arXiv subjects

Charlotte Micheloud

Publications and source records attributed to Charlotte Micheloud.

8 recordsLinked to original sources

arXiv2025

Assessing the replicability of RCTs in RWE emulations

Background: The standard regulatory approach to assess replication success is the two-trials rule, requiring both the original and the replication study to be significant with effect estimates in the same direction. The sceptical p-value was recently presented as an alternative method for the statistical assessment of the replicability of study results. Methods: We review the statistical properties of the sceptical p-value and compare those to the two-trials rule. We extend the methodology to non-inferiority trials and describe how to invert the sceptical p-value to obtain confidence intervals. We illustrate the performance of the different methods using real-world evidence emulations of randomized, controlled trials (RCTs) conducted within the RCT DUPLICATE initiative. Results: The sceptical p-value depends not only on the two p-values, but also on sample size and effect size of the two studies. It can be calibrated to have the same Type-I error rate as the two-trials rule, but has larger power to detect an existing effect. In the application to the results from the RCT DUPLICATE initiative, the sceptical p- value leads to qualitatively similar results than the two-trials rule, but tends to show more evidence for treatment effects compared to the two-trials rule. Conclusion: The sceptical p-value represents a valid statistical measure to assess the replicability of study results and is especially useful in the context of real-world evidence emulations.

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arXiv2024

The assessment of replicability using the sum of p-values

Statistical significance of both the original and the replication study is a commonly used criterion to assess replication attempts, also known as the two-trials rule in drug development. However, replication studies are sometimes conducted although the original study is non-significant, in which case Type-I error rate control across both studies is no longer guaranteed. We propose an alternative method to assess replicability using the sum of p-values from the two studies. The approach provides a combined p-value and can be calibrated to control the overall Type-I error rate at the same level as the two-trials rule but allows for replication success even if the original study is non-significant. The unweighted version requires a less restrictive level of significance at replication if the original study is already convincing which facilitates sample size reductions of up to 10%. Downweighting the original study accounts for possible bias and requires a more stringent significance level and larger samples sizes at replication. Data from four large-scale replication projects are used to illustrate and compare the proposed method with the two-trials rule, meta-analysis and Fisher's combination method.

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arXiv2024

The replication of equivalence studies

Replication studies are increasingly conducted to assess the credibility of scientific findings. Most of these replication attempts target studies with a superiority design, but there is a lack of methodology regarding the analysis of replication studies with alternative types of designs, such as equivalence. In order to fill this gap, we propose two approaches, the two-trials rule and the sceptical TOST procedure, adapted from methods used in superiority settings. Both methods have the same overall Type-I error rate, but the sceptical TOST procedure allows replication success even for non-significant original or replication studies. This leads to a larger project power and other differences in relevant operating characteristics. Both methods can be used for sample size calculation of the replication study, based on the results from the original one. The two methods are applied to data from the Reproducibility Project: Cancer Biology.

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arXiv2023

Replication of "null results" -- Absence of evidence or evidence of absence?

In several large-scale replication projects, statistically non-significant results in both the original and the replication study have been interpreted as a "replication success". Here we discuss the logical problems with this approach: Non-significance in both studies does not ensure that the studies provide evidence for the absence of an effect and "replication success" can virtually always be achieved if the sample sizes are small enough. In addition, the relevant error rates are not controlled. We show how methods, such as equivalence testing and Bayes factors, can be used to adequately quantify the evidence for the absence of an effect and how they can be applied in the replication setting. Using data from the Reproducibility Project: Cancer Biology, the Experimental Philosophy Replicability Project, and the Reproducibility Project: Psychology we illustrate that many original and replication studies with "null results" are in fact inconclusive. We conclude that it is important to also replicate studies with statistically non-significant results, but that they should be designed, analyzed, and interpreted appropriately.

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arXiv2023

Assessing replicability with the sceptical p-value: Type-I error control and sample size planning

We study a statistical framework for replicability based on a recently proposed quantitative measure of replication success, the sceptical $p$-value. A recalibration is proposed to obtain exact overall Type-I error control if the effect is null in both studies and additional bounds on the partial and conditional Type-I error rate, which represent the case where only one study has a null effect. The approach avoids the double dichotomization for significance of the two-trials rule and has larger project power to detect existing effects over both studies in combination. It can also be used for power calculations and requires a smaller replication sample size than the two-trials rule for already convincing original studies. We illustrate the performance of the proposed methodology in an application to data from the Experimental Economics Replication Project.

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arXiv2022

Combining Evidence from Clinical Trials in Conditional or Accelerated Approval

Conditional (European Medicines Agency) or accelerated (U.S. Food and Drug Administration) approval of drugs allow earlier access to promising new treatments that address unmet medical needs. Certain post-marketing requirements must typically be met in order to obtain full approval, such as conducting a new post-market clinical trial. We study the applicability of the recently developed harmonic mean Chi-squared test to this conditional or accelerated approval framework. The proposed approach can be used both to support the design of the post-market trial and the analysis of the combined evidence provided by both trials. Other methods considered are the two-trials rule, Fisher's criterion and Stouffer's method. In contrast to some of the traditional methods, the harmonic mean Chi-squared test always requires a post-market clinical trial. If the p-value from the pre-market clinical trial is << 0.025, a smaller sample size for the post-market clinical trial is needed than with the two-trials rule. For illustration, we apply the harmonic mean Chi-squared test to a drug which received conditional (and later full) market licensing by the EMA. A simulation study is conducted to study the operating characteristics of the harmonic mean Chi-squared test and two-trials rule in more detail. We finally investigate the applicability of these two methods to compute the power at interim of an ongoing post-market trial. These results are expected to aid in the design and assessment of the required post-market studies in terms of the level of evidence required for full approval.

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arXiv2021

Power Calculations for Replication Studies

The reproducibility crisis has led to an increasing number of replication studies being conducted. Sample sizes for replication studies are often calculated using conditional power based on the effect estimate from the original study. However, this approach is not well suited as it ignores the uncertainty of the original result. Bayesian methods are used in clinical trials to incorporate prior information into power calculations. We propose to adapt this methodology to the replication framework and promote the use of predictive instead of conditional power in the design of replication studies. Moreover, we describe how extensions of the methodology to sequential clinical trials can be tailored to replication studies. Conditional and predictive power calculated at an interim analysis are compared and we argue that predictive power is a useful tool to decide whether to stop a replication study prematurely. A recent project on the replicability of social sciences is used to illustrate the properties of the different methods.

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arXiv2021

The assessment of replication success based on relative effect size

Replication studies are increasingly conducted in order to confirm original findings. However, there is no established standard how to assess replication success and in practice many different approaches are used. The purpose of this paper is to refine and extend a recently proposed reverse-Bayes approach for the analysis of replication studies. We show how this method is directly related to the relative effect size, the ratio of the replication to the original effect estimate. This perspective leads to a new proposal to recalibrate the assessment of replication success, the golden level. The recalibration ensures that for borderline significant original studies replication success can only be achieved if the replication effect estimate is larger than the original one. Conditional power for replication success can then take any desired value if the original study is significant and the replication sample size is large enough. Compared to the standard approach to require statistical significance of both the original and replication study, replication success at the golden level offers uniform gains in project power and controls the Type-I error rate if the replication sample size is not smaller than the original one. An application to data from four large replication projects shows that the new approach leads to more appropriate inferences, as it penalizes shrinkage of the replication estimate compared to the original one, while ensuring that both effect estimates are sufficiently convincing on their own.

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