Statistical Challenges when Analyzing SARS-CoV-2 RNA Measurements Below the Assay Limit of Quantification in COVID-19 Clinical Trials
Moser, C. B.; Chew, K. W.; Giganti, M. J.; Li, J. Z.; Aga, E.; Ritz, J.; Greninger, A.; Javan, A. C.; Bender Ignacio, R. A.; Daar, E. S.; Wohl, D. A.; Currier, J. S.; Eron, J. J.; Smith, D. M.; Hughes, M. D.
Show abstract
Most clinical trials evaluating COVID-19 therapeutics include assessments of antiviral activity. In recently completed outpatient trials, changes in nasal SARS-CoV-2 RNA levels from baseline were commonly assessed using analysis of covariance (ANCOVA) or mixed models for repeated measures (MMRM) with single-imputation for results below assay lower limits of quantification (LLoQ). Analyzing changes in viral RNA levels with singly-imputed values can lead to biased estimates of treatment effects. In this paper, using an illustrative example from the ACTIV-2 trial, we highlight potential pitfalls of imputation when using ANCOVA or MMRM methods, and illustrate how these methods can be used when considering values <LLoQ as censored measurements. Best practices when analyzing quantitative viral RNA data should include details about the assay and its LLoQ, completeness summaries of viral RNA data, and outcomes among participants with baseline viral RNA [≥]LLoQ, as well as those with viral RNA <LLoQ. Trial RegistrationClinicalTrials.gov Identifier: NCT04518410
Matching journals
The top 7 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Clinical evaluation of the Diagnostic Analyzer for Selective Hybridization (DASH): a point-of-care PCR test for rapid detection of SARS-CoV-2 infection 92%
- Virologic outcomes on dolutegravir-, atazanavir-, or efavirenz-based ART in urban Zimbabwe: A longitudinal study 91%
- Correlation of National and Healthcare Workers COVID-19 Infection Data; Implications for Large-scale Viral Testing Programs 91%
Similar papers in this journal
- Favipiravir for treatment of outpatients with asymptomatic or uncomplicated COVID-19: a double-blind randomized, placebo-controlled, phase 2 trial 92%
- Evaluating Vaccine Efficacy Against SARS-CoV-2 Infection 91%
- High household transmission of SARS-CoV-2 in the United States: living density, viral load, and disproportionate impact on communities of color 91%
Similar papers in this journal
- SARS-CoV-2 subgenomic RNA kinetics in longitudinal clinical samples 92%
- Quantifying potential immortal time bias in observational studies in acute severe infection 91%
- Safety, Virology, Pharmacokinetics, and Clinical Experience of High-dose Intravenous Sotrovimab for the Treatment of Mild to Moderate COVID-19: An Open-label Clinical Trial 90%
Similar papers in this journal
- Incorporating efficacy data from initial trials into subsequent evaluations of vaccines against respiratory syncytial virus 92%
- Incorporating data from multiple endpoints in the analysis of clinical trials: example from RSV vaccines 91%
- Assessing Direct and Spillover Effects of Intervention Packages in Network-Randomized Studies 90%
Similar papers in this journal
- Estimating protection afforded by prior infection in preventing reinfection: Applying the test-negative study design 91%
- Missing data and missed infections: Investigating racial and ethnic disparities in SARS-CoV-2 testing and infection rates in Holyoke, Massachusetts 90%
- Performance of Existing and Novel Symptom- and Antigen Testing-Based COVID-19 Case Definitions in a Community Setting 90%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.