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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
PubMed

Insights

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.
Keywords:
MMRMT1E rate inflationmodel specificationmultiplicity issuesimulation study

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