Confidence interval estimation for the changepoint of treatment stratification in the presence of a qualitative covariate-treatment interaction

The goal in stratified medicine is to administer the \textquotedblbest\textquotedbl treatment to a patient. Not all patients might benefit from the same treatment; the choice of best treatment can depend on certain patient characteristics. In this article, it is assumed that a time-to-event outcome is considered as a patient-relevant outcome and a qualitative interaction between a continuous covariate and treatment exists, ie,~that patients with different values of one specific covariate should be treated differently. We suggest and investigate different methods for confidence interval estimation for the covariate value, where the treatment recommendation should be changed based on data collected in a randomized clinical trial. An adaptation of Fieller's theorem, the delta method, and different bootstrap approaches (normal, percentile-based, wild bootstrap) are investigated and compared in a simulation study. Extensions to multivariable problems are presented and evaluated. We observed appropriate confidence interval coverage following Fieller's theorem irrespective of sample size but at the cost of very wide or even infinite confidence intervals. The delta method and the wild bootstrap approach provided the smallest intervals but inadequate coverage for small to moderate event numbers, also depending on the location of the true changepoint. For the percentile-based bootstrap, wide intervals were observed, and it was slightly conservative regarding coverage, whereas the normal bootstrap did not provide acceptable results for many scenarios. The described methods were also applied to data from a randomized clinical trial comparing two treatments for patients with symptomatic, severe carotid artery stenosis, considering patient's age as predictive marker

Stimulation in vitro de l'attachement des cellules épithéliales gingivales humaines à la dentine par un conditionnement de surface

BACKGROUND: Chemical root conditioning is widely used to improve the outcome of regenerative periodontal therapies by favoring the attachment of the regenerated periodontal structures. Although the effect of root conditioning on periodontal mesenchymal cells is well documented, very little is known about its potential effect on the re-formation of the junctional epithelium, a crucial event for the protection of the wound. The goal of the present study was to test in vitro the consequences of dentin conditioning with citric acid or minocycline on the attachment kinetics and morphology of human gingival keratinocytes (HGK). METHODS: The attachment kinetics of HGK to samples of powdered human dentin (particle size 44 to 76 microm) were examined by use of 3H-labeled cells. The morphology of attached epithelial cells was then determined by scanning electron microscopy (SEM). RESULTS: When the initial adhesion kinetics of cells on untreated dentin were tested, the percentage of attached HGK proved to be dependent on the number of plated cells and the time of incubation (from 0 to 12 hours). Conditioning the dentin by 3% citric acid or by minocycline-HCl (at 0.01, 0.1, or 2.5%) significantly increased (P <0.005) keratinocyte attachment beyond 6 hours, without notable differences between the 2 substances at any concentration. The attachment kinetics of HGK preincubated for 24 hours by 10 microg/ml minocyline-HCl on untreated dentin was found to be similar to that observed for non-preincubated cells. These results are in agreement with the SEM observations: indeed, the surface conditioning of dentin significantly modified the morphology of attached HGK, whereas the preincubation of these cells with minocyline-HCl did not. CONCLUSIONS: These results suggest that minocycline-HCl does not exert a direct effect on human gingival epithelial cells. In contrast, conditioning the dentin by citric acid or by minocycline stimulates the attachment of HGK, which could lead to a rapid periodontal healing by favoring the re-formation of a junctional epithelium

Locus CFM1: a potential modifier of pancreatic disease in children with cystic fibrosis

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