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Assessing Statistical Methods for Estimating the Cerebrospinal Fluid Early Fungicidal Activity as an Endpoint for
Monica Fuszard1, David R Boulware2, Biyue Dai1
1Division of Biostatistics and Health Data Science, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA.
Background:
Cryptococcal meningitis is a life-threatening infection of the central nervous system. Early fungicidal activity (EFA), which measures how quickly Cryptococcus yeasts are cleared from cerebrospinal fluid (CSF) over time, is a key endpoint in phase 2 antifungal clinical trials. EFA is commonly estimated via a 2-step approach, where simple linear regressions are first fit to each individual's longitudinal measurements, and the slopes are then aggregated for statistical inference. Alternatively, a linear mixed model can estimate individual and group-level effects in one model. A systematic comparison of these methods is needed to understand and clarify their differences in analyzing EFA data in clinical trials.
Methods:
We conducted a systematic literature review to summarize the usage and reporting of both methods in cryptococcal meningitis clinical trials. We then evaluated their performance and operating characteristics under various simulation scenarios and applied both approaches to data from a phase 2 trial.
Results:
The 2-step approach and mixed model approach yielded discrepant CSF EFA estimates across literature review, simulation experiments, and real data analysis. The 2-step approach using linear regression produced steeper estimates and larger estimated treatment effects. The linear mixed model yielded smaller standard errors but estimates were biased toward the null, especially when early culture sterility was common.
Conclusions:
The 2-step approach is preferred for estimating EFA in cryptococcal meningitis studies, especially when early culture sterility occurs. EFA estimates should not be interpreted or compared across studies without accounting for the underlying statistical models and data preprocessing.
Insights
The 2-step approach is preferred for estimating early fungicidal activity (EFA) in cryptococcal meningitis trials, especially when early culture sterility is common. Statistical models significantly impact EFA estimates, necessitating careful consideration for cross-study comparisons.
Area of Science:
- Infectious Diseases
- Clinical Trials
- Statistical Modeling
Background:
- Cryptococcal meningitis is a critical central nervous system infection.
- Early fungicidal activity (EFA) is a key endpoint in phase 2 antifungal trials for cryptococcal meningitis.
- EFA measures the rate of *Cryptococcus* yeast clearance from cerebrospinal fluid (CSF).
Purpose of the Study:
- To systematically compare the 2-step linear regression and linear mixed model approaches for estimating EFA in cryptococcal meningitis.
- To evaluate the performance and operating characteristics of these statistical methods.
- To provide guidance on appropriate statistical methods for analyzing EFA data.
Main Methods:
- Conducted a systematic literature review of EFA estimation methods in cryptococcal meningitis trials.
- Performed simulation studies to assess method performance under various scenarios.
- Applied both the 2-step approach and linear mixed models to phase 2 trial data.
Main Results:
- The 2-step and mixed model approaches yielded discrepant EFA estimates.
- The 2-step approach showed steeper estimates and larger treatment effects.
- Linear mixed models produced smaller standard errors but were biased toward the null with early culture sterility.
Conclusions:
- The 2-step approach is recommended for EFA estimation in cryptococcal meningitis studies, particularly when early culture sterility is observed.
- EFA estimates and comparisons across studies must account for the statistical models and data preprocessing used.
- Clarification of statistical methods is crucial for accurate interpretation of EFA in clinical trials.
