| Bias | Author's judgement | Support for judgement |
| Confounding |
Moderate |
Comment: The following review confounders : Age, Gender, Comorbidities (all except obesity) , Severity were controlled for in the regression model. Review confounder site effects was not controlled for. |
| Selection of participants into the study |
Moderate |
Quote : "Patients who died (n=91) or who were discharged (n=196) within 24 hours after their admission were excluded, as well as patients receiving AZI alone (n=582) or patients who did not initiate HCQ and AZI the same day (more or less 24 hours, n=45)."
Comment: Start of follow up and start of treatment is not at the same moment for some patients. There is a risk of immortal time bias. |
| Intervention classification |
Low |
Quote: "Likewise, information on drugs prescriptions were not directly available in some ICU not using the ORBIS medication system. Consequently, data acquisition for the present study relied on both structured data (i.e. PMSI pertaining to past hospitalizations, if any, biological results, ORBIS medication system) and unstructured data (i.e. medical text records). For the latter, we used artificial intelligence algorithms based on Natural Language Processing (NLP), to extract information on patients diagnoses (including comorbidities, see below) and drugs prescriptions (including HCQ+/-AZI), considering contexts where mentions of drugs by name do not correspond to actual prescriptions (i.e. when the drug is mentioned in a negative context),13 and considering both International non-proprietary name (INN) and trade-marks." |
| Deviation from intended intervention |
NI |
Comment: The information reported is inadequate to assess whether there are deviations from the intended intervention beyond what would be expected in usual practice. No per arm data is provided related to co-interventions administered. They specifically mention that steroids and anticoagulation was administered and that the data was collected. |
| Missing data |
NI |
Comment: No infomation related to proportion per arm of missing data. Handling for missing data specified in Methods section. Quote: "To account for the potential influence of missing data on causal inference procedures, we used single imputation with a (regularized) iterative Factorial Analysis for Mixed Data model (FAMD), accounting for similarities between both individuals and relationships between covariates, treatment assignment and the outcome." |
| Measurements of outcomes |
Low |
Comment : Outcome assessors were likely aware of the intervention received however the outcomes Time to death are objective observer-reported outcome not involving judgement.Time to recovery are observer-reported outcome involving clinical decision-making. It could theoretically have been influenced by knowledge of the intervention received by the participants, but this is unlikely in the pandemic context Risk assessed to be low for outcomes: Time to death and Time to recovery. |
| Selection of the reported results |
Moderate |
Comment: The outcomes and analyses are clearly defined in the Methods section. There is no a-priori registered protocol or statistical analysis plan available. Risk assessed to be Moderate for the outcomes: Time to death and Time to recovery |