SPICE-GRADE: Simultaneous Processing of Indirect Causal Evidence in Complex Pathways Using GRADE -An Exploratory Case Study

BACKGROUND: Genetic mutations often result in antimicrobial resistance. Early identification of emerging resistance due to genetic mutations often relies on multiple co-existing pathways of indirect evidence. The GRADE approach, widely used to rate certainty in treatment comparisons, offers little guidance to address such situations. Motivated by the possibility of emerging resistance to malaria, we provide an example of how GRADE guidance might be adapted to address multiple pathways of indirect evidence, an approach, we term SPICE-GRADE (Simultaneous Processing of Indirect Sources of Causal Evidence using GRADE). PURPOSE: We developed and here illustrate a structured approach for integrating direct and indirect causal evidence within GRADE, using antimalarial drug resistance mediated by Plasmodium falciparum Kelch13 mutations as a case study. METHODS: Confronted by the problem of applying GRADE to the question of emerging antimicrobial resistance to malaria, we simultaneous considered low certainty direct evidence and two pathways of indirect evidence addressing a possible causal relation between Kelch13 mutations and malaria recrudescence. Links between Kelch13 mutations and ring-stage survival and between Kelch13 mutations and delayed parasite clearance constitute the two indirect pathways. We addressed each link was independently, and for the two indirect links the extent of indirectness informed the final judgment. RESULTS: All three links relied on observational studies and therefore started as low certainty evidence. For both the direct link between Kelch13 mutations and recrudescence, and the indirect link between Kelch13 mutations and ring-stage survival, we rated the certainty up two levels for a very strong association, and then down two levels due to imprecision from small sample size in the direct link, and due to very serious indirectness in the indirect link. The third link, between Kelch13 mutations and delayed parasite clearance, was rated up one level for a strong association and down one for serious indirectness. Although each link remained at low certainty, the consistent direction of effect and coherence across all links strengthened the overall causal inference. Situating the entire body of evidence on a continuum allowed us to rate the overall certainty toward the higher end of low certainty, providing a more robust conclusion than relying on direct evidence alone. CONCLUSION: In this case study, we illustrate SPICE-GRADE as a structured way of mapping and assessing multiple causal links within the GRADE framework. Establishing SPICE-GRADE as a robust methodology for GRADE assessment will require formal methodological development with application across multiple contexts.