Review of sample size determination methods for the intraclass correlation coefficient in the one-way analysis of variance model.

Reliability of measurement instruments providing quantitative outcomes is usually assessed by an intraclass correlation coefficient. When participants are repeatedly measured by a single rater or device, or, are each rated by a different group of raters, the intraclass correlation coefficient is based on a one-way analysis of variance model. When planning a reliability study, it is essential to determine the number of participants and measurements per participant (i.e. number of raters or number of repeated measurements). Three different sample size determination approaches under the one-way analysis of variance model were identified in the literature, all based on a confidence interval for the intraclass correlation coefficient. Although eight different confidence interval methods can be identified, Wald confidence interval with Fisher's large sample variance approximation remains most commonly used despite its well-known poor statistical properties. Therefore, a first objective of this work is comparing the statistical properties of all identified confidence interval methods-including those overlooked in previous studies. A second objective is developing a general procedure to determine the sample size using all approaches since a closed-form formula is not always available. This procedure is implemented in an R Shiny app. Finally, we provide advice for choosing an appropriate sample size determination method when planning a reliability study.

In situ kinetic measurements of α-synuclein aggregation reveal large population of short-lived oligomers.

Knowledge of the mechanisms of assembly of amyloid proteins into aggregates is of central importance in building an understanding of neurodegenerative disease. Given that oligomeric intermediates formed during the aggregation reaction are believed to be the major toxic species, methods to track such intermediates are clearly needed. Here we present a method, electron paramagnetic resonance (EPR), by which the amount of intermediates can be measured over the course of the aggregation, directly in the reacting solution, without the need for separation. We use this approach to investigate the aggregation of α-synuclein (αS), a synaptic protein implicated in Parkinson's disease and find a large population of oligomeric species. Our results show that these are primary oligomers, formed directly from monomeric species, rather than oligomers formed by secondary nucleation processes, and that they are short-lived, the majority of them dissociates rather than converts to fibrils. As demonstrated here, EPR offers the means to detect such short-lived intermediate species directly in situ. As it relies only on the change in size of the detected species, it will be applicable to a wide range of self-assembling systems, making accessible the kinetics of intermediates and thus allowing the determination of their rates of formation and conversion, key processes in the self-assembly reaction.