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In 1960, Cohen introduced the kappa coefficient to measure chance-corrected nominal scale agreement between two raters. Since then, numerous extensions and generalizations of this interrater agreement measure have been proposed in the literature. This paper reviews and critiques various approaches to the study of interrater agreement, for which the relevant data comprise either nominal or ordinal categorical ratings from multiple raters. It presents a comprehensive compilation of the main statistical approaches to this problem, descriptions and characterizations of the underlying models, and discussions of related statistical methodologies for estimation and confidence-interval construction. The emphasis is on various practical scenarios and designs that underlie the development of these measures, and the interrelationships between them. RESUME C'est en 1960 que Cohen a propost I'emploi du coefficient kappa comme outil de mesure de I'accord entre deux tvaluateurs exprimant leur jugement au moyen d'une Cchelle nominale. De nombreuses gentralisations de cette mesure d'accord ont Ct C proposies depuis lors. Les auteurs jettent ici un regard critique sur nombre de ces travaux traitant du cas ou I'Cchelle de rtponse est soit nominale, soit ordinale. Les principales approches statistiques sont passCes en revue, les modkles sous-jacents sont dicrits et caractCrisCs, et les problkmes liCs i I'estimation ponctuelle ou par intervalle sont abordCs. L'accent est m i s sur diffkrents scknarios concrets et sur des schtmas exp6rimentaux qui sous-tendent I'emploi de ces mesures et les relations existant entre elles.

Bromodomain and extra terminal protein (BET) inhibitors are first-in-class targeted therapies that deliver a new therapeutic opportunity by directly targeting bromodomain proteins that bind acetylated chromatin marks1,2. Early clinical trials have shown promise, especially in acute myeloid leukaemia3, and therefore the evaluation of resistance mechanisms is crucial to optimize the clinical efficacy of these drugs. Here we use primary mouse haematopoietic stem and progenitor cells immortalized with the fusion protein MLL-AF9 to generate several single-cell clones that demonstrate resistance, in vitro and in vivo, to the prototypical BET inhibitor, I-BET. Resistance to I-BET confers cross-resistance to chemically distinct BET inhibitors such as JQ1, as well as resistance to genetic knockdown of BET proteins. Resistance is not mediated through increased drug efflux or metabolism, but is shown to emerge from leukaemia stem cells both ex vivo and in vivo. Chromatin-bound BRD4 is globally reduced in resistant cells, whereas the expression of key target genes such as Myc remains unaltered, highlighting the existence of alternative mechanisms to regulate transcription. We demonstrate that resistance to BET inhibitors, in human and mouse leukaemia cells, is in part a consequence of increased Wnt/β-catenin signalling, and negative regulation of this pathway results in restoration of sensitivity to I-BET in vitro and in vivo. Together, these findings provide new insights into the biology of acute myeloid leukaemia, highlight potential therapeutic limitations of BET inhibitors, and identify strategies that may enhance the clinical utility of these unique targeted therapies.

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