for data analysis methods include high classification accuracy, accounting for errors in genotyping, and accounting for alleles matching by chance. All laboratory and data analysis methods used should be systematically validated and publicly documented so that TES results, which have major policy implications, can be relied upon for sound programmatic decision making.