SPICE-GRADE: simultaneous processing of indirect causal evidence in complex pathways using GRADE - an exploratory...

Area of Science:

• Genetics and Microbiology
• Epidemiology
• Evidence Synthesis

Background:

• Genetic mutations are a primary driver of antimicrobial resistance.
• Identifying emerging resistance often requires synthesizing indirect evidence from multiple sources.
• Existing frameworks like GRADE offer limited guidance for integrating diverse evidence pathways.

Purpose of the Study:

• To develop and demonstrate a structured approach for integrating direct and indirect causal evidence within the GRADE framework.
• To apply this novel approach, termed SPICE-GRADE, to antimalarial drug resistance.
• To assess the causal link between Plasmodium falciparum Kelch13 mutations and malaria recrudescence.

Main Methods:

• Simultaneously evaluated direct evidence and two indirect pathways (Kelch13 mutations to ring-stage survival, Kelch13 mutations to delayed parasite clearance).
• Assessed each causal link independently within the GRADE framework.
• Incorporated the degree of indirectness into the final certainty judgment.

Main Results:

• All assessed links originated from low-certainty observational studies.
• Consistent direction of effect and coherence across direct and indirect links strengthened causal inference.
• SPICE-GRADE allowed for a more robust overall certainty rating than direct evidence alone, situated at the higher end of low certainty.

Conclusions:

• SPICE-GRADE provides a structured method for mapping and assessing multiple causal links within the GRADE framework.
• This case study demonstrates SPICE-GRADE's utility in evaluating complex evidence for antimalarial drug resistance.
• Further methodological development and application are needed to establish SPICE-GRADE as a robust tool.