Association between APOL1 risk variants and progression from infection to sepsis

Joint Public Review:

The study has main limitations which need to be addressed and there is lack of functional explanation of carriage. These limitations are: a) the lack of inclusion of non-Black patients; and b) the lack of appropriate explanation if results are false-positive since APOL1 provides risk for chronic renal disease (CRD) and patients with CRD are predisposed to sepsis. Sepsis occurred in 565 Black subjects, of whom 105 (29% ) had APOL1 high-risk genotype and 460 had-low risk genotype. Importantly, the risk for sepsis associated with APOL1 HR variants was no longer significant after adjusting for subjects pre-existing severe renal disease or after excluding these subjects. Thus, the susceptibility pathway seems to be: APOL1 variants > CKD > sepsis diathesis.

Suggestions to the authors:
• The authors need to provide analysis of patients of non-Black origin.
• The Table of demographics needs to include the type of infections and the underlying pathogen.
• The authors need to provide convincing analysis if results are false-positive since APOL1 provides risk for chronic renal disease (CRD) and patients with CRD are predisposed to sepsis. For this purpose, they have to provide evidence if the sepsis causes (both type of infection and implicated pathogens) in patients with CRD who are carriers of APOL1 variants are different than in patients with CRD who are not carriers of APOL1 variants.
• Why concentrations of APOL1 were not measured in the plasma of patients?
• Why analysis towards risk for death is not done?
• The authors need to explain why functional information is not provided.
• n 162-172: too many assumptions have been used for the trial; thus, progression to sepsis is difficult to define. According to Sepsis-3 sepsis is no more a continuum from infection to sepsis and septic shock. Some patients presented with sepsis (-1, 0, 1 days considered by the authors) and when electronic health records are used, we are not able to detect the exact timepoint of SOFA score turning to a 2-point increase. This is a major limitation of the methodology presented.
Same applies for all comorbidities and data extracted from electronic health records.
• P value significance thresholds were set at 0.05, except for the PWAS where the threshold was set at 0.05/5 (p13). It would be helpful to list at this point what the 5 outcomes were that led to this adjusted threshold.
"Risk of sepsis was significantly increased among patients with high-risk genotypes (OR 1.29, 1.0 to 1.67, P1.29, CI 1.00-1.67, P<0.47)." Some would argue that a confidence interval that includes 1.0 indicates non-significance.
• The Discussion is too long and should be shortened.