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Type-I-error rate inflation in mixed models for repeated measures caused by ambiguous or incomplete model
Sebastian Häckl1, Armin Koch1, Florian Lasch2
1Hannover Medical School, Institute of Biostatistics, Hannover, Niedersachsen, Germany.
Pharmaceutical Statistics
|July 31, 2023
Summary
Imprecise specification of mixed models for repeated measures (MMRM) in clinical trials can inflate the family-wise type-I-error rate (T1E), potentially compromising confirmatory evidence. This study quantifies this inflation, showing significant T1E rate increases with ambiguous MMRM models.
Area of Science:
- Biostatistics
- Clinical Trial Methodology
- Statistical Inference
Background:
- Controlling the family-wise type-I-error rate (T1E) is crucial for confirmatory clinical trials.
- Mixed models for repeated measures (MMRM) are frequently used but often poorly specified in protocols.
- The impact of MMRM specification ambiguity on T1E has not been fully quantified.
Purpose of the Study:
- To quantify the magnitude of T1E rate inflation resulting from unspecified MMRM model items.
- To investigate how T1E inflation varies with the type and number of unspecified model parameters.
- To assess the influence of trial characteristics on T1E inflation in confirmatory trials.
Main Methods:
- Simulated a randomized, double-blind, parallel-group, phase III clinical trial assuming no treatment effect.
- Analyzed simulated data using multiple MMRMs compatible with imprecise protocol specifications.
- Estimated T1E rates for each cluster of MMRM analyses to assess inflation.
Main Results:
- Significant T1E rate inflation was observed for ambiguous MMRM specifications, reaching a maximum of 7.6% [7.1%; 8.1%].
- The extent of T1E inflation depends on the type and number of unspecified model items, sample size, and allocation ratio.
- Imprecise specification of nuisance parameters may not significantly inflate T1E, but results may underestimate true inflation.
Conclusions:
- Imprecise MMRM specifications in clinical trials can lead to substantial T1E rate inflation.
- This inflation can significantly impair the ability to generate reliable confirmatory evidence.
- Careful and precise specification of MMRMs is essential for maintaining statistical integrity in pivotal trials.
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